Citations

Aims: Alterations of mitochondrial bioenergetics and arginine metabolism are universally present and mechanistically linked to pulmonary arterial hypertension (PAH), but there is little knowledge of arginine metabolism and mitochondrial functions across the different pulmonary hypertension (PH) groups. We hypothesize that abnormalities in mitochondrial functions are present across all PH groups and associated with clinical phenotypes. We test the hypothesis in PH patients and healthy controls from the Pulmonary Vascular Disease Phenomics Program cohort, who had comprehensive clinical phenotyping and follow-up for at least 4 years for death or transplant status. Mitochondrial transmembrane potential, superoxide production, and mass were measured by flow cytometry in fresh platelets. Metabolomics analysis was performed on plasma samples. Global arginine bioavailability was calculated as the ratio of arginine/(ornithine+citrulline). Results: Global arginine bioavailability is consistently lower than controls in all PH groups. Although the mitochondrial mass is similar across all PH groups and controls, superoxide production and transmembrane potential vary across groups. Mitochondrial superoxide is higher in group 1 PAH and lowest in group 3 compared with other groups, while transmembrane potential is lower in group 1 PAH than controls or group 3. The alterations in mitochondrial functions of group 1 PAH are associated with changes in fatty acid metabolism. Mitochondrial transmembrane potential in group 1 PAH is associated with transplant-free survival. Conclusion: While alterations in mitochondrial function are found in all PH groups, group 1 PAH has a unique mitochondrial phenotype with greater superoxide and lower transmembrane potential linked to fatty acid metabolism, and clinically to survival. Antioxid. Redox Signal. 42, 361–377.

SummaryThe age‐associated mutational state of clonal haematopoiesis (CH) is linked to multiple adverse health outcomes. As higher risk CH can lead to progressive neoplastic or vascular disease, there is interest in developing clinical trials to mitigate risk associated with CH. Given the high prevalence of CH, data from clinical trials could have broad public health implications for screening and therapy. Thoughtful consideration is needed to design trials that are both clinically relevant and avoid overmedicalization. Here, we summarize clinical studies of CH to date and provide suggestions and guidance on how to approach designing CH‐focused therapeutic clinical trials. These recommendations are derived from discussions among clinical researchers and scientists emanating from the Inaugural Meeting on Somatic Mutations and Predisease in October 2021.

Objective To characterise the changing trends in the pharmacological management of SLE in the USA between 2007 and 2023 as new treatment options emerged. Methods In a retrospective cohort study using data from OptumLabs Data Warehouse, we characterised the annual prevalent (ie, all) and incident (ie, new) use of antimalarials, glucocorticoids and immunosuppressive medications among patients with SLE from 2007 to 2023 and assessed for changing trends over time. Results We identified 19 122 adults with SLE; they were 51.2 (SD 16.1) years of age, 89% were female, 61.3% were White, 18.5% were Black and 13.1% were Hispanic. The proportion of prevalent users of antimalarials has decreased from 79.4% in 2007 to 77.2% in 2023 (p=0.0055), while the proportion of incident users fluctuated between a lowest 5.8% in 2021 and a highest 8.1% in 2008 (p=0.008). The proportion of prevalent users of glucocorticoids increased from 64.6% in 2007 to 66.7% in 2023 (p=0.0132), as did the proportion of incident users (12.4% in 2007 to 21.7% in 2023; p<0.0001). The use of cyclophosphamide (2.0% in 2007 to 0.4% in 2023, p<0.0001) has decreased; the use of mycophenolate mofetil (7.7% in 2007 to 10.3% in 2023, p<0.0001), rituximab (1.4% in 2007 to 2.1% in 2023, p<0.0001) and belimumab (0.8% in 2011 to 6.1% in 2023, p=0.0001) has increased. Conclusions Despite increasing availability of alternative treatment options, patients with SLE in the USA increasingly rely on glucocorticoid-based therapy. Efforts to improve the use of antimalarials and steroid-sparing immunosuppressants are needed.

PURPOSE Breast density is a widely established independent breast cancer risk factor. With the increasing utilization of digital breast tomosynthesis (DBT) in breast cancer screening, there is an opportunity to estimate volumetric breast density (VBD) routinely. However, current available methods extrapolate VBD from two-dimensional (2D) images acquired using DBT and/or depend on the existence of raw DBT data, which is rarely archived by clinical centers because of storage constraints. METHODS We retrospectively analyzed 1,080 nonactionable three-dimensional (3D) reconstructed DBT screening examinations acquired between 2011 and 2016. Reference tissue segmentations were generated using previously validated software that uses 3D reconstructed slices and raw 2D DBT data. We developed a deep learning (DL) model that segments dense and fatty breast tissue from background. We then applied this model to estimate %VBD and absolute dense volume (ADV) in cm 3 in a separate case-control sample (180 cases and 654 controls). We created two conditional logistic regression models, relating each model-derived density measurement to likelihood of contralateral breast cancer diagnosis, adjusted for age, BMI, family history, and menopausal status. RESULTS The DL model achieved unweighted and weighted Dice scores of 0.88 (standard deviation [SD] = 0.08) and 0.76 (SD = 0.15), respectively, on the held-out test set, demonstrating good agreement between the model and 3D reference segmentations. There was a significant association between the odds of breast cancer diagnosis and model-derived VBD (odds ratio [OR], 1.41 [95 % CI, 1.13 to 1.77]; P = .002), with an AUC of 0.65 (95% CI, 0.60 to 0.69). ADV was also significantly associated with breast cancer diagnosis (OR, 1.45 [95% CI, 1.22 to 1.73]; P < .001) with an AUC of 0.67 (95% CI, 0.62 to 0.71). CONCLUSION DL-derived density measures derived from 3D reconstructed DBT images are associated with breast cancer diagnosis.

PURPOSE The TRK inhibitor larotrectinib is US Food and Drug Administration approved for NTRK fusion–positive solid tumors that lack a satisfactory alternative or have progressed after treatment but has not been systematically studied as a frontline therapy with a defined duration of treatment. ADVL1823 evaluated larotrectinib in patients with newly diagnosed NTRK fusion–positive solid tumors with response-adapted duration of therapy and local control. METHODS Patients received larotrectinib twice daily in 28-day cycles for a predefined duration of treatment, ranging from 6 to 26 cycles depending on response to therapy and surgical resectability. The primary end point was the objective response rate (ORR) within six cycles in patients with infantile fibrosarcoma (IFS); patients with other histologic diagnoses were analyzed in a separate cohort. Secondary objectives included event-free survival (EFS) and overall survival (OS). RESULTS Thirty-three patients were enrolled: 18 with IFS and 15 with other solid tumors. The ORR within six cycles was 94% (17/18; 95% adjusted CI, 72.7 to 98.6) among children with IFS and 60% (9/15; 95% CI, 32.3 to 83.7) among children with other solid tumors. Six percent (2/33; 95% CI, 0.7 to 22.2) patients developed progressive disease while on therapy. Two-year EFS and OS among these groups were 82.2% (95% CI, 54.3 to 93.9) and 93.8% (95% CI, 63.2 to 99.1) for IFS and 80% (95% CI, 50.0 to 93.1) and 93.3% (95% CI, 61.3 to 99.0) for other solid tumors, respectively. Patients undergoing surgical resection of their tumor had prolonged EFS, with only 1 of 16 such patients experiencing disease progression. Four of 33 patients had dose-limiting toxicities. CONCLUSION Larotrectinib is highly active in patients with newly diagnosed NTRK fusion–positive solid tumors. Larotrectinib should be a frontline option for patients with IFS and other NTRK fusion–positive solid tumors. Local control with surgical resection remains important in the treatment of patients with IFS.

Abstract: Background: It is generally recommended that patients not be on immunosuppressive medications for patch testing, as these medications may suppress delayed-type hypersensitivity and lead to false negative results. There is a paucity of literature describing organ transplant recipients who underwent patch testing. Objective: The aim of this study is to examine patch testing results in solid organ transplant recipients over a 13-year period at our institution. Methods: We performed a retrospective analysis of patch test data from adult transplant recipients at our institution. Transplant patients who underwent patch testing were identified from a clinical patch test database, and a chart review was conducted. Results: Eighteen patients were included in the study. Patients had received kidney, liver, or heart transplants. Seven patients (38.9%) had at least one positive reaction. The highest reaction rates were seen with methylisothiazolinone (12.5%), methyldibromo glutaronitrile (12.5%), and benzalkonium chloride (10.0%). Limitations included small sample size, data from a tertiary referral center, and retrospective analysis. Conclusions: Liver and kidney transplant recipients displayed allergic reactions during patch testing. Patients may benefit from patch testing even if receiving immunosuppressive therapy, but some reactions may be falsely negative because of immunosuppression.

We describe a method that lowers the limit of quantification of a glucagon immunoassay thereby enhancing the ability to differentiate between normal and abnormal α-cell responsiveness to glucagon.

Abstarct Introduction: (Z)-endoxifen (ENDX) is a potent orally bioavailable selective estrogen receptor modulator (SERM) and the most active metabolite of tamoxifen. Given its effective anti-estrogen activity and favorable safety profile, ENDX is being developed as a therapeutic solution in breast health. During its synthesis, two chemical biproducts (compound AT416 and AT402) with Z- and E- isomeric forms are produced. This study aimed to assess the anti-estrogenic activity of these four ENDX-related compounds with ENDX in ERα+ breast cancer. Methods: Compounds AT416E/Z are formed by acetylation of the final API with ethyl acetate during Step 3 of the manufacturing process of ENDX. Compounds AT402 E/Z are formed by coupling of impurity AT300 with propiophenone as a side reaction during Step 2 of the ENDX manufacturing process. The anti-cancer activities of the four ENDX-related compounds were tested across multiple ERα+ breast cancer cell lines (MCF7, T47D, UCD12), including those with ESR1 mutations (Y537S and D538G) known to confer endocrine resistance. Studies included cell proliferation, migration and invasion assays, cell cycle progression assessments, induction of apoptosis, activity of an estrogen response element (ERE) luciferase reporter construct and RT-qPCR analyses of ERα target gene expression. Results: In estrogen-containing media, ENDX exhibited strong anti-proliferative activity in MCF7 cells, regardless of ESR1 mutations. In MCF7 cells cultured in estrogen-deficient media, the four compounds demonstrated more pronounced anti-proliferative effects than ENDX. In T47D cells with the ESR1 Y537S mutation, AT416E showed superior anti-proliferative activity compared to ENDX, while in T47D cells with the D538G mutation, these two compounds exhibited comparable effects. In UCD12 cells, ENDX displayed the strongest anti-proliferative effects. Regarding the inhibition of migration and invasion, AT416E consistently outperformed ENDX in both T47D and MCF7 cells. ENDX was the most effective at inducing G1 phase cell cycle arrest followed. Both AT402E and AT402Z elicited pro-apoptotic effects comparable to ENDX in MCF7 cells, while in T47D cells, ENDX was the most effective at inducing apoptosis, followed by AT402E and AT402Z. In T47D and MCF7 cells, luciferase-based transactivation assays showed that ENDX was the most potent anti-estrogen followed by AT402Z. Finally, based on RT-qPCR analyses, ENDX was a more effective inhibitor of estrogen-induced ERα target gene expression, compared to the biproducts. Summary: These studies have revealed that four novel compounds derived from the manufacturing process of ENDX confer notable anti-tumor activity, with some performing comparably to or better than ENDX in several cancer-relevant cellular readouts. Future studies will validate these findings in additional in vitro/in vivo breast cancer models with the goal of identifying the basis for their varied anti-estrogenic and anti-cancer effects. Such discoveries should allow for the rational design of novel molecules with more potent therapeutic efficacy. Citation Format: Natalie Farris, Lena Batoon, Rajeev S. Muthyala, H. Lawrence Remmel, Sandra S. Hammer, John R. Hawse, Steven C. Quay. Anti-cancer activity of (Z)-endoxifen-related compounds in ERα+ breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A007.

ABSTRACTAlzheimer's disease (AD) is the most common neurodegenerative dementia with multi‐layered complexity in its molecular etiology. Multiple omics‐based approaches, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and lipidomics are enabling researchers to dissect this molecular complexity, and to uncover a plethora of alterations yielding insights into the pathophysiology of this disease. These approaches reveal multi‐omics alterations essentially in all cell types of the brain, including glia. In this systematic review, we screen the literature for human studies implementing any omics approach within the last 10 years, to discover AD‐associated molecular perturbations in brain glial cells. The findings from over 200 AD‐related studies are reviewed under four different glial cell categories: microglia, oligodendrocytes, astrocytes and brain vascular cells. Under each category, we summarize the shared and unique molecular alterations identified in glial cells through complementary omics approaches. We discuss the implications of these findings for the development, progression and ultimately treatment of this complex disease as well as directions for future omics studies in glia cells.