33 research outputs found
Kaiso (ZBTB33) subcellular partitioning functionally links LC3A/B, the tumor microenvironment, and breast cancer survival
No full textThe use of digital pathology for the histomorphologic profiling of pathological specimens is expanding the precision and specificity of quantitative tissue analysis at an unprecedented scale; thus, enabling the discovery of new and functionally relevant histological features of both predictive and prognostic significance. In this study, we apply quantitative automated image processing and computational methods to profile the subcellular distribution of the multi-functional transcriptional regulator, Kaiso (ZBTB33), in the tumors of a large racially diverse breast cancer cohort from a designated health disparities region in the United States. Multiplex multivariate analysis of the association of Kaiso’s subcellular distribution with other breast cancer biomarkers reveals novel functional and predictive linkages between Kaiso and the autophagy-related proteins, LC3A/B, that are associated with features of the tumor immune microenvironment, survival, and race. These findings identify effective modalities of Kaiso biomarker assessment and uncover unanticipated insights into Kaiso’s role in breast cancer progression.Fil: Singhal, Sandeep K.. North Dakota State University; Estados UnidosFil: Byun, Jung S.. National Institutes of Health; Estados UnidosFil: Park, Samson. National Institutes of Health; Estados UnidosFil: Yan, Tingfen. National Institutes of Health; Estados UnidosFil: Yancey, Ryan. Columbia University; Estados UnidosFil: Caban, Ambar. Columbia University; Estados UnidosFil: Hernandez, Sara Gil. National Institutes of Health; Estados UnidosFil: Hewitt, Stephen M.. U.S. Department of Health & Human Services. National Institute of Health. National Cancer Institute; Estados UnidosFil: Boisvert, Heike. Ultivue, Inc; Reino UnidoFil: Hennek, Stephanie. Ultivue Inc.; Reino UnidoFil: Bobrow, Mark. Ultivue Inc.; Reino UnidoFil: Ahmed, Md Shakir Uddin. Tuskegee University; Estados UnidosFil: White, Jason. Tuskegee University; Estados UnidosFil: Yates, Clayton. Tuskegee University; Estados UnidosFil: Aukerman, Andrew. Columbia University; Estados UnidosFil: Vanguri, Rami. Columbia University; Estados UnidosFil: Bareja, Rohan. Columbia University; Estados UnidosFil: Lenci, Romina. Columbia University; Estados UnidosFil: Farré, Paula Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Nápoles, Anna María. National Institutes of Health; Estados UnidosFil: Vohra, Nasreen. East Carolina University; Estados UnidosFil: Gardner, Kevin. Columbia University; Estados Unido
Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein
No full textThe C-terminal binding protein (CtBP) is an NADH-dependent dimeric family of nuclear proteins that scaffold interactions between transcriptional regulators and chromatin-modifying complexes. Its association with poor survival in several cancers implicates CtBP as a promising target for pharmacological intervention. We employed computer-assisted drug design to search for CtBP inhibitors, using quantitative structure-activity relationship (QSAR) modeling and docking. Functional screening of these drugs identified 4 compounds with low toxicity and high water solubility. Micro molar concentrations of these CtBP inhibitors produces significant de-repression of epigenetically silenced pro-epithelial genes, preferentially in the triple-negative breast cancer cell line MDA-MB-231. This epigenetic reprogramming occurs through eviction of CtBP from gene promoters; disrupted recruitment of chromatin-modifying protein complexes containing LSD1, and HDAC1; and re-wiring of activating histone marks at targeted genes. In functional assays, CtBP inhibition disrupts CtBP dimerization, decreases cell migration, abolishes cellular invasion, and improves DNA repair. Combinatorial use of CtBP inhibitors with the LSD1 inhibitor pargyline has synergistic influence. Finally, integrated correlation of gene expression in breast cancer patients with nuclear levels of CtBP1 and LSD1, reveals new potential therapeutic vulnerabilities. These findings implicate a broad role for this class of compounds in strategies for epigenetically targeted therapeutic intervention.Fil: Byun, Jung S.. Public Health Service. National Institute Of Health; Estados UnidosFil: Park, Samson. Public Health Service. National Institute Of Health; Estados UnidosFil: Yi, Dae Ik. Public Health Service. National Institute Of Health; Estados UnidosFil: Shin, Jee Hye. Public Health Service. National Institute Of Health; Estados UnidosFil: Hernandez, Sara Gil. Public Health Service. National Institute Of Health; Estados UnidosFil: Hewitt, Stephen M.. Public Health Service. National Institute Of Health; Estados UnidosFil: Nicklaus, Marc C.. Public Health Service. National Institute Of Health; Estados UnidosFil: Peach, Megan L.. Leidos Biomedical Research ; Estados UnidosFil: Guasch, Laura. Public Health Service. National Institute Of Health; Estados UnidosFil: Tang, Binwu. Public Health Service. National Institute Of Health; Estados UnidosFil: Wakefield, Lalage M.. Public Health Service. National Institute Of Health; Estados UnidosFil: Yan, Tingfen. Public Health Service. National Institute Of Health; Estados UnidosFil: Caban, Ambar. Public Health Service. National Institute Of Health; Estados UnidosFil: Jones, Alana. Public Health Service. National Institute Of Health; Estados UnidosFil: Kabbout, Mohamed. Public Health Service. National Institute Of Health; Estados UnidosFil: Vohra, Nasreen. East Carolina University; Estados UnidosFil: Nápoles, Anna María. Public Health Service. National Institute Of Health; Estados UnidosFil: Singhal, Sandeep. Columbia University; Estados UnidosFil: Yancey, Ryan. Columbia University; Estados UnidosFil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gardner, Kevin. Public Health Service. National Institute Of Health; Estados Unidos. Columbia University; Estados Unido
Leptospire Genomic Diversity Revealed by Microarray-Based Comparative Genomic Hybridization
No full textComparative genomic hybridization was used to compare genetic diversity of five strains of Leptospira (Leptospira interrogans serovars Bratislava, Canicola, and Hebdomadis and Leptospira kirschneri serovars Cynopteri and Grippotyphosa). The array was designed based on two available sequenced Leptospira reference genomes, those of L. interrogans serovar Copenhageni and L. interrogans serovar Lai. A comparison of genetic contents showed that L. interrogans serovar Bratislava was closest to the reference genomes while L. kirschneri serovar Grippotyphosa had the least similarity to the reference genomes. Cluster analysis indicated that L. interrogans serovars Bratislava and Hebdomadis clustered together first, followed by L. interrogans serovar Canicola, before the two L. kirschneri strains. Confirmed/potential virulence factors identified in previous research were also detected in the tested strains
Cultural Capital, Stigma, Class, and Hospice Care Access Among Low-Income Patients With Cancer
No full textEffects of garcinol supplementation on the performance, egg quality, and intestinal health of laying hens in the late laying period
No full textABSTRACT: The problem of rapid decline in egg production performance and poor egg quality is a key obstacle to improving the economic benefits of laying hens. Garcinol is an antioxidant polyphenol plant extract that has multiple physiological functions. Diets with the appropriate amount of garcinol might be able to improve the performance traits and health of late laying hens. Therefore, this study was conducted to evaluate the utilization of garcinol in late laying hens. A total of 400 healthy 59-wk-old Tingfen No. 6 hens were randomly allocated into 4 dietary treatment groups and fed a basal diet supplemented with 0, 100, 300, and 500 mg/kg garcinol for 12 wk, denoted the Con, LG, MG, and HG groups, respectively. The results showed that the addition of garcinol in the diet tended to increase the egg production rate compared with that of the control group (P = 0.080), while the average egg weight was significantly lower (P < 0.05) during the whole period of the experiment. The results showed that MG group hens had higher egg quality and strengthened antioxidant capacity in their serum (P < 0.05). Moreover, the laying hens in the MG group had significantly decreased crypt depth (CD) and increased villus height (VH) in the jejunum and ileum (P < 0.05), as well as an increased ratio of VH to CD (P < 0.05) and increased expression levels of Occludin (P < 0.05) and Claudin-2 (P < 0.05) in the jejunum to improve intestinal barrier function. In addition, dietary supplementation with garcinol influenced the cecal microbiota of laying hens, which was characterized by changes in the microbial community composition, including increased abundances of Firmicutes, Romboutsia, and Ruminococcus torques. In conclusion, dietary 300 mg/kg garcinol supplementation could increase the egg production and egg quality of late laying hens, which may be attributed to the antioxidant effects of garcinol and the improvement of intestinal morphology and epithelial barrier function as well as the regulation of mucosal immune status by altering microbial composition
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Transcript profiles of Nitrosomonas europaea during growth and upon deprivation of ammonia and carbonate
No full textAbstract
The transcriptome of Nitrosomonas europaea was analyzed with whole-genome microarrays. Growing cells were compared to cells deprived of (NH4)2SO4 and Na2CO3. Hybridization signals were detected for 76% of the genes represented on the array under either or both conditions. Transcript levels for 68% of the genes were at least twofold higher in growing cells than in deprived cells, while only 0.42% of the genes were present at more than twofold higher levels in deprived cells. Transcript levels for the remaining 7% of the genes did not change significantly with the treatments. These trends were confirmed for selected genes by Northern hybridizations and quantitative RT-PCR. Compared to heterotrophic bacteria, N. europaea downregulates a greater proportion of its genes and fewer genes appear to be associated with the adaptation to starvation
Impacts on microbial communities and cultivable isolates from groundwater contaminated with high levels of nitric acidâuranium waste
No full textAbstract B055: Characterization of immune cell subsets from tissue expression profiles in African American triple-negative breast cancer patients
No full textGeneration and validation of a Shewanella oneidensis MR-1 clone set for protein expression and phage display.
No full textA comprehensive gene collection for S. oneidensis was constructed using the lambda recombinase (Gateway) cloning system. A total of 3584 individual ORFs (85%) have been successfully cloned into the entry plasmids. To validate the use of the clone set, three sets of ORFs were examined within three different destination vectors constructed in this study. Success rates for heterologous protein expression of S. oneidensis His- or His/GST-tagged proteins in E. coli were approximately 70%. The ArcA and NarP transcription factor proteins were tested in an in vitro binding assay to demonstrate that functional proteins can be successfully produced using the clone set. Further functional validation of the clone set was obtained from phage display experiments in which a phage encoding thioredoxin was successfully isolated from a pool of 80 different clones after three rounds of biopanning using immobilized anti-thioredoxin antibody as a target. This clone set complements existing genomic (e.g., whole-genome microarray) and other proteomic tools (e.g., mass spectrometry-based proteomic analysis), and facilitates a wide variety of integrated studies, including protein expression, purification, and functional analyses of proteins both in vivo and in vitro
Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis
No full textGenetic studies have identified ≥240 loci associated with risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, the largest sequencing-based analysis of miRNA expression in human islets to date. We characterize the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans-acting genetic components and mapping cis-acting loci associated with miRNA expression (miRNA-eQTLs). We find (i) 84 heritable miRNAs, primarily regulated by trans-acting genetic effects, and (ii) 5 miRNA-eQTLs. We also use several different strategies to identify T2D-associated miRNAs. First, we colocalize miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersect miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and find 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we perform differential expression analysis and identify 14 miRNAs associated with T2D status—including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p—and 4 miRNAs associated with a polygenic score for HbA1c levels—miR-216a, miR-25, miR-30a-3p, and miR-30a-5p
