Citations

Background: Mindfulness-based interventions may improve cardiovascular health (CVH) by supporting behavioral change across multiple risk factors. This study evaluated the impact of Mindfulness-Based Blood Pressure Reduction (MB-BP), a mindfulness program targeting hypertension-related behaviors ( Image 1 ), on CVH using the American Heart Association’s Life’s Essential 8 framework. Methods: This secondary analysis of parallel-group, phase 2 randomized clinical trial evaluated the effects of MB-BP on CVH in 201 participants with elevated office BP (≥120/80 mmHg). The MB-BP group (n=101) received an 8-week program focused on mindfulness training and education targeting diet, physical activity, medication adherence, alcohol use, and stress, whereas the control group (n=100) received enhanced usual care ( Image 2 ). CVH was assessed using available Life’s Essential 8 components: systolic blood pressure, body mass index (BMI), diet (DASH adherence), physical activity, smoking, and sleep duration. Generalized estimating equations evaluated intervention effects through six months. Results: At six months follow-up, MB-BP participants significantly improved composite CVH scores compared to controls (standardized mean difference: 0.144; 95% CI: 0.023, 0.266) ( Image 3 ). MB-BP influenced most CVH components in healthier directions at trend levels, with the strongest responses for physical activity (47.9 MET min/week; 95% CI: -16.5, 112.3), sleep (0.34 hours/night; 95% CI: -0.10, 0.78), systolic blood pressure (-4.95 mmHg; 95% CI: -10.34, 0.44) and DASH diet score (0.27, 95% CI: -0.15, 0.69). Conclusions: MB-BP led to modest but clinically significant improvements in CVH, driven by multiple Life’s Essential 8 components. These findings suggest that MB-BP may be an effective behavioral intervention to support CVH and reduce risk for cardiovascular disease. ClinicalTrials.gov Preregistration Identifiers: NCT03256890, NCT03859076

Abstract Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. Present management summarized here is focused on early diagnosis, assiduous avoidance of injury and iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function. Twenty-one members of the International Clinical Council on FOP (ICC) and seven consultants from 15 countries, chosen for their clinical expertise in FOP, developed this summary statement. Further advances in therapeutics will be based on rigorous clinical trials to assess novel and emerging treatment and prevention strategies. A detailed and updated exploration of the topics outlined in this brief perspective can be found in “The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations” which can be found on the International Clinical Council on FOP (ICC) website (www.iccfop.org).

For over a century, scientists reported the disruption of normal nuclear shape and size in cancer. These changes have long been used as tools for diagnosis and staging of malignancies. However, to date, the mechanisms underlying these aberrant nuclear phenotypes and their biological significance remain poorly understood. Using a model of pancreatic ductal adenocarcinoma (PDAC), the major histological subtypes of pancreatic cancer, we found that oncogenic mutant KRAS reduces nuclear size. Transcriptomic and protein expression analysis of mutant KRAS–expressing PDAC cells revealed differential levels of several nuclear envelope–associated genes. Further analysis demonstrated the nuclear lamina protein, Emerin (EMD), acted downstream of KRAS to mediate nuclear size reduction in PDAC. Analysis of human PDAC samples showed that increased EMD expression associates with reduced nuclear size. Finally, in vivo genetic depletion of EMD in a mutant KRAS–driven PDAC model resulted in increased nuclear size and a reduced incidence of poorly differentiated PDAC. Thus, our data provide evidence of a potentially novel mechanism underlying nuclear size regulation and its effect in PDAC carcinogenesis.

Abstract Chronically elevated circulating excess free fatty acids (ie, lipotoxicity) is a pathological process implicated in several metabolic disorders, including obesity-driven type 2 diabetes (T2D). Lipotoxicity exerts detrimental effects on pancreatic islet β-cells by reducing glucose-stimulated insulin secretion (GSIS), altering β-cell transcriptional identity, and promoting apoptosis. While β-cell-derived small extracellular vesicles (sEV) have been shown to contribute to β-cell failure in T2D, their specific role in lipotoxicity-mediated β-cell failure remains to be elucidated. In this work, we demonstrate that lipotoxicity enhances the release of sEVs from β-cells, which exhibit altered proteomic and lipidomic profiles. These palmitate (PAL)-exposed extracellular vesicles (EVs) induce β-cell dysfunction in healthy mouse and human islets and trigger significant islet transcriptional changes, including the upregulation of genes associated with the TGFβ/Smad3 pathway, as noted by RNA sequencing. Importantly, pharmacological inhibition of the TGFβI/II receptor improved PAL EV-induced β-cell dysfunction, underscoring their involvement in activating the TGFβ/Smad3 pathway during this process. We have comprehensively characterized lipotoxic β-cell sEVs and implicated their role in inducing β-cell functional failure in T2D. These findings highlight potential avenues for therapeutic interventions targeting sEV-mediated pathways to preserve β-cell health in metabolic disorders.

11079 Background: Phase 3 randomized clinical trials (RCTs) inform the standard of care in cancer treatment yet have a mixed track record of success. In this study, we sought to 1) determine the overall success rate of phase 3 RCTs; 2) assess whether authorship patterns differ between successful (positive) and unsuccessful (negative) trials; and 3) explore if individual authors have distinct track records of success. Methods: The HemOnc knowledgebase (KB) was queried for initial publications of phase 3 RCTs of systemic anticancer therapy; those without primary outcome described were excluded. RCTs were labeled positive if the primary endpoint was met per HemOnc standard criteria (P value ≤ 0.05 or hazard ratio upper bound ≤ 1 for any experimental arm[s]) and negative if they did not meet these criteria or if the experimental arm was statistically inferior. Trial metadata and author information were extracted from the HemOnc KB. Author positive publication rate (PPR) was defined as % of publications reporting a positive result divided by total number of eligible publications. Prolific authors were defined as those with 6+ eligible publications. Author count for manuscripts reporting positive vs negative results was evaluated with the Mann-Whitney U test; other statistics were descriptive. Results: 3328 studies met criteria as of February 5, 2024; these were associated with 3305 initial publications between 1960-2023, involving 25,412 unique authors. 1474 (44.3%) of the studies were positive. Publications reporting positive trial results had, on average, 3 more authors, median (interquartile range) of 18 (12-23) vs 15 (11-20), p<0.0001. The mean (±SD) PPR for n=1967 prolific authors was 47.7% (±22.3%). The PPR was not related to individual author output; mean PPR for non-prolific authors was 48.0% (SD not reported). Differences in PPR were apparent by the disease under study and the years of publication (Table). Among the 46 prolific authors who had a PPR 2+ SD above the mean, 26 (55%) were from China followed by Italy with 3 (6%). Conclusions: Despite known positive publication bias, the success rate of published phase 3 RCTs remains <50%. Publications reporting positive results had significantly more authors; this finding requires further study including adjustment for trial sample size. Significant variation in PPR amongst fields could be due to watershed therapeutic advances, differential selection of primary endpoints, and/or selective reporting of results. Finally, a signal for geographic association of outlier PPRs suggests the need for further investigation. [Table: see text]

11030 Background: Drug regulators operate on their own timelines to assess the safety and efficacy of new drugs and/or extensions to existing indications, such that there are delays between regulators. During such a gap, patients in the “early” domain have access to the approved drug, while those in the “late” domain do not, outside of compassionate use. Our study aimed to quantify the “opportunity lost” for new therapies approved by FDA and EMA, assuming patients in the late domain receive standard-of-care (SOC) therapy – which is presumably inferior to the new drug – during the gap. Methods: Anticancer drugs approved by both FDA and EMA were identified through the HemOnc knowledgebase. Inclusion criteria included: 1) drugs approved in both domains based on the same randomized clinical trial (RCTs) for the same indication; 2) a primary time-to-event endpoint; and 3) a quantitated median time-to-event for the primary endpoint. For each included trial, the approval gap between FDA and EMA in days and the ratio of approval gap to median control arm time-to-event duration was calculated. A ratio ≥2 implies that, on average, no late domain patients starting treatment in the first half of the gap would be expected to have access to the new drug prior to an event. Results: Of 60 eligible RCTs, 59 had calculable median event durations. 25 (42%) had a primary overall survival endpoint; the most common surrogate endpoint was progression-free survival (PFS; 29/59; 49%). The median (interquartile range [IQR]) approval gap was 186 (124-271) days, with FDA being the first approver in 56/59 (95%) cases. The median (IQR) ratio of approval gap to median control arm event duration was 0.63 (0.35-1.11). Drugs with ratio ≥2 (Table) were targeted or immunotherapies; 7/8 (88%) were approved with PFS endpoint; 5/8 (62.5%) were approved for second line or later. Conclusions: Our study shows that FDA approves most drugs prior to EMA and a nontrivial number of patients may experience progression or death events while awaiting access to anticancer therapies already approved in another domain. The analysis does not take into consideration scenarios in which the new therapy is inferior to SOC or delays in patient access (due to slow uptake; regulatory barriers [in Europe/UK]; or patient affordability [in US]). Further regulatory collaboration (e.g., Project Orbis) between FDA and EMA could help to reduce and potentially ameliorate this differential in access to new cancer drugs in the future. [Table: see text]

11023 Background: Randomized clinical trials (RCTs) in cancer typically compare experimental to control arm regimens. The choice of an appropriate control (ctrl) arm can have a major impact on the expected success of an RCT. The frequency with which cancer RCTs use control arms based on established dosing and scheduling protocols has not been described. Methods: The HemOnc knowledgebase (KB) was used to identify systemic anti-cancer therapy (SACT) regimen variants, defined as regimens with identical components that differ in dosing, scheduling, and/or route. Non-cancer, nonrandomized, and non-SACT studies were excluded. Study publication year was used to define standard variants as those evaluated in the experimental arm of a positive phase 3 RCT >1 year prior to publication as a control arm, regardless of cancer type or context of treatment. Study-variant dyads were evaluated to determine whether the variant was standard. Success rates of RCTs with standard vs non-standard control arms were evaluated with Fisher’s exact test. Results: 5221 studies were associated with ≥1 named variant in the HemOnc KB, as of 2024-02-06. After exclusions, there were 3511 study-variant dyads (2386 studies; 1714 variants). The 9 most common regimens are shown in the Table. The median (IQR) number of variants per regimen was 2 (1-3); carboplatin & paclitaxel (CP) had the most variants (n=33). Across all control arm study-variant dyads, 2228/3492 (64%) utilized non-standard variants. For example, 60/97 studies (62%) of docetaxel as control used the 75 mg/m2 q3wk variant after it was established in 2000, whereas n=27 others used 19 non-standard variants. Trials that used a standard control arm had a numerically higher success rate, 45% vs 42% (OR 1.10, 95% CI 0.92-1.32). Conclusions: Non-standard regimen variants are frequently used in cancer RCTs. Reasons for this could include toxicity, patient convenience, or emerging data from smaller studies that establish comparable efficacy or improved toxicity to standard variants. However, the a priori efficacy of non-standard control arms is less rigorously established, and trials with standard control arms might be more successful. Future directions include quantifying the granular differences between standard and non-standard variants and investigating whether certain types of non-standard variation (e.g. fewer cycles, lower doses) associate with trial success rates. [Table: see text]

Dent disease 1, an X‐linked inherited kidney disease caused by mutations in the CLCN5 gene, is characterized by low molecular weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets, and progressive renal failure. CLCN5 encodes the CLC‐5 protein found at the apical membrane in the kidney proximal tubule as well as endosome membranes of other tubule segments. Approximately 80 human mutations of the CLCN5 gene have been identified consisting of nonsense, missense, splice site, insertion and deletion mutations. However, the genotype and phenotype correlation are poor, and the mechanisms of CLC‐5 dysfunction that cause disease are still unclear. Moreover, there has been a lack of systematic study of CLC‐5 mutational effects on Cl − /H + exchanger activity. To address this need we used ion selective microelectrodes to monitor intracellular pH (pH i ) and intracellular Cl − concentration ([Cl i ]) of Xenopus oocytes expressing WT and mutant CLC‐5 while clamping at +40 mV. Common and novel mutations were identified in Dent patients by collaborators in the Rare Kidney Stone Consortium. The apparent H + :Cl − coupling ratio through the CLC‐5 protein was calculated using the Gibbs‐free energy equation. Cellular localization and protein trafficking of WT and mutant CLC‐5 in renal epithelial cells were also examined by immunofluorescence microscopy using eGFP/HA double‐tagged CLC‐5 and organelle‐specific markers and quantified by flow cytometry. In the presence of 104 mM Cl − (ND96), the pH i and [Cl − ] i of the CLC‐5 WT increased 340 ± 59 ×10 −4 pH unit/min and 2.8 ± 0.5 mM/min, respectively. T657S increased at a similar rate as WT, while there was a significant decrease in the rate of pH i and [Cl − ] i change for S244L, R345W, and Q629X compared to WT. Decreasing extracellular chloride to 5 mM decreased WT ClC‐5 pH i and [Cl − ] i by reversing transport: −7 ± 65 ×10 −4 pH unit/min and −0.2 ± 0.2 mM/min, respectively. Using these measurements, the stoichiometry of WT CLC‐5 was calculated to be 1.80 ± 0.02 (nCl − :H + ) in ND96, similar to the stoichiometry estimated for T657S. However, the stoichiometry was significantly altered for S244L, R345W, and Q629X. WT ClC‐5 acts as Cl − /H + exchanger at +40mV with 104 mM Cl − in the extracellular solution. Lowering extracellular Cl − reverses the transport direction, and the ClC‐5 exchanger functions at a significantly slower rate. Although S244L has normal surface expression, S244L and R345W mutations have significantly decreased pH and Cl − exchange rates in response to solution manipulations, suggesting these mutations have an altered ion exchange coupling ratio (stoichiometry). Interestingly, while R345W was retained in the ER suggesting defective protein maturation, R345W surface localization was rescued by lowering the incubation temperature from 37 to 30°C. Q629X was retained in the ER, not localized in early endosomes, and also has abolished Cl − /H + exchange activity, suggesting that Q629X affects protein maturation and trafficking while T657S is a benign, non‐disease causing mutation. These data suggest studying CLC‐5 mutational effects on both transport function and cellular localization is essential to better understand divergent phenotypes in Dent disease. Support or Funding Information NIH DK101405, U54KD083908, U54DK100227, Mayo O'Brien Urology Research Center, Mayo Clinic Rare Kidney Stone Consortium

ABSTRACT Fibrodysplasia ossificans progressiva (FOP) is an ultra‐rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single‐arm, open‐label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged ≥4 years received palovarotene once daily (chronic: 5 mg; flare‐up: 20 mg for 4 weeks, then 10 mg for ≥8 weeks; weight‐adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low‐dose whole‐body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square‐root transformation. Twelve‐month interim analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18‐month interim analyses utilized BcPM with square‐root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed‐effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen‐month interim analyses included 97 MOVE and 101 NHS individuals with post‐baseline WBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS. wLME results were similar (54% reduction fitted; nominal p = 0.039). All palovarotene‐treated patients reported ≥1 adverse event (AE); 97.0% reported ≥1 retinoid‐associated AE; 29.3% reported ≥1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses using WBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene‐treated patients. Thus, post hoc analyses showed evidence for efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).