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PubMedDate not supplied

[Evaluation of the function of the hematoencephalic barrier in victims with craniocerebral trauma in critical state].

Estimates of the relative-entry coefficient, molecular profile of the cerebrospinal fluid and of the molecular blood profile based on the comparison of concentrations of proteins with different physical-and-chemical properties enable an evaluation of the function of the hematoencephalic barrier in victims with craniocerebral trauma in critical state. It was possible to state, with such approach in use, that the regulatory and protective functions of the hematoencephalic barrier were changing differently in favorable and unfavorable trauma outcomes, which must be duly considered in choosing a treatment tactics for the above category of victims.

Blood Proteins↗

PubMed2004

Biomarker profiling of plasma from acute coronary syndrome patients. Application of ProteinChip Array analysis.

AIM: Acute coronary syndrome (ACS) is one of the leading causes of death in the world and remains a complex pathophysiologic process involving inflammatory, hemostatic and vascular processes. The purpose of this study was to identify unique proteomic biomarkers present in patients with ACS using a newly developed proteomic profiling technique, surface enhanced laser desorption/ionization (SELDI). METHODS: Citrated plasma samples obtained from clinically confirmed cases of ACS (n=100) and age matched controls (n=25) were profiled using SELDI-time of flight (TOF)-mass spectrometry (Ciphergen Biosystems, Freemont, CA, USA). A strong anion exchange (SAX) ProteinChip Array was used to profile these samples. In addition to spectra profiles, protein density plots were be obtained from the generated molecular profile. RESULTS: The SELDI profile in the molecular weight (MW) range of 0-150 kDa revealed a prominent 66.3 kDa albumin peak along with several distinct components at 28 kDa, 13.7 kDa and 6.5 kDa. Additional minor molecular components were also noted in the lower MW range (<6 kDa). There was a cluster of peaks between 10 and 12 kDa that were unique to the patients with ACS; about 1/3 of the ACS patients exhibited these peaks as evident in the ProteinChip Array spectrum. None of the age-matched controls exhibited the peaks in this MW range, nor did the normal human plasma pool that was used as an additional control. The relative intensity of these novel molecular components in the range of 10-12 kDa represent unique proteins/peptides which are generated in specific pathologic states associated with ACS. CONCLUSIONS: These observations suggest that patients with ACS have a unique cluster of molecular components that are present in their SELDI profile. It might be possible to use these patterns to identify high-risk patients who may be more susceptible to the development of unstable plaque, which may eventually lead to myocardial infarction. Identification and characterization of these molecular components will also help in the understanding of the pathogenesis of ACS. These unique peaks may represent pathologic proteins, novel inflammatory mediators or protease cleavage products. Further studies need to be done to better characterize and identify these molecular components and their pathologic role in ACS.

Acute Disease↗

PubMed2005

Quantitative methylation profiling of renal tumors and the discovery of a new generation of molecular markers.

Evaluation of: Gonzalgo ML, Yegnasubramanian S, Yan G et al.: Molecular profiling and classification of sporadic renal cell carcinoma by quantitative methylation analysis. Clin. Cancer Res. 10 (21), 7276-7283 (2004). This study identified RASSF1A promoter methylation as a valuable epigenetic marker for renal cancer, eventually indicating more aggressive disease. Overall, 16 gene promoters were surveyed for hypermethylation in a series of 38 renal cell tumors (comprising papillary and clear-cell renal cell carcinoma, and oncocytoma) and paired normal tissue samples. Among the target genes analyzed, RASSF1A emerged as the most frequently methylated in renal tumors and also at higher levels. Statistical analyses showed a significant association between RASSF1A promoter methylation and higher pathological stage, but not with tumor size or nuclear grade. The discriminative power of a quantitative approach allowed for a segregation between renal carcinomas and oncocytomas, using a self-organizing hierarchical neural network. These results hold the promise that epigenetic-based markers might prove clinically useful for the management of patients with renal tumors. Nevertheless, further studies, including larger sets of patients and more diversified renal tumors, as well as benign lesions, are needed to validate these preliminary results.

Adenocarcinoma, Clear Cell↗

PubMed2006

Gene expression profiling of paired ovarian tumors obtained prior to and following adjuvant chemotherapy: molecular signatures of chemoresistant tumors.

Chemotherapy (CT) resistance in ovarian cancer is related to multiple factors, and assessment of these factors is necessary for the development of new drugs and therapeutic regimens. In an effort to identify such determinants, we evaluated the expression of approximately 21,000 genes using DNA microarray screening in paired tumor samples taken prior to and after CT treatment from 6 patients with predominantly advanced stage, high-grade epithelial ovarian cancer. A subset of differentially expressed genes was selected from all microarray data by initial filtering on confidence at p=0.05, followed by filtering on expression level (>or=2-fold). Using these selection criteria, we found 121 genes to be commonly up-regulated and 54 genes to be down-regulated in the post-CT tumors, compared to primary tumors. Up-regulated genes in post-CT tumors included substantial number of genes with previously known implication in mechanisms of chemoresistance (TOP2A, ETV4, ABCF2, PRDX2, COX2, COX7B, MUC1, MT3, MT2A), and tumorigenesis (SCGB2A2, S100A9, YWHAE, SFN, ATP6AP1, MGC5528, ASS, TACC3, ARHGAP4, SRA1; MGC35136, PSAP, SPTAN1, LGALS3BP, TUBA4, AMY2B, PPIA, COX1, GRB2, CTSL). Down-regulated genes in post-CT samples mostly included genes implicated in chemosensitivity (GRP, TRA1, ADPRTL1, TRF4-2), cell proliferation and cell cycle control (NGFRAP1, TPD52L1, TAX1BP1) and tumor suppression and apoptosis (SMOC2, TIMP3, AXIN1, CASP4, P53SCV). Additionally, gene clustering analysis revealed the existence of two distinct expression signatures of chemoresistant tumors, which was further confirmed by assessment of some genetic (p53 gene mutation status) and clinical parameters (CT regimens). Our data suggest that intrinsic and acquired chemoresistant phenotypes of post-CT tumors may be attributed to the combined action of different factors implicated in mechanisms of chemoresistance, tumor invasion/progression and control of cell proliferation. This type of molecular profiling could have important clinical implications in resolving chemoresistance and the development of novel treatment strategies designed to prevent its emergence.

Adult↗

PubMed2006

Profiling cancer stem cells using protein array technology.

Since cancer cells and somatic stem cells share the biological characteristics of self-renewal and proliferation, it has been suggested that the principles of stem cell biology can be applied to improve our understanding of cancer biology. Recent studies have shown that the majority of cancers appear to originate from a small subset of cells that have the ability of self-renewal and to proliferate, namely 'cancer stem cells'. The isolation of cancer stem cells has been demonstrated using cell surface markers in haematopoietic and non-haematopoietic malignancies. Advances in protein array technologies have enabled the use of minuscule amounts of biological materials to profile these cells at the molecular level. Using a combination of protein arrays and cancer stem cell isolation techniques, a higher resolution molecular profiling can be performed, which might improve therapies targeting the cancer stem cells.

Cell Communication↗

PubMed2003

Classifying human cancer by analysis of gene expression.

With the development and application of DNA microarrays, the expression of almost all human genes can now be systematically examined in human malignancies. This can lead to the identification of candidate molecular targets for therapeutic intervention and biomarkers for early detection of these diseases. However, perhaps the most exciting result to come from this research has been the demonstration that patterns of gene expression can distinguish between tumors of different anatomical origin, and define new subgroups of cancer with similar histological appearance, but distinct molecular profiles. Some of these new molecular subclasses of tumor appear to correlate with clinical behavior. If substantiated in larger studies, this might form a basis for stratifying patients so that they receive optimal therapeutic treatment and follow-up.

Gene Expression Regulation, Neoplastic↗

PubMedDate not supplied

Prospective clinical trials of brain tumor therapy: the critical role of neurosurgeons.

Prospective clinical trials are critical to the scientific evaluation of new treatments for brain tumors. This paper reviews basic concepts of early and late phase prospective clinical trials that are most relevant to neurosurgical oncologists, with an emphasis on the challenges associated with conducting clinical trials of brain tumor therapies. Novel clinical trial designs that meet these challenges by incorporating pretreatment 'molecular profiling' and post-treatment 'molecular endpoints' are described. Because of their ability to obtain brain tumor specimens from patients before and after treatment, neurosurgeons have been required to play an increasingly important role in the execution of these molecular-based clinical trials. Potential avenues for enhancing the participation of neurosurgeons in the design and development of clinical trials are discussed.

Brain Neoplasms↗

PubMed2026

Tumor Mutational Landscape and Its Correlation With Histopathological Characteristics in Breast Cancer.

BACKGROUND/AIM: In breast cancer, knowledge of the associations between clinicopathologic characteristics, genetic changes, and subtype-specific patterns is expanding. This study investigated how pathological and clinical variables affect the actionability of Next Generation Sequencing (NGS)-based tumor molecular data. MATERIALS AND METHODS: 227 breast cancer patients referred to Genekor's laboratory for tumor molecular profile analysis were included in the study. Pathology records were used to assess critical clinicopathological features, including HER2, ER, PR, Ki67, grade, metastatic site, and age. A 1021-gene NGS-based multigene panel was utilized to assess tumor biology alongside tumor mutational burden (TMB) and microsatellite instability (MSI). RESULTS: Comprehensive genomic profiling revealed that 95.6% of the patients harbored at least one oncogenic or likely oncogenic alteration, highlighting the high diagnostic yield of NGS-based testing. Distinct subtype-specific patterns were observed: HR+/HER2- tumors were enriched for PIK3CA and ESR1 gene alterations, whereas triple-negative breast cancer (TNBC) was dominated by TP53 alterations. Clinically actionable alterations were most common in HR+/HER2- tumors (~60% on-label), whereas TNBC more often harbored off-label or trial-associated targets. The inclusion of tumor-agnostic biomarkers (TMB/MSI) increased on-label actionability up to 64.5% in HR+/HER2- tumors, primarily driven by TMB-high cases. Median TMB values were low, and age was the only independent predictor. Furthermore, the presence of actionable alterations was significantly higher in metastatic tumors, and TP53 alterations were associated with aggressive tumor characteristics. CONCLUSION: Comprehensive NGS-based genomic profiling identifies clinically actionable alterations in over half of breast cancer patients, with substantial variability across molecular subtypes. The HR+/HER2- subtype demonstrates the highest prevalence of on-label actionable biomarkers. These findings support the routine implementation of comprehensive genomic profiling, especially in metastatic HER2-negative breast cancer, to guide precision oncology strategies and enable enrollment in biomarker-driven clinical trials.

Humans↗

PubMed1995

Translocation 11;14 in three children with acute lymphoblastic leukemia of T-cell origin.

Clinical, karyotypic, immunophenotypic, and molecular profiles of three TALL cases carrying a t(11;14) are discussed and compared with data in the literature. As previously reported, t(11;14)(p13;q11) was associated in one patient with a TALL profile of intermediate stage of maturation (CD7+, CD4+, CD8+). However, the same translocation was found to be present in another patient with a more immature, pro-TALL profile (CD7+, CD4-, CD8-). Both patients showed molecular rearrangements of the TCR beta chain gene. A third patient, with a very immature pro-TALL profile (CD34+, CD7+, CD4-, CD8-), carrying a t(11;14)(p15;q11), showed molecular rearrangements of the TCR beta and gamma chain genes, while the IgH chain genes were in germline configuration. Our data indicate that t(11;14) can also be present in TALLs of more immature stages of intrathymic development; the significant factor determining the clinical behavior of TALLs is apparently related more to cell differentiation than to the presence of this chromosome rearrangement.

Adolescent↗

PubMed2002

Molecular and biochemical profiling of a heparin-derived oligosaccharide, C3.

This study was designed to characterize a heparin-derived oligosaccharide (HDO), C3, using chemical and biochemical methods. Although previous studies have suggested C3 as a promising compound in the treatment of Alzheimer's disease (AD), its molecular and biochemical properties are still unknown. In this study, the molecular profiles and anticoagulant effects of C3 were investigated. To characterize the molecular and biochemical properties of C3, gel permeation chromatography (GPC), polyacrylmide gel electrophoresis (PAGE), radiolabeling and anticoagulant assays, such as activated partial thromboplastin time (APTT), Heptest, and anti-factor Xa assay, were used. The GPC profile revealed that C3 was an ultra-low-molecular-weight (MW) heparin mixture. The multiple components in C3 were studied with PAGE analysis. Tritium-labeled C3 exhibited similar biological properties as nonlabeled materials. The biological assays showed that C3 and its components exhibited weak anticoagulant effect. These results demonstrated the applicability of the combination of GPC, PAGE, and coagulation assays to characterize the molecular and biochemical profile of HDO. In addition, the low anticoagulant effect of C3 suggests that this compound could be a relatively low-risk adjunct in the treatment of AD.

Animals↗

PubMed2006

Quantitative PCR-based approach for rapid phage display analysis: a foundation for high throughput vascular proteomic profiling.

Functional proteomic strategies offer unique advantages over current molecular array approaches, as the epitopes identified can directly provide bioactive peptides for investigational and/or translational applications. The vascular endothelium is well suited to proteomic assessment by in vivo phage display, but extensive enrichment and sequencing steps limit its application for high throughput molecular profiling. To overcome these limitations we developed a quantitative PCR (Q-PCR) strategy to allow the rapid quantification of in vivo phage binding. Primers were designed for distinct clones selected from a defined phage pool to probe for age-associated changes in cardiac vascular epitopes. Sensitivity and specificity of the primer sets were tested and confirmed in vitro. Q-PCR quantification of phage in vivo confirmed the preferential homing of all phage clones to the young rather than old cardiac vasculature and demonstrated a close correlation with phage measurements previously determined using traditional bacterial-based titration methods. This Q-PCR approach provides quantification of phage within hours of phage injection and may therefore be used for rapid, high throughput analysis of binding of defined phage sequences both in vivo and in vitro, complementing nonbiased phage approaches for the proteomic mapping of vascular beds and other tissues.

Aging↗

PubMed2002

Identification of high risk breast-cancer patients by gene expression profiling.

We previously used DNA array analyses in the molecular profiling of breast cancers. By cluster analysis of 55 patients, we identified a subpopulation of breast cancers-designated class A-that contained a high number of nodal-positive tumours and that had frequently developed distant metastases at the time of diagnosis. We have now analysed follow-up data from these patients. We found that, despite a median of only 23.5 months of follow-up, 11 of 22 patients in class A progressed to metastatic disease, and three of five patients classified as having a nodal status of N0 in this subpopulation developed distant metastases. Our analysis identifies breast-cancer patients with a high risk of disease recurrence, and could act as a first step towards improved patient-adapted therapy.

Biomarkers, Tumor↗

PubMed2026

Pleomorphic Liposarcoma: Comprehensive Genomic Analysis of 39 Cases With Comparison to Other Genomically Complex Sarcomas.

Pleomorphic liposarcoma (PLPS) is an aggressive high-grade sarcoma that often shows diverse morphological features and can mimic high-grade undifferentiated pleomorphic sarcoma (UPS)/spindle cell sarcoma or myxofibrosarcoma (MFS), especially when pleomorphic lipoblasts are sparse. The molecular profile of PLPS is distinct from well differentiated/dedifferentiated liposarcoma and myxoid liposarcoma. In this study, we investigate 39 cases of PLPS by comprehensive genomic profiling, occurring in 32 patients with available molecular data. Cases were reviewed and morphologic parameters-lipoblastic component, UPS-like, and MFS-like areas were estimated. The genomic findings were collected and compared to UPS and MFS groups studied using the same platform. The cohort included 15 females and 17 males, with a median age of 56.5 (range, 34-78). The lower extremity (n = 17) was the most common site involved, followed by upper extremity (n = 5) and pelvis (n = 5). UPS-like and MFS-like patterns were the most common morphologic variants, ranging from 15% to 95% and 20% to 90%, respectively. TP53 (87%) and RB1 (51%) mutations and copy number alterations were the most common alterations seen, followed by ATRX (36%). Compared to UPS and MFS, TP53 and RB1 gene alterations were significantly more common in PLPS. Conversely, CDKN2A/B deletions were infrequent in PLPS. Survival analysis showed that MYC amplification was associated with significantly shorter overall survival in PLPS. Among histologic variants, CYSLTR2 alterations were found to be highest in cases with predominantly pleomorphic lipoblasts; additionally, strong correlations were found between gene alteration frequencies of MFS and MFS-like PLPS, and between UPS and UPS-like PLPS. RB1 allele-specific copy number analysis showed loss of heterozygosity in 82% of cases. Our cohort of PLPS showed a complex molecular landscape with distinct genetic alterations, histologic correlations, and clinical outcomes, highlighting its unique position among genomically complex sarcomas and providing insights that may inform future diagnostic and therapeutic approaches.

Humans↗

PubMed2002

Radiation oncology--linking technology and biology in the treatment of cancer.

Technical advances in radiation oncology including CT-simulation, 3D- conformal and intensity-modulated radiation therapy (IMRT) delivery techniques, and brachytherapy have allowed greater treatment precision and dose escalation. The ability to intensify treatment requires the identification of the critical targets within the treatment field, recognizing the unique biology of tumor, stroma and normal tissue. Precision is technology based while accuracy is biologically based. Therefore, the intensity of IMRT will undoubtedly mean an increase in both irradiation dose and the use of biological agents, the latter considered in the broadest sense. Radiation oncology has the potential and the opportunity to provide major contributions to the linkage between molecular and functional imaging, molecular profiling and novel therapeutics for the emerging molecular targets for cancer treatment. This process of 'credentialing' of molecular targets will require multi disciplinary imaging teams, clinicians and basic scientists. Future advances will depend on the appropriate integration of biology into the training of residents, continuing post graduate education, participation in innovative clinical research and commitment to the support of basic research as an essential component of the practice of radiation oncology.

Biology↗

PubMed2005

Personalised medicine for cancer: from drug development into clinical practice.

Personalised management of cancer means the prescription of specific therapeutics that are best suited for an individual patient and the type of tumour. Molecular diagnostics influences cancer management in several ways that aid personalisation. These technologies are enabling the classification of cancer, using molecular profiles, as a basis for more effective personalised therapies. Using microarrays, classification of a cancer based on the gene expression profile is important for personalising cancer therapy. Molecular imaging, such as by positron emission tomography, enables determination of tumour response to drug action at the molecular level. The combination of diagnostics with therapeutics--an important feature of personalised cancer therapy--is facilitated by the use of monoclonal antibodies and nanobiotechnology. Development of drug resistance--an important problem in cancer management--varies according to the anticancer agent, type of tumour and individual patient. There are no universal strategies to overcome drug resistance in cancer. Various efforts to deal with this problem should be tailored to each patient, and examples are given in this review. A better understanding of cancer biology will facilitate rational drug discovery for cancer, by linking the various pathways involved to targeted therapies. Oncoproteomics will play an important role in the development of personalised cancer therapy. Use of pharmacogenomic technologies in early clinical trials is enabling rapid assessment of the efficacy of anticancer agents, and reducing the time of drug development. Application of pharmacogenetics will reduce the adverse effect of anticancer drugs. Cell/gene therapies, cancer vaccines and RNA interference will facilitate the development of personalised cancer therapy.

Animals↗

PubMed2001

[A model for clinical study based on genome science--trials in disorders of the immune system and allergies].

Disorders of the immune system, such as allergies, have multi-factorial etiologies that include both genetic and environmental components. The recent advances in genome science have facilitated two strategies for studying the genetic basis of disease: (1) systematic analysis of gene expression profiles and (2) comprehensive analysis of gene variations, such as polymorphisms. Here, we describe a unique research institute, Genox Research Inc., that can relate the clinical profile of a patient to genotyping and molecular profiling. Systematic gene expression analyses using differential display have been performed to explore genes related to allergy, and revealed 93 differentially expressed candidate genes in T-cells. Also, a single nucleotide polymorphism(SNP) analysis project has been designed to mine disease-related and/or drug-response-related genes involved in allergic disorders using biochip technologies. As exemplified above, clinical studies based on these applications of genome science would be of considerable value in clarifying our understanding of multi-gene disorders.

Gene Expression Profiling↗

PubMed2004

The first Canadian indigenous case of bovine spongiform encephalopathy (BSE) has molecular characteristics for prion protein that are similar to those of BSE in the United Kingdom but differ from those of chronic wasting disease in captive elk and deer.

Brain tissue from a case of bovine spongiform encephalopathy (BSE) from Alberta was subjected to a Western immunoblotting technique to ascertain the molecular profile of any disease-specific, abnormal prion protein, that is, prion protein that is protease-resistant (PrP(res)). This technique can discriminate between isolates from BSE, ovine scrapie, and sheep experimentally infected with BSE. Isolates of brain tissue from the BSE case in Alberta, 3 farmed elk with chronic wasting disease (CWD) from different parts of Saskatchewan, and 1 farmed white-tailed deer with CWD from Edmonton, Alberta, were examined alongside isolates of brain tissue from BSE, ovine scrapie, and sheep experimentally infected with BSE from the United Kingdom (UK). The molecular weights of PrP(res) and the cross reactions to 2 specific monoclonal antibodies (mAbs) were determined for each sample. The BSE isolates from Canada and the UK had very similar PrP(res) molecular weights and reacted with only 1 of the 2 mAbs. The PrP(res) isolated from both elk and white-tailed deer with CWD had a higher molecular weight profile than did the corresponding PrP(res) from the scrapie and BSE isolates. The PrP(res) from CWD cases cross reacted with both mAbs, a property shared with PrP(res) in isolates from scrapie but not with PrP(res) isolates from BSE or sheep experimentally infected with BSE. The results from this study seem to confirm that the PrP(res) isolated from the BSE case in Alberta has similar molecular properties to the PrP(res) isolated from a BSE case in the UK, and that it differs in its molecular and immunological characteristics from the CWD and scrapie cases studied.

Animals↗

PubMedDate not supplied

Tissue microarray technology: principles, pitfalls and perspectives--lessons learned from hematological malignancies.

Detection, validation and incorporation into clinical use of new diagnostic, prognostic and therapeutic molecular targets in modern medical science should be time- and cost-efficient. Here, we discuss the principles, advantages, disadvantages and possible pitfalls of tissue microarray (TMA) technology, a powerful tool for high throughput large-scale morphological in situ analysis of molecular targets. Based on recent observations from molecular profiling of hematological malignancies, we review potential TMA applications assessing molecular targets in large collectives of tissue specimens.

Animals↗