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Blood-based biomarkers that reliably indicate disease activity in the intestinal tract are an important unmet need in the management of patients with IBD. Extracellular vesicles (EVs) are cell-derived membranous microparticles, which reflect the cellular and functional state of their site of site of origin. As ultrasound waves may lead to molecular shifts of EV contents, we hypothesized that application of ultrasound waves on inflamed intestinal tissue in IBD may amplify the inflammation-specific molecular shifts in EVs like altered EV-miRNA expression, which in turn can be detected in the peripheral blood. 26 patients with IBD were included in the prospective clinical study. Serum samples were collected before and 30 min after diagnostic transabdominal ultrasound. Differential miRNA expression was analyzed by sequencing. Candidate inducible EV-miRNAs were functionally assessed in vitro by transfection of miRNA mimics and qPCR of predicted target genes. Serum EV-miRNA concentration at baseline correlated with disease severity, as determined by clinical activity scores and sonographic findings. Three miRNAs (miR-942-5p, mir-5588, mir-3195) were significantly induced by sonography. Among the significantly regulated EV-miRNAs, miR-942-5p was strongly induced in higher grade intestinal inflammation and correlated with clinical activity in Crohn’s disease. Prediction of target regulation and transfection of miRNA mimics inferred a role of this EV-miRNA in regulating barrier function in inflammation. Induction of mir-5588 and mir-3195 did not correlate with inflammation grade. This proof-of-concept trial highlights the principle of induced molecular shifts in EVs from inflamed tissue through transabdominal ultrasound. These inducible EVs and their molecular cargo like miRNA could become novel biomarkers for intestinal inflammation in IBD.

Objective In an era where digital devices become increasingly available, passive and active capturing of patient data during their everyday life becomes possible. However, it is still unclear to what extent people with chronic diseases are willing to use digital health technology (DHT) to assess study-relevant endpoints. The aim of the present study was therefore to determine such acceptance rates for clinical studies and which type of DHT patients prefer. Methods A survey with 492 people with Parkinson's disease (64 ± 11 years, 41% female) and 75 people with an immune-mediated inflammatory disease (58 ± 15 years, 99% female) was conducted. Results The vast majority of people (93%) were willing to use at least two devices simultaneously during a clinical study. Two-thirds indicated that they would use DHT for ≥6 days following a visit in the context of a study. The appearance of the device turned out to be important as the most popular devices were smartwatches, whereas more complex DHT, clearly recognisable as medical-grade were least popular. The effects of gender, age and disease could be detected, such as, for example, a tendency for men to be willing to use more devices simultaneously than women. Conclusion Overall, our findings suggest a willingness among individuals with Parkinson's disease and immune-mediated inflammatory disease to engage in clinical studies involving DHT. It is also evident that elderly patients can be integrated into these studies provided that the participation demands are aligned with clinical imperatives and the devices are user friendly.

Aberrant CD4 + T cell reactivity against intestinal microorganisms is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microorganism-specific, pathogenic T cell phenotypes remain largely unknown. In the present study, we identified common gut commensal and food-derived yeasts, as direct activators of altered CD4 + T cell reactions in patients with Crohn’s disease (CD). Yeast-responsive CD4 + T cells in CD display a cytotoxic T helper cell (T H 1 cell) phenotype and show selective expansion of T cell clones that are highly cross-reactive to several commensal, as well as food-derived, fungal species. This indicates cross-reactive T cell selection by repeated encounter with conserved fungal antigens in the context of chronic intestinal disease. Our results highlighted a role of yeasts as drivers of aberrant CD4 + T cell reactivity in patients with CD and suggest that both gut-resident fungal commensals and daily dietary intake of yeasts might contribute to chronic activation of inflammatory CD4 + T cell responses in patients with CD. In patients with Crohn’s disease, CD4 + T cells with cytotoxic T H 1 cell-like effector functions reactive against dietary and commensal yeasts are increased in blood and inflamed tissue compared with patients with ulcerative colitis and healthy controls.

Aberrant CD4 T cell reactivity against intestinal microorganisms is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microorganism-specific, pathogenic T cell phenotypes remain largely unknown. In the present study, we identified common gut commensal and food-derived yeasts, as direct activators of altered CD4 T cell reactions in patients with Crohn's disease (CD). Yeast-responsive CD4 T cells in CD display a cytotoxic T helper cell (T 1 cell) phenotype and show selective expansion of T cell clones that are highly cross-reactive to several commensal, as well as food-derived, fungal species. This indicates cross-reactive T cell selection by repeated encounter with conserved fungal antigens in the context of chronic intestinal disease. Our results highlighted a role of yeasts as drivers of aberrant CD4 T cell reactivity in patients with CD and suggest that both gut-resident fungal commensals and daily dietary intake of yeasts might contribute to chronic activation of inflammatory CD4 T cell responses in patients with CD.

Background The oldest-old (subjects aged 90 years and older) population represents the fastest growing segment of society and shows a high dementia prevalence rate of up to 40%. Only a few studies have investigated protective factors for cognitive impairment in the oldest-old. The EMIF-AD 90+ Study aims to identify factors associated with resilience to cognitive impairment in the oldest-old. In this paper we reviewed previous studies on cognitive resilience in the oldest-old and described the design of the EMIF-AD 90+ Study. Methods The EMIF-AD 90+ Study aimed to enroll 80 cognitively normal subjects and 40 subjects with cognitive impairment aged 90 years or older. Cognitive impairment was operationalized as amnestic mild cognitive impairment (aMCI), or possible or probable Alzheimer’s Disease (AD). The study was part of the European Medical Information Framework for AD (EMIF-AD) and was conducted at the Amsterdam University Medical Centers (UMC) and at the University of Manchester. We will test whether cognitive resilience is associated with cognitive reserve, vascular comorbidities, mood, sleep, sensory system capacity, physical performance and capacity, genetic risk factors, hallmarks of ageing, and markers of neurodegeneration. Markers of neurodegeneration included an amyloid positron emission tomography, amyloid β and tau in cerebrospinal fluid/blood and neurophysiological measures. Discussion The EMIF-AD 90+ Study will extend our knowledge on resilience to cognitive impairment in the oldest-old by extensive phenotyping of the subjects and the measurement of a wide range of potential protective factors, hallmarks of aging and markers of neurodegeneration. Trial registration Nederlands Trial Register NTR5867 . Registered 20 May 2016.

Cellular therapy is a promising therapeutic strategy for malignant diseases. The efficacy of this therapy can be limited by poor infiltration of the tumor by immune effector cells. In particular, NK cell infiltration is often reduced relative to T cells. A novel class of fusion proteins was designed to enhance the recruitment of specific leukocyte subsets based on their expression of a given chemokine receptor. The proteins are composed of an N-terminal chemokine head, the mucin domain taken from the membrane-anchored chemokine CX3CL1, and a C-terminal glycosylphosphatidylinositol (GPI) membrane anchor replacing the normal transmembrane domain allowing integration of the proteins into cell membranes when injected into a solid tumor. The mucin domain in conjunction with the chemokine head acts to specifically recruit leukocytes expressing the corresponding chemokine receptor. A fusion protein comprising a CXCL10 chemokine head (CXCL10-mucin-GPI) was used for proof of concept for this approach and expressed constitutively in Chinese Hamster Ovary cells. FPLC was used to purify proteins. The recombinant proteins efficiently integrated into cell membranes in a process dependent upon the GPI anchor and were able to activate the CXCR3 receptor on lymphocytes. Endothelial cells incubated with CXCL10-mucin-GPI efficiently recruited NK cells in vitro under conditions of physiologic flow, which was shown to be dependent on the presence of the mucin domain. Experiments conducted in vivo using established tumors in mice suggested a positive effect of CXCL10-mucin-GPI on the recruitment of NK cells. The results suggest enhanced recruitment of NK cells by CXCL10-mucin-GPI. This class of fusion proteins represents a novel adjuvant in cellular immunotherapy. The underlying concept of a chemokine head fused to the mucin domain and a GPI anchor signal sequence may be expanded into a broader family of reagents that will allow targeted recruitment of cells in various settings.

RET gene rearrangements yield oncogenic fusion proteins that drive a subset of lung adenocarcinomas (LUAD). The tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved therapies for RET+ lung cancers and have markedly improved clinical outcomes in these patients, but acquired resistance remains a hurdle to their durable management. Using a recently developed murine model of RET+ lung cancer driven by a fusion protein, two cell lines (TR.1 and TR.2) were established. Orthotopic lung tumors generated by transplantation of these cell lines initially respond to selpercatinib followed by prompt progression within ~3 weeks of initiating TKI treatment. Cell lines derived from the selpercatinib-resistant TR.1 and TR.2 tumors exhibited sensitivity to MET and ERBB-targeted TKIs, indicating acquired bypass signaling through these receptor tyrosine kinases. Moreover, the selpercatinib-resistant TR.1 and TR.2 cell lines exhibited increased sensitivity to MEK and PTPN11 inhibitors relative to the parental cell lines, indicating a greater dependence on MAPK pathway signaling. The TKI-resistant cell lines showed no evidence for MET gene amplification, but exhibited varied induction of multiple genes that function within MET and ERBB2:ERBB4 interaction networks including ligands (HGF, NRG1), adaptors (GAB1) and co-receptors (NRP1). Consistent with an important role for MET signaling in driving acquired selpercatinib resistance, mice bearing orthotopic lung tumors derived from TR.1 or TR.2 cells that had progressed on selpercatinib treatment underwent significant re-shrinkage upon co-treatment with the MET inhibitor, crizotinib, although progression re-occurred. By contrast, upfront treatment with selpercatinib and crizotinib in orthotopic tumors yielded complete elimination of 78% of TR.1 tumors and a prolonged duration of response in TR.2 tumors. The findings highlight the failings inherent in treating acquired resistance mechanisms at progression and the potential therapeutic impact of predicting and targeting dominant mechanisms of resistance prior to or early after initiating oncogene-targeting TKI treatment in RTK-driven LUAD.

The induction of endoplasmic reticulum unfolded protein responses (UPRER) contributes to cancer development and progression. We recently linked microbiota-related triggers to the tumor-promoting role of signal transducer activating transcription factor 6 (ATF6) in the colon. Here we substantiate the clinical relevance of ATF6 and related bacterial genera in colorectal cancer patient cohorts. Spatial and longitudinal bacterial profiling in ATF6 transgenic mice (nATF6IEC) identified tumor-initiating and tumor-progressing shifts in the mucosa-associated microbiota. Transcriptional analysis in intestinal epithelial cells (IEC) of germ-free and specific pathogen-free nATF6IEC mice defined bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics, isotope-labeling in intestinal organoids and FASN inhibition confirmed ATF6-mediated involvement of long-chain fatty acids in tumorigenesis. Multi-omics data integration identified a bacteria-lipid network characterized by fatty acid efflux, catabolism and detoxification. We postulate chronic ATF6 signaling to drive a clinically relevant pathologic response altering lipid metabolism to select for a tumor-promoting microbiota.Competing Interest StatementThe authors have declared no competing interest.