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Results for “molecular profiling”

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PubMed2006

Classification of renal neoplasms based on molecular signatures.

PURPOSE: Gene expression microarray studies have demonstrated distinct molecular signatures for different types of renal neoplasms based on overall gene expression patterns. However, in most of these studies the investigators used renal tumors with defined histology. We analyzed a test set of renal tumors in double-blind fashion using recently established molecular profiles of renal tumors as benchmarks. MATERIALS AND METHODS: A total of 16 consecutive nephrectomies performed for neoplasms at a single urological service were subjected to gene expression profiling using cDNA chips containing 21,632 genes. Analysis was clustered with our previously established molecular profiles of 91 histologically defined kidney neoplasms and comparative genomic microarray analysis while blinded to tumor histology and clinical information. RESULTS: With molecular analysis 9, 4, 2 and 1 tumors were classified as clear cell, papillary RCC, chromophobe RCC, and renal oncocytoma, respectively. Histopathological evaluation was concordant in 14 tumors. One of the 2 tumors with a discrepancy between molecular and pathological diagnoses was composed of oncocytoma and high grade clear cell RCC, and the other was chromophobe RCC that histologically mimicked papillary RCC. CONCLUSIONS: We report the feasibility of the molecular diagnosis and classification of unknown renal neoplasms. Molecular diagnosis appears to be reliable and comparable to the standard of urological pathology. This molecular method may be a potentially useful test for establishing an accurate diagnosis that can impact clinical management.

Carcinoma, Renal Cell↗

PubMed2005

Whole-genome expression profiling of the melanoma progression pathway reveals marked molecular differences between nevi/melanoma in situ and advanced-stage melanomas.

Over the past two decades, several known genes have been shown to govern important functions in the development of primary and metastatic melanomas. However, from this limited number of genes, it is not possible to establish detailed molecular profiles for the early and advanced stages of melanoma development. To gain insights into the genetic profile of every stage of the melanoma progression pathway, and to determine to what extent these profiles are similar or distinct, we performed whole-genome expression profiling of tissue specimens representing normal skin, benign and atypical nevi, and early and advanced-stage melanomas. The results of this study provide first-time evidence that significant molecular changes occur distinctly at the border of/transition from melanoma in situ to primary melanoma, and that genes involved in mitotic cell cycle regulation and cell proliferation constitute the two leading categories of genes associated with these changes.

Carcinoma in Situ↗

PubMed2006

Transcriptional profiling of aging in human muscle reveals a common aging signature.

We analyzed expression of 81 normal muscle samples from humans of varying ages, and have identified a molecular profile for aging consisting of 250 age-regulated genes. This molecular profile correlates not only with chronological age but also with a measure of physiological age. We compared the transcriptional profile of muscle aging to previous transcriptional profiles of aging in the kidney and the brain, and found a common signature for aging in these diverse human tissues. The common aging signature consists of six genetic pathways; four pathways increase expression with age (genes in the extracellular matrix, genes involved in cell growth, genes encoding factors involved in complement activation, and genes encoding components of the cytosolic ribosome), while two pathways decrease expression with age (genes involved in chloride transport and genes encoding subunits of the mitochondrial electron transport chain). We also compared transcriptional profiles of aging in humans to those of the mouse and fly, and found that the electron transport chain pathway decreases expression with age in all three organisms, suggesting that this may be a public marker for aging across species.

Adolescent↗

PubMed2004

Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype.

We investigated the frequency of promoter region CpG island methylation (CIM) of hMLH1, MGMT, MINT1, MINT2, and p16 and K-ras mutations in a total of 79 hyperplastic (serrated) polyps (HPs) from 75 patients and correlated the molecular profiles to polyp location in the colorectum, histologic variation, and other factors. Methylation-specific PCR (MS-PCR) was used to assay CIM status. HPs that showed CIM of one or more or two or more of the genes assayed were classified as CpG island methylator phenotype (CIMP) and CIMP-high (CIMP-H), respectively. PCR restriction fragment length polymorphism was used to assay K-ras codon 12 and 13 mutations. Logistic regression indicated a statistically significant trend for increasing odds for CIMP (P = 0.002) and CIMP-H (P < 0.001) according to proximity to the cecum or distance from the rectum. Conversely, K-ras codon 12 mutation was present in 13 of 40 (32.5%) distally located HPs compared with 2 of 39 (5.1%) proximal HPs (P = 0.006). Histologic subtype distribution varied by proximal and distal locations. Frequency of CIMP in serrated polyps with abnormal proliferation (SPAPs), differed significantly from goblet cell serrated polyps (GCSPs) (24 of 26, 92.3% vs. 6 of 13, 46.2%) (P = 0.003) and microvesicular serrated polyps (MVSPs) (26 of 38, 68.4%) (P = 0.03). Frequency of K-ras mutation in GCSPs (7 of 13, 54%) differed from that of MVSPs (6 of 38, 16%) (P = 0.01) and SPAPs (2 of 26, 8%) (P = 0.003). Location in the colorectum and histologic subtype were major determinants of the molecular profile of HPs. The molecular findings of CIMP and K-ras mutations appear to encompass most if not all HPs; CIMP profiles suggest that SPAP is the most advanced morphologic variant. We postulate that MVSP and GCSP may be precursor lesions that, if proximally located or larger, can progress to SPAP. Frequent K-ras mutations and infrequent CIMP distinguish the distal GCSP variant.

Adult↗

PubMed2004

Genomic approaches to hematologic malignancies.

In the past several years, experiments using DNA microarrays have contributed to an increasingly refined molecular taxonomy of hematologic malignancies. In addition to the characterization of molecular profiles for known diagnostic classifications, studies have defined patterns of gene expression corresponding to specific molecular abnormalities, oncologic phenotypes, and clinical outcomes. Furthermore, novel subclasses with distinct molecular profiles and clinical behaviors have been identified. In some cases, specific cellular pathways have been highlighted that can be therapeutically targeted. The findings of microarray studies are beginning to enter clinical practice as novel diagnostic tests, and clinical trials are ongoing in which therapeutic agents are being used to target pathways that were identified by gene expression profiling. While the technology of DNA microarrays is becoming well established, genome-wide surveys of gene expression generate large data sets that can easily lead to spurious conclusions. Many challenges remain in the statistical interpretation of gene expression data and the biologic validation of findings. As data accumulate and analyses become more sophisticated, genomic technologies offer the potential to generate increasingly sophisticated insights into the complex molecular circuitry of hematologic malignancies. This review summarizes the current state of discovery and addresses key areas for future research.

Gene Expression Profiling↗

PubMed1993

Bombesin stimulates distinct time-dependent changes in the sn-1,2-diradylglycerol molecular species profile from Swiss 3T3 fibroblasts as analysed by 3,5-dinitrobenzoyl derivatization and h.p.l.c. separation.

We have developed procedures for the analysis of endogenous diradylglycerol (DRG) molecular species using derivatization with 3,5-dinitrobenzoyl chloride. The introduction of this strong chromatophore enabled us to separate less than 1 nmol of DRG into its three classes (diacylglycerol, alkylacylglycerol and alkenylacylglycerol) using a combination of h.p.l.c. and t.l.c. followed by reversed-phase h.p.l.c. to resolve these classes into their component molecular species. When applied to Swiss 3T3 mouse fibroblasts stimulated with bombesin for 25 s, 5 min or 30 min, subtle time-dependent changes in the DRG patterns were observed, with only certain polyunsaturated 1,2-diacyglycerol species [18:0/20:3(n-9), 18:0/20:4(n-6), 18:0/20:4(n-3), 18:0/20:5(n-3), 18:1(n-9)/20:3(n-9), 18:1(n-9)/20:4(n-6), 16:0/22:6(n-3), 18:0/20:3(n-6) and 16:0/20:5(n-3)] showing significant agonist-stimulated increases. The amounts of the first six species were all raised at 25 s, whereas all except the latter two were elevated at 5 min. By 30 min these last species were also increased but 18:0/20:3(n-9) had returned to basal levels. Overall DRG levels, as measured by total molecular-species peak area, remained effectively constant. No changes in the amount or species profile of 1-alkyl-2-acylglycerol were observed. Comparison of these species with the acyl-chain structure of phospholipids supports the idea that inositol lipids could be the source of DRG at early stimulation times, but phosphatidylcholine appears to be a phospholipase substrate at all times. These results indicate sequential activation of several phospholipases with different substrate specificities and/or access to different phospholipid pools. They also suggest that only polyunsaturated DRGs act as second messengers and that changes in the relative amounts of these species may trigger activation of different proteins and/or isoforms (e.g. the different isoforms of protein kinase C).

3T3 Cells↗

PubMed2005

Epidemiology of pediatric tuberculosis using traditional and molecular techniques: Houston, Texas.

OBJECTIVE: To investigate the transmission dynamics of pediatric tuberculosis (TB) by analyzing the clinical characteristics with the molecular profiles of Mycobacterium tuberculosis isolates during a 5-year period. METHODS: A retrospective review of a prospective population-based active surveillance and molecular epidemiology project was conducted in private and public pediatric clinics within Houston and Harris County, Texas. The study population consisted of patients who had pediatric TB diagnosed from October 1, 1995, through September 30, 2000. Cases and potential source cases (PSC) were interviewed using a standardized questionnaire. Available Mycobacterium tuberculosis isolates from cases and PSCs were characterized and compared by IS6110 restriction fragment length polymorphism, spoligotyping, and genetic group assignment. Clinical characteristics were described, and molecular characterizations were compared. Data were analyzed by using EpiInfo 6.02b and SAS 8.2. RESULTS: A total of 220 (92%) of 238 pediatric TB cases were included. Epidemiologic and clinical findings were consistent with previous studies. Molecular profiles from 3 cases did not match the profile of PSC. Four previously unknown PSCs were identified using molecular techniques. Fifty-one (71.8%) of 71 isolates matched at least 1 other Houston Tuberculosis Initiative TB database isolate and were grouped into 33 molecular clusters. Cases were more likely to be clustered when the patients were younger than 5 years, identified a source case, or were US born. CONCLUSIONS: Traditional contact tracing may not always be accurate, and molecular characterization can lead to identification of previously unrecognized source cases. Recent transmission plays a significant role in the transmission of TB to children as evident by the high degree of clustering found in our study population.

Adolescent↗

PubMed2006

The racial disparity in outcomes in endometrial cancer: could this be explained on a molecular level?

OBJECTIVE: The racial disparities among patients with endometrial carcinoma have been previously reported. The objective of this study is to analyze and compare the molecular profiles in endometrial cancer in Caucasian and African American patients using a number of known molecular markers. MATERIALS AND METHODS: 147 patients diagnosed with endometrial cancer between 1995 and 2001 were included in the study. Patients' demographics, clinical and pathological data were reviewed. Immunohistochemical staining for p53, VEGF, Ki-67 and HIF-1alpha was performed on tissue micro array sections. Tumors' expression of p53, VEGF, Ki-67, and HIF-1alpha was compared based on ethnicity and tumor type (Type I = endometrioid carcinomas and Type II = non-endometrioid carcinomas). Spearman's correlation and Fisher's Exact Tests were used for statistical analysis and Kaplan-Meier, log-rank and Cox regression were used for survival analysis. RESULTS: 97 patients were Caucasian and 50 patients were African American. The mean age was 62 (33-91) years for Caucasian patients and 63.5 (24-89) years for the African American patients. African American patients had more Type II carcinoma than Caucasian patients (P = 0.055). High p53 expression was statistically significant among the African American patients (49% vs. 30%, P = 0.035) versus Caucasian patients. There was no significant difference demonstrated when comparing the VEGF, Ki-67, and HIF-1alpha expression between the racial groups. Survival analysis showed a trend toward a shorter survival in the African American patients compared to the Caucasian patients; median survival 62 versus 77 months (P = 0.061). On the other hand, we did not find a significant difference in survival by ethnicity when we adjusted for tumor histology. CONCLUSION: While African American patients with endometrial cancer seem to show a trend toward a shorter survival, this seems to be mainly due to the fact that they have a higher proportion of Type II tumors. The molecular profiles for p53, Ki-67, VEGF and HIF-1alpha expression of histologically matched tumors were similar between the two ethnic groups.

Adult↗

PubMed2003

From microarrays to new therapeutic approaches in bladder cancer.

Bladder cancer is a model tumor progressing from superficial to locally invasive and finally metastatic disease. The likelihood of progression is determined to a large extent by the molecular profile of the tumor. From the pre-genomic era only p53 emerged as the molecular prognostic factor able to add value to existing clinical and pathological features of bladder cancer, however it was not introduced to the clinic. Microarray technologies enable us to study expression of thousands of genes in the tumor tissue. This method has already proven to add information to clinical classifiers, to find new tumor suppressor genes and to define p53 related pathways of cell-cycle regulation. In the last decade, progress in the treatment of locally invasive and metastatic bladder cancer was minimal; large Phase III trials with neo/adjuvant chemotherapy were inconclusive. The new paradigm of treatment tailored to an individual patient could be realized in bladder cancer for his chronic clinical course with opportunities to obtain tumor samples for microarray studies. Molecular profiling of two samples taken at the superficial stage and at cystectomy should enable us to study the microevolution of the tumor, to tailor existing treatment options, and to introduce new biologicals to the clinic.Introduction

Apoptosis↗

PubMed2006

Profile and molecular modeling of 3-(indole-3-yl)-4-(3,4,5-trimethoxyphenyl)-1 H-pyrrole-2,5-dione (1) as a highly selective VEGF-R2/3 inhibitor.

We report on selectivity profiling of 1 in a panel of 20 protein kinases and molecular modeling indicating 1 to be highly active and selective for VEGF-R2/3. Sequence alignment analysis and detailed insights into the ATP binding pockets of targeted protein kinases from the panel result in a unique structural architecture of VEGF-R2 mainly caused by the hydrophobic pocket I, determining the molecular basis for activity and selectivity of 1.

Amino Acid Sequence↗

PubMed2026

Molecular biomarker profiling in noninfectious uveitis: a chronological review of discovery.

PURPOSE OR REVIEW: Noninfectious uveitis (NIU) encompasses a heterogeneous group of immune-mediated intraocular inflammatory diseases whose complexity has driven systematic molecular biomarker discovery. This review presents NIU molecular biomarkers organized by biological category; autoantigens, human leukocyte antigens (HLA) and genetic markers, cellular immune subsets, cytokines, chemokines, and multiomics platforms including proteomics, microbiome metagenomics, metabolomics, and single-cell transcriptomics with each category presented in strict chronological order of landmark discovery. RECENT FINDINGS: We present a review organized along two nested timelines. Categories are presented in the order they historically emerged in the field, and within each category, landmark discoveries appear in chronological sequence. This allows the reader to trace how each biomarker category evolved: from foundational autoantigen identification in experimental uveitis models, through the genomic revolution of HLA association studies, into cellular immunophenotyping, cytokine profiling of aqueous humor, chemokine mapping of intraocular trafficking, and finally the emerging omics platforms that may potentially anchor precision medicine in NIU. Each biomarker is paired in line with its linked targeted therapeutic. SUMMARY: Biomarker research has transformed the understanding of NIU from a clinically defined syndrome into a group of molecularly distinct immune disorders. Advances spanning autoantigens, genetics, immune-cell profiling, cytokines, chemokines, and multiomics have revealed novel pathogenic mechanisms and therapeutic targets. Integration of these biomarkers with targeted therapies may accelerate the transition toward precision medicine in uveitis care.

cytokines↗

PubMed2004

Wheat digalactosyldiacylglycerol molecular species profiling using porous graphitic carbon stationary phase.

The potential of porous graphitic carbon stationary phase (PGC) was assessed for the separation of molecular species of digalactosyldiacylglycerol (DGDG). Detection was by an evaporative light scattering detector (ELSD). A conventional optimization strategy allowed definition of a quaternary non-aqueous mobile phase and separation of 9 wheat DGDG molecular species with isocratic elution: methanol/toluene/tetrahydrofuran/chloroform 64.3/21.5/13.7/0.5 v/v with 0.1% of triethylamine and a stoichiometric amount of formic acid. The molecular species were identified by LC/MS. The chromatographic behavior of DGDG on PGC was then compared to previous studies. The addition of a carbon double bond on the alkyl chain decreased the retention. This contribution was less important when the number of unsaturations increased in the alkyl chain. The consequence of this retention behavior with PGC was an elution order of molecular species which did not agree with the partition number as observed with C18 grafted stationary phases.

Chromatography, High Pressure Liquid↗

PubMed2026

Lung Squamous Cell Carcinoma Harbouring a Novel PAX8::PPARγ Fusion and a FGFR2 Exon 7 Missense Mutation.

Comprehensive molecular profiling is now routinely performed in newly diagnosed non-small cell lung carcinomas (NSCLCs) to identify actionable genomic alterations. Although numerous molecular abnormalities have been described in lung carcinomas, rare and unexpected gene fusions may create significant diagnostic challenges, particularly when they are characteristically associated with tumours of different lineages. To our knowledge, this is the first reported case of a primary lung squamous cell carcinoma harbouring an in-frame PAX8::PPARγ fusion with a concurrent FGFR2 exon 7 missense mutation (p.W290C). An 80-year-old man with a smoking history exceeding 50 years presented with a rapidly enlarging PET-avid right upper lobe pulmonary mass. Bronchial brushing cytology demonstrated a hypercellular malignant neoplasm composed of pleomorphic squamoid cells with hyperchromatic nuclei, dense cytoplasm and extensive necrosis. Cell block material showed squamous morphology and diffuse p40 positivity, supporting squamous differentiation. Reflex next-generation sequencing identified an FGFR2 exon 7 missense mutation (p.W290C; c.870G>C) and targeted RNA fusion analysis demonstrated an in-frame PAX8::PPARγ fusion resulting from a t(2;3)(q13;p25.2) translocation. Because PAX8::PPARγ rearrangements are strongly associated with follicular thyroid neoplasms, extensive clinicoradiologic and immunohistochemical correlation was performed to exclude metastatic thyroid carcinoma. Imaging studies showed no thyroid lesion or residual thyroid tissue, and tumour cells were negative for thyroglobulin, TTF-1 and PAX8. Correlation of the clinical history, radiologic findings, cytomorphology, immunophenotype and molecular profile supported the diagnosis of primary lung squamous cell carcinoma. This case expands the molecular spectrum of lung squamous cell carcinoma and highlights the importance of integrated cytopathologic, immunohistochemical, molecular and radiologic evaluation when unexpected gene fusions are identified in cytology specimens.

FGFR2 exon 7 missense mutation↗

PubMed1999

Molecular alterations in early gastric carcinomas. No apparent correlation with Helicobacter pylori status.

Data on the differences in molecular profile between H pylori-positive and H pylori-negative early gastric carcinomas, if any, are almost nonexistent. We therefore investigated whether molecular differences can be observed between H pylori-positive and H pylori-negative early gastric carcinomas. Forty-five early gastric carcinomas were analyzed for alterations in certain oncogenes (ras, MDM2, c-erbB-2, cyclin D1), the p53 tumor suppressor gene, and the e-cadherin gene. Of these 28 carcinomas were H pylori-positive, and 17 were H pylori-negative. No significant differences were found in the groups irrespective of Lauren type; ras (0% vs 0%), MDM2 (0% vs 0%), c-erbB-2 (0% vs 0%), cyclin D1 (18% vs 29%), p53 (68% vs 47%), and e-cadherin (46% vs 41%). Helicobacter pylori-positive and H pylori-negative early gastric carcinomas do not differ in molecular profile. Although they may prove different when tested for other abnormalities, our findings suggest that the acquisition of molecular alterations occurs via an H pylori independent pathway.

Cadherins↗

PubMed1999

Evaluation of the Cephalosporins, Cefepime, Cefpirome and Ceftazidime, against Clinical Isolates of Imipenem-Resistant Pseudomonas aeruginosa.

The level of resistance to imipenem in our institution has increased significantly in recent years, particularly in isolates of Pseudomonas aeruginosa. At present, 30% to 40% of P. aeruginosa isolated in clinical samples are imipenem resistant. The objective of this study was to test therapeutic alternatives within the class of beta-lactam antibiotics in the treatment of infections caused by imipenem-resistant strains of P. aeruginosa (IRPA). We tested 160 isolates of IRPA collected consecutively from in patients at Hospital São Paulo-UNIFESP (Federal University of São Paulo). Using the E-test method, these isolates were tested for cefepime, cefpirome, and ceftadizime susceptibility or resistance. The E-test was also used to confirm the resistance to imipenem. One group of samples was studied epidemiologically using the pulsed-field gel electrophoresis (PFGE) method to determine how this type of resistance spread in our institution. Cefepime was the most active antibiotic (MIC50, 24 µg/mL; MIC(90), 64 µg/mL) and only 57 (35.6%) of the samples showed cross-resistance between imipenem and this fourth-generation cephalosporin. The number of samples that were highly resistant (MIC(90), >256 µg/mL) to cefepime, ceftazidime or cefpirome was 8 (5.0%), 22 (13.8%) and 38 (23.8%), respectively. Molecular typing revealed the presence of 9 molecular profiles among 26 IRPA samples tested, suggesting that selection of resistant mutants occurred in each patient. However, identical molecular profiles were also found in more than one patient. This study showed that cefepime is the most effective cephalosporin against the IRPA samples isolated in our institution. In addition, we conclude that P.areuginosa resistant strains are selected in each patient, but patient to patient transmission also occurs.

Journal Article↗

PubMed2001

Anticoagulant and antiprotease profiles of a novel natural heparinomimetic mannopentaose phosphate sulfate (PI-88).

Heparinomimetic mannopentaose phosphate sulfate (PI-88) (Progen Industries Ltd. Brisbane, Australia), currently developed as an anticoagulant and antiproliferative agent, mainly is composed of a pentomannan. However, tetrasaccharide and disaccharide components are also present. The molecular profile and the anticoagulant potency of PI-88 are investigated in this study. Gel permeation chromatography and polyacrylamide gel electrophoresis analyses were carried out to determine the molecular profile and separation of components of PI-88, respectively. Potentiation of antithrombin III (ATIII) and heparin cofactor-II (HC-II) activity were measured using chromogenic substrate assay. In order to determine anticoagulant and antiprotease effects of PI-88, various global anticoagulant tests, such as the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), Hep-test (Haemachem Inc., St. Louis), ecarin clotting time (ECT), activated clotting time (ACT), and thromboelastography (TEG) were used. Anti-Xa and anti-IIa activities also were measured. The effect of PI-88 on the release of tissue factor pathway inhibitor (TFPI) was performed in nonhuman primates who received PI-88 and in endothelial cell culture systems. The relative susceptibility of PI-88 to heparinase I, protamine sulfate (PS), and platelet factor 4 (PF4) also was evaluated. The high-performance liquid chromatography profiles of PI-88 showed that its average molecular weight is approximately 2300 Da. Separation and gradient electrophoretic patterns of PI-88 showed that it is composed of five different fractions. This agent activates HC-II through inhibiting the thrombin generation but not inhibiting ATIII. Although PI-88 produced a concentration-dependent prolongation of all of the clotting tests, ECT gave the best correlation in the dose-response curve (ECT, r2 = 0.94; TT, r2 = 0.84; APTT, r2 = 0.69). Heparinomimetic mannopentaose phosphate sulfate (PI-88) exhibited marked inhibition of FIIa, but not of FXa. Heparinase I failed to produce significant neutralization of PI-88 in all the assays used, whereas PS and PF4 partially neutralized the effects of this compound. Heparinomimetic mannopentaose phosphate sulfate (PI-88) produced fivefold increase in the TFPI levels at 15 minutes after intravenous (IV) injection to primates. The incubation of PI-88 in endothelial cell culture system also showed a strong effect on TFPI release. These results suggest that PI-88 exhibited strong antithrombotic and anticoagulant activity in addition to its known antiproliferative properties. Because of the molecular characteristics and the dual nature of the pharmacologic action of PI-88, this agent represents an attractive pharmacologic agent for the control of thrombotic and proliferative disorders.

Anticoagulants↗

PubMed2004

Biological spectra analysis: Linking biological activity profiles to molecular structure.

Establishing quantitative relationships between molecular structure and broad biological effects has been a longstanding challenge in science. Currently, no method exists for forecasting broad biological activity profiles of medicinal agents even within narrow boundaries of structurally similar molecules. Starting from the premise that biological activity results from the capacity of small organic molecules to modulate the activity of the proteome, we set out to investigate whether descriptor sets could be developed for measuring and quantifying this molecular property. Using a 1,567-compound database, we show that percent inhibition values, determined at single high drug concentration in a battery of in vitro assays representing a cross section of the proteome, provide precise molecular property descriptors that identify the structure of molecules. When broad biological activity of molecules is represented in spectra form, organic molecules can be sorted by quantifying differences between biological spectra. Unlike traditional structure-activity relationship methods, sorting of molecules by using biospectra comparisons does not require knowledge of a molecule's putative drug targets. To illustrate this finding, we selected as starting point the biological activity spectra of clotrimazole and tioconazole because their putative target, lanosterol demethylase (CYP51), was not included in the bioassay array. Spectra similarity obtained through profile similarity measurements and hierarchical clustering provided an unbiased means for establishing quantitative relationships between chemical structures and biological activity spectra. This methodology, which we have termed biological spectra analysis, provides the capability not only of sorting molecules on the basis of biospectra similarity but also of predicting simultaneous interactions of new molecules with multiple proteins.

Molecular Structure↗

PubMed1994

Elution profiles and molecular weights of placental cystine aminopeptidase in animals.

Gel filtration was performed for cystine aminopeptidase (CAP) [EC 3.4.11.3] on full term placental extracts from human, cynomolgus monkey, dog, goat, pig and horse. The enzymatic profiles of CAP were examined and compared with that of CAP in pregnancy plasma on the basis of inhibitory effects. Elution profiles of placental extracts exhibited 2 CAP activity peaks in human and pig, 3 peaks in cynomolgus monkey, dog and goat, and 4 peaks in horse. The molecular weights of placental CAP that showed identical inhibitory effects to that of pregnancy plasma CAP were estimated to be approximately 325,000 in human, 350,000 in the cynomolgus monkey, 140,000 in the dog, 140,000 in the goat, 128,000 in the pig, and 115,000 in the horse. These molecular weights tended to decrease in accordance with the increase of barrier layers present between maternal blood and placental syncytiotrophoblasts in which CAP is synthesized.

Animals↗