Scotttolstrup1974

We investigated associations of habitual dietary intake with the taxonomic composition and diversity of the human gut microbiota in 222 Koreans aged 18-58 years in a cross-sectional study. Gut microbiota data were obtained by 16S rRNA gene sequencing on DNA extracted from fecal samples. The habitual diet for the previous year was assessed by a food frequency questionnaire. After multivariable adjustment, intake of several food groups including vegetables, fermented legumes, legumes, dairy products, processed meat, and non-alcoholic beverages were associated with major phyla of the gut microbiota. A dietary pattern related to higher α-diversity (HiαDP) derived by reduced rank regression was characterized by higher intakes of fermented legumes, vegetables, seaweeds, and nuts/seeds and lower intakes of non-alcoholic beverages. The HiαDP was positively associated with several genera of Firmicutes such as Lactobacillus, Ruminococcus, and Eubacterium (all p less then 0.05). Among enterotypes identified by principal coordinate analysis based on the β-diversity, the Ruminococcus enterotype had higher HiαDP scores and was strongly positively associated with intakes of vegetables, seaweeds, and nuts/seeds, compared to the two other enterotypes. We conclude that a plant- and fermented food-based diet was positively associated with some genera of Firmicutes (e.g., Lactobacillus, Ruminococcus, and Eubacterium) reflecting better gut microbial health.Radiotherapy (RT) is highly effective at directly killing tumor cells and plays an important part in cancer treatments being delivered to around 50% of all cancer patients. The additional immunomodulatory properties of RT have been investigated, and if exploited effectively, have the potential to further improve the efficacy of RT and cancer outcomes. The initial results of combining RT with immunomodulatory agents have generated promising data in pre-clinical studies, which has in turn led to a large number of RT and immunotherapy clinical trials. The overarching aim of these combinations is to enhance anti-tumor immune responses and improve responses rates and patient outcomes. In order to maximize this undoubted opportunity, there remain a number of important questions that need to be addressed, including (i) the optimal RT dose and fractionation schedule; (ii) the optimal RT target volume; (iii) the optimal immuno-oncology (IO) agent(s) to partner with RT; (iv) the optimal site(s)/route(s) of administration of IO agents; and finally, the optimal RT schedule. In this review, we will summarize progress to date and identify current gaps in knowledge that need to be addressed in order to facilitate effective clinical translation of RT and IO agent combinations.The CD137 receptor (4-1BB, TNF RSF9) is an activation induced molecule expressed by antigen-specific T-cells. The engagement with its ligand, CD137L, is capable of increasing T-cell survival, proliferation, and cytokine production. This allowed to identify the CD137+ T-cells as the real tumor-specific activated T-cell population. In fact, these cells express various TCRs that are specific for a wide range of tumor-derived peptides, both shared and neoantigenic ones. Moreover, their prevalence in sites close to the tumor and their unicity in killing cancer cells both in vitro and in vivo, raised particular interest in studying their potential role in different strategies of immunotherapy. They indeed showed to be a reliable marker able to predict patient's outcome to immune-based therapies as well as monitor their response. In addition, the possibility of isolating and expanding this population, turned promising in order to generate effector antitumor T-cells in the context of adoptive T-cell therapies. CD137-targeting monoclonal antibodies have already shown their antitumor efficacy in cancer patients and a number of clinical trials are thus ongoing to test their possible introduction in different combination approaches of immunotherapy. Finally, the intracellular domain of the CD137 receptor was introduced in the anti-CD19 CAR-T cells that were approved by FDA for the treatment of pediatric B-cell leukemia and refractory B-cell lymphoma.While selective inhibition is one of the key assets for a small molecule drug, many diseases can only be tackled by simultaneous inhibition of several proteins. An example where achieving selectivity is especially challenging are ligands targeting human kinases. This difficulty arises from the high structural conservation of the kinase ATP binding sites, the area targeted by most inhibitors. We investigated the possibility to identify novel small molecule ligands with pre-defined binding profiles for a series of kinase targets and anti-targets by in silico docking. The candidate ligands originating from these calculations were assayed to determine their experimental binding profiles. Compared to previous studies, the acquired hit rates were low in this specific setup, which aimed at not only selecting multi-target kinase ligands, but also designing out binding to anti-targets. Specifically, only a single profiled substance could be verified as a sub-micromolar, dual-specific EGFR/ErbB2 ligand that indeed avoided its selected anti-target BRAF. We subsequently re-analyzed our target choice and in silico strategy based on these findings, with a particular emphasis on the hit rates that can be expected from a given target combination. To that end, we supplemented the structure-based docking calculations with bioinformatic considerations of binding pocket sequence and structure similarity as well as ligand-centric comparisons of kinases. Taken together, our results provide a multi-faceted picture of how pocket space can determine the success of docking in multi-target drug discovery efforts.ApreciseKUre is a multi-purpose digital platform facilitating data collection, integration and analysis for patients affected by Alkaptonuria (AKU), an ultra-rare autosomal recessive genetic disease. It includes genetic, biochemical, histopathological, clinical, therapeutic resources and quality of life scores that can be shared among registered researchers and clinicians in order to create a Precision Medicine Ecosystem (PME). The combination of machine learning application to analyse and re-interpret data available in the ApreciseKUre shows the potential direct benefits to achieve patient stratification and the consequent tailoring of care and treatments to a specific subgroup of patients. In this study, we have developed a tool able to investigate the most suitable treatment for AKU patients in accordance with their Quality of Life scores, which indicates changes in health status before/after the assumption of a specific class of drugs. This fact highlights the necessity of development of patient databases for rare diseases, like ApreciseKUre. We believe this is not limited to the study of AKU, but it represents a proof of principle study that could be applied to other rare diseases, allowing data management, analysis, and interpretation.Central nervous system malignancies (CNSMs) are categorized among the most aggressive and deadly types of cancer. The low median survival in patients with CNSMs is partly explained by the objective difficulties of brain surgeries as well as by the acquired chemoresistance of CNSM cells. Flow Cytometry is an analytical technique with the ability to quantify cell phenotype and to categorize cell populations on the basis of their characteristics. In the current review, we summarize the Flow Cytometry methodologies that have been used to study different phenotypic aspects of CNSMs. These include DNA content analysis for the determination of malignancy status and phenotypic characterization, as well as the methodologies used during the development of novel therapeutic agents. We conclude with the historical and current utility of Flow Cytometry in the field, and we propose how we can exploit current and possible future methodologies in the battle against this dreadful type of malignancy.Spirocerca lupi is a parasitic nematode of canids that induces a myriad of clinical manifestations in its host and, in 25% of infections, leads to the formation of sarcomas. The description of the protein composition of the excretory and secretory products (Sl-ESP) of S. lupi has shed light on its possible interactions with the host environment, including migration within the host and mechanisms of immunomodulation. Despite this, the process by which S. lupi induces cancer in the dog remains poorly understood, and some hypotheses have arisen regarding these possible mechanisms. In this review, we discuss the role of specific ESP from the carcinogenic helminths Clonorchis sinensis, Opisthorchis viverrini and Schistosoma haematobium in inducing chronic inflammation and cancer in their host's tissues. The parasitic worms Taenia solium, Echinococcus granulosus, Heterakis gallinarum, Trichuris muris and Strongyloides stercoralis, which have less-characterized mechanisms of cancer induction, are also analyzed. Based on the pathological findings in spirocercosis and the mechanisms by which other parasitic helminths induce cancer, we propose that the sustained inflammatory response in the dog´s tissues produced in response to the release of Sl-ESP homologous to those of other carcinogenic worms may lead to the malignant process in infected dogs.With the rapid development of micro-electro-mechanical systems (MEMSs), the demand for glass microstructure is increasing. For the purpose of achieving high quality and stable machining of glass microstructures with a high aspect ratio, ultrasonic vibration is applied into the micro-wire electrochemical discharge machining (WECDM), which is proposed as ultrasonic vibration-assisted WECDM with a micro helical electrode. Firstly, the formation of a gas film on the surface of the helical electrode in WECDM machining is simulated, meaning the thickness of the gas film can be reduced by adding suitable ultrasonic amplitude, thus reducing the critical voltage, then the machining localization and stability were enhanced. Then, the micro helical electrode with a diameter of 100 μm is used to carry out sets of experiments that study the influence of ultrasonic amplitude, machining voltage, duty factor, pulse frequency, and feed rate on the slit width. The experimental results show that the machining stability and quality are significantly improved by adding suitable ultrasonic amplitude. When the amplitude was 5.25 μm, the average slit width was reduced to 128.63 μm with a decrease of 20.78%. Finally, with the optimized machining parameters, micro planar coil structure and microcantilever structure with a high aspect ratio were fabricated successfully on the glass plate. It is proved that ultrasonic vibration-assisted WECDM with the micro helical electrode method can meet the requirements of high aspect ratio microstructure machining for hard and brittle materials.Hepatitis B Virus (HBV) is a globally-distributed pathogen and is a major cause of liver disease. HBV (or closely-related animal hepadnaviruses) can integrate into the host genome, but (unlike retroviruses) this integrated form is replication-defective. The specific role(s) of the integrated HBV DNA has been a long-standing topic of debate. Novel in vitro models of HBV infection combined with sensitive molecular assays now enable researchers to investigate this under-characterised phenomenon with greater ease and precision. This review covers the contributions these systems have made to understanding how HBV DNA integration induces liver cancer and facilitates viral persistence. We summarise the current findings into a working model of chronic HBV infection and discuss the clinical implications of this hypothetical framework on the upcoming therapeutic strategies used to curb HBV-associated pathogenesis.