This study has examined the molecular mechanisms underlying sensitivity of sarcomas to Nutlin-3a, a non-genotoxic activator of the p53 pathway. Human patient material was collected immediately following surgical resection, dissected into small pieces and ex planted onto gelatin sponges immersed in media containing either vehicle control or Nutlin-3a (10uM and/or 50uM) for 48 hours.
Nutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling.
No sample metadata fields
View SamplesAlthough a number of animal model studies have addressed changes in gene expression in the parenchyma and their relationship to emphysema, much less is known about the pathogenesis of cigarette smoke-induced small airway remodeling. In this study, we exposed rat tracheal explants to whole smoke for 15 minutes, and then cultured the explants in air. The airway transcriptome was evaluated using RAE 230_2 GeneChips. By 2 hours after starting smoke exposure, expression levels of 502 genes were changed up or down by more than 1.5 times (p values <0.01 or less), and by 24 hours, 1870 genes were significantly changed up or down. These included genes involved in anti-oxidant protection, epithelial defense and remodeling, inflammatory mediators and transcription factors, and a number of unexpected genes including the MMP-12 inducer, tachykinin-1 (substance P). Pre-treatment of the explants with 1 x 10-7 M dexamethasone reduced the number of significantly changed genes by approximately 47% at 2 hr and 68% at 24 hours, and in almost all instances, reduced the magnitude of the smoke-induced changes. We conclude that even a very brief exposure to cigarette smoke can lead to rapid changes in the expression of a large number of genes in rat tracheal explants, and that these effects are directly mediated by smoke, without a need for exogenous inflammatory cells. Steroids, contrary to the usual belief, are able to ameliorate many of these changes, at least in this very acute model.
Modification of the rat airway explant transcriptome by cigarette smoke.
Specimen part, Treatment
View SamplesThe response to growth hormone in humans is dependent on phenotypic, genetic and environmental factors. The present study in children with growth hormone deficiency (GHD) collected worldwide characterised gene-environment interactions on growth response to recombinant human growth hormone (r-hGH). Growth responses in children are linked to latitude, and we found that a correlation of latitude, summer daylight exposure (SDE) was a key environmental factor related to growth response to r-hGH. In turn growth response was determined by an interaction between both SDE and genes known to affect growth response to r-hGH. In addition analysis of associated networks of gene expression implicated a role for circadian clock pathways and specifically the developmental transcription factor NANOG. This work provides the first observation of gene-environment interactions in children treated with r-hGH.
Effect of summer daylight exposure and genetic background on growth in growth hormone-deficient children.
Sex, Age
View SamplesDespite advances in contemporary chemotherapeutic strategies, long term survival still remains elusive for patients with metastatic colorectal cancer. A better understanding of the molecular markers of drug sensitivity to match therapy with patient is needed to improve clinical outcomes. In this study, we used in vitro drug sensitivity data from the NCI-60 cell lines together with their Affymetrix microarray data to develop a gene expression signature to predict sensitivity to oxaliplatin. In order to validate our oxaliplatin sensitivity signature, Patient-Derived Colorectal Cancer Explants (PDCCEs) were developed in NOD-SCID mice from resected human colorectal tumors. Analysis of gene expression profiles found similarities between the PDCCEs and their parental human tumors, suggesting their utility to study drug sensitivity in vivo. The oxaliplatin sensitivity signature was then validated in vivo with response data from 14 PDCCEs treated with oxaliplatin and was found to have an accuracy of 92.9% (Sensitivity=87.5%; Specificity=100%). Our findings suggest that PDCCEs can be a novel source to study drug sensitivity in colorectal cancer. Furthermore, genomic-based analysis has the potential to be incorporated into future strategies to optimize individual therapy for patients with metastatic colorectal cancer.
Characterization of an oxaliplatin sensitivity predictor in a preclinical murine model of colorectal cancer.
No sample metadata fields
View SamplesThe study is relevant to an understanding of the forces that lead to sex differences in the brain and other somatic tissues. Many neural and psychiatric diseases affect men and women differently, so the understanding of sex differences in brain function impacts on our understanding of why the male and female brain differ in their susceptibility to disease.
Sex bias and dosage compensation in the zebra finch versus chicken genomes: general and specialized patterns among birds.
No sample metadata fields
View SamplesThe study is relevant to an understanding of the forces that lead to sex differences in the brain. Many neural and psychiatric diseases affect men and women differently, so the understanding of sex differences in brain function impacts on our understanding of why the male and female brain differ in their susceptibility to disease.
Sex bias and dosage compensation in the zebra finch versus chicken genomes: general and specialized patterns among birds.
No sample metadata fields
View SamplesThe study is relevant to an understanding of the forces that lead to sex differences in the brain. Many neural and psychiatric diseases affect men and women differently, so the understanding of sex differences in brain function impacts on our understanding of why the male and female brain differ in their susceptibility to disease.
Sex bias and dosage compensation in the zebra finch versus chicken genomes: general and specialized patterns among birds.
No sample metadata fields
View SamplesIncreasing evidence suggests that Long non-coding RNAs (LncRNAs) represent a new class of regulators of stem cells. However, the roles of LncRNAs in stem cell maintenance and myogenesis remain largely unexamined. For this study, hundreds of novel intergenic LncRNAs were identified that are expressed in myoblasts and regulated during differentiation. One of these LncRNAs, termed LncMyoD, is encoded next to the Myod gene and is directly activated by MyoD during myoblast differentiation. Knockdown of LncMyoD strongly inhibits terminal muscle differentiation largely due to a failure to exit the cell cycle. LncMyoD directly binds to IGF2-mRNA-binding-protein 2 (IMP2) and negatively regulates IMP2-mediated translation of proliferation genes such as N-Ras and c-Myc. While the RNA sequence of LncMyoD is not well-conserved between human and mouse, its locus, gene structure and function is preserved. The MyoD-LncMyoD-IMP2 pathway elucidates a mechanism as to how MyoD blocks proliferation to create a permissive state for differentiation.
A long non-coding RNA, LncMyoD, regulates skeletal muscle differentiation by blocking IMP2-mediated mRNA translation.
Age
View SamplesHigh-throughput pyrosequencing of endogenous small RNAs from >95% male enriched populations of alg-3(tm1155);alg-4(ok1041);fog-2(q71) and fog-2(q71) worms as well as purified spermatids from fem-3(q20) adult worms. Gametogenesis is thermosensitive in numerous metazoa ranging from worms to man. In C. elegans a variety of germ-line nuage- (P-granule) -associated RNA-binding proteins including the Piwi-clade Argonaute, PRG-1, have been implicated in temperature-dependent fertility. Here, we describe the role of two AGO-class paralogs, alg-3 (T22B3.2) and alg-4 (ZK757.3) in promoting male fertility at elevated temperatures. A rescuing GFP::alg-3 transgene is localized in P-granules beginning at the late pachytene stage of male gametogenesis. alg-3/4 double mutants lack a subgroup of small RNAs, named 26G-RNAs, which target and appear to down-regulate numerous spermatogenesis-expressed mRNAs. These findings add to a growing number of AGO pathways required for temperature-dependent fertility in C. elegans and support a model in which AGOs and their small RNA co-factors function to promote robustness in gene-expression networks. Overall design: 3 samples examined. Small RNAs from alg-3(tm1155);alg-4(ok1041);fog-2(q71) males and fog-2(q71) males. Small RNAs from spermatids isolated from ferm-3(q20) worms.
Argonautes ALG-3 and ALG-4 are required for spermatogenesis-specific 26G-RNAs and thermotolerant sperm in Caenorhabditis elegans.
Cell line, Subject
View SamplesSamples of primary tumors collected from 23 ovarian cancer patients
Machine learning predicts individual cancer patient responses to therapeutic drugs with high accuracy.
Sex, Specimen part, Disease
View Samples