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IntroductionCancer stem cells (CSCs), a group of tumor-initiating and tumor-maintaining cells, may be major players in the treatment resistance and recurrence distinctive of chordoma. Characterizing CSCs is crucial to better targeting this subpopulation.MethodsUsing flow cytometry, six chordoma cell lines were evaluated for CSC composition. In vitro, cell lines were stained for B7H6, HER2, MICA-B, ULBP1, EGFR, and PD-L1 surface markers. Eighteen resected chordomas were stained using a multispectral immunofluorescence (mIF) antibody panel to identify CSCs in vivo. HALO software was used for quantitative CSC density and spatial analysis.ResultsIn vitro, chordoma CSCs express more B7H6, MICA-B, and ULBP1, assessed by percent positivity and mean fluorescence intensity (MFI), as compared to non-CSCs in all cell lines. PD- L1 percent positivity is increased by >20% in CSCs compared to non-CSCs in all cell lines except CH22. In vivo, CSCs comprise 1.39% of chordoma cells and most are PD-L1+ (75.18%). A spatial analysis suggests that chordoma CSCs cluster at an average distance of 71.51 mm (SD 73.40 mm) from stroma.DiscussionTo our knowledge, this study is the first to identify individual chordoma CSCs and describe their surface phenotypes using in vitro and in vivo methods. PD-L1 is overexpressed on CSCs in chordoma human cell lines and operative tumor samples. Similarly, potential immunotherapeutic targets on CSCs, including B7H6, MICA-B, ULBP1, EGFR, and HER2 are overexpressed across cell lines. Targeting these markers may have a preferential role in combating CSCs, an aggressive subpopulation likely consequential to chordoma’s high recurrence rate.

Cisplatin is the most frequently used chemotherapeutic agent for the treatment of patients with oral cavity squamous cell carcinoma (OCSCC), however, systemic administration is often associated with dose limiting side effects. Here the authors design and test a nano-engineered patch system (PRV111) for the local delivery of cisplatin-loaded chitosan nanoparticles and report the results of a phase 1/2 clinical trial of PRV111 in patients with OCSCC.

Anaerobic digestion is a complex microbial process that mediates the transformation of organic waste into biogas. The performance and stability of anaerobic digesters relies on the structure and function of the microbial community. In this study, we asked whether the deterministic effect of wastewater composition outweighs the effect of reactor configuration on the structure and dynamics of anaerobic digester archaeal and bacterial communities. Biotic and abiotic factors acting on microbial community assembly in two parallel anaerobic digestion systems, an upflow anaerobic sludge blanket digestor (UASB) and a closed digester tank with a solid recycling system (CDSR), from a brewery WWTP were analysed utilizing 16S rDNA and mcrA amplicon sequencing and genome-centric metagenomics. This study confirmed the deterministic effect of the wastewater composition on bacterial community structure, while the archaeal community composition resulted better explained by organic loading rate (ORL) and volatile free acids (VFA). According to the functions assigned to the differentially abundant metagenome-assembled genomes (MAGs) between reactors, CDSR was enriched in genes related to methanol and methylamines methanogenesis, protein degradation, and sulphate and alcohol utilization. Conversely, the UASB reactor was enriched in genes associated with carbohydrate and lipid degradation, as well as amino acid, fatty acid, and propionate fermentation. By comparing interactions derived from the co-occurrence network with predicted metabolic interactions of the prokaryotic communities in both anaerobic digesters, we conclude that the overall community structure is mainly determined by habitat filtering. [ABSTRACT FROM AUTHOR]

Abstract Background The Pehuén or Monkey puzzle tree (Araucaria araucana) is an evergreen coniferous tree, which has been historically used for social, medicinal, and nutritional purposes. We have recently showed the value of A. araucana seeds as a rich source of micronutrients and antioxidants. This endemic species present in a reduced area in Argentina and Chile is endangered because of the low germination rate and the overexploitation of its edible seeds. Thus, the massive extraction of its seeds is ecologically non-viable resulting in limited availability of its active metabolites. However, biotechnological approaches are attractive strategies of production of valuable metabolites and healthy specimens of endangered plants. The aim of this work was to develop a protocol for in vitro production of antioxidants derived from A. araucana seeds and to obtain healthy plants by optimized seed germination. Results Calli of Pehuén seeds were induced in Murashige and Skoog medium with different combinations of auxins and cytokinins, in light and dark conditions. Callus from embryonic axes developed in medium with 1 mg/l α-naphthaleneacetic acid and 1.5 mg/l 6-benzylaminopurine in light conditions had efficient biomass production, antioxidant activity, high phenolic, and flavonoid content and no cytotoxicity on mammalian cells. Additionally, 100 % germination was obtained in vitro and healthy plants were acclimatized to non-sterile conditions. Conclusion In conclusion, in vitro culture of A. araucana could provide new and sustainable options for production of its valuable metabolites with possible therapeutic and nutritional uses. Also, optimized plant germination and acclimatization of endangered species can contribute to the preservation of pristine environments.

Abstract Background Olfactory neuroblastoma (ONB) or esthesioneuroblastoma (ENB) is a rare malignancy of the nasal cavity believed to arise from the olfactory epithelium. The goal of this study was to systematically review the genomics, epigenetics, and cytogenetics of ONB and to understand the potential clinical implications of these studies. Methods A systematic literature review was performed for articles published before May 2020 using Cochrane, Embase, Pubmed, and Scopus databases. Inclusion criteria included genomics, cytogenetics, and epigenetics studies on ONB. Exclusion criteria included studies not in English or systematic reviews. Articles and abstracts were reviewed by two independent reviewers to reduce bias during article selection and synthesis of results. Of the 36 studies included in this review, 24 were research articles and 12 were abstracts. Results Although recurrent mutations among ONB tumors are uncommon, alterations in TP53, DMD, PIK3CA, NF1, CDKN2A, CDKN2C, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, SMAD4, FGFR3 and IDH2 genes have been reported in several recent studies. In addition, cytogenetic studies revealed that the landscape of chromosomal aberrations varies widely amongst ONB tumors. Conclusions The rare character of ONB has limited the sample size available for cytogenetic, genomic, and epigenetic studies and contributes to the limitations of this systematic review. Comprehensive genomic and epigenomic studies with larger cohorts are warranted to validate the initial reports summarized in this review and to identify potential therapeutic targets for ONB.

BackgroundChordoma is a rare, invasive, and devastating bone malignancy of residual notochord tissue that arises at the skull base, sacrum, or spine. In order to maximize immunotherapeutic approaches as a potential treatment strategy in chordoma it is important to fully characterize the tumor immune microenvironment (TIME). Multispectral immunofluorescence (MIF) allows for comprehensive evaluation of tumor compartments, molecular co-expression, and immune cell spatial relationships. Here we implement MIF to define the myeloid, T cell, and natural killer (NK) cell compartments in an effort to guide rational design of immunotherapeutic strategies for chordoma.MethodsChordoma tumor tissue from 57 patients was evaluated using MIF. Three panels were validated to assess myeloid cell, T cell, and NK cell populations. Slides were stained using an automated system and HALO software objective analysis was utilized for quantitative immune cell density and spatial comparisons between tumor and stroma compartments.ResultsChordoma TIME analysis revealed macrophage infiltration of the tumor parenchyma at a significantly higher density than stroma. In contrast, helper T cells, cytotoxic T cells, and T regulatory cells were significantly more abundant in stroma versus tumor. T cell compartment infiltration more commonly demonstrated a tumor parenchymal exclusion pattern, most markedly among cytotoxic T cells. NK cells were sparsely found within the chordoma TIME and few were in an activated state. No immune composition differences were seen in chordomas originating from diverse anatomic sites or between those resected at primary versus advanced disease stage.ConclusionThis is the first comprehensive evaluation of the chordoma TIME including myeloid, T cell, and NK cell appraisal using MIF. Our findings demonstrate that myeloid cells significantly infiltrate chordoma tumor parenchyma while T cells tend to be tumor parenchymal excluded with high stromal infiltration. On average, myeloid cells are found nearer to target tumor cells than T cells, potentially resulting in restriction of T effector cell function. This study suggests that future immunotherapy combinations for chordoma should be aimed at decreasing myeloid cell suppressive function while enhancing cytotoxic T cell and NK cell killing.