Design and Gamma-Ray Attenuation Features of New Concrete Materials for Low- and Moderate-Photons Energy Protection Applications.

We aimed, in this investigation, to prepare novel concretes which can be used in gamma-ray shielding applications. The experimental approach was performed using a NaI (Tl) detector to measure the concrete's shielding features for different energies, ranging from 0.081 MeV to 1.408 MeV. The density of the fabricated concretes decreased with increasing W/C ratio, where the density decreased by 2.680 g/cm3, 2.614 g/cm3, and 2.564 g/cm3 for concretes A, B, and C, respectively, with increases in the W/C ratio of 0.4, 0.6, and 0.8, respectively. When the energy was elevated between 0.08 MeV and 1.408 MeV, the highest values were attained for concrete A, with values ranging between 0.451 cm-1 and 0.179 cm-1. The lowest half-value layer (Δ0.5) values were achieved for concrete C, where the Δ0.5 values varied between 1.53 cm and 3.86 cm between 0.08 MeV and 1.408 MeV. The highest Δ0.5 values were achieved for concrete A, where the Δ0.5 varied between 1.77 cm and 4.67 cm between 0.08 MeV and 1.408 MeV. According to this investigation, concrete A has the highest promise in radiation shielding purposes because it has the most desirable properties of the concretes studied.

Recomendaciones para la realización de procedimientos en el laboratorio de función pulmonar en tiempos de COVID-19 / No disponible

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Infection rate of Schistosoma japonicum in the snail Oncomelania hupensis quadrasi in endemic villages in the Philippines: Need for snail surveillance technique.

Schistosomiasis japonica is one of seven NTDs endemic in the Philippines that continues to threaten public health in the country. The causative agent, the blood fluke Schistosoma japonicum, uses an amphibious snail Oncomelania hupensis quadrasi which can harbor larval stages that multiply asexually, eventually producing the infective cercariae which are shed into the water. Contamination of freshwater bodies inhabited by the snail intermediate host occurs through release of human and animal feces containing S. japonicum eggs. Miracidia hatching from these eggs subsequently infect the snails that inhabit these water bodies. The degree of fecal contamination can vary across snail sites and influences snail infection rates in these sites. In this study, conventional malacological surveys using intensive manual search for snails were conducted from 2015 to 2016 in seven selected endemic provinces, namely Leyte and Bohol in the Visayas and Surigao del Norte, Agusan del Sur, Bukidnon, Lanao del Norte and Compostela Valley in Mindanao. A total of 6,279 O. hupensis quadrasi snails were collected from 38 snail sites. The municipality of Trento in Agusan del Sur recorded the highest number of snail sites (7) that yielded O. hupensis quadrasi snails while only one snail site was found positive for O. hupensis quadrasi snails in Kapatagan in Lanao del Norte and Talibon in Bohol. Alegria in Surigao del Norte yielded the highest number of snail sites (5) that were found to harbor snails positive for S. japonicum infection. The snail infection rates in this municipality ranged from 0.43% to 14.71%. None of the snails collected from Talibon in Bohol was infected. Bohol is the only province among the 28 schistosomiasis-endemic provinces which has reached near elimination status. Snail infection rates were found to vary considerably across snail sites, which could be due to the degree of fecal contamination of the snail sites and their connectivity to water that can serve as contamination source.

Infection rate of Schistosoma japonicum in the snail Oncomelania hupensis quadrasi in endemic villages in the Philippines: Need for snail surveillance technique

@#Schistosomiasis japonica is one of seven NTDs endemic in the Philippines that continues to threaten public health in the country. The causative agent, the blood fluke Schistosoma japonicum, uses an amphibious snail Oncomelania hupensis quadrasi which can harbor larval stages that multiply asexually, eventually producing the infective cercariae which are shed into the water. Contamination of freshwater bodies inhabited by the snail intermediate host occurs through release of human and animal feces containing S. japonicum eggs. Miracidia hatching from these eggs subsequently infect the snails that inhabit these water bodies. The degree of fecal contamination can vary across snail sites and influences snail infection rates in these sites. In this study, conventional malacological surveys using intensive manual search for snails were conducted from 2015 to 2016 in seven selected endemic provinces, namely Leyte and Bohol in the Visayas and Surigao del Norte, Agusan del Sur, Bukidnon, Lanao del Norte and Compostela Valley in Mindanao. A total of 6,279 O. hupensis quadrasi snails were collected from 38 snail sites. The municipality of Trento in Agusan del Sur recorded the highest number of snail sites (7) that yielded O. hupensis quadrasi snails while only one snail site was found positive for O. hupensis quadrasi snails in Kapatagan in Lanao del Norte and Talibon in Bohol. Alegria in Surigao del Norte yielded the highest number of snail sites (5) that were found to harbor snails positive for S. japonicum infection. The snail infection rates in this municipality ranged from 0.43% to 14.71%. None of the snails collected from Talibon in Bohol was infected. Bohol is the only province among the 28 schistosomiasis-endemic provinces which has reached near elimination status. Snail infection rates were found to vary considerably across snail sites, which could be due to the degree of fecal contamination of the snail sites and their connectivity to water that can serve as contamination source.

18F-FDG PET/TC en el manejo clínico de los linfomas / 18F-FDG PET/CT in the clinical management of patients with lymphoma

El objetivo de la presente revisión es actualizar las recomendaciones sobre el papel de la tomografía por emisión de positrones (PET)/tomografía computarizada (TC) en la estadificación y valoración de la respuesta tras quimioterapia y/o trasplante de progenitores hematopoyéticos en pacientes con linfoma de Hodgkin (LH) y linfoma no-Hodgkin (LNH) en la práctica clínica habitual. En la primera reunión internacional sobre PET en linfoma, celebrada en 2009 en Deauville (Francia), se estableció una escala de 5 puntos para la valoración de la respuesta en pacientes con linfoma mediante la 18F-Fluordeoxiglucosa (FDG) PET/TC. Posteriormente, tras celebrarse la 11.a y 12.a Conferencia Internacional sobre Linfomas en Lugano (Suiza) en 2011 y 2013, respectivamente, se alcanzó un acuerdo en cuanto al uso de la PET/TC para la estadificación y se revisaron los criterios de respuesta en linfoma ávidos por la FDG en la práctica clínica y en ensayos clínicos; son los denominados criterios de valoración de respuesta de Lugano. Los principales consensos alcanzados fueron: I) la PET/TC con 18F-FDG fue formalmente incorporada en la estadificación de los linfomas con avidez por la FDG; II) la biopsia de médula ósea ya no está indicada en la estadificación rutinaria de pacientes con LH y en la mayoría de los pacientes con linfoma B difuso de células grandes (LBDCG), y III) la valoración de respuesta al tratamiento se hará mediante la PET/TC usando la escala de 5 puntos y la clasificación de Lugano. Actualmente, con la introducción de terapias basadas en agentes biológicos con mecanismos inmunes, los criterios de Lugano para valoración de la respuesta requieren una flexibilización y modificación, debido a que estos agentes pueden producir cambios en las técnicas de imagen que sugieren progresión de la enfermedad, a pesar de una respuesta clínica evidente (pseudoprogresión o tumor flare). Ello ha llevado a la adopción provisional de los criterios LYRIC (LYmphoma Response to Inmunomodulatory Therapy Criteria), con la introducción del término «respuesta indeterminada» para definir estos cambios hasta que sean confirmados o descartados como progresión de la enfermedad. El uso generalizado de todas estas recomendaciones mejorará la evaluación de pacientes con linfoma y hará posible la comparación de resultados procedentes de ensayos clínicos (AU)

The aim of this work was to review the current recommendations for staging and response assessment of patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) in routine clinical practice after chemotherapy and/or stem cell transplantation. A five-point scale (5-PS) from the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, was recommended as the standard tool to score imaging to assess treatment response in patients with lymphoma using 18F-Fluorodeoxyglucose (FDG) PET/CT. Following the recommendations of the 11th and 12th International Conferences on Malignant Lymphoma held in Lugano (Switzerland), in 2011 and 2013, respectively, a consensus (the so-called Lugano Classification) was reached regarding the use of PET/CT for staging and response assessment in FDG-avid lymphomas. As a result, 18F-FDG PET/CT was formally incorporated into standard staging for FDG-avid lymphomas. A bone marrow biopsy is no longer indicated for the routine staging of HL and most diffuse large B-cell lymphomas. PET/CT will be used to assess response in FDG-avid histologies using the 5-point scale. The recent introduction of biological agents with immune mechanisms requires flexibility in interpretations of the Lugano criteria due to tumour flare or a pseudo-progression effect produced by these agents. Provisional criteria have been proposed (Lymphoma Response to Immunomodulatory Therapy Criteria) with the introduction of the term ‘Indeterminate Response’ in order to identify this phenomenon until confirmed as flare/pseudoprogression or true progression. All these recommendations will improve evaluations of patients with lymphoma, and allow comparison of results from clinical practice and trials (AU)

18F-FDG PET/CT in the clinical management of patients with lymphoma. / 18F-FDG PET/TC en el manejo clínico de los linfomas.

The aim of this work was to review the current recommendations for staging and response assessment of patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) in routine clinical practice after chemotherapy and/or stem cell transplantation. A five-point scale (5-PS) from the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, was recommended as the standard tool to score imaging to assess treatment response in patients with lymphoma using 18F-Fluorodeoxyglucose (FDG) PET/CT. Following the recommendations of the 11th and 12th International Conferences on Malignant Lymphoma held in Lugano (Switzerland), in 2011 and 2013, respectively, a consensus (the so-called Lugano Classification) was reached regarding the use of PET/CT for staging and response assessment in FDG-avid lymphomas. As a result, 18F-FDG PET/CT was formally incorporated into standard staging for FDG-avid lymphomas. A bone marrow biopsy is no longer indicated for the routine staging of HL and most diffuse large B-cell lymphomas. PET/CT will be used to assess response in FDG-avid histologies using the 5-point scale. The recent introduction of biological agents with immune mechanisms requires flexibility in interpretations of the Lugano criteria due to tumour flare or a pseudo-progression effect produced by these agents. Provisional criteria have been proposed (Lymphoma Response to Immunomodulatory Therapy Criteria) with the introduction of the term 'Indeterminate Response' in order to identify this phenomenon until confirmed as flare/pseudoprogression or true progression. All these recommendations will improve evaluations of patients with lymphoma, and allow comparison of results from clinical practice and trials.

A novel, fully automated, observer-independent program for semiquantifying striatal 123I-FP-CIT uptake / Un nuevo programa, totalmente automático e independiente del observador para semi-cuantificar la captación estriatal de 123I-FP-CIT

Objective: To describe and validate a novel, fully automated program specifically designed for the semi- quantification of striatal 123I-FP-CIT uptake using volumes of interest (VOI) analysis. Material and methods: The proposed algorithm is based on a template that mimics the striatal 123 I-FP-CIT uptake in a healthy subjects, derived from defined anatomical VOIs available from WFU PickAtlas. Four SPECT studies of the anthropomorphic Alderson phantom filled with variable radioactive concentrations were acquired for the experimental validation. Experimental SPECT images were spatially normalized with respect to the previously created template. The binary VOIs corresponding to left caudate and puta- men and right caudate and putamen, which were used to construct the template, were projected onto the experimental images to obtain the counts for these regions. To minimize the partial volume effect, a percentage of the voxels in these regions (threshold), rather than all of them, was used. A binary occipital VOI was used to quantify the non-specific uptake. Experimental binding potentials (BPs) were calculated from the counts in these regions. True BPs were calculated from aliquots taken from the solutions used to fill the phantom. Results: There were statistically significant differences in the experimental BP values (p < 0.002) accord- ing to the percentage of voxels used. A highly significant correlation was achieved between true and experimental BP values, regardless of the percentage of voxels included for quantification. Conclusions: Our novel, observer-independent program automatically performs the semiquantification of striatal 123I-FP-CIT uptake in experimental studies (AU)

Objetivos: Describir y validar un nuevo software, totalmente automático, específicamente diseñado para semicuantificar la captación estriatal de 123I-FP-CIT usando volúmenes de interés (VOIs). Material y métodos: El algoritmo propuesto se basa en una plantilla que remeda la captación estriatal de 123I-FP-CIT en un sujeto sano, obtenida a partir de VOIs anatómicos definidos en WFU PickAtlas. Para la validación experimental de este algoritmo se adquirieron 4 estudios SPECT del maniquí antropomórfico Alderson llenado con concentraciones radioactivas variables. Las imágenes SPECT experimentales se normalizaron espacialmente respecto a la plantilla creada. Los VOIs binarios correspondientes a núcleo caudado y putámen derechos e izquierdos, utilizados para disen ̃ar la plantilla, se proyectaron sobre las imágenes experimentales para obtener las cuentas en estas regiones. Para minimizar los efectos de volumen parcial se utilizó un porcentaje de vóxeles, en vez de utilizar todos los vóxeles contenidos en estos VOIs. Se ha utilizado un VOI binario situado en región occipital para cuantificar la unión no específica. Los potenciales de unión (BPs) experimentales se calcularon a partir de las cuentas obtenidas en estas regiones. Los BPs reales se calcularon a partir de alícuotas tomadas de las soluciones utilizadas para llenar el maniquí. Resultados: Hubo diferencias estadísticamente significativas en los BPs experimentales en función del porcentaje de vóxeles utilizados para la cuantificación (p < 0.002). Se alcanzó una alta correlación entre los BPs reales y los experimentales, independientemente del porcentaje de vóxeles utilizados para la cuantificación. Conclusiones: Este nuevo programa automático e independiente del observador realiza la semicuantificación de la captación estriatal de 123I-FP-CIT en estudios experimentales (AU)

A novel, fully automated, observer-independent program for semiquantifying striatal ¹²³I-FP-CIT uptake.

OBJECTIVE: To describe and validate a novel, fully automated program specifically designed for the semiquantification of striatal (123)I-FP-CIT uptake using volumes of interest (VOI) analysis. MATERIAL AND METHODS: The proposed algorithm is based on a template that mimics the striatal (123)I-FP-CIT uptake in a healthy subjects, derived from defined anatomical VOIs available from WFU PickAtlas. Four SPECT studies of the anthropomorphic Alderson phantom filled with variable radioactive concentrations were acquired for the experimental validation. Experimental SPECT images were spatially normalized with respect to the previously created template. The binary VOIs corresponding to left caudate and putamen and right caudate and putamen, which were used to construct the template, were projected onto the experimental images to obtain the counts for these regions. To minimize the partial volume effect, a percentage of the voxels in these regions (threshold), rather than all of them, was used. A binary occipital VOI was used to quantify the non-specific uptake. Experimental binding potentials (BPs) were calculated from the counts in these regions. True BPs were calculated from aliquots taken from the solutions used to fill the phantom. RESULTS: There were statistically significant differences in the experimental BP values (p<0.002) according to the percentage of voxels used. A highly significant correlation was achieved between true and experimental BP values, regardless of the percentage of voxels included for quantification. CONCLUSIONS: Our novel, observer-independent program automatically performs the semiquantification of striatal (123)I-FP-CIT uptake in experimental studies.

Correlation between prepulse inhibition and cortical perfusion during an attentional test in schizophrenia. A pilot study.

BACKGROUND: Processes underlying cortical hypoactivation in schizophrenia are poorly understood but some evidence suggests that a deficient sensory filtering is associated with the condition. This filtering deficit can be studied by using measures of prepulse inhibition (PPI) of the startle reflex. OBJECTIVE: To evaluate the contribution of sensory filtering deficits to cortical hypoperfusion during an attention test in schizophrenia. METHOD: Measurements of PPI of the startle reflex and perfusion during the performance of a Stroop test (assessed with single photon emission tomography) were obtained in 10 acutely treated schizophrenia patients (6 with recent onset, RO) and 16 control subjects. These measurements were compared between patients and controls and the correlation between PPI and perfusion was evaluated within each group, using Statistical Parametric Mapping. RESULTS: In comparison with normal subjects, the patients exhibited lower PPI, although the difference was not statistically significant. Perfusion was significantly lower in the prefrontal and premotor regions of the patients. In the patient group, a statistically significant difference was observed between PPI and perfusion in the parietal, premotor, and cingulate regions. When the associations were analyzed in the RO patients alone, a positive correlation was also found between prefrontal perfusion and PPI, while anterior hippocampal perfusion was inversely related to PPI. CONCLUSIONS: These results support the notion that deficient sensory-motor filtering is associated with decreased cortical task-related activation in schizophrenia.

Clozapine may partially compensate for task-related brain perfusion abnormalities in risperidone-resistant schizophrenia patients.

BACKGROUND: Previous reports show different cerebral activity patterns during treatment with clozapine and typical neuroleptics. However, to date no study has directly compared the brain activity patterns while subjects are undergoing treatment with clozapine and other atypical antipsychotics. This comparison is of interest, given the probably different mechanism of action of clozapine in comparison with other atypicals. OBJECTIVE: To assess the effect of clozapine on perfusion deviations still evident during treatment with risperidone. METHODS: Here we used hexamethylene-propylenaminoxime single photon emission computed tomography to compare the perfusion patterns observed during the performance of a Stroop test in 10 patients sequentially treated with risperidone and clozapine, owing to a lack of response to the former, and in 10 healthy controls. RESULTS: Patients on risperidone showed decreased perfusion as compared to controls in the medial prefrontal, middle cingulate and insular regions, as well as increased activities in brain stem and the posterior hippocampus. After receiving clozapine, the same patients showed an even wider prefrontal perfusion deficit and the brain stem was still hyperactive, but the abnormalities in the cingulate cortex, insula and hippocampus had disappeared. Clinical improvement was directly related to an increase in thalamic perfusion. CONCLUSION: Clozapine may alleviate hyperactivity in the limbic system in schizophrenia and may facilitate activation of the regions involved in cognitive tasks to a greater degree than risperidone, as well as eliciting greater inhibition of the PF region.

Distinct physiological states of Plasmodium falciparum in malaria-infected patients.

Infection with the malaria parasite Plasmodium falciparum leads to widely different clinical conditions in children, ranging from mild flu-like symptoms to coma and death. Despite the immense medical implications, the genetic and molecular basis of this diversity remains largely unknown. Studies of in vitro gene expression have found few transcriptional differences between different parasite strains. Here we present a large study of in vivo expression profiles of parasites derived directly from blood samples from infected patients. The in vivo expression profiles define three distinct transcriptional states. The biological basis of these states can be interpreted by comparison with an extensive compendium of expression data in the yeast Saccharomyces cerevisiae. The three states in vivo closely resemble, first, active growth based on glycolytic metabolism, second, a starvation response accompanied by metabolism of alternative carbon sources, and third, an environmental stress response. The glycolytic state is highly similar to the known profile of the ring stage in vitro, but the other states have not been observed in vitro. The results reveal a previously unknown physiological diversity in the in vivo biology of the malaria parasite, in particular evidence for a functional mitochondrion in the asexual-stage parasite, and indicate in vivo and in vitro studies to determine how this variation may affect disease manifestations and treatment.

GeneCluster 2.0: an advanced toolset for bioarray analysis.

SUMMARY: GeneCluster 2.0 is a software package for analyzing gene expression and other bioarray data, giving users a variety of methods to build and evaluate class predictors, visualize marker lists, cluster data and validate results. GeneCluster 2.0 greatly expands the data analysis capabilities of GeneCluster 1.0 by adding classification, class discovery and permutation test methods. It includes algorithms for building and testing supervised models using weighted voting and k-nearest neighbor algorithms, a module for systematically finding and evaluating clustering via self-organizing maps, and modules for marker gene selection and heat map visualization that allow users to view and sort samples and genes by many criteria. GeneCluster 2.0 is a stand-alone Java application and runs on any platform that supports the Java Runtime Environment version 1.3.1 or greater. AVAILABILITY: http://www.broad.mit.edu/cancer/software

Multiclass cancer diagnosis using tumor gene expression signatures.

The optimal treatment of patients with cancer depends on establishing accurate diagnoses by using a complex combination of clinical and histopathological data. In some instances, this task is difficult or impossible because of atypical clinical presentation or histopathology. To determine whether the diagnosis of multiple common adult malignancies could be achieved purely by molecular classification, we subjected 218 tumor samples, spanning 14 common tumor types, and 90 normal tissue samples to oligonucleotide microarray gene expression analysis. The expression levels of 16,063 genes and expressed sequence tags were used to evaluate the accuracy of a multiclass classifier based on a support vector machine algorithm. Overall classification accuracy was 78%, far exceeding the accuracy of random classification (9%). Poorly differentiated cancers resulted in low-confidence predictions and could not be accurately classified according to their tissue of origin, indicating that they are molecularly distinct entities with dramatically different gene expression patterns compared with their well differentiated counterparts. Taken together, these results demonstrate the feasibility of accurate, multiclass molecular cancer classification and suggest a strategy for future clinical implementation of molecular cancer diagnostics.

Chemosensitivity prediction by transcriptional profiling.

In an effort to develop a genomics-based approach to the prediction of drug response, we have developed an algorithm for classification of cell line chemosensitivity based on gene expression profiles alone. Using oligonucleotide microarrays, the expression levels of 6,817 genes were measured in a panel of 60 human cancer cell lines (the NCI-60) for which the chemosensitivity profiles of thousands of chemical compounds have been determined. We sought to determine whether the gene expression signatures of untreated cells were sufficient for the prediction of chemosensitivity. Gene expression-based classifiers of sensitivity or resistance for 232 compounds were generated and then evaluated on independent sets of data. The classifiers were designed to be independent of the cells' tissue of origin. The accuracy of chemosensitivity prediction was considerably better than would be expected by chance. Eighty-eight of 232 expression-based classifiers performed accurately (with P < 0.05) on an independent test set, whereas only 12 of the 232 would be expected to do so by chance. These results suggest that at least for a subset of compounds genomic approaches to chemosensitivity prediction are feasible.

Cascades of transcriptional induction during human lymphocyte activation.

Lymphocyte activation is known to be associated with the induction of genes implicated in cytokine signaling and cellular proliferation. High-density microarrays offer the means to monitor global cellular expression profiles, temporal relationships between classes of transcripts, and alterations associated with human disease or immunosuppression. We sought to determine whether microarray analysis would accurately reflect the normal pattern of gene expression following human T cell activation, and whether the complex expression patterns identified could be analyzed to produce a functional profile of lymphocyte activation. We examined a time course of sequential expression profiles for 6,800 cellular transcripts in human lymphocytes activated with concanavalin A. Expression patterns were grouped using clustering analysis and validated using Northern blotting. Genes known to be induced following T cell activation were accurately identified, and the qualitative patterns of gene expression were well correlated between Northern and microarray analyses. Quantitative differences in gene expression levels were less well correlated between these two techniques. Expression profile analysis revealed the sequential induction of groups of functionally similar genes, whose temporal coregulation underscores known cellular events during T cell activation. This functional "fingerprint" of lymphocyte activation may prove useful for comparisons of lymphocyte responses under experimental conditions and in disease states.

Molecular classification of multiple tumor types.

Using gene expression data to classify tumor types is a very promising tool in cancer diagnosis. Previous works show several pairs of tumor types can be successfully distinguished by their gene expression patterns (Golub et al. 1999, Ben-Dor et al. 2000, Alizadeh et al. 2000). However, the simultaneous classification across a heterogeneous set of tumor types has not been well studied yet. We obtained 190 samples from 14 tumor classes and generated a combined expression dataset containing 16063 genes for each of those samples. We performed multi-class classification by combining the outputs of binary classifiers. Three binary classifiers (k-nearest neighbors, weighted voting, and support vector machines) were applied in conjunction with three combination scenarios (one-vs-all, all-pairs, hierarchical partitioning). We achieved the best cross validation error rate of 18.75% and the best test error rate of 21.74% by using the one-vs-all support vector machine algorithm. The results demonstrate the feasibility of performing clinically useful classification from samples of multiple tumor types.

Discovering functional relationships between RNA expression and chemotherapeutic susceptibility using relevance networks.

In an effort to find gene regulatory networks and clusters of genes that affect cancer susceptibility to anticancer agents, we joined a database with baseline expression levels of 7,245 genes measured by using microarrays in 60 cancer cell lines, to a database with the amounts of 5,084 anticancer agents needed to inhibit growth of those same cell lines. Comprehensive pair-wise correlations were calculated between gene expression and measures of agent susceptibility. Associations weaker than a threshold strength were removed, leaving networks of highly correlated genes and agents called relevance networks. Hypotheses for potential single-gene determinants of anticancer agent susceptibility were constructed. The effect of random chance in the large number of calculations performed was empirically determined by repeated random permutation testing; only associations stronger than those seen in multiply permuted data were used in clustering. We discuss the advantages of this methodology over alternative approaches, such as phylogenetic-type tree clustering and self-organizing maps.

Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion.

MYC affects normal and neoplastic cell proliferation by altering gene expression, but the precise pathways remain unclear. We used oligonucleotide microarray analysis of 6,416 genes and expressed sequence tags to determine changes in gene expression caused by activation of c-MYC in primary human fibroblasts. In these experiments, 27 genes were consistently induced, and 9 genes were repressed. The identity of the genes revealed that MYC may affect many aspects of cell physiology altered in transformed cells: cell growth, cell cycle, adhesion, and cytoskeletal organization. Identified targets possibly linked to MYC's effects on cell growth include the nucleolar proteins nucleolin and fibrillarin, as well as the eukaryotic initiation factor 5A. Among the cell cycle genes identified as targets, the G1 cyclin D2 and the cyclin-dependent kinase binding protein CksHs2 were induced whereas the cyclin-dependent kinase inhibitor p21(Cip1) was repressed. A role for MYC in regulating cell adhesion and structure is suggested by repression of genes encoding the extracellular matrix proteins fibronectin and collagen, and the cytoskeletal protein tropomyosin. A possible mechanism for MYC-mediated apoptosis was revealed by identification of the tumor necrosis factor receptor associated protein TRAP1 as a MYC target. Finally, two immunophilins, peptidyl-prolyl cis-trans isomerase F and FKBP52, the latter of which plays a role in cell division in Arabidopsis, were up-regulated by MYC. We also explored pattern-matching methods as an alternative approach for identifying MYC target genes. The genes that displayed an expression profile most similar to endogenous Myc in microarray-based expression profiling of myeloid differentiation models were highly enriched for MYC target genes.

Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.

Although cancer classification has improved over the past 30 years, there has been no general approach for identifying new cancer classes (class discovery) or for assigning tumors to known classes (class prediction). Here, a generic approach to cancer classification based on gene expression monitoring by DNA microarrays is described and applied to human acute leukemias as a test case. A class discovery procedure automatically discovered the distinction between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) without previous knowledge of these classes. An automatically derived class predictor was able to determine the class of new leukemia cases. The results demonstrate the feasibility of cancer classification based solely on gene expression monitoring and suggest a general strategy for discovering and predicting cancer classes for other types of cancer, independent of previous biological knowledge.