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Background: Lung cancer is the leading cause of cancer-related mortality globally, with late-stage diagnoses contributing to poor survival rates. While lung cancer screening with low-dose computed tomography (LDCT) has proven effective in reducing mortality among heavy smokers, its limitations, including high false-positive rates and resource intensiveness, restrict widespread use. Liquid biopsy, particularly using microRNA (miRNA) biomarkers, offers a promising adjunct to current screening strategies. This study aimed to evaluate the predictive power of a panel of serum miRNA biomarkers for lung cancer detection. Patients and Methods: A case-control study was conducted at two tertiary hospitals, enrolling 82 lung cancer cases and 123 controls. We performed an extensive literature review to shortlist 25 candidate miRNAs, of which 16 showed a significant two-fold increase in expression compared to the controls. Machine learning techniques, including Random Forest, K-Nearest Neighbors, Neural Networks, and Support Vector Machines, were employed to identify the top six miRNAs. We then evaluated predictive models, incorporating these biomarkers with lung nodule characteristics on LDCT. Results: A prediction model utilising six miRNA biomarkers (mir-196a, mir-1268, mir-130b, mir-1290, mir-106b and mir-1246) alone achieved area under the curve (AUC) values ranging from 0.78 to 0.86, with sensitivities of 70–78% and specificities of 73–85%. Incorporating lung nodule size significantly improved model performance, yielding AUC values between 0.96 and 0.99, with sensitivities of 92–98% and specificities of 93–98%. Conclusions: A prediction model combining serum miRNA biomarkers and nodule size showed high predictive power for lung cancer. Integration of the prediction model into current lung cancer screening protocols may improve patient outcomes.

Screen test for stem-cell cues If the full potential of human embryonic stem (ES) cells in research and clinical applications is to be realized, we need a detailed understanding of the genetic network that governs their unique properties. A genome-wide RNA interference screen identifies a wealth of regulators of self-renewal and pluripotency properties in human embryonic stem cells. PRDM14, for example, represents a key transcription factor required for the maintenance of human ES cell identity and reprogramming of somatic cells to pluripotency. Realizing the full potential of human embryonic stem cells (hESCs) in research and clinical applications requires a detailed understanding of the genetic network that governs their unique properties. A genome-wide RNA interference screen identifies a wealth of new regulators of self-renewal and pluripotency properties in hESCs. The transcription factor PRDM14, for example, is required for the maintenance of hESC identity and reprogramming of somatic cells to pluripotency. The derivation of human ES cells (hESCs) from human blastocysts represents one of the milestones in stem cell biology 1 . The full potential of hESCs in research and clinical applications requires a detailed understanding of the genetic network that governs the unique properties of hESCs. Here, we report a genome-wide RNA interference screen to identify genes which regulate self-renewal and pluripotency properties in hESCs. Interestingly, functionally distinct complexes involved in transcriptional regulation and chromatin remodelling are among the factors identified in the screen. To understand the roles of these potential regulators of hESCs, we studied transcription factor PRDM14 to gain new insights into its functional roles in the regulation of pluripotency. We showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer. Genome-wide location profiling experiments revealed that PRDM14 colocalized extensively with other key transcription factors such as OCT4, NANOG and SOX2, indicating that PRDM14 is integrated into the core transcriptional regulatory network. More importantly, in a gain-of-function assay, we showed that PRDM14 is able to enhance the efficiency of reprogramming of human fibroblasts in conjunction with OCT4, SOX2 and KLF4. Altogether, our study uncovers a wealth of novel hESC regulators wherein PRDM14 exemplifies a key transcription factor required for the maintenance of hESC identity and the reacquisition of pluripotency in human somatic cells.

Objective Gastric cancer (GC) is a deadly malignancy for which new therapeutic strategies are needed. Three transcription factors, KLF5, GATA4 and GATA6, have been previously reported to exhibit genomic amplification in GC. We sought to validate these findings, investigate how these factors function to promote GC, and identify potential treatment strategies for GCs harbouring these amplifications. Design KLF5, GATA4 and GATA6 copy number and gene expression was examined in multiple GC cohorts. Chromatin immunoprecipitation with DNA sequencing was used to identify KLF5/GATA4/GATA6 genomic binding sites in GC cell lines, and integrated with transcriptomics to highlight direct target genes. Phenotypical assays were conducted to assess the function of these factors in GC cell lines and xenografts in nude mice. Results KLF5, GATA4 and GATA6 amplifications were confirmed in independent GC cohorts. Although factor amplifications occurred in distinct sets of GCs, they exhibited significant mRNA coexpression in primary GCs, consistent with KLF5/GATA4/GATA6 cross-regulation. Chromatin immunoprecipitation with DNA sequencing revealed a large number of genomic sites co-occupied by KLF5 and GATA4/GATA6, primarily located at gene promoters and exhibiting higher binding strengths. KLF5 physically interacted with GATA factors, supporting KLF5/GATA4/GATA6 cooperative regulation on co-occupied genes. Depletion and overexpression of these factors, singly or in combination, reduced and promoted cancer proliferation, respectively, in vitro and in vivo. Among the KLF5/GATA4/GATA6 direct target genes relevant for cancer development, one target gene, HNF4α, was also required for GC proliferation and could be targeted by the antidiabetic drug metformin, revealing a therapeutic opportunity for KLF5/GATA4/GATA6 amplified GCs. Conclusions KLF5/GATA4/GATA6 may promote GC development by engaging in mutual crosstalk, collaborating to maintain a pro-oncogenic transcriptional regulatory network in GC cells.

BackgroundGI stromal tumours (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients.ObjectivesWe sought to identify genetic alterations associated with high-risk GIST, explore their molecular consequences, and test their utility as prognostic markers.DesignsExome sequencing of 18 GISTs was performed (9 patients with high-risk/metastatic and 5 patients with low/intermediate-risk), corresponding to 11 primary and 7 metastatic tumours. Candidate alterations were validated by prevalence screening in an independent patient cohort (n=120). Functional consequences of SETD2 mutations were investigated in primary tissues and cell lines. Transcriptomic profiles for 8 GISTs (4 SETD2 mutated, 4 SETD2 wild type) and DNA methylation profiles for 22 GISTs (10 SETD2 mutated, 12 SETD2 wild type) were analysed. Statistical associations between molecular, clinicopathological factors, and relapse-free survival were determined.ResultsHigh-risk GISTs harboured increased numbers of somatic mutations compared with low-risk GISTs (25.2 mutations/high-risk cases vs 6.8 mutations/low-risk cases; two sample t test p=3.1×10−5). Somatic alterations in the SETD2 histone modifier gene occurred in 3 out of 9 high-risk/metastatic cases but no low/intermediate-risk cases. Prevalence screening identified additional SETD2 mutations in 7 out of 80 high-risk/metastatic cases but no low/intermediate-risk cases (n=29). Combined, the frequency of SETD2 mutations was 11.2% (10/89) and 0% (0/34) in high-risk and low-risk GISTs respectively. SETD2 mutant GISTs exhibited decreased H3K36me3 expression while SETD2 silencing promoted DNA damage in GIST-T1 cells. In gastric GISTs, SETD2 mutations were associated with overexpression of HOXC cluster genes and a DNA methylation signature of hypomethylated heterochromatin. Gastric GISTs with SETD2 mutations, or GISTs with hypomethylated heterochromatin, showed significantly shorter relapse-free survival on univariate analysis (log rank p=4.1×10−5).ConclusionsOur data suggest that SETD2 is a novel GIST tumour suppressor gene associated with disease progression. Assessing SETD2 genetic status and SETD2-associated epigenomic phenotypes may guide risk stratification and provide insights into mechanisms of GIST clinical aggressiveness.

Guillaume Bourque and colleagues report genome-wide binding profiles of the OCT4, NANOG and CTCF proteins in human ES cells as determined by ChIP-sequencing. They find that the binding profiles of OCT4 and NANOG are different in human and mouse ES cells, and some of the differences in bound sites are due to transposable elements. Detection of new genomic control elements is critical in understanding transcriptional regulatory networks in their entirety. We studied the genome-wide binding locations of three key regulatory proteins (POU5F1, also known as OCT4; NANOG; and CTCF) in human and mouse embryonic stem cells. In contrast to CTCF, we found that the binding profiles of OCT4 and NANOG are markedly different, with only ∼5% of the regions being homologously occupied. We show that transposable elements contributed up to 25% of the bound sites in humans and mice and have wired new genes into the core regulatory network of embryonic stem cells. These data indicate that species-specific transposable elements have substantially altered the transcriptional circuitry of pluripotent stem cells.