Faculty Bibliography

OBJECTIVES/OBJECTIVE:The gut microbiome plays a crucial role in regulating systemic immunity and has been implicated in several chronic inflammatory diseases. Intestinal expansions of Ruminococcus gnavus (RG), a dominant gut commensal, correlate with disease flares in lupus nephritis (LN), but the underlying mechanism remains unknown. METHODS:In a Pilot cohort of patients with biopsy-proven LN, subsetted by gut microbiota community, immune status was characterised using bulk-blood RNA sequencing libraries, serum levels of representative host proteins, and levels of immunoglobulin (Ig)G antibodies to the novel lipoglycan (LG) produced by pathogenic RG strains. A Validation LN cohort was evaluated for blood transcriptomic profiles and levels of anti-LG antibodies. In murine models, mechanistic hypotheses were tested after RG gut colonisation or after intraperitoneal injection with an LG preparation, with outcomes determined by transcriptomic analyses, platelet functional readouts, and tissue histology. RESULTS:In a Pilot cohort of patients with LN, RG gut expansions were associated with high-level platelet, neutrophil, and monocyte activation. Serum levels of platelet factor 4 and release of neutrophil extracellular traps (NETs) were significantly higher in patients with high serum IgG antibody against the novel RG-specific LG, a marker of in vivo immune exposure. An LN Validation cohort confirmed these correlates and showed that anti-LG antibodies serve as a surrogate for thromboinflammatory profile in this LN-associated endotype. In mice, gut colonisation with LG-producing RG strains or a single LG injection caused megakaryocytosis and platelet activation; RG colonisation with LG-producing strains induced tubulointerstitial injury with NETosis. In vivo responses to LG toxin were Toll-like receptor 2-dependent. CONCLUSIONS:Gut expansions of the RG pathobiont may contribute to autoimmune pathogenesis through the LG toxin and cause LN flares through thromboinflammatory mechanisms in this previously unrecognised LN endotype.

The protein activating molecule in Beclin1-regulated autophagy1 (AMBRA1), discovered in 2007, is crucial for autophagy and plays roles in nervous system development, cell survival, and proliferation. Here, we investigated AMBRA1's involvement in various cellular processes using a systems-based "omics" approach, focusing on melanoma. Transcriptomic analysis of AMBRA1 overexpression or knock-down was shown to result in significant dysregulation of several transcripts. We identified several novel roles for AMBRA1 in a range of cellular pathways including cancer signaling pathways such as MAPK, angiogenesis, tissue growth factor signaling, axon guidance, and Wnt signaling. Furthermore, using yeast two-hybrid assays, we identified novel binding partners which provide evidence of new roles for AMBRA1 in different cellular processes. Ultimately, we conclude that AMBRA1 loss upregulates metastatic genes/proteins highlighting AMBRA1 as a tumor suppressor gene in melanoma.

INTRODUCTION/BACKGROUND:Management of relapsed mantle cell lymphoma (MCL) has included Bruton's tyrosine kinase (BTK) inhibitors for more than 10 years, but finding an optimal combination partner that meaningfully improves outcomes while limiting toxicity has been difficult. We conducted a phase 1/2 trial of ibrutinib and the proteasome inhibitor, ixazomib, in patients with relapsed/refractory MCL. PATIENTS AND METHODS/METHODS:Patients and Methods: The primary endpoint for the phase 1 study was to determine the recommended phase 2 dose (RP2D), and for the phase 2 study was the complete response (CR) rate, compared with the previously reported single-agent CR rate of ibrutinib. After the phase 1 portion of the study identified a recommended phase 2 dose of ixazomib 4 mg days 1, 8, and 15, of a 28-day cycle combined with ibrutinib 560 mg daily until progression or unacceptable toxicity. RESULTS:We enrolled 35 BTK-naïve patients to the phase 2 portion of the study. Overall response rate was 77%, and 37% of patients achieved a CR. The 2-year progression-free survival is 44%, and the duration of response is 47%. Treatment-related adverse events were common, resulting in treatment discontinuation for 37% of patients. CONCLUSION/CONCLUSIONS:Given that the progression-free survival (PFS) was not significantly improved compared to historical reports for single-agent BTK inhibitors and the high rate of treatment-related toxicity, this combination does not merit further study in this setting. Additional trials evaluating newer BTK inhibitors and alternative combination partners are warranted.

The atopic dermatitis (AD) Yardstick articles aim to provide an up-to-date review of AD therapy for clinicians. The first two AD Yardstick articles were published in 2018 and 2023. Since the last update, multiple medications have been added to armamentarium of AD. These include roflumilast cream, tapinarof cream, lebrikizumab and nemolizumab. In the current AD Yardstick article, we aim to provide evidence-based information on these new treatments, as well as updated information on previously reviewed therapy. A new feature of the AD Yardstick article is the addition of patient vignettes, which provide practical guide and clinical pearls for clinicians.

BACKGROUND/UNASSIGNED:The EARLY TAVR trial demonstrated that early transcatheter aortic valve replacement (TAVR) was superior to clinical surveillance (CS) in asymptomatic severe aortic stenosis. The relative impact of early TAVR versus a CS strategy by age is unknown. METHODS/UNASSIGNED:The study population of the EARLY TAVR trial was stratified into 4 age groups: 65 to 69 years (n=141), 70 to 74 years (n=263), 75 to 79 years (n=250), and ≥80 years (n=247). Associations between age and the trial primary end point of death, stroke, or unplanned cardiovascular hospitalization; the composite end point of death, stroke, or heart failure hospitalization; and its individual components were examined. Interaction tests evaluated whether the treatment effect of early TAVR versus CS differed by age. RESULTS/UNASSIGNED:=0.06). CONCLUSIONS/UNASSIGNED:In the EARLY TAVR trial, the relative benefit of early TAVR over CS was consistent among all age groups. The greatest absolute reduction in stroke rate with early TAVR compared with CS appeared in the youngest and oldest groups, whereas reduction in heart failure hospitalization was most pronounced in the oldest patients. These data suggest that early TAVR should be considered in all age groups above 65 years. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03042104.

BACKGROUND/UNASSIGNED:The coronavirus disease 2019 (COVID-19) pandemic spurred a tremendous increase in the adoption and use of remote patient monitoring (RPM) for hypertension (HTN) management. However, limited evidence exists on the associations between frequency of utilization and uncontrolled blood pressure (BP). OBJECTIVES/UNASSIGNED:The present study comprehensively explores the associations between RPM use frequency and uncontrolled BP among a metropolitan-dwelling sample of hypertensive patients. METHODS/UNASSIGNED:Of 2,920 participants from a single urban health system, we employed a range of analytical perspectives to evaluate the RPM utilization-uncontrolled BP relationship across widely used engagement metrics: Frequency of BP transmission, digitally enabled clinician interactions, patient portal interactions, and a composite measure of utilization. Our dichotomized primary and secondary endpoints were BP >140/90 mm Hg and BP >130/80 mm Hg. RESULTS/UNASSIGNED:Fifty-nine percent of participants were females (59%), one-third (37%) were ≥65 years old, and Hispanic patients were most represented (39%). Our primary uncontrolled BP endpoint demonstrated strong adjusted associations with suboptimal RPM use across dichotomized measures: Low BP transmission (odds ratio [OR]: 2.02, 95% confidence interval [CI]: 1.41-2.96), low clinician interactions (OR: 1.83, 95% CI: 1.43-2.36), low patient portal interactions (OR: 1.83, 95% 1.46-2.30), and low overall engagement (OR: 3.50, 95% 2.77-4.46). Our causal evaluations mirrored these findings, showing moderate causal associations after comprehensive adjustment for confounding. Assessments using other data types, such as continuous and quartiles, showed significant associations and an apparent dose-response relationship, though not at a similar magnitude. CONCLUSION/UNASSIGNED:We observed strong associations between low RPM utilization and uncontrolled BP, with promising implications for patients with collectively high RPM use. These findings highlight the need to strengthen digital inclusion initiatives to improve RPM uptake and support existing efforts aimed at developing RPM clinical practice guidelines and expanding RPM reimbursement policies. Further research is warranted across diverse utilization components to better understand the linkages between engagement frequency and improved clinical outcomes.

Among the ways by which oncogenic KRAS upregulates glycolysis in cancer is direct interaction of KRAS4A with hexokinase 1 (HK1), but the mechanism is unknown. HK1 associates with the outer mitochondrial membrane (OMM) where its allosteric regulation depends on homodimerization. Using affinity capture, FRET, and blue native gels, we show that KRAS4A enhances oligomerization of HK1 on the OMM. Modeling the HK1/KRAS4A complex with AlphaFold3 predicts that the membrane association sequences of both HK1 and KRAS4A are oriented toward the OMM. Super-resolution microscopy showed colocalization of HK1 and KRAS4A on the OMM with HK1 enriched at discrete locations. Single-molecule tracking reveals HK1 diffusing freely along the OMM and dwelling at discrete regions where two molecules can be seen to colocalize transiently. KRAS4A expression decreased the diffusion coefficient of HK1 on the organelle. Thus, KRAS4A alters the dynamics of HK1 on the OMM and promotes oligomerization.

Pancreatic ductal adenocarcinoma (PDAC) relies on elevated autophagy to support metabolism, proliferation, and immune evasion. Inhibiting autophagy has been reported to improve response rates in patients with PDAC. In this work, we identified a mechanism to explain how loss of autophagy in PDAC triggers reprogramming of the tumor microenvironment (TME) to ultimately stimulate an antitumor response. Autophagy inhibition in PDAC recruited macrophages via the CXCL1/2-CXCR2 axis. Simultaneously, loss of autophagy resulted in a decrease of the canonical "don't eat me" ligand CD47 on tumor cells, thereby inducing their susceptibility to macrophage phagocytosis. While CD8+ T cells were critical to the anti-tumor immune response to autophagy inhibition in PDAC, they were not directly involved in cytotoxicity but played a critical role in stimulating macrophage phagocytosis of tumor cells. Taken together, this study strongly supports the implementation of autophagy inhibition in pancreatic cancer and highlights a crucial link between PDAC biology and the TME-macrophage crosstalk that effectively promotes tumor cell killing.

Transgender and gender diverse (TGD) people weather stigma and discrimination and experience significant barriers to preventive health care, contributing to disproportionate burdens of chronic diseases. Affirming approaches to preventive care improve trust, and every encounter presents an opportunity to support affirming clinical relationships with TGD patients. This article reviews best practices in preventive health in TGD populations including cancer screening, bone health, vaccinations, sexual health, cardiovascular risk, and behavioral health. Given limited data specific to trans patients, clinicians must use shared decision-making approaches to reduce disparities and improve the health of TGD individuals.