Citations

ABSTRACT Introduction Chronic gastroduodenal disorders remain challenging to manage, and new diagnostic approaches are needed to better delineate underlying causes and guide therapeutic decisions. Body Surface Gastric Mapping (BSGM) technologies combine high‐resolution gastric myoelectrical activity measurements with symptom and psychological profiling to provide mechanistic insights into gastric motor and sensory dysfunction. An International Working Group convened to derive the first consensus classification of BSGM phenotypes (the “Auckland Classification”). Methods A Technical Group conducted a systematic literature and clinical database review to identify objective test biomarkers and candidate disease mechanisms. Evidence was synthesized across 50 studies (primarily in gastroparesis, chronic nausea and vomiting, and functional dyspepsia), and BSGM phenotypes were mapped to existing treatment guidelines. Subsequently, iterative review and development of consensus was performed by a Consensus Group composed of international clinical experts familiar with BSGM. Eleven statements underlying the classification were then derived and circulated as a final survey to establish agreement. Results Six BSGM phenotypes were endorsed: three defined by myoelectrical abnormalities (Dysrhythmic, High Frequency, and Low Meal Response) and three by characteristic symptom associations (Sensorimotor, Continuous, and Delayed Onset Symptoms). Published studies plausibly linked these phenotypes to mechanisms including interstitial cell of Cajal depletion, vagal impairment, hypomotility, visceral hypersensitivity, gut‐brain dysregulation, and small bowel dysfunction. Phenotypes were also mapped to existing mechanism‐based treatment guidelines. Ten out of the eleven statements had > 80% agreement. Conclusions The Auckland Classification, derived by international consensus, presents a structured framework for BSGM‐defined patient phenotypes. Evidence and mechanism‐based treatment options are suggested for each phenotype to provide a foundation for research, further validation, and a pathway for integrating BSGM into clinical care.

Abstract Background Patients with breast cancer undergoing chemotherapy experience multiple symptoms that cause decrements in quality of life. A deeper understanding of serum metabolites as biomarkers may guide in predicting symptom occurrence and severity. This study evaluated change in serum metabolite levels from before chemotherapy (T1) to after the initial first or second cycle of chemotherapy (T2), after the third cycle of chemotherapy (T3) and finally after a month of chemotherapy completion (T4). Change in metabolite levels were analyzed in association with symptom occurrence. Methods Patients with breast cancer (n = 10) completed study measures at four timepoints. Neuropsychological and gastrointestinal (GI) symptoms were evaluated using the Memorial Symptom Assessment Scale. Dietary intake was assessed using the NHANES Dietary Screener Questionnaire. Serum metabolites were analyzed using gas chromatography-mass spectrophotometry. Results Five patients experienced > 3 GI symptoms at T2 and T3. At all 4 timepoints, ≥ 6 patients experienced moderate to severe neuropsychological symptoms severity. Daily mean intake of fiber, whole grain, and calcium were less than the recommended guidelines. Compared to T1, long chain fatty acid and amino acid derivative levels decreased at T2 and T3 (p < 0.05). Increase in metabolite levels of glucose-6-phosphate (p = 0.02) and 6-phosphogluconate (p = 0.05) at T2 were associated with fatigue occurrence. Conclusions Patients experienced several gastrointestinal and neuropsychological symptoms during chemotherapy and early survivorship. Chemotherapy-induced changes in metabolites involved in cellular energy metabolism may explain patient symptom experience. Metabolite level changes overtime may reflect inadequate dietary intake. Larger sample size studies may guide in building metabolic prediction models for symptom burden.

Abstract Objective To describe the presenting symptoms, treatment regimens, and outcomes associated with oropharyngeal adenoid cystic carcinoma. Data Sources Ovid MEDLINE(R), Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, and Scopus via Elsevier. Review Methods This review followed the Preferred Reporting Items for Systematic Reviews and Meta‐analyses. A medical librarian conducted the literature search using controlled vocabulary and keywords, with investigator input. Eligible articles were clinical trials and observational studies reporting on clinical features, treatment, or outcomes for oropharyngeal adenoid cystic carcinoma. Results Our search identified 233 unique citations, with 44 articles included covering 195 patients. The female‐to‐male ratio was 1.7:1, and the base of the tongue was the most common subsite (73%). Presenting symptoms were mainly pain/discomfort (n = 31), followed by a palpable mass (n = 19) and dysphagia (n = 12). At diagnosis, 22.3% (29 patients) had positive lymph nodes. Treatment was primarily surgical (n = 102), with definitive radiation therapy used in 58 cases. Disease progression was noted in 86 patients, 36% (n = 31) of whom developed distant metastases—primarily to the lungs (n = 26). Long‐term outcomes (n = 76) showed 3‐ and 5‐year overall survival rates of 71.5% to 100% and 47.6% to 79.0%, and disease‐free survival rates of 54.7% to 70.0% and 21.9% to 44.0%, respectively. Conclusion Among patients with available data, oropharyngeal adenoid cystic carcinoma appeared more common in women and has a predilection for the base of the tongue. However, this finding should be interpreted with caution, given the high proportion of missing data. These tumors appear to carry a higher risk for nodal metastases and may lead to poor outcomes.

ABSTRACT Blood culture contamination can lead to false-positive blood culture results, potentially contributing to increased costs and unneeded antibiotic utilization. Initial specimen diversion devices (ISDD) have been proposed to reduce blood culture contamination rates. A single-center, observational study conducted at Mayo Clinic Rochester compared blood culture contamination rates using Steripath or Kurin ISDDs versus standard blood culture collection protocols. Over 255 phlebotomists were trained in the use of the ISDDs, with 31,215 blood cultures, 410 of which were contaminated, collected from adults in the emergency department and inpatient wards. Baseline contamination rates were 1.29%–2.53% with standard collection methods. The Steripath ISDD with direct-to-media inoculation of blood culture bottles (Steripath-DTM) reduced blood culture contamination compared to standard practice (0.34% vs. 1.43%, respectively, P < 0.001). Follow-up studies with the alternative Steripath configuration with an integrated syringe (Steripath-syringe), and then the Kurin ISDD with syringe collection (Kurin-syringe), did not meet the primary endpoint of <0.5% contamination (Steripath-syringe: 1.28%; Kurin-syringe: 1.76%). All three ISDD configurations failed to meet our goal of >75% utilization, with an average measured utilization of 26% for the Steripath-DTM, 26.4% for the Steripath ISDD (combined DTM and syringe) in a follow-up study, and 41.5% in the Kurin study. Additionally, a survey of phlebotomists revealed low staff satisfaction with both Steripath ISDD configurations. Staff reported multiple ergonomic barriers limiting the Steripath ISDD’s utility, which precluded implementation of the Steripath-DTM in routine clinical practice. IMPORTANCE We conducted a very large, real-world study of two blood diversion devices to determine whether either would meet goals for reduced blood culture contamination and a high rate of utilization by phlebotomists.

ABSTRACT Objective Little is known about shifting from pediatric to adult‐focused multiple sclerosis (MS) care. This study aims to explore transition of care and follow‐up in the US pediatric‐onset MS (POMS) population. Methods Surveys were distributed to 10 sites in the US Network of Pediatric MS Centers (US NPMSC) about transition‐of‐care practices. A cohort of POMS/clinically isolated syndrome (CIS) at 12 US NPMSC sites was analyzed. The primary comparison was between < 18 and ≥ 18‐years of age. The primary outcome was 1‐ and 2‐year lapse in last follow‐up visit, measured from last recorded database visit to data lock date or, if ≥ 18 years of age, up to 1 year after a patient reached their site's typical transition age, if earlier. Secondary outcomes were baseline factors associated with follow‐up lapse. The model was adjusted for preidentified confounders. Results Compared with < 18 years, age ≥ 18 was associated with greater hazard of 1‐ and 2‐year follow‐up lapse. In POMS/CIS, the estimated hazard was 1.61 for 1‐year lapse (95% confidence interval [CI] 1.32–1.97, p < 0.001) and 1.40 for 2‐year lapse (95% CI 1.11–1.76, p = 0.004). In POMS‐only, the estimated hazard was 1.70 for 1‐year lapse (95% CI 1.33–2.18, p < 0.001) and 1.49 for 2‐year lapse (95% CI 1.11–1.99, p = 0.007). Platform injectable disease‐modifying therapy was associated with greater and intravenous with lesser hazard of lapse in follow‐up, while MS was associated with lower hazard than CIS. Conclusion Variable transition‐of‐care practices and barriers were reported by major US POMS centers. Before typical transition age, age ≥ 18 was associated with greater hazard of 1‐ and 2‐year follow‐up lapse than < 18. Developing standardized, targeted transition‐of‐care practices in POMS may be important.

Abstract Background: Antigen receptor stimulation induces assembly of the CARMA1-BCL10-MALT1 (CBM) signaling complex, which leads to activation of downstream transcriptional regulators including NF-κB and subsequent lymphocyte activation. Gain-of-function mutations in B-cell receptor subunits, CARMA1, or BCL10 which lead to constitutive activation of MALT1 underly the pathogenesis of multiple lymphoid malignancies, including activated B-cell–type diffuse large B-cell lymphoma (ABC-DLBCL). During previous efforts to identify regulators of MALT1 activity in lymphocytes, we discovered that G-protein-coupled receptor kinase 2 (GRK2) binds to MALT1, inhibits MALT1 scaffolding and proteolytic activities, and functions as a tumor suppressor in MALT1-dependent lymphomas. Notably, GRK2 mRNA expression is markedly lower in a subset of DLBCL tumors in comparison to normal B cells and lower GRK2 is associated with decreased patient survival in ABC-DLBCL. In light of these findings, we investigated the molecular mechanisms regulating GRK2 expression and then characterized the roles of specific GRK2-targeting miRNAs in ABC-DLBCL. Methods and Results: After finding that global impairment of miRNA processing through DICER1 depletion leads to increased GRK2 protein, we conducted bioinformatic analyses of patient tumor samples and microRNA Data Integration Portal screening to identify candidate microRNAs that target GRK2 in ABC-DLBCL. Direct targeting of GRK2 by candidate miRNAs was then confirmed by GRK2 3’UTR reporter assay. We tested for expression of three candidate microRNAs in ABC-DLBCL cells and observed elevated expression in both OCI-LY3 and TMD8 cells, which exhibited reduced GRK2 mRNA expression compared with primary B cells. Inhibition of candidate miRNAs in ABC-DLBCL cells, using anti-miRNA Locked Nucleic Acids (LNA) inhibitors, led to enhanced GRK2 expression, reduced MALT1 activity and decreased cell proliferation. Conversely, stable overexpression of candidate microRNAs led to reduced GRK2 expression, enhanced MALT1 activity and increased cell proliferation. In vivo, treatment of mice with inhibitors of candidate microRNAs abrogates the growth of ABC-DLBCL xenograft tumors. Conclusion: We have identified three miRNAs that negatively regulate GRK2 expression in ABC-DLBCL. By targeting GRK2 for downregulation, these miRNAs promote MALT1 oncoprotein scaffold and protease activities. Furthermore, inhibitors of these miRNAs enhance GRK2 expression and thereby suppress MALT1 activity and MALT1-dependent tumor cell proliferation in vitro and inhibit MALT1-dependent tumor growth in vivo. MicroRNA inhibitors that enhance GRK2 expression could represent a new approach for restraining MALT1-dependent lymphoma. Citation Format: Jing Cheng, Mei Smyers, Matt Trotta, Neil M. Carleton, Lisa M. Maurer, Uma R. Chandran, Min Xia, Ari M. Melnick, Peter C. Lucas, Linda M. McAllister-Lucas. Inhibitors of GRK2-targeting-microRNAs: New therapeutic strategies for MALT1-dependent lymphomas [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A033.

Key Points Alanyl-transfer RNA synthetase 1 (AARS1) was upregulated and promoted cyst growth in autosomal dominant polycystic kidney disease. AARS1 promoted lysine lactylation of signal transducer and activator of transcription 3 (K140) and NF-κB p65 (K310), enhancing their phosphorylation, interaction, and transcriptional activity. AARS1 transcriptionally repressed its novel targets, Atg5 and Dusp4, to impair autophagy but activate polycystic kidney disease signaling pathways. Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, characterized by metabolic reprogramming with enhanced glycolysis and lactate accumulation. However, the enzyme that senses lactate and uses it as a substrate for protein lactylation in ADPKD remains unknown. Alanyl-transfer RNA synthetase 1 (AARS1) is a lactate-responsive enzyme with lactyltransferase activity, while its role and mechanisms in ADPKD have not been defined. Methods To investigate the role of AARS1, we generated Pkd1 and Aars1 double conditional knockout Pkd1 fl/fl :Aars1 fl/fl :Ksp-Cre mice and evaluated the effect of AARS1 inhibitor β -alanine in two ADPKD mouse models. Coimmunoprecipitation and Cleavage Under Targets and Tagmentation analyses were performed to identify novel AARS1 substrates and downstream target genes involved in cystogenesis. Results AARS1 was elevated in Pkd1 mutant renal epithelial cells and kidneys, and genetic deletion of Aars1 significantly delayed cyst growth, preserved kidney function, and reduced renal lactylation in Pkd1 mutant mice. Mechanistically, AARS1 promoted lactylation-dependent activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB (p65), specifically at STAT3 K140 and p65 K310, thereby amplifying pro-proliferative and proinflammatory transcriptional programs. AARS1 also associated with promoter regions and mediated histone H3 lysine 14 lactylation, thereby repressing the transcription of Atg5 to impair autophagy and suppressing the transcription of Dusp4 to sustain phosphorylation of cAMP response element–binding protein and retinoblastoma protein. Cytokine signaling through IL-6 and TNF- α further reinforced AARS1 expression through STAT3- and NF-κB–dependent feed-forward loops. Importantly, inhibition of AARS1 with β -alanine markedly slowed cyst progression in Pkd1 mutant mouse models. Conclusions Our study identified AARS1 as a central metabolic sensor linking lactate-driven lysine lactylation to transcriptional, epigenetic, and signaling pathways that drive ADPKD progression.

ABSTRACT Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth, inflammation, fibrosis, and renal failure. Klotho is a renoprotective protein with antiproliferative, anti-inflammatory, and antioxidant properties, but its mechanistic role in ADPKD remains poorly defined. Methods Klotho expression was analyzed in human ADPKD kidneys, public bulk and single-cell RNA sequencing datasets, Pkd1 mutant renal epithelial cells, and Pkd1 mouse models. The therapeutic effects of recombinant Klotho were evaluated in late-onset Pkd1fl/fl:tamoxifen-Cre mice. Molecular mechanisms were investigated using cell viability assays, western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry, ferroptosis assays, DNA methylation analysis, and chromatin immunoprecipitation assay. Results Klotho expression was markedly reduced in human ADPKD kidneys and Pkd1-deficient cells and mice, particularly in distal nephron segments. Recombinant Klotho treatment significantly reduced cyst burden, kidney enlargement, and blood urea nitrogen levels, while decreasing epithelial proliferation and increasing apoptosis in cyst-lining cells. Mechanistically, Klotho suppressed PKD-associated signaling pathways, including protein kinase B (AKT), signal transducer and activator of transcription 3 (STAT3), and retinoblastoma protein (Rb), reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated inflammation via downregulation of Smyd2, and attenuated transforming growth factor-beta (TGF-β)-Smad-dependent renal fibrosis. Klotho also inhibited ferroptosis by upregulating GPX-4 and reducing lipid peroxidation. Epigenetic analyses revealed DNA methyltransferase 1 (DNMT1)-mediated hypermethylation of the Klotho promoter and gene body in ADPKD kidneys, contributing to Klotho silencing. Inhibition of DNMT1 restored Klotho expression, and recombinant Klotho reduced DNMT1 levels, suggesting a negative feedback loop. Conclusions Klotho is epigenetically repressed in ADPKD and functions as a central regulator of cyst growth, inflammation, fibrosis, and ferroptosis. Restoration of Klotho signaling markedly attenuates disease progression in Pkd1 mutant mice, identifying the Klotho–DNMT1 axis as a promising therapeutic target for ADPKD.

Abstract Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma. To comprehensively investigate somatic drivers in relation to inherited genetics in multiple myeloma, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing multiple myeloma between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiologic data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop multiple myeloma at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes. Significance: Multiple myeloma is reported to occur at higher rates in individuals who self-identify as non-Hispanic Black. In this large dataset, genomic drivers occur at the same rate among ancestry groups, except for APOBEC mutagenesis. With equivalent therapy, clinical outcomes did not differ for patients grouped by genetic ancestry similarity.