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Targeting lineage-defined transcriptional dependencies has emerged as an effective therapeutic strategy in cancer treatment. Through screening for molecular vulnerabilities of mantle cell lymphoma (MCL), we identified a set of transcription factors (TFs) including FOXO1, EBF1, PAX5, and IRF4 that are essential for MCL propagation. Integrated chromatin immunoprecipitation and sequencing (ChIP-Seq) with transcriptional network reconstruction analysis revealed FOXO1 as a master regulator that acts upstream in the regulatory TF hierarchy. FOXO1 is both necessary and sufficient to drive MCL lineage commitment through supporting the lineage-specific transcription programs. We further show that FOXO1, but not its close paralog FOXO3, can reprogram myeloid leukemia cells and induce B-lineage gene expression. Finally, we demonstrate that cpd10, a small molecule identified from an enriched FOXO1 inhibitor library, induces a robust cytotoxic response in MCL cells in vitro and suppresses MCL progression in vivo. Our findings establish FOXO1 inhibition as a therapeutic strategy targeting lineage-driven transcriptional addiction in MCL., Introduction Mantle cell lymphoma (MCL) is a lethal mature B cell lymphoma manifested by cyclin D1 overexpression due to a t(11;14) (q13;q32) chromosomal translocation and mutations of genes associated with [...]

Although most commonly benign, neurofibromas (NFs) can have devastating functional and cosmetic effects in addition to the possibility of malignant transformation. Orbitofacial NFs, in particular, may cause progressive, disfiguring tumors of the lid, brow, temple, face, and orbit, and clinical evidence suggests that they may have increased local aggressiveness compared to NFs developing at other sites. The purpose of this study was to identify biological differences between orbitofacial NFs and those occurring at other anatomic sites. We performed RNA‐sequencing in orbitofacial (n = 10) and non‐orbitofacial (n = 9) NFs. Differential gene expression analysis demonstrated that a variety of gene sets including genes involved in cell proliferation, interferon, and immune‐related pathways were enriched in orbitofacial NF. Comparisons with publicly available databases of various Schwann cell tumors and malignant peripheral nerve sheath tumor (MPNST) revealed a significant overlap of differentially expressed genes between orbitofacial versus non‐orbitofacial NF and plexiform NF versus MPNST. In summary, we identified gene expression differences between orbitofacial NF and NFs occurring at other locations. Further investigation may be warranted, given that orbitofacial NF are notoriously difficult to treat and associated with disproportionate morbidity. [ABSTRACT FROM AUTHOR]

Since the beginning of the coronavirus disease-2019 (COVID-19) pandemic in 2020, there has been a tremendous accumulation of data capturing different statistics including the number of tests, confirmed cases and deaths. This data wealth offers a great opportunity for researchers to model the effect of certain variables on COVID-19 morbidity and mortality and to get a better understanding of the disease at the epidemiological level. However, in order to draw any reliable and unbiased estimate, models also need to take into account other variables and metrics available from a plurality of official and unofficial heterogenous resources. In this study, we introduce covid19census, an R package that extracts from many different repositories and combines together COVID-19 metrics and other demographic, environment- and health-related variables of the USA and Italy at the county and regional levels, respectively. The package is equipped with a number of user-friendly functions that dynamically extract the data over different timepoints and contains a detailed description of the included variables. To demonstrate the utility of this tool, we used it to extract and combine different county-level data from the USA, which we subsequently used to model the effect of diabetes on COVID-19 mortality at the county level, taking into account other variables that may influence such effects. In conclusion, it was observed that the 'covid19census' package allows to easily extract area-level data from both the USA and Italy using few functions. These comprehensive data can be used to provide reliable estimates of the effect of certain variables on COVID-19 outcomes. Database URL: https://github.com/c1au6i0/covid19census [ABSTRACT FROM AUTHOR]

Gluconacetobacter diazotrophicus is a beneficial nitrogen-fixing endophyte found in association with sugarcane plants and other important crops. Beneficial effects of G. diazotrophicus on sugarcane growth and productivity have been attributed to biological nitrogen fixation process and production of phytohormones especially indole-3-acetic acid (IAA); however, information about the biosynthesis and function of IAA in G. diazotrophicus is still scarce. Therefore, the aim of this work was to identify genes and pathways involved in IAA biosynthesis in this bacterium. In our study, the screening of two independent Tn5 mutant libraries of PAL5T strain using the Salkowski colorimetric assay revealed two mutants (Gdiaa34 and Gdiaa01), which exhibited 95% less indolic compounds than the parental strain when grown in LGIP medium supplemented with L-tryptophan. HPLC chromatograms of the wild-type strain revealed the presence of IAA and of the biosynthetic intermediates indole-3-pyruvic acid (IPyA) and indole-3-lactate (ILA). In contrast, the HPLC profiles of both mutants showed no IAA but only a large peak of non-metabolized tryptophan and low levels of IPyA and ILA were detected. Molecular characterization revealed that Gdiaa01 and Gdiaa34 mutants had unique Tn5 insertions at different sites within the GDI2456 open read frame, which is predicted to encode a L-amino acid oxidase (LAAO). GDI2456 (lao gene) forms a cluster with GDI2455 and GDI2454 ORFs, which are predicted to encode a cytochrome C and an RidA protein, respectively. RT-qPCR showed that transcript levels of lao. cccA, and ridA genes were reduced in the Gdiaa01 as compared to PAL5T. In addition, rice plants inoculated with Gdiaa01 showed significantly smaller root development (length, surface area, number of forks and tips) than those plants inoculated with PAL5T. In conclusion, our study demonstrated that G. diazotrophicus PAL5T produces IAA via the IPyA pathway in cultures supplemented with tryptophan and provides evidence for the involvement of an L-amino acid oxidase gene cluster in the biosynthesis of IAA. Furthermore, we showed that the mutant strains with reduction in IAA biosynthesis ability, in consequence of the lower transcription levels of genes of the lao cluster, had remarkable effects on development of rice roots. [ABSTRACT FROM AUTHOR]

The COVID-19 mortality rate is higher in the elderly and in those with pre-existing chronic medical conditions. The elderly also suffer from increased morbidity and mortality from seasonal influenza infections; thus, an annual influenza vaccination is recommended for them. In this study, we explore a possible county-level association between influenza vaccination coverage in people aged 65 years and older and the number of deaths from COVID-19. To this end, we used COVID-19 data up to 14 December 2020 and US population health data at the county level. We fit quasi-Poisson regression models using influenza vaccination coverage in the elderly population as the independent variable and the COVID-19 mortality rate as the outcome variable. We adjusted for an array of potential confounders using different propensity score regression methods. Results show that, on the county level, influenza vaccination coverage in the elderly population is negatively associated with mortality from COVID-19, using different methodologies for confounding adjustment. These findings point to the need for studying the relationship between influenza vaccination and COVID-19 mortality at the individual level to investigate any underlying biological mechanisms. [ABSTRACT FROM AUTHOR]

Background and Objective: Echinacea angustifolia DC. and Zingiber officinale Roscoe are two natural products with documented immunomodulatory activity, both able to modulate the expression of important immune-related genes. Thus, their use in combination seems to be particularly promising. In this context, we have considered the oral supplementation of a highly standardized lipophilic extract combining both above-mentioned phytocomplexes, formulated in attractive softgel capsules, with two objectives: on the one hand to study oral pharmacokinetic of main active extracts' components and on the other hand to examine the immunomodulation and anti-inflammatory properties by gene expression profiling.Methods: Softgel capsules containing a combination of E. angustifolia DC. and Z. officinale Roscoe (5 mg and 25 mg, respectively) were given by oral administration to 10 healthy volunteers. The plasma concentrations of dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamide (tetraene) for E. angustifolia DC., 6-gingerol and 6-shogaol (free and glucuronide) for Z. officinale Roscoe were determined by LC-MS analysis, and the pharmacokinetic analysis was performed. To understand the functional mechanisms responsible for the documented health benefits, we also examined the overall transcriptional remodeling induced in the peripheral blood mononuclear cells and performed an integrative functional analysis on the generated gene expression.Results: All bioactive components were absorbed very rapidly, and their tmax were detected in plasma from 30 min to 1.40 h. The peak concentrations of tetraene, 6-gingerol, 6-shogaol and their glucuronide metabolites were 14.74, 5.66, 9.25, 29.2 and 22.24 ng/ml, respectively. Integrated analysis performed on the generated gene expression data highlighted immunomodulatory and anti-inflammatory effects similar to those exerted by hydrocortisone.Conclusion: These data demonstrated that the bioactive ingredients are highly and rapidly absorbed from softgel capsules containing the combination of the above-mentioned lipophilic extracts, providing evidence to support their immunomodulatory and anti-inflammatory properties. These data also help in defining the mechanistic pathways underlying the health benefits of these plant-derived bioactive compounds. [ABSTRACT FROM AUTHOR]

Targeting lineage-defined transcriptional dependencies has emerged as an effective therapeutic strategy in cancer treatment. Through screening for molecular vulnerabilities of mantle cell lymphoma (MCL), we identified a set of transcription factors (TFs) including FOXO1, EBF1, PAX5, and IRF4 that are essential for MCL propagation. Integrated chromatin immunoprecipitation and sequencing (ChIP-Seq) with transcriptional network reconstruction analysis revealed FOXO1 as a master regulator that acts upstream in the regulatory TF hierarchy. FOXO1 is both necessary and sufficient to drive MCL lineage commitment through supporting the lineage-specific transcription programs. We further show that FOXO1, but not its close paralog FOXO3, can reprogram myeloid leukemia cells and induce B-lineage gene expression. Finally, we demonstrate that cpd10, a small molecule identified from an enriched FOXO1 inhibitor library, induces a robust cytotoxic response in MCL cells in vitro and suppresses MCL progression in vivo. Our findings establish FOXO1 inhibition as a therapeutic strategy targeting lineage-driven transcriptional addiction in MCL. [ABSTRACT FROM AUTHOR]