Madison Group (United States)

Abstract Background: There is a critical need to develop novel therapeutic strategies and diagnostic tools to precisely deliver treatments to improve survival for men with prostate cancer (PCa). To support this development, improved strategies are needed to better understand heterogenous tumor microenvironments and tumor biology that associate with variable treatment responses. We hypothesized that the tumor immune microenvironment (TIME) plays a critical role in treatment resistance. In this study we aimed to evaluate TIME signatures of treatment response and resistance utilizing a novel, integrated technological tool to identify response patterns and enable precision sampling for comparative cellular and molecular analysis. Methods: 30 patients with newly-diagnosed, locally advanced, high-risk, primary PCa underwent 18F-DCFPyL PSMA PET with multiparametric MRI (mpMRI) imaging on a dedicated PET/MRI scanner followed by 3 cycles of chemohormonal therapy (NCT03358563). Repeat PSMA PET/MRI was performed prior to prostatectomy and scans were interpreted by an experienced radiologist and nuclear medicine physician as complete response (CR), partial response (PR), no response (NR) or normal tissue. MRI scans were used to print a 3D mold of the prostate to allow PET and MRI directed mapping and microdissection of regions of interest from the resected prostate with slice-by-slice and lesion-to-lesion correlation. Cellular infiltrates were analyzed by flow cytometry in 3 to 5 tissue specimens per patient. Results: The frequency of CD8+ T cells in the total CD45+ infiltrate was highest in normal and CR areas and was significantly reduced in PR vs CR (p<0.01). CXCR3+CD8+ and CD103+CD8+ Tcell frequencies were also reduced in PR vs CR foci (p<0.01, p<0.05, respectively). Meanwhile, the frequency of CXCR3+CD8+ T and CXCR3+++CD8+ T cells was highest and significantly elevated in CR vs normal tissue suggesting enrichment of activated, homing, Tc1 CD8T cells. An increase in total CD8+ and CD103+CD8+ T cells was associated with longer progression-free survival. DESeq2 analysis of bulk mRNA sequencing showed enrichment of CD8a and ITGAE (CD103) gene expression differential in CR vs PR lesions (p=0.028, p=0.00029, respectively). CD8a expression was reduced in panCK- AOI of resistant (PR) foci by GeoMx WTA spatial transcriptomic analysis in two model patients with multi-focal tumors. Flow analysis of EpCAM+ cells had a significant increase in B7H3 expression in PR vs CR lesions (p<0.05). We are currently integrating analysis of myeloid cells and expand spatial transcriptomic analysis of matched multi-focal tumors to further dissect patterns of therapeutic response in our study cohort. Conclusions: In conclusion, PSMA /PET and mpMRI based precision sampling of tumor tissue associated with differential therapeutic response patterns captured differences in the TIME infiltrates and these observations may provide hypothesis to test biological mechanisms to expedite discovery of targetable mechanisms to improve tumor stratification and targeting in high-risk prostate cancer. Citation Format: Erika Heninger, Jamie M. Sperger, Kristin Weinstein, Brian P. Johnson, Peter G. Geiger, Shane A. Wells, Steve Y. Cho, Wei Huang, Philippos Tsourkas, Sean McIlwain, Irene M. Ong, David Quigley, David F. Jarrard, Sheena C. Kerr, David J. Beebe, Joshua M. Lang. Differential Patterns of Immune Infiltration in the Tumor Immune Microenvironment Associate with Therapeutic Response in Primary Prostate Cancer Following Chemohormonal Therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A023.

Abstract America’s fragmented water sector is unsustainable, with tens of thousands of utilities operating nearly 50,000 community water systems. Most of these water utilities lack the technical, managerial, and financial capacity to operate efficiently and effectively. Sweeping consolidation is the clear solution. Congress recognized the need for consolidation when it passed the Safe Drinking Water Act (SDWA) in 1974; water sector leaders repeated the call for consolidation on the law’s 25th anniversary in 1999. Yet the drinking water industry remains highly fragmented 25 years later. Consolidation will not solve all of the nation’s drinking water problems, but without significant consolidation no other reform is likely to work in the long run. How much to consolidate is not as clear. How big is big enough? This chapter analyzes data on SDWA compliance, utility performance, and operational efficiency to identify a scale of consolidation that offers the best chance at sustainable excellence. A remarkably consistent picture emerges: the greatest potential improvements from consolidation are achieved when utilities serve around 20,000 or more customer connections. Taken together, these results suggest that consolidating the American drinking water sector to about 6,000 utilities with a minimum size of 20,000 connections would deliver better health, greater efficiency, more effective regulation, and lower prices.

Abstract BACKGROUND BRAF gene alterations play a significant role in driving disease in pediatric low-grade glioma (LGG), the most prevalent brain tumor in children. Tumors with BRAFV600E mutation, especially with CDKN2A deletion, are prone to progression to high-grade glioma (HGG), which has poor outcomes and limited therapeutic options. The mechanisms underlying this progression, particularly within the tumor microenvironment (TME), remain poorly understood. OBJECTIVES To elucidate mechanisms of progression in BRAFV600E-mutated/CDKN2A-deleted gliomas, with a focus on the evolving TME and phosphokinome activity. We aim to identify critical mediators, including kinases and specific cell populations such as glioma-associated oligodendroglia (GA-Olig), as potential therapeutic targets. METHODS We developed a novel transgenic mouse model allowing conditional BRAFV600E activation and CDKN2A deletion via adenovirus-Cre injection into the mouse brain, generating tumors that recapitulate LGG-to-HGG progression. We analyzed TME dynamics across progression stages using magnetic resonance imaging, histology, single-cell RNA sequencing, immunofluorescence, and phosphoproteomics of patient samples with BRAFV600E-mutated LGG and HGG. Pediatric glioma datasets were used for cross-species validation of our mouse data. RESULTS We identified dynamic TME remodeling across glioma progression stages. Notably, GA-Oligo, including both oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs), exhibited grade-dependent functional heterogeneity related to phagocytosis, immunomodulation, metabolism, neuronal regulation, and myelination. Key GA-Oligo-mediated molecular candidates were identified from mouse and human datasets for further ongoing investigation. Phosphokinome profiling of patient samples revealed activation of kinase signaling pathways associated with tumor-TME interactions. Several kinases involved in PI3K-Akt, ErbB, and immune-related signaling (phagocytosis) were differentially expressed. Validation of kinase expression in our glioma progression mouse model is ongoing. CONCLUSIONS Our study reveals coordinated transcriptomic and phosphokinomic remodeling of the TME during glioma progression, with previously underappreciated contributions from GA-Oligo within the TME. These findings support developing therapies targeting both the TME and oncogenic signaling to prevent malignant transformation in high-risk pediatric gliomas.

Abstract PURPOSE Isocitrate dehydrogenase (IDH)-mutant gliomas are the most common malignant brain tumors in young adults and commonly present with tumor-related epilepsy. One proposed mechanism for seizure generation in IDH-mutant gliomas is the accumulation of 2-hydroxyglutarate (2-HG), which may promote neuronal hyper-excitability. While ketogenic diet therapy (KDT) is an established adjunct in drug-resistant epilepsy, its use in tumor-related epilepsy remains investigational. Here, we present a case report of two patients with IDH-mutant glioma and drug-resistant epilepsy who were self-referred to the UW Health Adult Neurology KDT Clinic. METHODS A retrospective review was conducted on two patients with IDH-mutant gliomas and drug-resistant epilepsy who elected to start on the modified Atkins diet (MAD) version of KDT following tumor treatment with standard maximal safe resection, radiation, and adjuvant chemotherapy. Both patients had drug-resistant epilepsy, and further adjustments of antiseizure medications failed to provide meaningful seizure control. Seizure frequency was documented before and after initiation of MAD. Ketone levels were tracked while on MAD, indicating adherence. RESULTS Both patients maintained compliance with MAD for an average of 33 months. Patient 1 had a 69% reduction in seizure frequency over 14 months with a mean beta-hydroxybutyrate level of 3.83 mmol/L (ketosis defined as >0.5 mmol/L). Even when seizure frequency was at baseline, the patient reported decreased seizure severity. Patient 2 had a 46% reduction in seizure days per month over 6 months and was in ketosis with moderate to large urine ketones. CONCLUSION These cases suggest that KDT may be an effective treatment for IDH-mutant glioma patients with tumor-related and drug-resistant epilepsy. Both patients demonstrated significant reductions in seizure frequency and/or severity. These data highlight the potential utility of diet interventions in tumor-related epilepsy and emphasizes the need for further investigation of the efficacy, tolerability, and mechanistic role of ketone metabolism in these populations.

ABSTRACT Objective This paper investigates contemporary household economies of gratitude and resentment, assessing how discrepancies between partners' expectations relate to their emotions and household labor allocation. Background Women shoulder greater shares of cognitive and physical housework than men. Prior research suggests expressions of gratitude reveal the underlying expectations that reproduce and/or challenge gender‐traditional labor allocations. Methods This article draws on qualitative analysis of 209 interviews with 37 men and 41 women in dual‐income, mixed‐gender couples with children, interviewed two or three times each. Results Expressions of gratitude and resentment revealed considerable divergence between men's and women's expectations. Some women were grateful for men's participation in physical labor; others expected significant physical and cognitive contributions and resented their absence. Most men expected to contribute physical household labor and were grateful when women's unpaid housework left more time than expected for men's paid work. Men's resentment emerged when they felt their physical contributions were underappreciated or their partner had unreasonable expectations for their cognitive labor participation. Resentment eased in cases where men increased their attunement and women their use of delegation. Conclusion Our longitudinal dataset enabled us to examine implicit gender ideologies as reflected in respondents' gratitude and resentment and to chart shifts in expectations and labor allocations in close to real time. These findings broaden our understanding of why household labor remains strongly gender‐typed and reveal how quantitative measures of gender ideology may not capture nuanced perspectives—particularly vis‐à‐vis the division of cognitive labor.

Abstract Politicians rely on political brokers to buy votes throughout much of the developing world. We investigate how social networks facilitate these vote-buying exchanges. Our conceptual framework suggests brokers should be particularly well-placed within the network to learn about non-copartisans’ reciprocity in order to target transfers effectively. As a result, parties should recruit brokers who are central among non-copartisans. We combine village network data from brokers and citizens with broker reports of vote buying, allowing us to use broker and citizen fixed effects. We show that networks diffuse information about citizens to brokers who leverage it to target transfers. In particular, among those citizens who are not registered to their party, brokers target reciprocal citizens about whom they can learn more through their network, and these citizens are more likely to support the brokers’ party. Moreover, recruited brokers are significantly more central than other citizens among non-copartisans, but not among copartisans. These results highlight the importance of information diffusion through social networks for vote buying, broker recruitment, and ultimately for political outcomes.

Electrical propulsion and power systems in naval shipboard applications offer efficient propulsion arrangements for various types of vessels. Adoption has been propelled by the development of semiconductor switching devices since the 1980s. Presently these systems use a rectifier stage to convert the generator side AC system into a regulated DC bus that is distributed to drive the traction motors. The rectification stage typically features either passive diode bridge or thyristorbased line-commutated circuits. These rectifiers interface to the AC distribution using line-frequency transformers which provide galvanic isolation; but are bulky and deteriorate the power density of the overall system. This paper introduces a family of high-frequency isolated and direct AC-DC converters that tap into the emerging technologies of high-frequency high-power transformers and four-quadrant devices. Advantages include increased power density due to elimination of bulky line-frequency transformers, direct AC-DC conversion without multiple power conversion stages, and minimized filtering elements sized for switching frequency harmonics only. The paper also presents broader design and sizing aspects and simulation results of one of the selected candidates.