Combined plasma protein and Tmem profiling discern IBD-patient-immunotypes related to intestinal disease and treatment outcomes: Short title: Defining immunotypes in CD and UC.

Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn's disease, CD: n=62; ulcerative colitis, UC: n=20; age-matched controls n=43), and after 10-12 weeks' induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-γ production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-γ pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.

An IL-1ß-driven neutrophil-stromal cell axis fosters a BAFF-rich protumor microenvironment in individuals with multiple myeloma.

Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner, and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting antimyeloma treatment, human bone marrow retains residual stromal inflammation, and newly formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.

A novel clip-on device for electromagnetic tracking in endobronchial ultrasound bronchoscopy.

INTRODUCTION: The established method for assessment of mediastinal and hilar lymph nodes is endobronchial ultrasound bronchoscopy (EBUS) with needle aspirations. Previously, we presented an electromagnetic navigation platform for this purpose. There were several issues with the permanent electromagnetic tracking (EMT) sensor attachment on the tip of the experimental EBUS bronchoscope. The purpose was to develop a device for on-site attachment of the EMT sensor. MATERIAL AND METHODS: A clip-on EMT sensor attachment device was 3D-printed in Ultem™ and attached to an EBUS bronchoscope. A specially designed ultrasound probe calibration adapter was developed for on-site and quick probe calibration. Navigation accuracy was studied using a wire cross water phantom and clinical feasibility was tested in a healthy volunteer. RESULTS: The device attached to the EBUS bronchoscope increased its diameter from 6.9 mm to 9.5 mm. Average preclinical navigation accuracy was 3.9 mm after adapter calibration. The maneuvering of the bronchoscope examining a healthy volunteer was adequate without harming the respiratory epithelium, and the device stayed firmly attached. CONCLUSION: Development, calibration and testing of a clip-on EMT sensor attachment device for EBUS bronchoscopy was successfully demonstrated. Acceptable accuracy results were obtained, and the device is ready to be tested in patient studies.