Recorded Rates of Trauma-Exposure in a Retrospective Epidemiologically Complete First-Episode Psychosis Cohort.

Background: Trauma plays an important role in the development and maintenance of psychosis. However, it is still under-examined in daily clinical practice. The current study investigated the rates of recording of trauma-exposure in the clinical histories of a first-episode psychosis (FEP) cohort attending an early intervention psychosis service.

Disentangling oncogenic amplicons in esophageal adenocarcinoma.

Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms.

Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia.

Unlabelled: Intestinal metaplasia in the esophagus (Barrett's esophagus IM, or BE-IM) and stomach (GIM) are considered precursors for esophageal and gastric adenocarcinoma, respectively. We hypothesize that BE-IM and GIM follow parallel developmental trajectories in response to differing inflammatory insults. Here, we construct a single-cell RNA-sequencing atlas, supported by protein expression studies, of the entire gastrointestinal tract spanning physiologically normal and pathologic states including gastric metaplasia in the esophagus (E-GM), BE-IM, atrophic gastritis, and GIM.

In vitro and in vivo assessments of the genotoxic potential of 3-chloroallyl alcohol.

3-Chloroallyl alcohol (3-CAA) can be found in the environment following the application of plant protection products. 3-CAA is formed in groundwater following the injection of 1,3-dichloropropene, a fumigant used to control nematodes. 3-CAA is also formed, in leafy crops, as a glycoside conjugate following application of the herbicide, clethodim.

The efficacy and complications of retropubic tension-free vaginal tapes after 20 years: A prospective observational study.

Objective: Long-term data regarding risks associated with tension-free vaginal tapes (TVT) are sparse, and where available are limited to small numbers. We analyse patient-reported outcomes of TVT after 16-24 years.

Design: Prospective observational study.

Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas.

Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes.

LINE retrotransposons characterize mammalian tissue-specific and evolutionarily dynamic regulatory regions.

Background: To investigate the mechanisms driving regulatory evolution across tissues, we experimentally mapped promoters, enhancers, and gene expression in the liver, brain, muscle, and testis from ten diverse mammals.

Results: The regulatory landscape around genes included both tissue-shared and tissue-specific regulatory regions, where tissue-specific promoters and enhancers evolved most rapidly. Genomic regions switching between promoters and enhancers were more common across species, and less common across tissues within a single species.

Comparative analysis of the AIB1 interactome in breast cancer reveals MTA2 as a repressive partner which silences E-Cadherin to promote EMT and associates with a pro-metastatic phenotype.

Steroid regulated cancer cells use nuclear receptors and associated regulatory proteins to orchestrate transcriptional networks to drive disease progression. In primary breast cancer, the coactivator AIB1 promotes estrogen receptor (ER) transcriptional activity to enhance cell proliferation. The function of the coactivator in ER metastasis however is not established.

Pervasive lesion segregation shapes cancer genome evolution.

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations.

A high-content RNAi screen reveals multiple roles for long noncoding RNAs in cell division.

Genome stability relies on proper coordination of mitosis and cytokinesis, where dynamic microtubules capture and faithfully segregate chromosomes into daughter cells. With a high-content RNAi imaging screen targeting more than 2,000 human lncRNAs, we identify numerous lncRNAs involved in key steps of cell division such as chromosome segregation, mitotic duration and cytokinesis. Here, we provide evidence that the chromatin-associated lncRNA, linc00899, leads to robust mitotic delay upon its depletion in multiple cell types.

Analysis of HER2 genomic binding in breast cancer cells identifies a global role in direct gene regulation.

HER2 is a transmembrane receptor tyrosine kinase, which plays a key role in breast cancer due to a common genomic amplification. It is used as a marker to stratify patients in the clinic and is targeted by a number of drugs including Trastuzumab and Lapatinib. HER2 has previously been shown to translocate to the nucleus.

Network analysis of SRC-1 reveals a novel transcription factor hub which regulates endocrine resistant breast cancer.

Steroid receptor coactivator 1 (SRC-1) interacts with nuclear receptors and other transcription factors (TFs) to initiate transcriptional networks and regulate downstream genes which enable the cancer cell to evade therapy and metastasise. Here we took a top-down discovery approach to map out the SRC-1 transcriptional network in endocrine resistant breast cancer. First, rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) was employed to uncover new SRC-1 TF partners.

Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution.

Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Here we measure allele-specific transcription factor binding occupancy of three liver-specific transcription factors between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor binding variations in mammals. Our results highlight the pre-eminence of cis-acting variants on transcription factor occupancy divergence.

Adaptation to AI Therapy in Breast Cancer Can Induce Dynamic Alterations in ER Activity Resulting in Estrogen-Independent Metastatic Tumors.

Purpose: Acquired resistance to aromatase inhibitor (AI) therapy is a major clinical problem in the treatment of breast cancer. The detailed mechanisms of how tumor cells develop this resistance remain unclear. Here, the adapted function of estrogen receptor (ER) to an estrogen-depleted environment following AI treatment is reported.

Enhancer-derived RNAs: 'spicing up' transcription programs.

Nature 498, 511–515 doi:; DOI: 10.1038/nature12209; published online May 02 2013 Nature 498, 516–520 doi:; DOI: 10.1038/nature12210; published online May 02 2013 Recent reports established transcription of enhancer-derived RNAs (eRNAs), while the evidence for their functional significance remained mostly speculative.

RuvBl2 cooperates with Ets2 to transcriptionally regulate hTERT in colon cancer.

Human cancers utilise telomerase to maintain telomeres and prohibit cell senescence. Human telomerase reverse transcriptase (hTERT), an essential component of this complex, is regulated at the level of gene transcription. Using SILAC-proteomic analysis and molecular studies, we identified the AAA+ ATPase, RuvBl2 as a transcriptional regulator of hTERT and established that this regulation is through cooperation with Ets-2.

Defining and targeting transcription factors in cancer.

A report from the Keystone Symposium on Molecular and Cellular Biology, 'Deregulation of transcription in cancer: controlling cell fate decisions', Killarney, Ireland, 21-26 July 2009.

Coassociation of estrogen receptor and p160 proteins predicts resistance to endocrine treatment; SRC-1 is an independent predictor of breast cancer recurrence.

Purpose: This study investigates the role of the p160 coactivators AIB1 and SRC-1 independently, and their interactions with the estrogen receptor, in the development of resistance to endocrine treatments.

Experimental Design: The expression of the p160s and the estrogen receptor, and their interactions, was analyzed by immunohistochemistry and quantitative coassociation immunofluorescent microscopy, using cell lines, primary breast tumor cell cultures, and a tissue microarray with breast cancer samples from 560 patients.

Results: Coassociation of the p160s and estrogen receptor alpha was increased in the LY2 endocrine-resistant cell line following treatment with tamoxifen in comparison with endocrine-sensitive MCF-7 cells.

The AIB1 oncogene promotes breast cancer metastasis by activation of PEA3-mediated matrix metalloproteinase 2 (MMP2) and MMP9 expression.

Amplified-in-breast cancer 1 (AIB1) is an overexpressed transcriptional coactivator in breast cancer. Although overproduced AIB1 is oncogenic, its role and underlying mechanisms in metastasis remain unclear. Here, mammary tumorigenesis and lung metastasis were investigated in wild-type (WT) and AIB1(-/-) mice harboring the mouse mammary tumor virus-polyomavirus middle T (PyMT) transgene.

Cyclooxygenase-2 predicts adverse effects of tamoxifen: a possible mechanism of role for nuclear HER2 in breast cancer patients.

Cyclooxygenase-2 (COX-2) is associated with breast tumour progression. Clinical and molecular studies implicate human epidermal growth factor receptor 2 (HER2) in the regulation of COX-2 expression. Recent reports raise the possibility that HER2 could mediate these effects through direct transcriptional mechanisms.