Additional Quantitative Trait Loci and Candidate Genes for Seed Isoflavone Content in Soybean

Seed isoflavone content of soybean (Glycine max L. Merr.) is a trait of moderate heritablity and an ideal target for marker selection. To date over 20 QTL have been identified underlying this trait among seven populations. The objectives of this study were to identify additional QTL and candidate genes controlling isoflavone content in a set of recombinant inbred line (RIL) populations of soybean grown in two different seasons. Variations of isoflavones namely daidzein, glycitein and genistein contents over two growing seasons and locations suggests that isoflavones are influenced by both genes and environments. Six QTL were identified on five different chromosomes (Chr) or linkage groups (LG) that controlled daidzein (Chr_2/LG-M; Chr_17a/LG-D2), glycitein (Chr_2/LG-D1b; Chr_8/LG-A2) and genistein (Chr_8/LG-A2; Chr_12/LG-H) respectively in the seeds grown in season 2010. Two QTL were identified for daidzein (Chr_6/LG-C2; Chr_13b/LG-F), two QTLs for glycitein (Chr_1/LG-D1a; Chr_17c/LG-D2) and five QTLs for genistein (Chr_3/ LG-N; Chr_8/LG-A2; Chr_9/LG-K; Chr_18/LG-G) in the seeds of the 2011 growing season. Genes located within QTL confidence intervals were retrieved and gene ontology (GO) terms were used to identify those related to the flavonoid biosynthesis process. Twenty six candidate genes were identified that may be involved in isoflavones accumulation in soybean seeds

JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition

Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617Fand mutant IDH1R132Hor Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617FIdh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mutand IDH2mutmutations. Taken together, these data suggest that combined JAK and IDH inhibition May offer a therapeutic advantage in this high-risk MPN subtype.Damon Runyon Cancer Research Foundation (DRG-2241-15)Howard Hughes Medical Institute (Faculty Scholars Award)Stand Up To CancerNational Cancer Institute (U.S.) (P50CA165962)National Cancer Institute (U.S.) (P30CA14051)Koch Institute for Integrative Cancer Research ( Dana-Farber Harvard Cancer Center Bridge Project)Leukemia & Lymphoma Society of America. Specialized Center of Research (SCOR) ProgramNational Institutes of Health (U.S.) (grant U54OD020355-01)National Institutes of Health (U.S.) (grant NCI R01CA172636)National Institutes of Health (U.S.) (grant R35CA197594)National Cancer Institute (U.S.) (Cancer Center Support Grant (P30 CA008747)

Somatic LKB1 Mutations Promote Cervical Cancer Progression

Human Papilloma Virus (HPV) is the etiologic agent for cervical cancer. Yet, infection with HPV is not sufficient to cause cervical cancer, because most infected women develop transient epithelial dysplasias that spontaneously regress. Progression to invasive cancer has been attributed to diverse host factors such as immune or hormonal status, as no recurrent genetic alterations have been identified in cervical cancers. Thus, the pressing question as to the biological basis of cervical cancer progression has remained unresolved, hampering the development of novel therapies and prognostic tests. Here we show that at least 20% of cervical cancers harbor somatically-acquired mutations in the LKB1 tumor suppressor. Approximately one-half of tumors with mutations harbored single nucleotide substitutions or microdeletions identifiable by exon sequencing, while the other half harbored larger monoallelic or biallelic deletions detectable by multiplex ligation probe amplification (MLPA). Biallelic mutations were identified in most cervical cancer cell lines; HeLa, the first human cell line, harbors a homozygous 25 kb deletion that occurred in vivo. LKB1 inactivation in primary tumors was associated with accelerated disease progression. Median survival was only 13 months for patients with LKB1-deficient tumors, but >100 months for patients with LKB1-wild type tumors (P = 0.015, log rank test; hazard ratio = 0.25, 95% CI = 0.083 to 0.77). LKB1 is thus a major cervical tumor suppressor, demonstrating that acquired genetic alterations drive progression of HPV-induced dysplasias to invasive, lethal cancers. Furthermore, LKB1 status can be exploited clinically to predict disease recurrence

Diet supplementation for 5 weeks with polyphenol-rich cereals improves several functions and the redox state of mouse leucocytes

BACKGROUND: Cereals naturally contain a great variety of polyphenols, which exert a wide range of physiological effects both in vitro and in vivo. Many of their protective effects, including an improvement of the function and redox state of immune cells in unhealthy or aged subjects come from their properties as powerful antioxidant compounds. However, whether cereal-based dietary supplementation positively affects the immune function and cellular redox state of healthy subjects remains unclear. AIM OF THE STUDY: To investigate the effects of supplementation (20% wt/wt) for 5 weeks with four different cereal fractions on healthy mice. METHODS: Several parameters of function and redox state of peritoneal leukocytes were measured. The cereals, named B (wheat germ), C (buckwheat flour), D (fine rice bran) and E (wheat middlings) contained different amounts of gallic acid, p-hydroxybenzoic acid, vanillic acid, sinapic acid, p-coumaric acid, ferulic acid, quercetin, catechin, rutin and oryzanol as major polyphenols. RESULTS: In general, all cereal fractions caused an improvement of the leukocyte parameters studied such as chemotaxis capacity, microbicidal activity, lymphoproliferative response to mitogens, interleukin-2 (IL-2) and tumor necrosis factor (TNFα) release, as well as oxidized glutathione (GSSG), GSSG/GSH ratio, catalase (CAT) activity and lipid oxidative damage. We observed similar effects among the cereal fractions. CONCLUSIONS: The results suggest that some of these effects may due, at least partially, to the antioxidant activity of the polyphenols naturally present in cereals. Since an appropriate function of the leukocytes has been proposed as marker of the health state, a short-term intake of cereals seems to be sufficient to exert a benefit in the health of the general population. However, further studies are needed to assess the optimal doses and to find out which active polyphenols are able to mediate the observed physiological effects before recommending their regular consumption

AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells

Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.publishedVersio

Low-surface energy surfactants with branched hydrocarbon architectures

International audienceSurface tensiometry and small-angle neutron scattering have been used to characterize a new class of low-surface energy surfactants (LSESs), "hedgehog" surfactants. These surfactants are based on highly branched hydrocarbon (HC) chains as replacements for environmentally hazardous fluorocarbon surfactants and polymers. Tensiometric analyses indicate that a subtle structural modification in the tails and headgroup results in significant effects on limiting surface tensions γcmc at the critical micelle concentration: a higher level of branching and an increased counterion size promote an effective reduction of surface tension to low values for HC surfactants (γcmc 24 mN m-1). These LSESs present a new class of potentially very important materials, which form lamellar aggregates in aqueous solutions independent of dilution

\u3cem\u3eLkb1\u3c/em\u3e Inactivation Drives Lung Cancer Lineage Switching Governed by Polycomb Repressive Complex 2

Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours