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PubMed2003

CI-1033, an irreversible pan-erbB receptor inhibitor and its potential application for the treatment of breast cancer.

The erbB family of cell surface receptor proteins consists of four members, all of which play a role in the development and growth of the normal breast. The activity of this signaling pathway is normally tightly controlled, and dysregulation has been shown to play a significant role in the pathogenesis and progression of breast and other cancers. The potent transforming potential of these receptors is further enhanced by the coexpression of multiple members of this receptor family, which worsens prognosis. Therapeutic blockade of erbB-2 receptor signaling has to date been shown to be effective in only a subset of chemotherapy-resistant breast cancer patients. CI-1033 is a highly potent and selective pan-erbB inhibitor that efficiently blocks signal transduction through all four members of the erbB receptor family. In addition, it covalently binds to these receptors, irreversibility inhibiting them, and thereby provides for prolonged suppression of erbB receptor-mediated signaling. Clinically, it has been shown to have an acceptable side effect profile at potentially therapeutic doses and schedules. Biomarker studies have shown target inhibition in patients, and evidence of antitumor activity has also been observed in phase I studies. Given the broad expression pattern of the erbB family of receptors in solid tumors, and the important proliferative effect of co-expression of multiple erbB receptors, CI-1033, as an irreversible, pan-erbB inhibitor, has the potential to have an important role in the future treatment of breast and other cancers.

Animals↗
PubMed2003

Plasma fatty acid composition and incidence of diabetes in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: The results of some epidemiologic studies conducted by using questionnaires suggest that dietary fat composition influences diabetes risk. Confirmation of this finding with use of a biomarker is warranted. OBJECTIVE: We prospectively investigated the relation of plasma cholesterol ester (CE) and phospholipid (PL) fatty acid composition with the incidence of diabetes mellitus. DESIGN: In 2909 adults aged 45-64 y, plasma fatty acid composition was quantified by using gas-liquid chromatography and was expressed as a percentage of total fatty acids. Incident diabetes (n = 252) was identified during 9 y of follow-up. RESULTS: After adjustment for age, sex, baseline body mass index, waist-to-hip ratio, alcohol intake, cigarette smoking, physical activity, education, and parental history of diabetes, diabetes incidence was significantly and positively associated with the proportions of total saturated fatty acids in plasma CE and PL. The rate ratios of incident diabetes across quintiles of saturated fatty acids were 1.00, 1.36, 1.16, 1.60, and 2.08 (P = 0.0013) in CE and 1.00, 1.75, 1.87, 2.40, and 3.37 (P < 0.0001) in PL. In CE, the incidence of diabetes was also positively associated with the proportions of palmitic (16:0), palmitoleic (16:1n-7), and dihomo-gamma-linolenic (20:3n-6) acids and inversely associated with the proportion of linoleic acid (18:2n-6). In PL, incident diabetes was positively associated with the proportions of 16:0 and stearic acid (18:0). CONCLUSIONS: The proportional saturated fatty acid composition of plasma is positively associated with the development of diabetes. Our findings with the use of this biomarker suggest indirectly that the dietary fat profile, particularly that of saturated fat, may contribute to the etiology of diabetes.

Cholesterol Esters↗
PubMed2005

Real-time quantification of microRNAs by stem-loop RT-PCR.

A novel microRNA (miRNA) quantification method has been developed using stem-loop RT followed by TaqMan PCR analysis. Stem-loop RT primers are better than conventional ones in terms of RT efficiency and specificity. TaqMan miRNA assays are specific for mature miRNAs and discriminate among related miRNAs that differ by as little as one nucleotide. Furthermore, they are not affected by genomic DNA contamination. Precise quantification is achieved routinely with as little as 25 pg of total RNA for most miRNAs. In fact, the high sensitivity, specificity and precision of this method allows for direct analysis of a single cell without nucleic acid purification. Like standard TaqMan gene expression assays, TaqMan miRNA assays exhibit a dynamic range of seven orders of magnitude. Quantification of five miRNAs in seven mouse tissues showed variation from less than 10 to more than 30,000 copies per cell. This method enables fast, accurate and sensitive miRNA expression profiling and can identify and monitor potential biomarkers specific to tissues or diseases. Stem-loop RT-PCR can be used for the quantification of other small RNA molecules such as short interfering RNAs (siRNAs). Furthermore, the concept of stem-loop RT primer design could be applied in small RNA cloning and multiplex assays for better specificity and efficiency.

Animals↗
PubMed2026

Integrative Analysis Uncover the Effects and Multi-Omics Features of Thigh Muscle Fat Infiltration.

The health impacts and underlying biological pathways of thigh muscle fat infiltration (TMFI) remain incompletely understood. In this study, we analyzed TMFI measured by magnetic resonance imaging in 55,120 UK Biobank participants and found that higher TMFI was significantly associated with all-cause mortality as well as with all major system-specific diseases examined (p values ranged from 2.50&#x2009;&#xd7;&#x2009;10-88 to 9.97&#x2009;&#xd7;&#x2009;10-04). TMFI also mediated the effects of lifestyle factors on health-related outcomes, with mediation proportions ranging from 6.7% to 71.7%. A genome-wide association study (GWAS) identified 79 lead single nucleotide polymorphisms (SNPs) linked to TMFI, and the polygenic risk score for TMFI was significantly associated with mortality and all incident diseases across examined organ systems in an independent subset of UK Biobank participants of European ancestry who were not included in the TMFI GWAS (n&#x2009;=&#x2009;362,286, all p&#x2009;<&#x2009;0.05). Gene-drug interactions identified multiple drugs that could potentially modulate TMFI. Analysis of single-cell transcriptomic data indicated that myogenic cells were strongly linked to TMFI (p&#x2009;=&#x2009;7.08&#x2009;&#xd7;&#x2009;10-08). Summary-data-based Mendelian randomization and Transcriptome-Wide Association Study analyses revealed numerous genes whose expression in specific tissues was associated with TMFI. Proteomic and metabolomic profiling uncovered a broad array of circulating biomarkers associated with TMFI, many of which mediated the effects of modifiable factors and genetic risk on TMFI. Overall, our results highlight the biological relevance of TMFI to human health and provide insights into the multi-omics mechanisms underlying TMFI, identifying potential targets for interventions.

Humans↗
PubMed2004

Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer.

PURPOSE: A better understanding of the molecular pathways underlying the development of epithelial ovarian cancer (EOC) is critical to identify ovarian tumor markers for use in diagnostic or therapeutic applications. The aims of this study were to integrate the results from 14 transcript profiling studies of EOC to identify novel biomarkers and to examine their expression in early and late stages of the disease. EXPERIMENTAL DESIGN: A database incorporating genes identified as being highly up-regulated in each study was constructed. Candidate tumor markers were selected from genes that overlapped between studies and by evidence of surface membrane or secreted expression. The expression patterns of three integral membrane proteins, discoidin domain receptor 1 (DDR1), claudin 3 (CLDN3), and epithelial cell adhesion molecule, all of which are involved in cell adhesion, were evaluated in a cohort of 158 primary EOC using immunohistochemistry. RESULTS: We confirmed that these genes are highly overexpressed in all histological subtypes of EOC compared with normal ovarian surface epithelium, identifying DDR1 and CLDN3 as new biomarkers of EOC. Furthermore, we determined that these genes are also expressed in ovarian epithelial inclusion cysts, a site of metaplastic changes within the normal ovary, in borderline tumors and in low-grade and stage cancer. A trend toward an association between low CLDN3 expression and poor patient outcome was also observed. CONCLUSIONS: These results suggest that up-regulation of DDR1, CLDN3, and epithelial cell adhesion molecule are early events in the development of EOC and have potential application in the early detection of disease.

Antigens, Neoplasm↗
PubMed2006

Proteome analysis of cultured fibroblasts from type 1 diabetic patients and normal subjects.

CONTEXT: Protein profiling of diabetic tissues could provide useful biomarkers for early diagnosis, therapeutic targets, and disease response markers. Cultured fibroblasts are a useful in vitro model for proteome analysis and study of the molecular mechanisms involved in diabetes. OBJECTIVE: The objective of the study was to isolate and characterize the proteins of cultured fibroblasts, obtained by skin biopsy, from long-term type 1 diabetic patients without complications and age- and sex-matched normal subjects as controls. DESIGN: Proteins were separated by two-dimensional electrophoresis (2-DE), and the gel images were qualitatively and quantitatively analyzed. Protein identification was performed by matrix-assisted laser desorption/ionization mass spectrometry. RESULTS: Reproducible protein maps of fibroblasts from diabetic and healthy subjects were obtained. A total of 125 protein spots were isolated and identified, among them 27 proteins not previously reported in published human fibroblast 2-DE maps, including 20 proteins never reported previously in the literature in human skin fibroblasts. Quantitative analyses revealed six protein spots differentially expressed in the fibroblasts from the diabetic vs. the control subjects (P < 0.05), representing glycolytic enzymes and structural proteins. An increase of triosephosphate I isomerase of two splice isoforms of pyruvate kinase and alpha-actinin 4 and a decrease of tubulin-beta2 and splice isoform 2 of tropomyosin beta-chain were detected. CONCLUSIONS: We generated 2-DE reference maps of the proteome of human skin fibroblasts from both normal and uncomplicated type 1 diabetic patients. Differences in glycolytic enzymes and structural proteins were found. The functional implications of the identified proteins are discussed.

Adult↗
PubMed2004

High-throughput proteomics using antibody microarrays.

Antibody-based microarrays are a novel technology that hold great promise in proteomics. Microarrays can be printed with thousands of recombinant antibodies carrying the desired specificities, the biologic sample (e.g., an entire proteome) and any specifically bound analytes detected. The microarray patterns that are generated can then be converted into proteomic maps, or molecular fingerprints, revealing the composition of the proteome. Using this tool, global proteome analysis and protein expression profiling will thus provide new opportunities for biomarker discovery, drug target identification and disease diagnostics, as well as providing insights into disease biology. Intense work is currently underway to develop this novel technology platform into the high-throughput proteomic tool required by the research community.

Antibodies↗
PubMed2026

Meta-Merging the Transcriptomes of Gastric Tumors Redefines the Connections among Molecular and Clinical Subtypes.

INTRODUCTION: The availability of a large number of cancer expression profiles presents an excellent opportunity to re-investigate various biological and clinical questions. While several expression profiles have been established for different cancers, merging them may provide a more powerful platform for extensively extrapolating molecular and clinical features across multiple cohorts. MATERIALS AND METHODS: In this study, five gastric tumor expression profiles from the Gene Expression Omnibus [GEO] and one in-house cohort comprising a total of 1,060 samples were merged. The batch effect was removed using non-parametric ComBat analysis, and the seamless merging of datasets was confirmed through various parameters. RESULTS: Extrapolation of ACRG [Asian Cancer Research Group] and TCGA [The Cancer Genome Atlas] molecular subtypes in the merged cohort of 1,060 gastric tumors revealed nine distinct clusters. Notably, the following patterns were observed: [i] mutual exclusivity between Epithelial to Mesenchymal Transition [EMT] and Microsatellite Instability [MSI] subtypes in 90% of tumors; [ii] overlapping occurrence of EMT and MSI subtypes in the remaining tumors; [iii] overlap between MSI and Epstein-Barr Virus [EBV] subtype tumors; [iv] both commonalities and differences between EMT and Genomically Stable [GS] subtypes; and [v] an association between EBV positivity and PI3K mutation. CONCLUSION: The current study demonstrates that compiling a larger expression profile is valuable for revisiting the molecular features and epidemiology associated with molecular subtypes, thereby aiding in the development of novel diagnostics and targeted therapeutics.

Humans↗
PubMedDate not supplied

Molecular aspects of prostate cancer: implications for future directions.

Many studies have been developed trying to understand the complex molecular mechanisms involved in oncogenesis and progression of prostate cancer (PCa). Current biotechnological methodologies, especially genomic studies, are adding important aspects to this area. The construction of extensive DNA sequence data and gene expression profiles have been intensively explored to search for candidate biomarkers to evaluate PCa. The use of DNA micro-array robotic systems constitutes a powerful approach to simultaneously monitor the expression of a great number of genes. The resulting gene expressing profiles can be used to specifically describe tumor staging and response to cancer therapies. Also, it is possible to follow PCa pathological properties and to identify genes that anticipate the behavior of clinical disease. The molecular pathogenesis of PCa involves many contributing factors, such as alterations in signal transduction pathways, angiogenesis, adhesion molecules expression and cell cycle control. Also, molecular studies are making clear that many genes, scattered through several different chromosomal regions probably cause predisposition to PCa. The discovery of new molecular markers for PCa is another relevant advance resulting from molecular biology studies of prostate tumors. Interesting tissue and serum markers have been reported, resulting in many cases in useful novelties to diagnostic and prognostic approaches to follow-up PCa. Finally, gene therapy comes as an important approach for therapeutic intervention in PCa. Clinical trials for PCa have been demonstrating that gene therapy is relatively safe and well tolerated, although some improvements are yet to be developed.

Journal Article↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2004

Molecular signatures of lymphoma.

Hematologic malignancies have historically been characterized by morphologic, immunophenotypic, molecular, and genetic features. However, morphologically identical tumors can have clearly distinct clinical outcomes, suggesting underlying biological heterogeneity. Recent advances in microarray technology have helped the classification of lymphoid malignancies evolve to a new refined level. In addition to the discovery of new disease subclasses defined by unique molecular profiles, gene expression patterns can be correlated with specific genetic abnormalities and prognoses. Furthermore, the discovery of new disease subtypes has provided further insight into lymphoma biology and pathogenesis. Unique gene signatures can highlight key deregulated pathways that are active in molecular disease categories, and in some cases these findings have elucidated new targets for novel therapeutic approaches. This review summarizes the current status of molecular profiling in non-Hodgkin lymphomas. In this review, we have endeavored to include data from multiple investigator groups and tried to cover the breadth of lymphoid tumors, excluding acute and chronic leukemias.

Biomarkers, Tumor↗
PubMed2004

DNA microarrays in the diagnosis and management of acute lymphoblastic leukemia.

The significant progress in the treatment of acute lymphoblastic leukemia (ALL) experienced over the last 3 decades has been driven mainly by the empirical combination of antileukemic drugs in highly intensive therapies. Further progress in the management of ALL is currently limited, however, by our incomplete understanding of the molecular pathways involved in leukemia pathogenesis and by the lack of useful prognostic markers for most patients. The recent development of microarray technology, which allows the simultaneous analysis of gene expression levels for thousands of transcripts, has accelerated significantly the rate of progress in our understanding of the molecular basis of ALL. During the last few years, analysis of ALL samples with DNA arrays has facilitated the recognition of molecularly distinct leukemia groups, advanced our knowledge of the mechanisms of sensitivity and resistance to chemotherapy, generated novel prognostic prediction tools, and identified new targets for the development of molecularly tailored antileukemic agents. Thus, the introduction of microarray gene expression profiling has opened the opportunity for accelerated progress in the diagnosis and therapy of ALL, which will ultimately result in the development of novel highly effective and less toxic treatments for this disease.

Biomarkers, Tumor↗
PubMed2006

Profiling bladder cancer using targeted antibody arrays.

Bladder cancer is a common malignancy requiring a high degree of surveillance because of the frequent recurrences and the poor clinical outcome of invasive disease. To date, serum biomarkers for bladder cancer lack optimal sensitivity and specificity to assist in diagnosis and disease categorization. Here, we designed antibody arrays for bladder cancer by selecting antibodies against targets differentially expressed in bladder tumors. Serum protein profiles measured by an antibody array containing 254 antibodies discriminated bladder cancer patients from controls (n = 95) with a correct classification rate of 93.7%. A second independent antibody array containing 144 antibodies revealed that protein profiles provide predictive information by stratifying patients with bladder tumors (n = 37) based on their overall survival (P = 0.0479). In addition, serum proteins, such as c-met, that were top ranked at identifying bladder cancer patients were associated with pathological stage, tumor grade, and survival when validated by immunohistochemistry of tissue microarrays containing bladder tumors (n = 173). This study provides experimental evidence for the use of several integrated technologies strengthening the process of biomarker discovery. Serum protein profiles obtained by antibody arrays represent comprehensive means for bladder cancer diagnosis and clinical outcome stratification, which could potentially assist in selection of cancer patients who would benefit from early, individualized therapeutic intervention.

Adult↗
PubMed2006

An approach to the validation of biomarkers of harm for use in a tobacco context.

There is both a call and a need for biomarkers of harm that are validated for use in a tobacco context. Currently, there are no validated biomarkers and there is no consensus about which ones may be suitable for this purpose. To advance the science in this area a working definition of biomarkers of harm and a shortlist of candidate biomarkers are proposed. A framework for the validation of biomarkers of harm using of a series of epidemiological studies culminating in a targeted prospective study is outlined. The candidate biomarkers have advanced to preliminary testing although this does not imply that any on the shortlist will become validated. This framework could also be used for the evaluation of proteomic, genomic, transcriptosomic or metabonomic profiles, which may turn out to be the preferred biomarkers for use in harm prediction. Biomarker studies would complement data that are generated from specific in vitro tests and from animal studies to evaluate tobacco products.

Animals↗
PubMed2026

Menopausal timing and senescent-immune coupling in age-related lobular involution of the human breast: a longitudinal cohort study.

BACKGROUND: Incomplete postmenopausal breast involution leaves persistent epithelial-rich lobules and elevated breast density in about 40% of women and is associated with higher breast cancer risk, but why remodelling stalls remains unclear. METHODS: We studied a longitudinal cohort of 81 women with paired benign breast biopsies (baseline age 45-55 years; follow-up 2-10 years), all with baseline NanoString transcriptomics and two-timepoint digital morphometry, and with multiplex immunofluorescence in spatial-imaging subsets (baseline n = 14-16 depending on panel; follow-up n = 14). A separate postmenopausal endpoint cohort (12 women: eight noninvoluted, four completely involuted), profiled by genome-wide expression array and multiplex immunofluorescence, defined the persistent-lobule phenotype. FINDINGS: Noninvoluted postmenopausal tissue retained a proliferation-competent, tumour-associated epithelial state and showed immune accumulation at lobular boundaries with reduced access to p16+ (senescence-associated) epithelial foci. The same SASP and innate immune programmes that predicted slower involution across the menopausal transition predicted faster involution after menopause. Follow-up boundary CD45&#x2192;p16 engagement was directionally consistent with this reversal in Pre&#x2192;Post and Post&#x2192;Post women. Spatial imaging resolved this reversal into a perimenopausal stall architecture and a postmenopausal clearance-associated architecture marked by direct CD16+ innate-effector engagement of p16+ epithelium; macrophage targeting provided convergent support (two-sided exact permutation interaction p = 0.0077). INTERPRETATION: Menopausal timing conditions whether senescent-immune programmes couple to productive clearance or to spatially uncoupled surveillance and persistent risk-associated tissue. Biomarker interpretation should therefore be anchored to menopausal timing. FUNDING: Casey DeSantis Cancer Fund and US National Cancer Institute.

Humans↗
PubMed2005

The influence of HER2 genotypes as molecular markers in ovarian cancer outcome.

A relevant clinical problem in the treatment of ovarian cancer (OC) is the development of resistance to chemotherapy, frequently due to genetic variations in enzymes and receptors. Changes in the HER2 receptor have been associated with breast and ovarian cancers. The role of a polymorphism in the HER2 gene in the clinical outcome of OC patients was investigated in this study. We characterized DNA samples from 111 patients with OC treated with cisplatin and paclitaxel, using PCR-RFLP. Our results indicate that patients carrying the valine homozygotic genotype present a lower overall survival mean, suggesting a role for this polymorphism in the outcome of ovarian cancer patients. The G allele has been implicated in the formation of active HER2 receptors, with a more aggressive phenotype. We hypothesize that HER2 genotypes can be predictive biomarkers in ovarian cancer, contributing to a genetic individual profile of great interest in clinical oncology.

Antineoplastic Agents↗
PubMed2004

Urinary arsenic speciation and porphyrins in C57Bl/6J mice chronically exposed to low doses of sodium arsenate.

Arsenic has been classified as a human carcinogen based on epidemiological data however the mechanism of its carcinogenicity is still unclear. Urinary biomarkers for chronic arsenic exposure would be valuable as an early warning indicator for timely interventions. In this study, young female C57Bl/6J mice were given drinking water containing 0, 100, 250 and 500 microg Asv/L as sodium arsenate ad libitum for 12 months. Urine was collected bimonthly for urinary arsenic methylation assay and porphyrin analysis. All detectable arsenic species showed strong linear correlation with administered dosage and the arsenic methylation patterns were similar in all three treatment groups. No significant changes of methylation patterns were observed over time for either the control or test groups. Urinary coproporphyrin III was significantly increased in the 8th month in 250 and 500 microg/L groups and remained significantly dose-related after 10 and 12 months. Coproporphyrin I also showed a significant dose-response relationship after 12 months. Our results confirm that urinary arsenic is a useful biomarker for internal dose. The alteration of porphyrin profile suggests that arsenic can affect the heme metabolism and this may occur prior to the onset of arsenic induced carcinogenesis.

Administration, Oral↗