Kids' Brain Tumor Cure Foundation

Persons living with dementia (PLWDs) and their care partners (CPs) have seldomly been included during early intervention development stages despite the potential for greater user engagement and adherence. Moreover, there is limited existing guidance for investigators to incorporate PLWDs and CPs in intervention design. In developing an emergency department care transition intervention, our goal was to conduct a Design Thinking Workshop (DTW), identify lessons learned, and provide recommendations for future intervention design processes targeting the population of PLWDs and CPs. Inclusive of PLWDs and their CPs, a total of 23 individuals participated in a DTW with components including empathy map review, preliminary technology intervention demonstration and feedback, current and future state discussion, among others. The design team collectively grouped challenges, successes, and processes of the DTW into 10 "lessons learned" with associated recommendations for effective inclusion of PLWDs and CPs. The 10 lessons learned and associated recommendations were categorized into three groups, including pre-workshop considerations (lessons 1 to 2), workshop principles and attitudes (lessons 3 to 7), and additive resources (lessons 8 to 10). Collectively, they are: (1) Recruit a participant pool resembling the target population; (2) Provide clear, detailed logistics information; (3) Ensure PLWDs and CP dyads are central in every aspect; (4) Dedicate sufficient time for introductions and contextualization; (5) Balance agenda items and time demands; (6) Select a lead facilitator(s) possessing direct experience with the target population and in design thinking; (7) Allow exercise flexibility; (8) Use multiple modalities to promote participant engagement; (9) Engage a transcriber and a visual artist; and (10) Ensure formal collection of post-workshop feedback. Investigators including PLWDs and their CPs during intervention development phases may benefit from the Design Thinking Workshop lessons learned and recommendations to refine workshop practices and maximize end user engagement.

Aim: The mechanistic target of rapamycin (mTOR) signaling pathway represents a critical regulatory hub controlling cellular growth, metabolism, and survival, with its dysregulation implicated in numerous pathological conditions, including cancer, metabolic disorders, and aging. While conventional mTOR inhibitors such as rapamycin and its analogs have shown therapeutic promise, their clinical efficacy is often limited by incomplete pathway inhibition, feedback activation of compensatory pathways, and significant side effects. This study aimed to investigate the multi-target modulatory effects of metadichol, a nanoemulsion of long-chain alcohols, on the mTOR signaling network and its downstream effectors, with particular focus on DNA damage inducible transcript 4 (DDIT4) and ribosomal protein S6 kinase B1 (p70S6K) regulation across diverse cellular contexts. Scope: The scope of this investigation encompassed comprehensive molecular analysis of metadichol's effects on key components of the mTOR signaling cascade in both immune cells (peripheral blood mononuclear cells, PBMCs) and multiple cancer cell lines representing different tissue origins (U87 glioblastoma, A549 lung adenocarcinoma, MDA-MB-231 breast cancer, HCT116 colorectal cancer, and HepG2 hepatocellular carcinoma). The study employed quantitative real-time polymerase chain reaction (qRT-PCR) analysis to evaluate gene expression changes and Western blot techniques to assess protein-level modifications. Concentration-response relationships were established across a range from 1 pg/mL to 100 ng/mL to determine the minimal effective dose and characterize dose-dependent effects. Methods: Primary human PBMCs were isolated using density gradient centrifugation and treated with various concentrations of metadichol for 24 hours. Cancer cell lines were cultured under standard conditions and subjected to identical treatment protocols. RNA extraction was performed using TRIzol methodology, followed by cDNA synthesis and qRT-PCR analysis using specific primers for mTOR, DDIT4, and p70S6K genes. Protein expression analysis was conducted using Western blot techniques with specific antibodies. Gene expression changes were calculated using the ΔΔCt method with β-actin as the housekeeping gene reference. Key Findings: Metadichol demonstrated remarkable potency in modulating mTOR signaling components at concentrations as low as 1 pg/mL, representing activity levels several orders of magnitude lower than conventional mTOR inhibitors. The compound consistently upregulated DDIT4 expression across all tested cell types, with concurrent downregulation of both mTOR and p70S6K expression. In PBMCs, metadichol induced significant DDIT4 upregulation while suppressing mTOR expression, with p70S6K showing delayed dose-dependent inhibition at higher concentrations (100 ng/mL). Cancer cell lines exhibited robust responses with DDIT4 upregulation accompanied by substantial downregulation of both mTOR and p70S6K across multiple concentrations. Notably, the hepatocellular carcinoma cell line HepG2 showed resistance to p70S6K inhibition despite effective mTOR suppression, suggesting cell-type-specific response patterns and potential alternative pathway activation. involvement of high-affinity receptor- mediated mechanisms or amplification through secondary messenger systems. Conclusions: Metadichol represents a paradigm shift in mTOR pathway modulation, demonstrating unprecedented potency and multi-target activity that distinguishes it from conventional rapamycin-based inhibitors. The compound's ability to coordinately regulate DDIT4, mTOR, and p70S6K at picomolar concentrations suggests novel mechanisms of action that warrant further investigation. The unique pharmacological profile of metadichol may herald the development of next-generation mTOR modulators with enhanced efficacy and improved safety characteristics for treating cancer, metabolic disorders, and age-related diseases.

Significance: The 2025 Nobel Prize in Physiology or Medicine was awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their groundbreaking discoveries concerning peripheral immune tolerance, specifically identifying the FOXP3 gene as the master regulator of regulatory T cells (Tregs). Their work demonstrated that FOXP3 mutations cause severe autoimmune disease (IPEX syndrome), establishing FOXP3 as essential for immune self-tolerance. This study demonstrates that Metadichol significantly upregulates FOXP3 expression (5.46-fold), providing a novel pharmacological approach to enhance regulatory T-cell function and immune homeostasis—directly relevant to the Nobel Prize-winning discoveries. Background: Forkhead box (FOX) transcription factors constitute a large family of regulatory proteins that control diverse cellular processes, including development, metabolism, immunity, and aging. Metadichol, a nano lipid formulation derived from long-chain alcohols, has demonstrated pleiotropic biological effects, including immunomodulation and metabolic regulation. Objective: To comprehensively evaluate the effects of metadichol treatment on FOX transcription factor gene expression in human peripheral blood mononuclear cells (PBMCs) via quantitative PCR analysis. Methods: Human PBMCs were isolated via Histopaque density gradient centrifugation and treated with Metadichol at concentrations of 1 pg/ml, 100 pg/ml, 1 ng/ml, and 100 ng/ml. Total RNA was extracted, reverse- transcribed, and analyzed by quantitative PCR for 45 FOX genes. Gene expression changes were calculated via normalization to GAPDH via the 2^-ΔΔCq method. Results: Metadichol treatment resulted in dose-dependent modulation of FOX gene expression. At the highest concentration (100 ng/ml), significant upregulation of multiple FOX genes was observed, with FOXO1 showing the greatest increase (8.74-fold), followed by FOXA1 (7.39-fold) and FOXH1 (7.22-fold). Additional substantial increases were noted for FOXA2 (6.57-fold), FOXA3 (6.98-fold), FOXB1 (6.79-fold), FOXP3 (5.46-fold), and FOXP4 (6.23-fold). Conversely, selective downregulation was observed for FOXL2 (0.16-fold), FOXL1 (0.54- fold), and FOXD4L1 (0.56-fold). Conclusions: Metadichol has potent and selective effects on FOX transcription factor expression in human PBMCs, with preferential upregulation of genes involved in metabolic regulation, immune homeostasis, induced pluripotency and cellular longevity pathways. These findings suggest potential therapeutic applications in age- related diseases, metabolic disorders, and immunomodulation, and regenerative medicine. Importantly, the coordinated upregulation of pluripotency-associated genes, including FOXD3, FOXO1, and FOXM1, establishes Metadichol as a compelling modulator of cellular reprogramming networks with significant implications for advancing stem cell-based regenerative therapies. The differential expression patterns indicate complex regulatory mechanisms that warrant further investigation to elucidate their clinical translation potential. Key words: Fox family, Metadichol, immune metabolic rejuvenation, nuclear receptors, SOX family, Toll-like receptors, KLFs, sirtuins, circadian genes, GDF11, TERT, Klotho, induced pluripotency, regenerative medicine, 2025 Nobel Prize, FOXP3, regulatory T cells, immune tolerance.

The reprogramming of somatic cells into embryonic-like stem cells requires the activation of four essential transcription factors, referred to as the Yamanaka factors: Sox2, Oct4, Klf4, and c-Myc. However, the utilization of these genes and viral vectors for their delivery presents a risk of carcinogenesis, which renders induced pluripotent stem cell (iPSC) lines unsuitable for clinical applications. Typically, direct reprogramming involves the use of viral vectors to induce the expression of these factors. In contrast, metadichol, a novel approach, enhances the expression of Yamanaka factors in cells using a dose ranging from 1 pg to 100 ng, thereby preventing the need for viral vectors. This non-viral method renders cellular reprogramming safer and more clinically viable. Treatment with metadichol within the specific dose range resulted in a substantial augmentation of the fibroblast expression of OCT4, SOX2, KLF4, KLF2, and Nanog, which was confirmed through qRT-PCR and western blot analyses. The expression levels of OCT4, KLF4, Nanog, and Sox2, exhibited an increase of 4.01-, 3.51-, 1.26-, and 2.5-fold, respectively, compared to the controls. Notably, A549 and Colo-205 cancer cells demonstrated a marked elevation in expression levels. The reprogramming of primary human cancer cells presents considerable challenges. However, in triple-negative primary breast cancer cells, metadichol treatment led to the substantial upregulation of the expression levels of OCT4, KLF4, Nanog, and Sox2 by 19.6-, 8.07-, 2.45-, and 6.91-fold, respectively, across the dose range of 1 pg to 100 ng. Klotho, an antiaging gene that is modulated by metadichol, down regulates TP53, a crucial factor for the production of somatic cell iPSCs. Additionally, metadichol enhances the availability of vitamin C, which is essential for generating iPSCs from somatic cells. Increased levels of alkaline phosphatase, indicative of cellular differentiation, were observed in the treated group compared to the controls. Metadichol is a nontoxic nanoemulsion that is derived from long-chain C26–C28 alcohols from food sources and activates Yamanaka factors across various cell types without requiring the use of viral or CRISPR-based methodologies, thus substantially advancing somatic cell reprogramming.

To sustainably control urban rat infestations, management efforts need to encompass large areas of urban centers. Therefore, the objective of this review and narrative synthesis was to collate what is known about municipal-scale rat management. We explored the management frameworks that have been used at a large scale in cities and we describe the expectations of experts who have designed and implemented these frameworks. We found that there has been a persistent “war on rats” paradigm driving this literature since the early 1900s. Not only was there little quantitative evidence to support this paradigm and associated methodologies, but together, they failed to meet the expectations of those who designed and implemented them due to real-world constraints (i.e., limited resources). To improve the field of municipal management, we identify two distinct options. First, stakeholders may continue to wage the “war on rats” while improving existing strategies within this paradigm. Key pathways forward include developing evaluation metrics aligned with program objectives, establishing the cost-effectiveness of methodologies, and improving control efficacy. Second, we suggest a new paradigm, one that considers that rat management is a complex system that must be approached by first mapping its complexity to highlight and prioritize the many complex upstream determinants of infestations. This perspective highlights how rat management may be a wicked problem for which there is no overarching solution and instead can only be managed by making incremental gains in individual components of the problem over time. Importantly, we propose an alternative management objective that places a priority on improving the overall health of the community, instead of on eliminating rats, and we stress that management goals must address stakeholders’ goals as their investment is essential for a sustained program.

Applications developed using blockchain technology have the potential to create a step increase in productivity. However, all business problems do not require a blockchain solution. Blockchain applications are more complex to build than traditional applications and should only be built when dictated by the business problem.

The promise of blockchain is achieved by innovatively integrating existing technology concepts from distributed systems, cryptography, and peer-to-peer networking. These technologies also impose limitations that drive engineering design decisions for blockchain implementations.

BackgroundAs use of oral cancer therapies increases, patient adherence has become critical when evaluating the effectiveness of therapy. In a phase III trial for renal cell carcinoma, we: (a) characterized adherence to sorafenib, sunitinib, and/or placebo and (b) identified factors associated with non‐adherence.MethodsECOG‐ACRIN E2805 was a double‐blind, placebo‐controlled, randomized trial comparing adjuvant sorafenib or sunitinib in patients with resected primary renal cell carcinoma at high risk for recurrence. We used patient‐completed pill diaries to measure adherence as the number of pills taken divided by the number of pills prescribed. Log‐binomial regression was used to identify correlates of non‐adherence (<80% of prescribed pills reported as taken).ResultsMean adherence was 90.7% among those assigned to sunitinib (n = 613) and 84.8% among those assigned to sorafenib (n = 616). Among those assigned to placebo, mean adherence was 94.9% and 92.4% to sunitinib and sorafenib placebo, respectively. Non‐adherence was associated with race/ethnicity (non‐Hispanic Black: prevalence ratio [PR] 2.22, 95% CI 1.63, 3.01; Hispanic: PR 1.54, 95% CI 1.05, 2.26), high volume enrollment (≥10 patients: PR 1.30, 95% CI 1.03, 1.64), treatment group (sunitinib: PR 2.24, 95% CI 1.66, 3.02; sorafenib: PR 2.37, 95% CI 1.74, 3.22), and skin rash (PR 1.36, 95% CI 1.03, 1.80).ConclusionAmong patients participating in a randomized clinical trial, adherence to oral cancer therapies was lower compared to placebo. Adherence was also worse in racial/ethnic minorities, those experiencing toxicities, and high volume enrolling sites. Our findings highlight several challenges to address in clinical practice as use of oral therapies continues to increase.Clinical trial registration numberThis trial is registered with ClinicalTrials.gov, number NCT00326898.