Citations

This cohort study examines the validity of an electronic health record data model for organ transplantation.

Abstract Introduction DISTINCT is a randomized controlled trial evaluating passive recharge burst SCS compared with CMM in improving pain and pain‐related physical function in patients suffering from chronic back pain without prior lumbar surgery, and for whom corrective surgery is not an option. Sub‐analyses of outcome measures are presented for a subset implanted with paddle leads at both 6 and 12 months. Objective To investigate the treatment effect of using BurstDR‐capable SCS in nonsurgical low back pain (NSLBP) patients with paddle leads. Methods An independent board‐certified spine surgeon reviewed each case, confirming a lack of corrective surgical options. Out of 29 sites and 115 implants, 10 sites implanted 50 patients with paddle leads. Primary and secondary endpoints assessed improvements in low back pain intensity (NRS), low back pain‐related disability (ODI), pain catastrophizing (PCS), and patient global impression of change (PGIC). Results Data for patients with NSLBP and implanted with paddle leads are available for 47 and 44 patients at 6 and 12 months, respectively. Patients reported significant reductions in pain relief at 6 and 12 months, decreasing from 7.8 ± 1.2 at baseline to 2.0 ± 1.6 and 2.2 ± 2.2, respectively ( p < 0.0001). Disability was substantially reduced (> 20 points) from severe to mild at 6 and 12 months; ODI reduced from 54.4 ± 15.0 at baseline to 19.9 ± 14.1 and 22.1 ± 13.6, respectively ( p < 0.0001). Pain catastrophizing improved to reflect the average of a non‐chronic pain population; decreased from 27.6 ± 13.1 at baseline to 8.1 ± 8.2 and 7.8 ± 9.9 ( p < 0.0001). 93.2% of patients reported a moderately better‐much‐improved outcome on PGIC. Ten complications occurred in 9 patients, 3 being severe device‐related events. Two explants were required; one due to infection and one due to persistent pain at the IPG site, and one lead‐related event was resolved by surgical repositioning. Conclusions Passive recharge burst using paddle leads provides substantial relief to patients suffering from severe, debilitating, NSLBP. Patients report significant improvements in pain, function, and pain‐related emotional distress. In addition, the rate of adverse events is low, supporting a favorable safety profile.

Abstract Despite the advent of novel targeted therapies with high overall response rates, chronic lymphocytic leukemia (CLL) is still largely incurable due to the development of resistance. The bone marrow microenvironment (BMME) plays an important role in the survival and drug resistance in CLL. BM stromal cells (BMSCs) are considered a key component of BMME. Our long-term goal is to gain further insights of BMSCs-CLL crosstalk influencing both survival and drug resistance in CLL. To understand the global biologic changes that occur in leukemic CLL cells when in contact with BMSCs, we assessed RNA-seq in paired CLL cells isolated from untreated blood and BM and in untreated patients’ CLL cells cultured alone or with BMSCs. CLL cells from blood/BM and cultured alone/with BMSCs were also examined by Immunoprecipitation (IP), Western blot (WB), untargeted metabolomics (LCMS+GCMS), and preclinical drug sensitivity assays. We detected only 13 upregulated genes that overlap between CLL cells from BM and cocultured with BMSCs (p&lt0.05, fold change &gt1.5). When we analyzed the expression of these 13 genes in CLL cells from a cohort of 162 untreated patients by RNA-seq, we found associations between 4 genes (PNP, C16orf54, MOB3A, CDK2AP2) and clinical outcomes including overall survival (OS), progression free survival (PFS), and time to first treatment (TTFT) [multivariable Cox proportional hazards models, p&lt0.05]. Of the 4 genes, purine nucleoside phosphorylase (PNP), an enzyme in the purine pathway, had the most significant association with OS, PFS, and TTFT. Metabolomic profiling indicated an increased level of purine pathway metabolites adenosine, adenine, inosine, and hypoxanthine in cocultured CLL cells. WB analysis showed variable baseline PNP protein expression with 2 cohorts: low /no (L) and high (H) PNP using CLL blood cells. An induction in PNP protein levels were noticed in CLL cells expressing only LPNP when cocultured. Given the association of HPNP with adverse clinical outcomes, we tested for L vs. HPNP cohorts drug sensitivity to known BTK inhibitors(is) or Bcl2is. Treatment of CLL cells from untreated patients with Bcl2is venetoclax, S55746, and LP-118 (Bcl2-Bclxli, Newave) showed increased sensitivity to the Bcl2/Bclxlis in HPNP but not in LPNP cells. In addition, BTKis showed no difference in drug sensitivity associated with CLL PNP levels. To explain this discrepancy, WB and IP analyses were conducted in L vs. HPNP leukemic cells for apoptotic profiles, where we found increased phosphorylated-Bcl2(S70) and an increased association of Bcl2 with Bax in LPNP-expressing CLL cells compared to HPNP. These findings support increased resistance to apoptosis afforded by inhibiting Bcl2 for LPNP vs. HPNP-expressing CLL cells. Our future goals are to continue to understand the prognostic significance of the 4 genes with adverse clinical outcomes and to investigate how best to exploit the peculiar, enhanced sensitivity to Bcl2/Bclxlis found in the HPNP CLL cells. Citation Format: Sutapa Sinha, Weiguo Han, Zhiquan Wang, Brianna M. Finke, Heather C. Darby, Kari G. Rabe, Susan L. Slager, Chantal E. McCabe, Daniel R. O'Brien, Sameer A. Parikh, Esteban Braggio, Yi Chen, Fenlai Tan, Stephen P. Anthony, Yu Chen, Bing Dai, Yue Shen, Neil E. Kay. CLL drug resistance- A multifaceted mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4423.

Abstract Uveal melanoma (UM), a rare yet aggressive intraocular cancer with an estimated 5 cases per million people annually, presents a high metastatic risk and poor prognosis, highlighting an immeasurable need for novel diagnostic and therapeutic strategies. Not only is UM characterized by complex genetic and epigenetic aberrations, but it is also prone to deregulation of non-coding RNAs that could be used as therapeutic targets of diagnostic markers. In this study, we analyzed whole exome sequencing data from tumor and control samples of patients diagnosed with both uveal and cutaneous melanoma, focusing on a patient with a germline mutation in MBD4. Our framework, made up to work with long non-coding RNAs (lncRNAs), aims to flesh out these molecules' novel roles in disease etiology and progression. We identified several lncRNAs significantly associated with UM progression and computationally validated them in conjunction with microenvironmental factors in existing literature. LncRNAs are instructive in maintaining cellular homeostasis and, when deregulated, contribute to oncogenesis. Our results implied that the interaction between lncRNAs and other non-coding RNAs might be one of the most relevant mechanisms influencing UM pathogenesis. More interestingly, microenvironmental factors and lncRNA interplay are crucial in disease progression. The clinical relevance of our findings was tested using radiation treatment to evaluate potential therapeutic implications. Over and above that, we assessed the potential of lncRNAs as biomarkers and therapeutic targets in personalized medicine for UM patients to address ineffective treatments. The new lncRNA panels could serve as a new avenue for targeted therapy. With an in-depth understanding of the descent of molecular alterations and how lncRNAs interact within the tumor microenvironment, we can better size up potential strategies to cast off the challenges UM poses. Our work provides instructive insights into lncRNAs underpinnings of UM, emphasizing the significance of lncRNAs in tumor biology and their interactions within the microenvironment. We believe our findings will lay the groundwork for future therapeutic strategies and underscore the necessity for continued research to unravel the complex mechanisms in UM pathogenesis. Citation Format: Vasileios Alevizos, Nikitas Gerolimos, Sabrina Edralin, Clark Xu, Akebu Simasiku, Georgios Priniotakis, George A. Papakostas, Zongliang Yue. Unraveling long non-coding RNA dynamics in uveal melanoma: Insights into pathogenesis, biomarkers, and targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2800.

Coral reefs play an essential ecological role in maintaining marine water quality by naturally filtering contaminants. This study investigates the quantitative capability of coral reef ecosystems to reduce waterborne pollutants using biologically mediated processes. A systematic methodology, combining in situ observations, laboratory simulations, and analytical modeling, was adopted to determine the filtration efficiency of coral reefs. Remote sensing and photogrammetry characterized reef morphology, while microbial consortia transformations and coral polyp assimilation rates were quantified using biochemical assays. Results demonstrated significant nutrient uptake by coral polyps, particularly nitrogenous compounds, with higher removal efficiencies under stable salinity conditions. Temperature-induced stress was found to reduce polyp functionality. Enhanced sediment attenuation near reef structures improved coastal water transparency. The integration of vegetation buffers adjacent to reefs further augmented pollutant removal efficiency, with combined ecological strategies for effective pollution management.

ABSTRACT The insulin‐like growth factor‐1 (IGF‐1) signaling pathway is known as a potent aging modifier, disruption of which consistently associates with lifespan extension across diverse species. Despite this established association, the mechanisms by which IGF‐1 signaling modulates organ aging remain poorly understood. In this study, we assessed age‐related changes in IGF‐1 expression across multiple organs in mice and identified a more prominent increase in skin IGF‐1 levels with aging—a phenomenon also observed in human skin. To explore the consequences of elevated IGF‐1, we developed transgenic mice ectopically expressing human IGF‐1 in the epidermis, driven by the bovine keratin 5 promoter (IGF‐1 Tg). These mice exhibited premature aging of hair follicles, as evidenced by accelerated hair graying and loss. Single‐cell RNA sequencing analyses of dorsal skin highlighted an upsurge in cellular senescence markers and the senescence‐associated secretory phenotype (SASP) in hair follicle stem cells (HFSCs), alongside a decline in hair growth and HFSC exhaustion. Our findings indicate that excessive IGF‐1 triggers HFSC senescence, thereby disrupting hair follicle homeostasis. Remarkably, interventions in IGF‐1 signaling via downstream mechanisms—specifically blocking Ac‐p53 activation via SIRT1 overexpression or senolytic treatment for senescent cell clearance, or reducing IGF‐1 through dietary restriction—significantly reduced senescence markers, mitigated premature hair follicle aging phenotypes, and restored the stem cell pool. Our findings provide fundamental insights into the biological processes of hair aging and highlight the therapeutic promise of targeted interventions to rejuvenate aged HFSCs and promote hair follicle health.

OBJECTIVES: The goal of this scoping review was to review some of the challenges hospitals faced in dealing with the shortage of ventilators during the COVID-19 pandemic and the solutions they were able to implement or suggested. By highlighting these problems and solutions, we hope this review can catalyze further discussions about how to better prepare for future pandemics and medical supply shortages. DATA SOURCES: A comprehensive search strategy using identifying key words was applied to several different databases to procure relevant literature. STUDY SELECTION: Four thousand two hundred fifty-nine studies were found in the initial search. Inclusion and exclusion criteria were created and applied to screen studies. Included studies focused on the supply and distribution of ventilators during the COVID-19 pandemic. In the case where reviewers disagreed about whether a study should be included, a third reviewer acted as a tie-breaker. DATA EXTRACTION: Thirty-three studies were included for final data extraction. Two independent reviewers collected various data points from these studies, including the main challenges discussed by the authors, the level of ventilator shortage being addressed, whether ventilator sharing was discussed, and the limitations of the study. DATA SYNTHESIS: A third reviewer compared the collected data and decided on the results. CONCLUSIONS: Some of the common solutions for the ventilator shortage discussed included augmenting overall ventilator supply through increased production, transporting ventilators between hospitals, ventilator sharing, designing new ventilators, and repurposing other resources to help address shortages of supplies.

Microglia actively survey the brain and dynamically interact with neurons to maintain brain homeostasis. Microglial Gi protein–coupled receptors (Gi-GPCRs) play a critical role in microglia-neuron communications. However, the impact of temporally activating microglial Gi signaling on microglial dynamics and neuronal activity in the homeostatic brain remains largely unknown. In this study, we used Gi-based designer receptors exclusively activated by designer drugs (Gi-DREADD) to selectively and temporally modulate microglial Gi signaling pathway. By integrating this chemogenetic approach with in vivo two-photon imaging, we observed that exogenous activation of microglial Gi signaling transiently inhibited microglial process dynamics, reduced neuronal activity, and impaired neuronal synchronization. These altered neuronal functions were associated with a decrease in interactions between microglia and neuron somata. Together, this study demonstrates that acute, exogenous activation of microglial Gi signaling regulates neuronal circuit function, offering a potential pharmacological target for the neuromodulation through microglia.

121 Background: In the Phase 3 VISION trial, treatment with the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) + protocol-permitted standard of care (SoC) significantly improved median radiographic progression-free survival (rPFS; 8.7 vs 3.4 months [mo]) and overall survival (OS; 15.3 vs 11.3 mo) in patients with metastatic castration-resistant prostate cancer (mCRPC) vs SoC alone. However, it is unclear how the addition of androgen receptor pathway inhibitors (ARPIs) affected 177 Lu-PSMA-617 treatment outcomes. Here we compared the efficacy and safety of 177 Lu-PSMA-617 in patients treated with vs without concomitant ARPIs. Methods: In VISION, adult patients with PSMA-positive mCRPC previously treated with ≥1 prior ARPI and 1–2 taxane chemotherapy regimens were randomized 2:1 to receive 177 Lu-PSMA-617 (7.4 GBq Q6W, 4–6 cycles) + SoC (which included ARPIs) vs SoC alone. In this secondary analysis, we assessed baseline characteristics, OS, rPFS, prostate-specific antigen (PSA) response rate, duration of PSA response, PSA-PFS, and safety among patients in the intervention arm who were treated with vs without concomitant ARPIs. Results: In total, 289 patients were treated with concomitant ARPIs and 262 patients were not (N=551). Imbalances between the groups were observed in some baseline characteristics: patients treated with concomitant ARPIs were younger, had lower ECOG performance scores, lower mean PSA and lactate dehydrogenase levels, and fewer prior taxane chemotherapy regimens. Baseline mean standardized [ 68 Ga]Ga-PSMA-11 uptake values and mean hemoglobin levels were well-balanced. A statistically significant difference in median OS was observed in patients treated with concomitant ARPIs vs those without (17.8 vs 12.4 mo; HR, 0.72; 95% CI, 0.58–0.89; nominal P=0.001). No statistically significant between-group differences were observed for rPFS, PSA response rate, duration of PSA response or PSA-PFS. The proportion of adverse events reported was similar in patients with or without concurrent ARPI, except for the number of adverse events leading to interruption of best supportive care/SoC, which was higher in patients treated with concurrent ARPIs. Conclusions: OS was significantly different in patients treated with concomitant ARPIs vs those without, while other efficacy endpoints were not. No new safety signals were observed for 177 Lu-PSMA-617 with concomitant ARPI. These findings may be confounded by varied exposure to ARPIs, or differing patient characteristics; patients who received concomitant ARPIs may represent a more favorable treatment population than those who did not. These findings should be considered as hypothesis-generating, and a multivariate analysis has been planned to ascertain the influence of these potential biases. Clinical trial information: NCT03511664 .