Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-todate lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.

Purpose The purpose of this study is to demonstrate a method for specific absorption rate (SAR) reduction for 2D T2‐FLAIR MRI sequences at 7 T by predicting the required adiabatic radiofrequency (RF) pulse power and scaling the RF amplitude in a slice‐wise fashion. Methods We used a time‐resampled frequency‐offset corrected inversion (TR‐FOCI) adiabatic pulse for spin inversion in a T2‐FLAIR sequence to improve B1+ homogeneity and calculated the pulse power required for adiabaticity slice‐by‐slice to minimize the SAR. Drawing on the implicit B1+ inhomogeneity in a standard localizer scan, we acquired 3D AutoAlign localizers and SA2RAGE B1+ maps in 28 volunteers. Then, we trained a convolutional neural network (CNN) to estimate the B1+ profile from the localizers and calculated pulse scale factors for each slice. We assessed the predicted B1+ profiles and the effect of scaled pulse amplitudes on the FLAIR inversion efficiency in oblique transverse, sagittal, and coronal orientations. Results The predicted B1+ amplitude maps matched the measured ones with a mean difference of 9.5% across all slices and participants. The slice‐by‐slice scaling of the TR‐FOCI inversion pulse was most effective in oblique transverse orientation and resulted in a 1 min and 30 s reduction in SAR induced delay time while delivering identical image quality. Conclusion We propose a SAR reduction technique based on the estimation of B1+ profiles from standard localizer scans using a CNN and show that scaling the inversion pulse power slice‐by‐slice for FLAIR sequences at 7T reduces SAR and scan time without compromising image quality.

Background The E-cadherin gene (CDH1) is frequently mutated in diffuse gastric cancer and lobular breast cancer, and germline mutations predispose to the cancer syndrome Hereditary Diffuse Gastric Cancer. We are taking a synthetic lethal approach to identify druggable vulnerabilities in CDH1-mutant cancers. Methods Density distributions of cell viability data from a genome-wide RNAi screen of isogenic MCF10A and MCF10A-CDH1 −/− cells were used to identify protein classes affected by CDH1 mutation. The synthetic lethal relationship between selected protein classes and E-cadherin was characterised by drug sensitivity assays in both the isogenic breast MCF10A cells and CDH1-isogenic gastric NCI-N87. Endocytosis efficiency was quantified using cholera toxin B uptake. Pathway metagene expression of 415 TCGA gastric tumours was statistically correlated with CDH1 expression. Results MCF10A-CDH1 −/− cells showed significantly altered sensitivity to RNAi inhibition of groups of genes including the PI3K/AKT pathway, GPCRs, ion channels, proteosomal subunit proteins and ubiquitinylation enzymes. Both MCF10A-CDH1 −/− and NCI-N87-CDH1 −/− cells were more sensitive than wild-type cells to compounds that disrupted plasma membrane composition and trafficking, but showed contrasting sensitivities to inhibitors of actin polymerisation and the chloride channel inhibitor NS3728. The MCF10A-CDH1 −/− cell lines showed reduced capacity to endocytose cholera toxin B. Pathway metagene analysis identified 20 Reactome pathways that were potentially synthetic lethal in tumours. Genes involved in GPCR signalling, vesicle transport and the metabolism of PI3K and membrane lipids were strongly represented amongst the candidate synthetic lethal genes. Conclusions E-cadherin loss leads to disturbances in receptor signalling and plasma membrane trafficking and organisation, creating druggable vulnerabilities.

Long non-coding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes and yet, their functions remain largely unknown. We systematically knockdown 285 lncRNAs expression in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNA exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest to-date lncRNA knockdown dataset with molecular phenotyping (over 1,000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.