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PubMed2006

The temporal signatures of semantic and phonological activations for Chinese sublexical processing: an event-related potential study.

A large number of Chinese characters are made up by pairing a semantic radical and a phonetic radical. The phonetic radical usually gives a phonological clue for the pronunciation of the whole character but does not contribute to its meaning. Using an event-related potential (ERP) measurement, the present study was able to trace the very intricate interplay between phonological and semantic information embedded in the phonetic radical. It was found that, within the first 50 to 100 ms of perceiving the character, the semantic information of the phonetic radical was better preserved when the constituent phonetic radical provided a valid phonological clue (e.g., regular phonogram) than when it contained an invalid phonetic cue (e.g., irregular phonogram). However, no trace of semantic information from the phonetic radical was preserved after 300 ms. These ERP results detail the neuropsychological steps in reading Chinese and support the framework of the lexical constituent model.

Adult↗
PubMed2026

Transcriptomic signatures of mind-body transformations therapy in breast cancer: Downregulation of the interferon signaling pathway.

BACKGROUND: Growing evidence has shown that Mind-Body Transformations-Therapies (MBT-T) are able to modulate chronic inflammation, a well-known driver of cancer progression and drug resistance. In our previous work, we showed that a specific MBT-T protocol was able to reduce the release of various pro-inflammatory cytokines and chemokines in the sera of patients with breast cancer that completed adjuvant chemotherapy. Despite these clinical observations, the underlying molecular pathways through which this therapy exerts its effects remain unclear. This study aims to address this gap by characterizing genome-wide transcriptional profiles in patients undergoing a novel MBT-T protocol. METHODS: In this proof-of-concept study, patients with breast cancer were randomized into two groups: Group 1 (CTL), receiving standard follow-up care, and Group 2 (MBT-T), receiving standard follow-up plus biweekly MBT-T for 4 months. Blood samples were collected at different timepoints during the treatment. After RNA extraction from whole blood, gene expression was analyzed on twenty-one patients (CTL, n = 7; MBT-T, n = 14) using the nCounter® Human Inflammation Panel (249 genes). RESULTS: Patients undergoing MBT-T showed a significant global downregulation of inflammatory gene expression compared to the control group. The analysis revealed that the Interferon (IFN) signaling pathway was the most significantly suppressed, by downregulation of key genes such as IFIT1, IFIT3, IFI44, MX1 and OASL in the MBT-T group. CONCLUSIONS: MBT-T acts as a biological modulator capable of downregulating key inflammatory pathways at the transcriptional level. These findings provide a genomic basis for the clinical benefits of mind-body interventions in oncology.

Breast cancer↗
PubMed2004

Genome signatures of colon carcinoma cell lines.

In cancer biology, cell lines are often used instead of primary tumors because of their widespread availability and close reflection of the in vivo state. Cancer is a genetic disease, commonly caused by small- and large-scale DNA rearrangements. Therefore, it is essential to know the genomic profiles of tumor cell lines to enable their correct and efficient use as experimental tools. Here, we present a comprehensive study of the genomic profiles of 20 colon cancer cell lines combining conventional karyotyping (G-banding), comparative genomic hybridization (CGH), and multicolor fluorescence in situ hybridization (M-FISH). Major differences between the microsatellite instability (MSI) and chromosome instability (CIN) cell lines are shown; the CIN cell lines exhibited complex karyotypes involving many chromosomes (mean: 8.5 copy number changes), whereas the MSI cell lines showed considerably fewer aberrations (mean: 2.6). The 3 techniques complement each other to provide a detailed picture of the numerical and structural chromosomal changes that characterize cancer cells. Therefore, 7 of the cell lines (Colo320, EB, Fri, IS2, IS3, SW480, and V9P) are here completely karyotyped for the first time and, among these, 5 have not previously been cytogenetically described. By hierarchical cluster analysis, we show that the cell lines are representative models for primary carcinomas at the genome level. We also present the genomic profiles of an experimental model for tumor progression, including 3 cell lines (IS1, IS2, and IS3) established from a primary carcinoma, its corresponding liver- and peritoneal metastasis from the same patient. To address the question of clonality, we compared the genome of 3 common cell lines grown in 2 laboratories. Finally, we compared all our results with previously published CGH data and karyotypes of colorectal cell lines. In conclusion, the large variation in genetic complexity of the cell lines highlights the importance of a comprehensive reference of genomic profiles for investigators engaged in functional studies using these research tools.

Cell Line, Tumor↗
PubMed2004

Molecular signature linked to acquired resistance to cisplatin in esophageal cancer cells.

To clarify the molecular basis of acquired cisplatin (CDDP) resistance in esophageal squamous cell carcinoma (ESCC), we used cDNA microarray technology. A CDDP-resistant cell line (YES-2/CDDP), which shows a 7.5-fold increase in resistance to CDDP and a 3-fold decrease in CDDP accumulation compared with the parental YES-2 ESCC cell line, was generated from YES-2 by exposure to increased concentrations of CDDP. By cDNA microarray analysis, we identified 44 genes with significantly different expression levels between YES-2/CDDP and YES-2 cells. Interestingly, 15 of these 44 genes encoded ribosome-related proteins, almost all of which were underexpressed in YES-2/CDDP cells. Our present data suggest that many ribosome-related genes may be involved in the acquired resistance to CDDP in ESCC and that such information may allow us to better understand the mechanism of CDDP resistance.

Antineoplastic Agents↗
PubMed2005

Transcriptional signatures of environmentally relevant exposures in normal human mammary epithelial cells: benzo[a]pyrene.

Changes in gene expression in a panel of primary normal human mammary epithelial cell strains, developed from healthy breast tissue obtained at reduction mammoplasty from different donors, in response to benzo[a]pyrene exposure have been investigated. It was expected that both gene expression changes common to cell strains derived from different donors as well as inter-individual variation would be observed. Therefore, the strategy that has been adopted is to identify potentially important changes, or useful changes from a biomonitoring perspective, using gene-array technology and a small number of donors; then investigate selected transcription responses using a large number of tissue donors and a cheaper method of transcript detection (real-time polymerase chain reaction). Here we report results from four primary normal human mammary epithelial cell strains that were treated with benzo[a]pyrene in vitro for either 6 or 24 h. Transcription was monitored using high-density oligonucleotide arrays (Affymetrix HuGeneFL). Total RNA was used for the preparation of labeled targets that were hybridized to microarrays containing probes representing more than 6800 human genes and expressed sequence tags. Gene expression data were analyzed using the GeneChip software (MAS 5.0). Altered gene expression patterns were observed in response to benzo[a]pyrene in human mammary epithelial cell strains from different donors. Specifically, the dioxin inducible cytochrome P450 CYP1B1 was consistently induced in response to 6 and 24 h exposure to benzo[a]pyrene in cell strains from all four donors. Two other genes that were relatively consistently induced were IL1beta and MMP1. Less consistent changes in other metabolism genes (CYP1A1, CYP11B2, and NQO1) and certain cell cycle control genes GOS2 and AF1Q were also induced, while EGR1 was suppressed. Although no change in p53 transcription was observed, an accumulation of p53 protein was detected using antibodies. A similar accumulation of Waf1 (p21) was also observed using immunohistochemistry, this was expected since p53 is p21's transcription factor. Significant inter-individual variations in both the levels and patterns of gene expression were observed, in response to benzo[a]pyrene exposure. These studies provide a complementary approach to molecular epidemiology for the investigation of differential susceptibility to chemical carcinogens, and specifically polycyclic aromatic hydrocarbons.

Air Pollutants↗
PubMed2006

The pattern of glycosyl- and sulfotransferase activities in cancer cell lines: a predictor of individual cancer-associated distinct carbohydrate structures for the structural identification of signature glycans.

Carbohydrate chains of cancer glycoprotein antigens contain major outer changes dictated by tissue-specific regulation of glycosyltransferase genes, the availability of sugar nucleotides, and competition between enzymes for acceptor intermediates during glycan elongation. However, it is evident from recent studies with recombinant mucin probes that the final glycosylation profiles of mucin glycoproteins are mainly determined by the cellular repertoire of glycosyltransferases. Hence, we examined various cancer cell lines for the levels of fucosyl-, beta-galactosyl, beta-N-acetylgalactosaminyl-, sialyl-, and sulfotransferase activities that generate the outer ends of the oligosaccharide chains. We have identified glycosyltransferases activities at the levels that would give rise to O-glycan chains as reported by others in breast cancer cell lines, T47D, ZR75-1, MCF-7, and MDA-MB-231. Most breast cancer cells express Gal-3-O-sulfotransferase specific for T-hapten Gal beta1-->3GalNAc alpha-, whereas the enzyme from colon cancer cells exhibits a vast preference for the Gal beta1,4GlcNAc terminal unit in O-glycans. We also studied ovarian cancer cells SW626 and PA-1 and hepatic cancer cells HepG2. Our studies show that alpha1,2-L-fucosyl-T, alpha(2,3) sialyl-T, and 3-O-Sulfo-T capable of acting on the mucin core 2 tetrasaccharide, Gal beta1,4GlcNAc beta1,6(Gal beta1,3)GalNAc alpha-, can also act on the Globo H antigen backbone, Gal beta1,3GalNAc beta1,3Gal alpha-, suggesting the existence of unique carbohydrate moieties in certain cancer-associated glycolipids. Briefly, our study indicates the following: (i) 3'-Sulfo-T-hapten has an apparent relationship to the tumorigenic potential of breast cancer cells; (ii) the 3'-sulfo Lewis(x), the 3-O-sulfo-Globo unit, and the 3-fucosylchitobiose core could be uniquely associated with colon cancer cells; (iii) synthesis of a polylactosamine chain and T-hapten are favorable in ovarian cancer cells due to negligible sialyltransferase activities; and (iv) a 6'-sialyl LacNAc unit and 3'-sialyl T-hapten appear to be prevalent structures in hepatic cancer cell glycans. Thus, it is apparent that different cancer cells are expressing unique glycan epitopes, which could be novel targets for cancer diagnosis and treatment.

Breast Neoplasms↗
PubMed2006

Dietary macronutrients influence 13C and 15N signatures of pinnipeds: captive feeding studies with harbor seals (Phoca vitulina).

Metabolic effects of dietary macronutrients on diet-tissue isotopic discrimination factors were investigated in harbor seals. Three seals were fed either high fat/low protein herring (H), or low fat/high protein pollock (P), and switched to the alternative every 4 months. This allowed each seal to be subjected to two dietary treatments in each of three metabolically defined seasons (breeding from May to September, molting from September to January, and late winter/early spring period from January to May) over a 2 year cycle, and function as its internal control regardless of physiological changes over season. One seal was fed a constant equal mix of H and P over the entire trial. Up to 1 per thousand differences in serum delta15N values of one seal fed alternatively on H and P were observed. Progressively more enriched serum delta15N values as diet switching from H to P might link to changes in seal digestive physiology and protein metabolism in response to very high protein intake on P diet. These findings demonstrate that dietary macronutrients of prey species and protein intake level of consumers also play important roles in shaping isotopic patterns of a consumer's tissues, and thus influence accurate data interpretation of stable isotope techniques in ecological applications.

Animal Nutritional Physiological Phenomena↗
PubMed2005

Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression.

Molecular profiling of cancer at the transcript level has become routine. Large-scale analysis of proteomic alterations during cancer progression has been a more daunting task. Here, we employed high-throughput immunoblotting in order to interrogate tissue extracts derived from prostate cancer. We identified 64 proteins that were altered in prostate cancer relative to benign prostate and 156 additional proteins that were altered in metastatic disease. An integrative analysis of this compendium of proteomic alterations and transcriptomic data was performed, revealing only 48%-64% concordance between protein and transcript levels. Importantly, differential proteomic alterations between metastatic and clinically localized prostate cancer that mapped concordantly to gene transcripts served as predictors of clinical outcome in prostate cancer as well as other solid tumors.

Disease Progression↗
PubMed2006

Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators.

Although androgen receptor (AR)-mediated signaling is central to prostate cancer, the ability to modulate AR signaling states is limited. Here we establish a chemical genomic approach for discovery and target prediction of modulators of cancer phenotypes, as exemplified by AR signaling. We first identify AR activation inhibitors, including a group of structurally related compounds comprising celastrol, gedunin, and derivatives. To develop an in silico approach for target pathway identification, we apply a gene expression-based analysis that classifies HSP90 inhibitors as having similar activity to celastrol and gedunin. Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy.

Antibiotics, Antineoplastic↗
PubMed2006

Signature combinatorial splicing profiles of rat cardiac- and smooth-muscle Cav1.2 channels with distinct biophysical properties.

l-type (Ca(v)1.2) voltage-gated calcium channels play an essential role in muscle contraction in the cardiovascular system. Alternative splicing of the pore-forming Ca(v)1.2 subunit provides potent means to enrich the functional diversity of the channels. There are 11 alternatively spliced exons identified in rat Ca(v)1.2 gene and random rearrangements may generate up to hundreds of combinatorial splicing profiles. Due to such complexity, the real combinatorial splicing profiles of Ca(v)1.2 have not been solved. This study investigated whether the 11 alternatively spliced exons are spliced randomly or linked and if linked, how many combinatorial splicing profiles can be arranged in cardiac- and smooth-muscle cells. By examining three full-length cDNA libraries of the Ca(v)1.2 transcripts isolated from rat heart and aorta, our results showed that the arrangements of some of the alternatively spliced exons are tissue-specific and tightly linked, giving rise to only 41 alternative combinatorial profiles, of which 29 have not been reported. Interestingly, the 41 combinatorial profiles were distinctively distributed in the three Ca(v)1.2 libraries and the one named "heart 1-50" contained unexpected splice variants. Significantly, the tissue-specific cardiac- and smooth-muscle combinatorial splicing profiles of Ca(v)1.2 channels demonstrated distinct electrophysiological properties that may help rationalize the differences observed in native currents. The unique sequences in these tissue-specific splice variants may provide the potential targets for drug design and screening.

Alternative Splicing↗
PubMed2005

Cellular and molecular signatures of muscle regeneration: current concepts and controversies in adult myogenesis.

Adult skeletal muscle generates force in a controlled and directed manner through the contraction of highly specialized, postmitotic, multinucleated myofibers. Life-long muscle function relies on maintenance and regeneration of myofibers through a highly regulated process beginning with activation of normally quiescent muscle precursor cells and proceeding with formation of proliferating progenitors that fuse to generate differentiated myofibers. In this review, we describe the historical basis and current evidence for the identification of satellite cells as adult muscle stem cells, critically evaluate contributions of other cells to adult myogenesis, and summarize existing data regarding the origins, genetic markers, and molecular regulation of satellite cells in normal, diseased, and aged muscle.

Adult↗
PubMedDate not supplied

The spatial and temporal signatures of word production components.

This paper presents the results of a comprehensive meta-analysis of the relevant imaging literature on word production (82 experiments). In addition to the spatial overlap of activated regions, we also analyzed the available data on the time course of activations. The analysis specified regions and time windows of activation for the core processes of word production: lexical selection, phonological code retrieval, syllabification, and phonetic/articulatory preparation. A comparison of the word production results with studies on auditory word/non-word perception and reading showed that the time course of activations in word production is, on the whole, compatible with the temporal constraints that perception processes impose on the production processes they affect in picture/word interference paradigms.

Humans↗
PubMed2026

An immune exhaustion signature predicts prognosis and identifies patients with diffuse large B-cell lymphoma (DLBCL) who derive preferential benefit from chimeric antigen receptor (CAR)-T cell therapy.

BACKGROUND: The tumor microenvironment (TME) is a key determinant of prognosis in diffuse large B-cell lymphoma (DLBCL). While T-cell exhaustion is implicated in therapeutic failure, its precise molecular hallmarks and utility for predicting response to modern immunotherapies, such as chimeric antigen receptor (CAR)-T cell therapy, remain unclear. METHODS: We performed an integrative analysis of transcriptomic and clinical data from multiple DLBCL cohorts (The Cancer Genome Atlas [TCGA], GSE181063, GSE10846, GSE248835, GSE182434). We used unsupervised clustering, exploratory analysis of single-cell RNA sequencing data, and the least absolute shrinkage and selection operator for variable selection (LASSO-Cox) regression to characterize the exhausted TME, construct a prognostic model, and evaluate its predictive value for CAR-T cell therapy. The model's dynamic behavior was assessed in a proof-of-concept longitudinal cohort of patients treated with the T-cell-engaging bispecific antibody glofitamab. RESULTS: We identified a "high-exhaustion" subtype associated with significantly poorer overall survival (OS; log-rank P = 0.016). Based on this, we developed a five-gene immune exhaustion-Related Prognostic Score (IERPS) that served as a robust independent predictor of poor OS across multiple cohorts. Critically, in a cohort of 256 relapsed/refractory patients, the IERPS was strongly prognostic for event-free survival (EFS) in the standard-of-care (SOC) arm (HR = 2.02, 95% confidence interval [95% CI]: 1.07-3.81, P = 0.029) but lost prognostic significance in the CAR-T arm (HR = 0.70, 95 % CI: 0.35-1.40, P = 0.314). This significant interaction suggests that CAR-T cell therapy may abrogate the poor prognosis associated with a high IERPS. Biologically, exploratory single-cell analysis (n = 4 samples) defined the high-IERPS state by hallmarks of classical T-cell exhaustion, and a descriptive case study showed the score dynamically tracked clinical response to glofitamab. CONCLUSIONS: A state of active T-cell exhaustion and a suppressive TME drive the adverse immune phenotype in DLBCL. Our IERPS model captures this dysfunctional state, acting as a powerful prognostic tool and, more importantly, as a potential predictive biomarker to identify high-risk patients who appear to overcome their inherently poor prognosis through CAR-T cell therapy.

Biomarkers↗
PubMed2004

Invariant chlorine isotopic signatures during microbial PCB reductive dechlorination.

In order to develop more robust insight into the natural attenuation of polychlorinated biphenyls (PCBs), the chlorine isotopic composition of residual 2,3,4,5-tetrachlorobiphenyl (2,3,4,5-CB) was monitored as it underwent microbial reductive dechlorination to 2,3,5-trichlorobiphenyl (2,3,5-CB) in laboratory cultures. Reverse-phase high performance liquid chromatography (HPLC) was employed to isolate the former compound from the experimental matrix for delta37Cl measurement. No detectable isotopic fractionation was observed over the 90 day incubation with sterile control, standard, and inoculated samples all exhibiting delta37Cl values with a range of approximately 0.5 per thousand. These results show that this type of biological activity can be discriminated from other transformations by the absence of a measurable isotope effect during microbial reductive dechlorination. The utility of HPLC isolation for compound-specific delta37Cl analyses of environmentally relevant species is also demonstrated.

Bacteria↗
PubMed2005

Natural and anthropogenic geochemical signatures of floodplain and deltaic sedimentary strata, Sacramento-San Joaquin Delta, California, USA.

The geochemical history of an upper deltaic plain pending tidal wetland restoration was reconstructed to assess remobilization of redox-sensitive constituents in sediment, identify depositional processes promoting geochemical retention, and determine the extent of contamination with Hg, As, Pb, Cu, and Zn. Three 12-14-m sediment cores were analyzed for bulk sediment geochemistry using ICP-AES. Rather than showing similar stratigraphic and geochemical down-core trends, cores had a unique record indicative of strong spatial gradients in deposition processes. Each strata type (e.g. basal clay, sand channel, distal floodplain, and agriculturally impacted surficial horizon) had a unique geochemical "fingerprint". The agriculturally impacted surficial layer showed high [Hg], [As], and [Pb]. The significance is that a restored upper delta will have a complex geomorphology defying conventional criteria of "success" in a restoration framework. Also, there is a significant risk of generating toxic, bio-available CH3Hg+ that would be hazardous to fish.

Arsenic↗