Summary• Recent years have seen rapid advances in our knowledge of the transcriptomic consequences of allopolyploidy, primarily through the study of polyploid crops and model systems. However, few studies have distinguished between homoeologs and between tissues, and still fewer have examined young natural allopolyploid populations of independent origin, whose parental species are still present in the same location.• Here, we examined the expression of 13 homoeolog pairs in seven tissues of 10 plants of allotetraploid Tragopogon mirus from two natural populations formed by independent polyploidizations between Tragopogon dubius and Tragopogon porrifolius c. 40 generations ago. We compare these with patterns of expression in the diploid parental species from the same locality.• Of the 910 assays in T. mirus, 576 (63%) showed expression of both homoeologs, 63 (7%) showed no expression of either homoeolog, 186 (20%) showed nonexpression of one homoeolog across all tissues of a plant, and 72 (8%) showed non-expression of a homoeolog in a particular tissue within a plant. We found two cases of reciprocal tissue-specific expression between homoeologs, potentially indicative of subfunctionalization.• Our study shows that tissue-specific silencing, and even apparent subfunctionalization, can arise rapidly in the early generations of natural allopolyploidy.

Solid cancers that metastasize to the lungs represent a major therapeutic challenge. Current treatment paradigms for lung metastases consist of radiation therapy, chemotherapies, and surgical resection, but there is no single treatment or combination that is effective for all tumor types. To address this, oncolytic myxoma virus (MYXV) engineered to express human tumor necrosis factor (vMyx-hTNF) was tested after systemic administration in an immunocompetent mouse K7M2-Luc lung metastatic osteosarcoma model. Virus therapy efficacy against pre-seeded lung metastases was assessed after systemic infusion of either naked virus or ex vivo -loaded autologous bone marrow leukocytes or peripheral blood mononuclear cells (PBMCs). Results of this study showed that the PBMC pre-loaded strategy was the most effective at reducing tumor burden and increasing median survival time, but sequential intravenous multi-dosing with naked virus was comparably effective to a single infusion of PBMC-loaded virus. PBMC-loaded vMyx-hTNF also potentially synergized very effectively with immune checkpoint inhibitors anti-PD-1, anti-PD-L1, and anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4). Finally, in addition to the pro-immune stimulation caused by unarmed MYXV, the TNF transgene of vMyx-hTNF further induced the unique expression of numerous additional cytokines associated with the innate and adaptive immune responses in this model. We conclude that systemic ex vivo virotherapy with TNF-α-armed MYXV represents a new potential strategy against lung metastatic cancers like osteosarcoma and can potentially act synergistically with established checkpoint immunotherapies.

BackgroundAlzheimer's disease (AD) is the most common cause of dementia, accounting for an estimated 60 to 80% of cases, and is the sixth-leading cause of death in the United States. While considerable advancements have been made in the clinical care of AD, it remains a complicated disorder that can be di cult to identify de nitively in its earliest stages. Recently, mass spectrometry (MS)-based metabolomics has shown signi cant potential for elucidation of disease mechanisms and identi cation of therapeutic targets as well diagnostic and prognostic markers that may be useful in resolving some of the di culties affecting clinical AD studies, such as effective strati cation. MethodsIn this study, complementary gas chromatography-and liquid chromatography-MS platforms were used to detect and monitor 2,080 metabolites and features in 48 post-mortem tissue samples harvested from the superior frontal gyrus of male and female subjects. Samples were taken from four groups: 12 normal control (NC) patients, 12 cognitively normal subjects characterized as high pathology controls (HPC), 12 subjects with non-speci c mild cognitive impairment (MCI), and 12 subjects with AD. ResultsMultivariate statistics informed the construction and cross-validation (p < 0.01) of partial least squaresdiscriminant analysis (PLS-DA) models de ned by a 9-metabolite panel of disease markers (lauric acid, stearic acid, myristic acid, palmitic acid, palmitoleic acid, and four unidenti ed mass spectral features). Receiver operating characteristic analysis showed high predictive accuracy of the resulting PLS-DA models for discrimination of NC (97%), HPC (92%), MCI (~ 96%), and AD (~ 96%) groups. Pathway analysis revealed signi cant disturbances in lysine degradation, fatty acid metabolism, and the degradation of branched-chain amino acids. Network analysis showed signi cant enrichment of 11 enzymes, predominantly within the mitochondria. ConclusionsThe results expand basic knowledge of the metabolome related to AD and reveal pathways that can be targeted therapeutically. This study also provides a promising basis for the development of larger multisite projects to validate these candidate markers in readily available biospecimens such as blood to enable the effective screening, rapid diagnosis, accurate surveillance, and therapeutic monitoring of AD. BackgroundImportantly, this study provides clinically relevant candidate biomarkers capable of accurate post-mortem classi cation which may, eventually, prove useful to in vivo diagnosis and disease monitoring. Methods ReagentsAcetonitrile (ACN), methanol (MeOH), ammonium acetate (NH 4 OAc), acetic acid (AcOH), and isopropanol (IPA), all LC-MS grade, were purchased from Fisher Scienti c (Pittsburgh, PA). Ammonium hydroxide (NH 4 OH), methyl tert-butyl ether (MTBE), O-methylhydroxylamine hydrochloride (MeOX), and N-Methyl-N-(tert-butyldimethylsilyl) tri uoroacetamide (MTBSTFA) were bought from Sigma-Aldrich (Saint Louis, MO). High performance LC grade chloroform (CHCl 3 ) was obtained from VWR (Radnor, P...

Morreton virus (MORV) is a novel oncolytic Vesiculovirus, genetically distinct from vesicular stomatitis virus (VSV). we report that MORV induced potent cytopathic effects in a panel of cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) cell lines. In addition, high intranasal doses of MORV were not associated with significant adverse effects and were well tolerated in mice bearing liver tumor xenografts and syngeneic liver cancers. Furthermore, single intratumoral treatments with MORV (1 x 10 7 TCID 50 ) triggered a robust antitumor immune response leading to substantial tumor regression and disease control in a syngeneic CCA model, using 10-fold lower dose compared to VSV (1 x 10 8 TCID 50 ). In addition, MORV and VSV both induced prominent tumor growth delay in immunodeficient mice bearing Hep3B hepatocellular carcinoma (HCC) but not in mice bearing HuCCT-1 CCA xenografts. Our findings indicate that wild-type MORV is safe and can induce potent tumor regression in HCC and CCA animal models without adverse events via immune-mediated and immune-independent mechanisms. Further development and clinical translation of MORV as virotherapy for liver cancers are warranted.