Publications by Year: 2026

UNLABELLED: There is significant interest in antigen-specific approaches to delaying type 1 diabetes in preclinical stages and supporting tolerance after diagnosis. We conducted a phase I trial of a nonintegrating DNA plasmid constructed to secrete the type 1 diabetes antigen preproinsulin (PPI) and the immune modulatory cytokines transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), and IL-2. In this placebo-controlled, double-masked study of 47 adults with stage 3 type 1 diabetes, we showed that the drug is safe and well tolerated, with most reported adverse events (AEs) categorized as grade 1 and with no clinically significant difference in AEs among treatment groups. There were no untoward metabolic or immune effects. We found pharmacodynamic evidence of treatment, as demonstrated by a dose-dependent type 1 interferon (IFN) signature. Plasmid DNA, representing a pharmocokinetic measure, was detected in the two highest dosing groups. We did not find global or antigen-specific immune cell changes following treatment with a DNA plasmid expressing PPI, IL-2, IL-10, and TGF-β1, and we did not detect immune changes driven by IL-2, IL-10, or TGF-β1. Our results support further trials of this novel tolerizing antigen construct.

ARTICLE HIGHLIGHTS: Antigen-specific therapy is needed to induce tolerance in type 1 diabetes at early disease stages or in combination with immunotherapy. We conducted a phase I trial in type 1 diabetes of a novel plasmid construct expressing the islet antigen preproinsulin (PPI) and immunomodulatory cytokines transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), and IL-2. The therapy was safe and well tolerated. Dose-dependent changes in DNA plasmid levels and type 1 interferon signatures were detected; however, global and antigen-specific immune changes to PPI, IL-2, IL-10, or TGF-β1 were not observed. Further trials are needed to assess efficacy.

The authors of this commentary published two peer-reviewed online articles in 2020 and 2022 on the U.S. Agency for Healthcare Research and Quality (AHRQ) PSNet that were removed by the Trump administration because they violated White House policy on websites that "inculcate or promote gender ideology." Ours were among thousands of articles and websites that had been removed or censored during the first month of the Trump administration. We describe the details of this censorship of our two articles one on suicide prevention, the other on endometriosis diagnosis challenges, neither of which was directly related to LGBT issues but used what are now banned terms. We further discuss the historical and political context of this removal, and the subsequent merger of AHRQ into a new Trump administration "Office of Strategy" that purports to target "the effectiveness of federal health programs" for improvement. In light of these censorship actions, large scale staff layoffs, and this reorganization, the fate of AHRQ's mission, current activities, and future project funding is currently uncertain. We offer strategic suggestions for resisting such attacks on academic freedom and restoring scientific integrity for patient safety, quality, and public health.

Antibiotic resistance in respiratory infections is an escalating global concern that requires innovative antimicrobial approaches. Pseudomonas aeruginosa is a common multidrug-resistant pathogen and a major cause of hospital-acquired pneumonia. Accumulating evidence suggests that, at high doses, inhaled nitric oxide (iNO) acts as a potent antimicrobial agent. This study evaluated the efficacy and safety of iNO at 300 parts per million (iNO300) as a treatment for P. aeruginosa infection. In vitro, P. aeruginosa exhibited a dose-dependent reduction when exposed to an NO donor. In a mechanically ventilated swine model of P. aeruginosa pneumonia, intermittent iNO300 therapy resulted in a two-log reduction in bacterial burden, improved oxygenation and lung compliance, and reduced histopathological lung injury. A phase 1 clinical trial in 10 healthy individuals confirmed the safety of intermittent iNO300 therapy with no adverse events. In two critically ill patients with multidrug-resistant bacteria, who were in the intensive care unit, iNO300 was well tolerated, demonstrating clinical feasibility. Long-term follow-up of patients exposed to high-dose iNO for more than 6 years revealed no adverse outcomes. Our findings establish iNO300 as a promising antimicrobial agent against P. aeruginosa pneumonia, warranting further clinical evaluation.

Sarcomas are rare cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) is among the most commonly diagnosed sarcomas and provides insights into dysfunctional differentiation through its well- and dedifferentiated subtypes (WDLPS and DDLPS). Despite differences in histology and clinical behavior, the molecular pathways underlying each subtype remain poorly defined, leaving patients with DDLPS reliant on empiric chemotherapies. We applied single-nucleus multiome sequencing and spatial profiling to human normal adipose, WDLPS, and DDLPS tissues and identified lineage-specific blocks in differentiation within LPS. We found that DDLPS is characterized by loss of insulin-like growth factor 1 (IGF1) signaling and activation of early mesenchymal and glucagon-like peptide-1 (GLP-1)-associated programs. IGF1 signaling loss was restricted to the DDLPS component within mixed histology tumors and correlated with poor survival in patients with LPS. In normal adipocytes, IGF1 drives differentiation through peroxisome proliferator-activated receptor gamma 2 (PPARG2). We found that DDLPS cells lack PPARG2, causing a barrier to differentiation. This defect rendered DDLPS cells unresponsive to exogenous proadipogenic signals. Restoration of PPARG2 expression alone was sufficient to reenable adipogenesis, pinpointing PPARG2 as the key molecular determinant of lineage fate. Last, IGF1 deficiency in DDLPS was associated with up-regulation of the IGF1 receptor (IGF1R), creating a selective vulnerability to IGF1R-targeted antibody-drug conjugates. In summary, we identified lineage-specific defects in DDLPS, with PPARG2 as the molecular mediator of differentiation state in LPS. More broadly, our findings demonstrate how defining lineage-specific mechanisms of tumor state can inform the development of nonchemotherapeutic treatment approaches.

BACKGROUND: Lymphatic anatomy has primarily been described in cadaveric dissections. Mapping of the upper extremity superficial lymphatic system with indocyanine green (ICG) lymphography provides functional insights and detail to major anatomic variations.

METHODS: Healthy female volunteers underwent lymphatic mapping of the upper extremities with ICG lymphography. ICG was injected in six standard sites in the hand/wrist and upper arm. Major anatomic variations of four main forearm pathways and connectivity to four upper arm pathways were described.

RESULTS: 90 arms of 45 volunteers were included. The posterior radial channel predominantly courses in the dorsal forearm (98%). The posterior ulnar forearm pathway courses in the dorsal forearm in the majority of arms (70%). The anterior radial and anterior ulnar forearm channels exclusively course in the volar forearm (100%). The posterior radial pathway connects to the bicipital (80%), lateral (48%), medial (9%), and tricipital (7%) upper am pathways. The posterior ulnar pathway connects to the lateral (54%), tricipital (51%), medial (21%), and bicipital (14%) upper arm pathways. The anterior radial pathway connects to the medial (50%) and bicipital (60%) pathways. The anterior ulnar pathway connects to the medial (54%) and bicipital (59%) pathways.

CONCLUSIONS: Upper extremity lymphatic drainage to the lateral and tricipital pathways is enabled exclusively by the dorsal forearm channels suggesting their importance in BCRL risk. Variations of upper extremity lymphatic anatomy are relevant to the risk, prevention, and treatment of breast cancer-related lymphedema risk and warrant further study.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disorder involving disrupted BMP (bone morphogenetic protein) signaling, pulmonary inflammation, and endothelial-to-mesenchymal transition (EndMT). We hypothesized that IL (interleukin)-33 signaling contributes to PAH progression by inducing EndMT and interacting with BMP9, a key modulator of inflammation and vascular remodeling.

METHODS: IL-33 expression was assessed in lung tissues from Sugen/hypoxia and control mice, as well as in pulmonary arterial endothelial cells (PAECs) and lung tissues from patients with PAH and healthy donors. EndMT and signaling pathways were analyzed in PAECs and microvascular endothelial cells (MVECs) exposed to IL-33, BMP9, and sST2 (soluble supression of tumorigenicity 2) using quantitative polymerase chain reaction, Western blotting, ELISA, and immunostaining. Plasma BMP9 and sST2 levels were quantified in patients with PAH.

RESULTS: Immunofluorescent analysis revealed elevated IL-33 expression in pulmonary endothelial cells of Sugen/hypoxia mice compared with controls, consistent with findings in PAECs from patients with PAH. BMP9 significantly upregulated sST2 expression in human PAEC and microvascular endothelial cells, inhibited IL-33 target gene expression, and effectively suppressed IL-33-induced EndMT. Notably, BMP9 demonstrated greater efficacy in preventing EndMT compared with rsST2 (recombinant soluble ST2) or ST2L-neutralizing antibodies. Circulating BMP9 and sST2 levels in the plasma of patients with PAH were positively correlated in specific patient groups stratified by sex, age, and New York Heart Association functional class, suggesting a protective role of BMP9 in modulating IL-33-induced EndMT.

CONCLUSIONS: BMP9 plays a protective role against IL-33-induced EndMT in PAECs by upregulating sST2 expression and neutralizing IL-33, suggesting that targeting the IL-33 signaling pathway may represent a promising therapeutic strategy to mitigate EndMT in PAH.

IMPORTANCE: Home blood pressure monitoring (HBPM) is essential and universally recommended for hypertension management, but patterns of real-world patient engagement with HBPM have not been studied and remain largely unknown.

OBJECTIVE: To evaluate patient engagement with HBPM in a remote hypertension management program.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study analyzing prospectively collected program data was conducted within a remote hypertension management program at a large academic health care system, Mass General Brigham, in Boston, Massachusetts. Data were collected from from September 2018 to June 2022. Adults with uncontrolled hypertension enrolled in the program were eligible for inclusion. Data analyses were conducted from February to April 2025.

INTERVENTIONS: Patients received free automated HBPM devices, education, and ongoing personalized support from health care navigators via telephone and messaging, with algorithm-guided medication titration.

MAIN OUTCOMES AND MEASURES: The primary outcome was engagement at baseline. Weekly HBPM frequency was categorized as no engagement (0 measurements), low engagement (1-11 measurements/week), intermediate engagement (12-23 measurements/week), and high engagement (24-28 measurements/week).

RESULTS: A total of 3390 patients were enrolled in the remote hypertension program; median (IQR) patient age was 61 (52-69) years, with 1958 (57.8%) female patients. Mean (SD) systolic BP at baseline was 143 (13) mm Hg, and most patients had comorbidities, including 1369 patients (40.4%) with atherosclerotic cardiovascular disease and 996 (29.4%) with diabetes. At baseline, 1107 patients (32.7%) had no engagement, 484 (14.3%) had low engagement, 618 (18.2%) had intermediate engagement, and 1181 (34.8%) had high engagement.

CONCLUSIONS AND RELEVANCE: In this cohort study of a remote hypertension management program, patient engagement with HBPM was suboptimal despite free devices, education, and personalized support with a navigator. To support optimal HBPM, innovative methods of BP monitoring that are more convenient and less burdensome for patients may enhance engagement and improve hypertension management outcomes.