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A hallmark of cancer is the avoidance of immune destruction. This process has been primarily investigated in locally advanced or metastatic cancer1–3; however, much less is known about how pre-malignant or early invasive tumours evade immune detection. Here, to understand this process in early colorectal cancers (CRCs), we investigated how naive colon cancer organoids that were engineered in vitro to harbour Apc-null, KrasG12D and Trp53-null (AKP) mutations adapted to the in vivo native colonic environment. Comprehensive transcriptomic and chromatin analyses revealed that the endoderm-specifying transcription factor SOX17 became strongly upregulated in vivo. Notably, whereas SOX17 loss did not affect AKP organoid propagation in vitro, its loss markedly reduced the ability of AKP tumours to persist in vivo. The small fraction of SOX17-null tumours that grew displayed notable interferon-γ (IFNγ)-producing effector-like CD8+ T cell infiltrates in contrast to the immune-suppressive microenvironment in wild-type counterparts. Mechanistically, in both endogenous Apc-null pre-malignant adenomas and transplanted organoid-derived AKP CRCs, SOX17 suppresses the ability of tumour cells to sense and respond to IFNγ, preventing anti-tumour T cell responses. Finally, SOX17 engages a fetal intestinal programme that drives differentiation away from LGR5+ tumour cells to produce immune-evasive LGR5− tumour cells with lower expression of major histocompatibility complex class I (MHC-I). We propose that SOX17 is a transcription factor that is engaged during the early steps of colon cancer to orchestrate an immune-evasive programme that permits CRC initiation and progression.Transcriptomic and chromatin accessibility analyses of naive and transplanted colon cancer organoids in a mouse model reveal a key role for the transcription factor SOX17 in establishing a permissive immune environment for tumour cells. [ABSTRACT FROM AUTHOR]

In vivo interrogation of the function of genes implicated in tumorigenesis is limited by the need to generate and cross germline mutant mice. Here we describe approaches to model colorectal cancer (CRC) and metastasis, which rely on in situ gene editing and orthotopic organoid transplantation in mice without cancer-predisposing mutations. Autochthonous tumor formation is induced by CRISPR-Cas9-based editing of the Apc and Trp53 tumor suppressor genes in colon epithelial cells and by orthotopic transplantation of Apc-edited colon organoids. ApcΔ/Δ;KrasG12D/+;Trp53Δ/Δ (AKP) mouse colon organoids and human CRC organoids engraft in the distal colon and metastasize to the liver. Finally, we apply the orthotopic transplantation model to characterize the clonal dynamics of Lgr5+ stem cells and demonstrate sequential activation of an oncogene in established colon adenomas. These experimental systems enable rapid in vivo characterization of cancer-associated genes and reproduce the entire spectrum of tumor progression and metastasis. [ABSTRACT FROM AUTHOR]

Accurate and rapid classification of cardiac amyloidosis is important for patient management. We have optimized the use of serum free light chain kappa and lambda values to differentiate immunoglobulin light chain amyloid (AL) amyloidosis from transthyretin amyloid and amyloid A using 85 cases of tissue-proven cardiac amyloidosis, in which there was direct classification of amyloidosis by mass spectrometry or immunofluorescence. The serum free light chain kappa/lambda ratios were non-overlapping for the three major groups: AL-lambda (0.01-0.41, n = 30), non-AL (0.52-2.7, n = 43), and AL-kappa (6.7-967, n = 12). A kappa/lambda ratio value between 0.5 and 5.0 had 100 % sensitivity and 100 % specificity for distinguishing AL amyloidosis from non-AL amyloidosis. This optimized range for serum light chain kappa/lambda ratio provides extremely robust classification of cardiac amyloidosis. Cases of cardiac amyloidosis in which the serum kappa/lambda free light chain ratio falls close to these new cutoff values may benefit most from direct amyloid subtyping. [ABSTRACT FROM AUTHOR]

Four new triphenyltin(IV) complexes containing [(( E)-1-{2-hydroxy-5-[( E)-2-(aryl)-1-diazenyl]phenyl}methylidene)amino]acetate ligands (L) have been synthesized with formulations of Ph3SnLH. They have been studied by multinuclear (1H, 13C, 119Sn) NMR, 119Sn Mössbauer and IR spectroscopy. A full characterization of one complex, Ph3SnL1H ( 1), was accomplished by single crystal X-ray crystallography, which revealed the compound to be a macrocyclic tetramer. In the tetramer, the five coordinate tin atoms have distorted trigonal bipyramidal geometries with the three phenyl groups occupying equatorial positions, while an oxygen atom of the carboxylate group of one L ligand and the oxide O-atom (formerly the hydroxy group) of a second L ligand in an apical positions. The carboxylate ligands bridge adjacent tin atoms and coordinate in the zwitterionic form with the phenolic proton moved to the nearby nitrogen atom. 119Sn NMR results indicate that the tetrameric structures of the complexes in the solid state, in which the tin atoms are five-coordinated, dissociate in solution to yield four coordinate monomeric species. [ABSTRACT FROM AUTHOR]

A series of tributyltin(IV) complexes of 4-[(( E)-1-{2-hydroxy-5-[( E)-2-(aryl)-1-diazenyl]phenyl}methylidene)amino]benzoates have been investigated by 1H, 13C, 119Sn NMR, IR and 119Sn Mössbauer spectroscopic techniques in combination with elemental analyses. Single crystal X-ray crystallography of Bu3Sn[O2CC6H4{N=C(H)C6H3-2-OH(N=NC6H4CH3-4)}- p] reveals a distorted tetrahedral structure which is further supported by 119Sn Mössbauer data. Toxicity studies of the tributyltin(IV) complexes along with their ligands 4-[(( E)-1-{2-hydroxy-5-[( E)-2-(aryl)-1-diazenyl]phenyl}methylidene)amino]benzoic acids on the second larval instar of the Anopheles stephensi mosquito larvae are also reported. [ABSTRACT FROM AUTHOR]

Some new di- and triorganotin(IV) derivatives of the formulae, R2SnL, where R =Me, Ph, and n-Oct, and L is the dianion of histidinylleucine (H2L abbreviated as H2(His-Leu)) and R′3 SnHL, where R′ = Me and Ph, HL = monoanion of histidinylleucine, have been synthesized. The bonding and coordination behaviour in these derivatives are discussed on the basis of FT-IR and 119Sn Mössbauer spectroscopic studies. The 119Sn Mössbauer studies, together with the IR data suggest that the ligand in R2Sn(His-Leu) acts as dianionic tridentate coordinating through C(O)O − , –NH2 at axial positions and Npeptide at equatorial position while in case of R′3Sn(HHis − Leu) the ligand acts as a monoanionic bidentate coordinating through C(O)O − and –NH2 giving a distorted trigonal–bipyramidal environment around tin. [ABSTRACT FROM AUTHOR]

This corrects the article DOI: 10.1038/nbt.3836 [ABSTRACT FROM AUTHOR]