[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

/pdf/imaging-biomarker-roadmap-for-cancer-studies-4h34ouolr8.pdf

Imaging biomarker roadmap for cancer studies.

Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood.Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+ Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors.Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012-24. ©2016 AACR.

/pdf/potential-predictive-value-of-tp53-and-kras-mutation-status-4xwfh0yjm0.pdf

Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma

TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β-driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

https://rupress.org/jem/article-pdf/217/3/e20190103/1050682/jem_20190103.pdf

Transforming growth factor–β in tissue fibrosis

https://www.jto.org/article/S1556-0864(15)30307-5/pdf

Primary Tumor Standardized Uptake Value Measured on F18-Fluorodeoxyglucose Positron Emission Tomography Is of Prediction Value for Survival and Local Control in Non–Small-Cell Lung Cancer Receiving Radiotherapy: Meta-Analysis

The regenerative capacity of lung and liver is sometimes impaired by chronic or overwhelming injury. Orthotopic transplantation of parenchymal stem cells to damaged organs might reinstate their self-repair ability. However, parenchymal cell engraftment is frequently hampered by the microenvironment in diseased recipient organs. We show that targeting both the vascular niche and perivascular fibroblasts establishes "hospitable soil" to foster the incorporation of "seed," in this case, the engraftment of parenchymal cells in injured organs. Specifically, ectopic induction of endothelial cell (EC)-expressed paracrine/angiocrine hepatocyte growth factor (HGF) and inhibition of perivascular NOX4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 4] synergistically enabled reconstitution of mouse and human parenchymal cells in damaged organs. Reciprocally, genetic knockout of Hgf in mouse ECs (HgfiΔEC/iΔEC) aberrantly up-regulated perivascular NOX4 during liver and lung regeneration. Dysregulated HGF and NOX4 pathways subverted the function of vascular and perivascular cells from an epithelially inductive niche to a microenvironment that inhibited parenchymal reconstitution. Perivascular NOX4 induction in HgfiΔEC/iΔEC mice recapitulated the phenotype of human and mouse liver and lung fibrosis. Consequently, EC-directed HGF and NOX4 inhibitor GKT137831 stimulated regenerative integration of mouse and human parenchymal cells in chronically injured lung and liver. Our data suggest that targeting dysfunctional perivascular and vascular cells in diseased organs can bypass fibrosis and enable reparative cell engraftment to reinstate lung and liver regeneration.

Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis

Association of PDCD1 and CTLA-4 Gene Expression with Clinicopathological Factors and Survival in Non–Small-Cell Lung Cancer: Results from a Large and Pooled Microarray Database

Enhanced radioresponse with a novel recombinant human endostatin protein via tumor vasculature remodeling: Experimental and clinical evidence

Tumor organoids recapitulate pathological properties and would serve as an excellent ex vivo model for drug discovery Here, we performed an unbiased drug screening on drivers-defined tumor organoids from mouse endometrial cancer, the most prevalent gynecological malignancy in human, with a small molecule library targeting epigenetic factors Among them, menin-MLL inhibitors MI-136 and MI-463 scored The therapeutic capacity of MI-136 was further validated in tumor organoids in vitro and an orthotopic model in vivo CRISPR/cas9-mediated mutations of major components of the menin-MLL complex, Men1, Kmt2a and Ash2l, inhibited the growth of tumor organoids, suggesting that the complex was the target of MI-136 Transcriptome analysis showed that the hypoxia-inducible factor (HIF) pathway was the most significantly downregulated pathway by MI-136 treatment Consistently, Men1, Kmt2a, and Ash2l knockout also repressed the expressions of the HIF target genes Loss of Hif1a or Hif1b partially phenocopied the inhibition of the menin-MLL complex by MI-136 or mutations in term of tumor organoid growth Further, we found that MEN1 was upregulated in human endometrial cancers, which were tightly correlated with the expression levels of HIF1A, and associated with poor prognosis Importantly, MI-136 also significantly inhibited the growth of endometrial cancer organoids derived from patients Thus, our study identified MI-136 as a potential inhibitor for endometrial cancer through regulating the HIF pathway, a novel molecular mechanism distinguished from those in AML and prostate cancer

Feifei Na

Papers

Primary Tumor Standardized Uptake Value Measured on F18-Fluorodeoxyglucose Positron Emission Tomography Is of Prediction Value for Survival and Local Control in Non–Small-Cell Lung Cancer Receiving Radiotherapy: Meta-Analysis

Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis

Association of PDCD1 and CTLA-4 Gene Expression with Clinicopathological Factors and Survival in Non–Small-Cell Lung Cancer: Results from a Large and Pooled Microarray Database

Enhanced radioresponse with a novel recombinant human endostatin protein via tumor vasculature remodeling: Experimental and clinical evidence

An organoid-based drug screening identified a menin-MLL inhibitor for endometrial cancer through regulating the HIF pathway.