Highlights d Living biobank with 80 tumor organoids was derived from treatment-naive CRC patients d Tumor organoids recapitulate histological and genetic features of original tumors d Interpatient variability in the PDO response to chemoradiation treatments d PDOs can predict locally advanced rectal cancer patient responses in the clinic

Our understanding of the genetic basis of systemic lupus erythematosus (SLE) has been rapidly advanced using large-scale, case–control, candidate gene studies as well as genome-wide association studies during the past 3 years. These techniques have identified more than 30 robust genetic associations with SLE including genetic variants of HLA and Fcγ receptor genes, IRF5, STAT4, PTPN22, TNFAIP3, BLK, BANK1, TNFSF4 and ITGAM. Most SLE-associated gene products participate in key pathogenic pathways, including Toll-like receptor and type I interferon signaling pathways, immune regulation pathways and those that control the clearance of immune complexes. Disease-associated loci that have not yet been demonstrated to have important functions in the immune system might provide new clues to the underlying molecular mechanisms that contribute to the pathogenesis or progression of SLE. Of note, genetic risk factors that are shared between SLE and other immune-related diseases highlight common pathways in the pathophysiology of these diseases, and might provide innovative molecular targets for therapeutic interventions.

Fruit characteristics of sweet watermelon are largely the result of human selection. Here we report an improved watermelon reference genome and whole-genome resequencing of 414 accessions representing all extant species in the Citrullus genus. Population genomic analyses reveal the evolutionary history of Citrullus, suggesting independent evolutions in Citrullus amarus and the lineage containing Citrullus lanatus and Citrullus mucosospermus. Our findings indicate that different loci affecting watermelon fruit size have been under selection during speciation, domestication and improvement. A non-bitter allele, arising in the progenitor of sweet watermelon, is largely fixed in C. lanatus. Selection for flesh sweetness started in the progenitor of C. lanatus and continues through modern breeding on loci controlling raffinose catabolism and sugar transport. Fruit flesh coloration and sugar accumulation might have co-evolved through shared genetic components including a sugar transporter gene. This study provides valuable genomic resources and sheds light on watermelon speciation and breeding history.

Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease that predominantly affects women. Previous findings that duplicated Toll-like receptor 7 (Tlr7) promotes lupus-like disease in male BXSB mice prompted us to evaluate TLR7 in human SLE. By using a candidate gene approach, we identified and replicated association of a TLR7 3′UTR SNP, rs3853839 (G/C), with SLE in 9,274 Eastern Asians (P combined = 6.5 × 10 −10 ), with a stronger effect in male than female subjects [odds ratio, male vs. female = 2.33 (95% CI = 1.64-3.30) vs. 1.24 (95% CI = 1.14-1.34); P = 4.1 × 10]. G-allele carriers had increased TLR7 transcripts and more pronounced IFN signature than C-allele carriers; heterozygotes had 2.7-fold higher transcripts of G-allele than C-allele. These data established a functional polymorphism in type I IFN pathway gene TLR7 predisposing to SLE, especially in Chinese and Japanese male subjects. functional polymorphism | disease susceptibility | autoimmunity | type I interferon S ystemic lupus erythematosus [SLE; Online Mendelian Inheritance in Man (OMIM) no. 152700] is a multisystem, autoimmune disease with strong genetic and environmental components (1). SLE predominantly affects women, with a female-to-male ratio of approximately 9:1. Male patients with SLE, although rare, tend to have more severe disease and poorer outcome (2), suggesting potential sex dimorphism in the disease development. Although the sex effect has often been attributed to sex hormones, the fact that XXY male subjects have approximately a 14-fold higher risk of developing SLE than 46 XY men indicates that X-linked genes may be risk factors for human SLE (3).Located at Xp22.2, Toll-like receptor 7 (TLR7; OMIM no. 300365) and its functionally related gene TLR8 (OMIM no. 300366) encode proteins that play critical roles in pathogen recognition and activation of innate immunity (4). They recognize endogenous RNA-containing autoantigens and induce the expression of type I IFN, a pivotal cytokine in the pathogenesis of SLE (5). In lupus-prone BXSB mice, the translocation of a segmental duplication of X chromosome to Y chromosome creates the Y-linked autoimmune accelerator (Yaa) locus, which was associated with autoreactive B cell responses to RNA-related antigens and exacerbation of glomerulonephritis in male mice (6). Although translocated X chromosome segment in Yaa may contain as many as 16 genes, the major gene for causation of the autoimmune phenotypes was identified to be TLR7 (7), making it a potential susceptibility gene for SLE. By using a candidate gene approach, we report herein that a functional polymorphism in 3′UTR of TLR7 is associated with SLE in Chinese and Japanese populations, with a stronger effect in male than female subjects. ResultsDiscovery and Replication of the Association of a TLR7 3′UTR SNP with SLE in Eastern Asian Population. We genotyped 27 SNPs from the TLR7-TLR8 region (12 in TLR7 and 15 in TLR8) in 1,434 SLE cases and 1,591 control subjects of Eastern Asian ancestry using the Beadstation Infinium II...

The aim of the study was to investigate the characteristics of adult clinically amyopathic dermatomyositis (CADM) with rapid progressive interstitial lung disease (ILD). Hospitalized patients with dermatomyositis (DM) and polymyositis (PM) between 1998 and 2005 in the Shanghai Renji Hospital were retrospectively studied. One hundred and forty-five patients were classified into CADM, classic DM or PM according to the modified Sontheimer's definition or Bohan-Peter's classification criteria. They were further stratified based on the presence or absence of clinical ILD. The Kaplan-Meier survival analysis and COX regression were performed. The predictive factors for ILD and other clinical properties of CADM-ILD were explored. The presence of clinical ILD was a significant risk factor for the poor outcome of DM/PM (OR = 4.237, CI 95%: 1.239-14.49, p = 0.021). Other risk factors are the presence of rashes and elevated urea nitrogen. Patients with DM/PM complicated by ILD had different clinical courses. Patients with CADM-ILD showed a rapidly progressive pattern with 6-month survival rate of 40.8%. The DM-ILD manifested a progressive pattern with a 5-year survival rate of 54%, while PM-ILD was chronic with 5- and 10-year survival rate of 72.4% and 60.3%, respectively. Better preserved muscle strength, elevated erythrocyte sedimentation rate, and hypoalbuminemia may herald ILD in DM/PM. Patients with CADM-ILD who later died had lower PO(2), higher lactate dehydrogenase, and prominent arthritis/arthralgia compared with those who survived. The presence of antinuclear antibody seems to be protective. Rapid progressive CADM-ILD is refractory to conventional treatment. ILD is a common complication in over 40% of our hospitalized DM/PM cohort and is also a prominent prognostic indicator. CADM is a special phenotype of DM/PM. CADM-ILD, which is usually rapidly progressive and fatal, requires further investigation.

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Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type I interferon signature1. Here we report a missense variant (g.74779296G>A; p.Arg90His) in NCF1, encoding the p47phox subunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by the Immunochip in the GTF2IRD1-GTF2I region at 7q11.23 with a complex genomic structure. We show that the p.Arg90His substitution, which is reported to cause reduced reactive oxygen species (ROS) production2, predisposes to SLE (odds ratio (OR)=3.47 in Asians (Pmeta=3.1×10−104), OR=2.61 in European Americans, OR=2.02 in African Americans) and other autoimmune diseases, including primary Sjögren’s syndrome (OR=2.45 in Chinese, OR=2.35 in European Americans) and rheumatoid arthritis (OR=1.65 in Koreans). Additionally, decreased and increased copy numbers of NCF1 predispose to and protect against SLE, respectively. Our data highlight the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.

A nonribosomal peptide synthetase (NRPS) gene cluster (sfa) was identified in Streptomyces thioluteus to direct the biosynthesis of the diisonitrile antibiotic SF2768. Its biosynthetic pathway was reasonably proposed based on bioinformatics analysis, metabolic profiles of mutants, and the elucidation of the intermediate and shunt product structures. Bioinformatics-based alignment found a putative ATP-binding cassette (ABC) transporter related to iron import within the biosynthetic gene cluster, which implied that the product might be a siderophore. However, characterization of the metal-binding properties by high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), metal-ligand titration, thin-layer chromatography (TLC), and chrome azurol S (CAS) assays revealed that the final product SF2768 and its diisonitrile derivatives specifically bind copper, rather than iron, to form stable complexes. Inductively coupled plasma mass spectrometry (ICP-MS) analysis revealed that the intracellular cupric content of S. thioluteus significantly increased upon incubation with the copper-SF2768 complex, direct evidence for the copper acquisition function of SF2768. Further in vivo functional characterization of the transport elements for the copper-SF2768 complexes not only confirmed the chalkophore identity of the compound but also gave initial clues into the copper uptake mechanism of this nonmethanotrophic microorganism.