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PubMed2001

In vivo confocal Raman microspectroscopy of the skin: noninvasive determination of molecular concentration profiles.

Confocal Raman spectroscopy is introduced as a noninvasive in vivo optical method to measure molecular concentration profiles in the skin. It is shown how it can be applied to determine the water concentration in the stratum corneum as a function of distance to the skin surface, with a depth resolution of 5 microm. The resulting in vivo concentration profiles are in qualitative and quantitative agreement with published data, obtained by in vitro X-ray microanalysis of skin samples. Semi-quantitative concentration profiles were determined for the major constituents of natural moisturizing factor (serine, glycine, pyrrolidone-5-carboxylic acid, arginine, ornithine, citrulline, alanine, histidine, urocanic acid) and for the sweat constituents lactate and urea. A detailed description is given of the signal analysis methodology that enables the extraction of this information from the skin Raman spectra. No other noninvasive in vivo method exists that enables an analysis of skin molecular composition as a function of distance to the skin surface with similar detail and spatial resolution. Therefore, it may be expected that in vivo confocal Raman spectroscopy will find many applications in basic and applied dermatologic research.

Adult↗

PubMed1992

A profile for molecular biology databases and information resources.

This paper examines the requirements for building database management systems and multi-database information resources to support molecular biology research. The paper profiles the most important features of 16 integrated resources and 102 databases related to molecular biology research. The aspects surveyed in this paper include the nature of information in these databases, their sizes, update properties, cross-references, database management system heterogeneity, geographical distribution, data quality, use of temporal information and level of interpretation. The paper also comments on the access patterns to these databases. Since not all these aspects were available for all databases, specific comparisons sometimes compare fewer than the full 102 databases. Consequently, the same set of databases is not necessarily always being compared with respect to every aspect. The paper is organized primarily according to these comparison aspects and ends with some concluding remarks.

Databases, Bibliographic↗

PubMed2002

Effects of Lentinus edodes on fatty acid and molecular species profiles of phosphatidylcholine in rats fed different levels of corn oil.

Shiitake mushrooms (Lentinus edodes) are a hypocholesterolemic and affect phospholipid and fatty acid metabolism in rats. In this study, the effects of 2% shiitake in the diet on fatty acid and molecular species profiles of liver microsomal and plasma phosphatidylcholine (PC) were investigated in rats fed diets containing different levels (1-20%) of corn oil, a linoleic-acid-rich fat. The proportion of 18:2n-6 in PC increased depending on the parcent corn oil, and L. edodes further increased the proportion at all corn oil levels. The proportion of 20:4n-6 was lower in rats fed L. edodes than in rats fed control diets irrespective of the parcent corn oil. L. edodes selectively increased the proportion of 16:0-18:2 molecular species and decreased the proportion of 18:0-20:4 molecular species in PC. These results indicate that the effects of L. edodes on fatty acid and molecular species profiles of PC are stronger than that of the dietary corn oil level.

Animals↗

PubMed2007

Molecular optical imaging of therapeutic targets of cancer.

Recent progress in discerning the molecular events that accompany carcinogenesis has led to development of new cancer therapies directly targeted against the molecular changes of neoplasia. Molecular-targeted therapeutics have shown significant improvements in response rates and decreased toxicity as compared to conventional cytotoxic therapies which lack specificity for tumor cells. In order to fully explore the potential of molecular-targeted therapy, a new set of tools is required to dynamically and quantitatively image and monitor the heterogeneous molecular profiles of tumors in vivo. Currently, molecular markers can only be visualized in vitro using complex immunohistochemical staining protocols. In this chapter, we discuss emerging optical tools to image in vivo a molecular profile of risk-based hallmarks of cancer for selecting and monitoring therapy. We present the combination of optically active, targeted nanoparticles for molecular imaging with advances in minimally invasive optical imaging systems, which can be used to dynamically image both a molecular and phenotypic profile of risk and to monitor changes in this profile during therapy.

Animals↗

PubMed2004

Molecular depth profiling of histamine in ice using a buckminsterfullerene probe.

We employ a buckminsterfullerene ion source to probe the distribution of histamine molecules at the water-ice/vacuum interface. The experiments utilize secondary ion mass spectrometry to detect molecular ions that are desorbed from a frozen aqueous histamine solution. The results show that this cluster ion probe induces an extraordinarily high sputter yield of 2400 ice molecules per impact event as determined by a quartz crystal microbalance. As a consequence of this high yield, we show that it is possible to produce molecular depth profiles of the top several hundred nanometers below the ice surface without destruction of the molecular ion signal by accumulation of beam-induced chemical damage. Similar profiles are reported for desorbed neutral molecular fragments by utilizing a high-power femtosecond-pulsed laser for photoionization. While this type of information could not be achieved using atomic projectiles, it is possible to remove the damage induced by such projectiles by subsequent cluster bombardment. These experiments are particularly important for organic surface analysis since they suggest that cluster ion probes may successfully be employed to remove overlayers that may mask the desired molecular information in static secondary ion mass spectral analysis.

Combinatorial Chemistry Techniques↗

PubMed2003

Biosensor profiling of molecular interactions in pharmacology.

Techniques employed to profile the pharmacological properties of a molecule in vitro normally require some type of radio-, enzymatic- or fluorescent-labeling of the ligand and/or the receptor. In contrast, biosensor techniques do not require labeling, and they allow virtually any complex to be screened with minimal assay development. Scientists in both academia and industry are now using biosensors in areas that encompass almost all sectors of drug discovery, diagnostics and the life sciences. Assays have been developed for the analysis of small molecules, proteins, oligonucleotides, bacteriophage, viruses, bacteria and cells. In addition, novel biosensor applications are being developed for the predictive profiling of key pharmacokinetic parameters of a molecule (adsorption, distribution, metabolism, excretion and toxicity).

Animals↗

PubMed2006

Application of UL144 molecular typing to determine epidemiology of cytomegalovirus infections in preterm infants.

Sequence analysis of the UL144 gene of human cytomegalovirus (CMV) was used to investigate the epidemiology of CMV infections in preterm infants. Nosocomial transmission of CMV from congenitally infected infant to preterm twins was excluded based on distinct molecular profiles of CMV strains. Indistinguishable molecular profiles between strains from the mother and the infant indicated postnatal acquisition of CMV through breastfeeding.

Base Sequence↗

PubMed2006

Novel integrative genomics strategies to identify genes for complex traits.

Forward genetics is a common approach to dissecting complex traits like common human diseases. The ultimate aim of this approach was the identification of genes that are causal for disease or other phenotypes of interest. However, the forward genetics approach is by definition restricted to the identification of genes that have incurred mutations over the course of evolution or that incurred mutations as a result of chemical mutagenesis, and that as a result lead to disease or to variations in other phenotypes of interest. Genes that harbour no such mutations, but that play key roles in parts of the biological network that lead to disease, are systematically missed by this class of approaches. Recently, a class of novel integrative genomics approaches has been devised to elucidate the complexity of common human diseases by intersecting genotypic, molecular profiling, and clinical data in segregating populations. These novel approaches take a more holistic view of biological systems and leverage the vast network of gene-gene interactions, in combination with DNA variation data, to establish causal relationships among molecular profiling traits and between molecular profiling and disease (or other classic phenotypes). A number of novel genes for disease phenotypes have been identified as a result of these approaches, highlighting the utility of integrating orthogonal sources of data to get at the underlying causes of disease.

Animals↗

PubMed2005

Prognostic and therapeutic significance of myeloma genetics and gene expression profiling.

Molecular diagnostic tools and novel therapeutics now offer the potential for accurate prognostic and personalized treatment road maps for patients with multiple myeloma (MM). We will review the evidence and provide specific recommendations for routine clinical molecular genetic testing and use of such information to guide therapeutic decision making. In particular, the negative prognostic impact of specific IgH translocations such as the t(4;14), t(14;16), chromosome 13 deletion by conventional cytogenetics and loss of 17p13 by interphase fluorescence in situ hybridization are now established. Preliminary gene expression profiling studies have also demonstrated that individual genes (CSK1-B) or groups of genes can define prognosis with greater accuracy than conventional genetic markers and can provide pharmacogenomic and biologic insight into the pathophysiology, therapeutics, and future targets of myeloma. Importantly, we recommend that all clinical trials now adopt routine genetic testing and risk stratification.

Chromosome Aberrations↗

PubMed2006

Molecular depth profiling with cluster ion beams.

Peptide-doped trehalose thin films have been characterized by bombardment with energetic cluster ion beams of C60+ and Aux+ (x = 1, 2, 3). The aim of these studies is to acquire information about the molecular sputtering process of the peptide and trehalose by measurement of secondary ion mass spectra during erosion. This system is important since uniform thin films of approximately 300 nm thickness can be reproducibly prepared on a Si substrate, allowing detailed characterization of the resulting depth profile with different projectiles. The basic form of the molecular ion intensity as a function of ion dose is described by a simple analytical model. The model includes parameters such as the molecular sputtering yield, the damage cross section of the trehalose or the peptide, and the thickness of a surface layer altered by the projectile. The results show that favorable conditions for successful molecular depth profiling are achieved when the total sputtering yield is high and the altered layer thickness is low. Successful molecular depth profiles are achieved with all of the cluster projectiles, although the degree of chemical damage accumulation was slightly lower with C60. With C60 bombardment, the altered layer thickness of about 20 nm and the damage cross section of about 5 nm2 are physically consistent with predictions of molecular dynamics calculations available for similar chemical systems. In general, the model presented should provide guidance in optimizing experimental parameters for maximizing the information content of molecular depth profiling experiments with complex molecular thin film substrates.

Algorithms↗

PubMed2002

Clinical significance of molecular expression profiles of Hürthle cell tumors of the thyroid gland analyzed via tissue microarrays.

Hürthle cell tumors are rare thyroid neoplasms for which disease biology is poorly understood and diagnosis of carcinoma can be challenging. The aim of the study was to characterize molecular expression profiles of Hürthle cell tumors and to determine the clinical significance of identified phenotypes. Paraffin-embedded tissue cores of normal thyroid (n = 18), and histopathologically well-defined Hürthle cell adenomas (n = 27), Hürthle cell tumors of unknown malignant behavior (n = 7), and minimally (n = 14) and widely (n = 21) invasive Hürthle cell carcinomas were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, and Ki-67 were detected by immunohistochemistry and correlated with clinicopathological data and patient outcome using standard statistical methodology. Median follow-up time was 8 years. High Ki-67 proliferative index was evident only in the clinically aggressive widely invasive Hürthle cell carcinomas and was associated with significantly reduced relapse-free (P = 0.001) and disease-specific (P < 0.001) survival. The molecular phenotype of Hürthle cell tumors, independent of histopathological subtype diagnosis, was characterized by p53(-), mdm-2(+), p21(+/-), cyclin D1(-), and Bcl-2(+/-). Normal thyroid tissue demonstrated a p53(-), mdm-2(-), p21(-), cyclin D1(-), and Bcl-2(+) phenotype. The Bcl-2(+) phenotype was associated with improved relapse-free survival (P = 0.04) and disease-specific survival (P = 0.01) in widely invasive carcinomas and the Ki-67(+)/Bcl-2(-) phenotype was associated with the diagnosis of widely invasive Hürthle cell carcinoma (P < 0.001). This study demonstrates that tissue microarray-based profiling allows identification of molecular markers that are associated with patient prognosis. High Ki-67 proliferative index was associated with adverse outcome in Hürthle cell neoplasms. Together with down-regulation of Bcl-2, high Ki-67 proliferative index may be useful for diagnosing widely invasive Hürthle cell carcinomas. Molecular alterations in the p53 pathway play a role in Hürthle cell tumorigenesis, but other unidentified molecular changes seem to be required to induce the malignant phenotype.

Adenoma, Oxyphilic↗

PubMed2001

A timely expression profile.

Molecular genetic analysis has yielded a detailed mechanistic understanding of invertebrate and vertebrate circadian oscillators, but we still know little about how such molecular oscillators are connected to rhythmic physiological processes. Two recent papers in Cell and Neuron now address this scientific issue through the use of gene chip technology to identify clock-regulated genes in an animal species.

Animals↗

PubMed2002

Development and validation of a method for using breast core needle biopsies for gene expression microarray analyses.

PURPOSE: Gene expression microarray technologies have the potential to define molecular profiles that may identify specific phenotypes(diagnosis), establish a patient's expected clinical outcome (prognosis), and indicate the likelihood of a beneficial effect of a specific therapy (prediction). We wished to develop optimal tissue acquisition, processing, and analysis procedures for exploring the gene expression profiles of breast core needle biopsies representing cancer and noncancer tissues. EXPERIMENTAL DESIGN: Human breast cancer xenografts were used to evaluate several processing methods for prospectively collecting adequate amounts of high-quality RNA for gene expression microarray studies. Samples were assessed for the preservation of tissue architecture and the quality and quantity of RNA recovered. An optimized protocol was applied to a small study of core needle breast biopsies from patients, in which we compared the molecular profiles from cancer with those from noncancer biopsies. Gene expression data were obtained using Research Genetics, Inc. Named Genes cDNA microarrays. Data were visualized using simple hierarchical clustering and a novel principal component analysis-based multidimensional scaling. Data dimensionality was reduced by simple statistical approaches. Predictive neural networks were built using a multilayer perceptron and evaluated in an independent data set from snap-frozen mastectomy specimens. RESULTS: Processing tissue through RNALater preserves tissue architecture when biopsies are washed for 5 min on ice with ice-cold PBS before histopathological analysis. Cell margins are clear, tissue folding and fragmentation are not observed, and integrity of the cores is maintained, allowing optimal pathological interpretation and preservation of important diagnostic information. Adequate concentrations of high-quality RNA are recovered; 51 of 55 biopsies produced a median of 1.34 microg of total RNA (range, 100 ng to 12.60 microg). Snap-freezing or the use of RNALater does not affect RNA recovery or the molecular profiles obtained from biopsies. The neural network predictors accurately discriminate between predominantly cancer and noncancer breast biopsies. CONCLUSIONS: The approaches generated in these studies provide a simple, safe, and effective method for prospectively acquiring and processing breast core needle biopsies for gene expression studies. Gene expression data from these studies can be used to build accurate predictive models that separate different molecular profiles. The data establish the use and effectiveness of these approaches for future prospective studies.

Animals↗

PubMed1998

Identification of Brucella by ribosomal-spacer-region PCR and differentiation of Brucella canis from other Brucella spp. pathogenic for humans by carbohydrate profiles.

Molecular and chemical characteristics often provide complementary information in the differentiation of closely related organisms. The genus Brucella consists of a highly conserved group of organisms. Identification of the four species pathogenic in humans (Brucella melitensis, Brucella abortus, Brucella suis, and Brucella canis) is problematic for many clinical laboratories that depend primarily on serology and phenotypic characteristics to differentiate species. PCR amplification of the 16S-23S ribosomal DNA interspace region was evaluated for species-specific polymorphism. B. abortus, B. melitensis, B. suis, and B. canis produced identical PCR interspace profiles. However, these PCR products were unique to brucellae, allowing them to be readily distinguished from other gram-negative bacteria (including Bartonella spp. and Agrobacterium spp.). Carbohydrate profiles differentiated B. canis from the other three Brucella species due to the absence of the rare amino sugar quinovosamine in the three other species. PCR of the rRNA interspace region is useful in identification of the genus Brucella, while carbohydrate profiling is capable of differentiating B. canis from the other Brucella species.

Base Sequence↗

PubMed2004

Molecular and pharmacologic profile of tinzaparin and a comparable low-molecular-weight bacterial sulfaminoheparosan.

Low-molecular-weight heparins (LMWH) represent depolymerized porcine mucosal heparin derivatives, which are commonly used for the management of thrombotic disorders. Because of their widespread usage, the supplies of the raw material namely unfractionated heparin are nearly exhausted. Porcine mucosal tissue is almost exclusively used for the preparation of these agents. Thus, there is a timely need for the production of heparin like drugs from other sources. Fermentation techniques have been used to produce carbohydrates such as dextran and innulin for therapeutic purposes. Bacterial cell wall polysaccharide mimics the linear hexose units, which constitute heparin. Utilizing Escherichia coli cell membranes produced by fermentation technology, chemical sulfation and enzymatic epimerization, sulfaminoheparosan type of polymer mimicking the structure of heparin has been produced. These semi-synthetic sulfaminoheparosans exhibit biologic actions comparable to that observed with heparin. The sulfaminoheparosan core can also be degraded to obtain low-molecular-weight (LMW) derivatives mimicking LMWHs. Using this technique, a novel LMW sulfaminoheparosan derivative (Q93C/239) was produced by Inalco, Milan, Italy. To compare this heparin analogue, a LMWH, namely tinzaparin, was used to determine the relative anticoagulant, antiprotease, and molecular profile. Additional studies were carried out to determine the susceptibility of this agent to heparinase-I. These comparative studies exhibited both antiprotease and anticoagulant properties similar to those of tinzaparin. However LMW sulfaminoheparosan resisted heparinase-I digestion at low heparinase-I concentrations. These studies demonstrate that the sulfaminoheparosan derived LMW components exhibit similar molecular and anticoagulant profile as tinzaparin and warrant additional preclinical and clinical development to determine their potential usefulness as antithrombotic agents.

Anticoagulants↗

PubMed1999

Tubular Carcinoma of the Breast: Immunohistochemical and DNA Flow Cytometric Profile.

Molecular markers of ordinary invasive ductal carcinoma of the breast have been extensively studied and their prognostic significance has been assessed. A common variant of breast cancer, tubular carcinoma, has an excellent prognosis as judged from several clinicopathologic studies. One would assume that tubular carcinomas have "favorable" molecular markers, however, published series of tubular carcinomas do not include molecular markers. We describe the molecular markers of 39 consecutive tubular carcinomas collected between January 1995 and July 1997. DNA ploidy, S-phase, estrogen and progesterone receptor (ER and PR, respectively) expression, and immunoreactivity for MIB-1, p53, and erbB2 were evaluated. Seventy-two percent of tubular carcinomas were DNA diploid, 49% had an S-phase less than 5%, 95% were ER positive, 69% were PR positive, 88% had less than 10% MIB-1-positive cells, 97% were p53 negative, and 97% did not overexpress erbB2 protein. Thus tubular carcinomas exhibit favorable molecular characteristics, which may play a role in their good prognosis.

Journal Article↗

PubMed1992

Abnormal molecular weight profile of urinary protein in rats with streptozotocin-induced diabetes.

A quantitative analysis of the molecular weight (MW) profile of urinary protein by SDS-PAGE was performed in streptozotocin (STZ)-injected, non-ketotic diabetic rats (DM group), diabetic rats receiving dipyridamole (DM-DIP group), normal rats (C group) and STZ-injected rats with near-normal glycemia due to insulin treatment (DM-INSULIN group). In the DM group, decrease of a small MW protein (SMWP) (MW 19.5 k) was found at 2.5 weeks, and an increase of larger MW proteins (LMWP) (MW 68 [albumin], 55 and 29 k) together with a decrease of SMWPs (MW 19.5 and 15 k) was found at 15 weeks, as compared to the C group: the MW profile of urinary protein in the DM-INSULIN and C groups was indistinguishable. At 15 weeks, creatinine clearance (Ccr) was significantly depressed and an increase in the mesangial matrix with electron dense deposits was evident in the DM group. The urinary protein abnormalities were partially corrected and the reduction of Ccr was absent in the DM-DIP group with no effect on glomerular morphology. STZ-induced diabetes in rats is accompanied by a reduction of urinary SMWP, and a subsequent increase of LMWP and depression of Ccr: dipyridamole ameliorates urinary protein abnormalities and prevents the reduction of Ccr.

Animals↗

PubMed2005

Molecular forensic profiling of Cryptosporidium species and genotypes in raw water.

The emerging concept of host specificity of Cryptosporidium spp. was exploited to characterize sources of fecal contamination in a watershed. A method of molecular forensic profiling of Cryptosporidium oocysts on microscope slides prepared from raw water samples processed by U.S. Environmental Protection Agency Method 1623 was developed. The method was based on a repetitive nested PCR-restriction fragment length polymorphism-DNA sequencing approach that permitted the resolution of multiple species/genotypes of Cryptosporidium in a single water sample.

Animals↗