Participant Experience with Protocol Research Kidney Biopsies in the Kidney Precision Medicine Project.

BACKGROUND: Kidney biopsies are procedures commonly performed in clinical nephrology and are increasingly used in research. In this study we aimed to evaluate the experiences of participants who underwent research kidney biopsies in the Kidney Precision Medicine Project (KPMP). METHODS: KPMP research participants with acute kidney injury (AKI) or chronic kidney disease (CKD) were enrolled at nine recruitment sites in the United States between September 2019 to January 2023. At 28 days post-biopsy, participants were invited to complete a survey to share their experiences, including: motivation to participate in research; comprehension of informed consent; pain and anxiety during and after the biopsy procedure; overall satisfaction with KPMP participation; and impact of the study on their lives. The survey was developed in collaboration with the KPMP Community Engagement Committee and the Institute of Translational Health Sciences at the University of Washington. RESULTS: 111 participants completed the survey, 23 enrolled for AKI and 88 for CKD. Median age was 61 (IQR 48-67) years, 43% were women, 28% were Black, and 18% were of Hispanic ethnicity. Survey respondents most commonly joined KPMP to help future patients (59%). The consent form was understood by 99% and 97% recognized their important role in the study. Pain during the biopsy was reported by 50%, at a median level of 1 (IQR 0-3) on a 0-10 scale. Anxiety during the biopsy was described by 64% at a median level of 3 (IQR 1-5) on a 0-10 scale. More than half conveyed that KPMP participation impacted their diet, physical activity, and how they think about kidney disease. CONCLUSIONS: KPMP survey respondents were most commonly motivated to participate in research protocol kidney biopsies by altruism, with excellent understanding of the informed consent process.

Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 (22) showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.

Macrophage targeted triptolide micelles capable of cGAS-STING pathway inhibition for rheumatoid arthritis treatment.

The abundant M1 macrophages in the joint synovium were the main factors that exacerbate rheumatoid arthritis (RA) by secreting various types of inflammatory cytokines. Here, we note that cGAS-STING, an important pro-inflammatory pathway, was significantly up-regulated in RA, enabling it be the potential target for RA therapy. Therefore, in this work, we developed M1 macrophages targeted micelles capable of cGAS-STING pathway inhibition for the smart treatment of RA. The folic acid (FA) and lauric acid (LA) were modified on dextran to obtain an amphiphilic polymer (FDL). Then, FDL was subsequently applied to encapsulate triptolide (TP) to form FDL@TP nanomicelles. The FDL@TP could target the joint and enhance the cell uptake of TP by M1 macrophages (overexpressing folate receptor-ß), which also reduced the side effects of TP on normal tissues. In M1 macrophages, the released TP, acted as an anti-inflammatory and immunosuppressant, obviously down-regulated the expressions of cGAS and STING protein, and thus reduced the secretion of TNF-α, IL-1ß and IL-6. Importantly, compared with the same dose of free TP, FDL@TP could significantly enhance the anti-inflammatory effect. Therefore, FDL@TP nanomicelles were believed to be superior candidates for the clinical treatment of RA.

Functional and Phenotypic Characterization of Siglec-6 on Human Mast Cells.

Mast cells are tissue-resident cells that contribute to allergic diseases, among others, due to excessive or inappropriate cellular activation and degranulation. Therapeutic approaches to modulate mast cell activation are urgently needed. Siglec-6 is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptor selectively expressed by mast cells, making it a promising target for therapeutic intervention. However, the effects of its engagement on mast cells are poorly defined. Siglec-6 expression and endocytosis on primary human mast cells and mast cell lines were assessed by flow cytometry. SIGLEC6 mRNA expression was examined by single-cell RNAseq in esophageal tissue biopsy samples. The ability of Siglec-6 engagement or co-engagement to prevent primary mast cell activation was determined based on assessments of mediator and cytokine secretion and degranulation markers. Siglec-6 was highly expressed by all mast cells examined, and the SIGLEC6 transcript was restricted to mast cells in esophageal biopsy samples. Siglec-6 endocytosis occurred with delayed kinetics relative to the related receptor Siglec-8. Co-crosslinking of Siglec-6 with FcεRIα enhanced the inhibition of mast cell activation and diminished downstream ERK1/2 and p38 phosphorylation. The selective, stable expression and potent inhibitory capacity of Siglec-6 on human mast cells are favorable for its use as a therapeutic target in mast cell-driven diseases.

Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme.

Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme that mediates the rate-limiting step in the metabolism of l-tryptophan to kynurenine, has been widely explored as a potential immunotherapeutic target in oncology. We developed a class of inhibitors with a conformationally constrained bicyclo[3.1.0]hexane core. These potently inhibited IDO1 in a cellular context by binding to the apoenzyme, as elucidated by biochemical characterization and X-ray crystallography. A SKOV3 tumor model was instrumental in differentiating compounds, leading to the identification of IACS-9779 (62) and IACS-70465 (71). IACS-70465 has excellent cellular potency, a robust pharmacodynamic response, and in a human whole blood assay was more potent than linrodostat (BMS-986205). IACS-9779 with a predicted human efficacious once daily dose below 1 mg/kg to sustain >90% inhibition of IDO1 displayed an acceptable safety margin in rodent toxicology and dog cardiovascular studies to support advancement into preclinical safety evaluation for human development.

Pulmonary AL amyloidosis and multiple myeloma presenting as cough with diffuse pulmonary opacities.

Amyloidosis is an uncommon multisystem disease that can affect many organs. However, interstitial lung involvement is very rare. A 68-year-old man presented with long-standing dyspnoea and productive cough. After extensive investigation, including two non-diagnostic bronchoscopies, a surgical lung biopsy demonstrated pulmonary amyloidosis. A bone marrow biopsy confirmed multiple myeloma. The patient was treated with chemotherapy and an autologous stem cell transplant.

A monoclonal antibody to Siglec-8 suppresses non-allergic airway inflammation and inhibits IgE-independent mast cell activation.

In addition to their well characterized role in mediating IgE-dependent allergic diseases, aberrant accumulation and activation of mast cells (MCs) is associated with many non-allergic inflammatory diseases, whereby their activation is likely triggered by non-IgE stimuli (e.g., IL-33). Siglec-8 is an inhibitory receptor expressed on MCs and eosinophils that has been shown to inhibit IgE-mediated MC responses and reduce allergic inflammation upon ligation with a monoclonal antibody (mAb). Herein, we evaluated the effects of an anti-Siglec-8 mAb (anti-S8) in non-allergic disease models of experimental cigarette-smoke-induced chronic obstructive pulmonary disease and bleomycin-induced lung injury in Siglec-8 transgenic mice. Therapeutic treatment with anti-S8 inhibited MC activation and reduced recruitment of immune cells, airway inflammation, and lung fibrosis. Similarly, using a model of MC-dependent, IL-33-induced inflammation, anti-S8 treatment suppressed neutrophil influx, and cytokine production through MC inhibition. Transcriptomic profiling of MCs further demonstrated anti-S8-mediated downregulation of MC signaling pathways induced by IL-33, including TNF signaling via NF-κB. Collectively, these findings demonstrate that ligating Siglec-8 with an antibody reduces non-allergic inflammation and inhibits IgE-independent MC activation, supporting the evaluation of an anti-Siglec-8 mAb as a therapeutic approach in both allergic and non-allergic inflammatory diseases in which MCs play a role.

Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.

GSH depletion liposome adjuvant for augmenting the photothermal immunotherapy of breast cancer.

The high redox level of tumor microenvironment inhibits the oxidation treatment and the immune response. Here, we innovatively develop maleimide liposome (ML) adjuvants to promote immunogenic cell death (ICD) induction and dendritic cells (DCs) maturation by glutathione (GSH) depletion for augmenting the photothermal immunotherapy of breast cancer. The ML effectively depletes the intracellular GSH and up-regulates reactive oxygen species (ROS) in both tumor cells and DCs. In tumor cells, the ROS boosted the ABTS·+ production to activate photothermal-induced ICD. In DCs, it relieved the immunosuppression, promoting DC maturation (57%) and antigen presenting. As a result of the ML assistant, the therapeutic systems improved the infiltration of CD8+ T cells to 53% in tumor tissues, eliciting strong abscopal effect and antimetastasis effect. The MLs were believed to be a superior candidate of adjuvants for enhancing immune response and cancer therapeutic efficacy.

Imaging of radiation damage using complementary field ion microscopy and atom probe tomography.

Radiation damage in tungsten and a tungsten-tantalum alloy, both of relevance to nuclear fusion research, has been characterized using a combination of field ion microscopy (FIM) imaging and atom probe tomography (APT). While APT provides 3D analytical imaging with sub-nanometer resolution, FIM is capable of imaging the arrangements of single atoms on a crystal lattice and has the potential to provide insights into radiation induced crystal damage, all the way down to its smallest manifestation--a single vacancy. This paper demonstrates the strength of combining these characterization techniques. In ion implanted tungsten, it was found that atomic scale lattice damage is best imaged using FIM. In certain cases, APT reveals an identifiable imprint in the data via the segregation of solute and impurities and trajectory aberrations. In a W-5at%Ta alloy, a combined APT-FIM study was able to determine the atomic distribution of tantalum inside the tungsten matrix. An indirect method was implemented to identify tantalum atoms inside the tungsten matrix in FIM images. By tracing irregularities in the evaporation sequence of atoms imaged with FIM, this method enables the benefit of FIM's atomic resolution in chemical distinction between the two species.

False positive for malignancy of a lung nodule on FDG PET/CT scans--a lesion with high FDG uptake but stable in size.

A highly F-18 fluorodeoxyglucose-avid lung nodule was stable in both size and metabolic activity over 4 months. This was most likely nonneoplastic because a true tumor would grown in volume overtime. The high level of energy consumption was contributing functional activities or by inflammatory cells. Because the speed of tumor growth is proportional to its energy consumption, we consider the higher the metabolic activity of a lesion, the less likely of malignant if it was stable in size over time.

Significance of upper urinary tract urothelial thickening and filling defect seen on MDCT urography in patients with a history of urothelial neoplasms.

OBJECTIVE: The purpose of this article is to assess the ability of CT urography to depict urothelial tumors in the upper renal collecting systems, compared with ureteroscopy and pathologic analysis, and to describe the relative implication of the radiologic signs of urothelial thickening and endoluminal filling defects. MATERIALS AND METHODS: We conducted a retrospective study to evaluate 326 consecutive CT urography examinations (using the split-bolus technique) performed at our institution between February 2006 and May 2009 in 188 patients (145 men and 43 women; median age, 65.5 years; range, 32.4-90.2 years) undergoing surveillance because of a history of urothelial tumor. Initial CT urography reports from multiple board-certified body imaging radiologists were reviewed for upper tract lesions and were classified by radiologic sign (filling defect or urothelial wall thickening) and lesion location (pelvicalyceal or ureteral) by one of the authors. The reference standard for comparison was pathologic analysis or visualization of tumor on ureteroscopy. Sensitivity and positive predictive values (PPVs) were calculated for upper tract tumors. RESULTS: Thirty-eight lesions were reported on initial CT urography examinations, 24 of which were subsequently confirmed to be tumors (PPV, 63.2%). Urothelial thickening was reported in 14 lesions, nine of which were tumors (PPV, 64%). Endoluminal filling defects were seen in 24 lesions, 15 of which were tumors (PPV, 62.5%). When stratified by location, urothelial thickening was more predictive of tumor in the pelvicalyceal system (PPV, 87.5% [7/8]) than in the ureter (PPV, 33.3% [2/6]). In contrast, filling defects were more predictive in the ureter (PPV, 87.5% [7/8]) than in the pelvicalyceal system (PPV, 50% [8/16]). CT urography failed to depict four tumors. CONCLUSION: Our data confirm that CT urography has utility in the surveillance of upper tract tumors. Urothelial thickening is an important radiologic sign of tumor, especially in the pelvicalyceal system.