Temporary Response Research Articles

Localization and developmentality: Policy pragmatism in pandemic times

AbstractMotivationLocalization is increasingly invoked in debates about how to reform international aid: to improve aid effectiveness and address ethical concerns by turning hierarchical aid relations on their head. This has proved to be easier said than done. The COVID‐19 pandemic produced logistical impediments to aid practitioners, which translated into a renewed, if temporary, interest in localization.PurposeThe initial scope of the research engaged with the notion of partnership during COVID‐19, but almost all informants drew attention to the concept of localization. The article maps and analyses the challenges and advantages of localization, as seen from the practitioners' perspective.Approach and methodsThe article draws on 24 interviews conducted in Oslo with representatives of various Norwegian development and humanitarian non‐governmental organizations and government agencies, in addition to policy and grey literature review.FindingsThe article shows that the re‐emergence of the localization debate during COVID‐19 occurred not because of any ambition to reform aid, but as a pragmatic and temporary response to the logistical impediments caused by the pandemic. Reflections from the interviewees on the pros and cons offer more substantial insights into why localization fails to change practice, while at the same time localization enables a form of indirect governance related to accountability regimes. This is analysed as developmentality, reflecting the logic that localization takes place when recipients do as donors want, but they do so voluntarily, which suggests that localization counterintuitively may reinforce existing power structures.Policy implicationsLocalization is poorly conceptualized. While a definition could be helpful in practice, one that is too rigid could undermine the diversity of actors and knowledge that localization aims to advance. At the operational level, localization requires greater flexibility and slack throughout the aid chain, especially in the audit and accountability regimes of donor and funding authorities, which permeate and uphold lopsided aid relations.

Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing.

Senescent cells (SnC) accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating SnCs in specific aged tissues. In this study, we focused on eliminating SnC skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period. Following topical ABT-263, aged skin demonstrated decreased gene expression of senescent markers p16 and p21, accompanied by reductions in SA-β-gal and p21-positive cells compared to DMSO controls. However, ABT-263 also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice skin pre-treated with topical ABT-263 exhibited accelerated wound closure. In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.

Effect of information delivery techniques in reducing pre-procedural anxiety in computed tomography

ObjectivesPatients undergoing medical procedures often experience heightened anxiety, which can affect their experience and overall health. The current study aimed at looking at a quality improvement initiative to compare written and audiovisual information delivery methods to reduce anxiety prior to Computed Tomography (CT). MethodsIn this prospective interventional study, we assessed state and trait anxiety in patients scheduled for their first CT scan. Three PDSA cycles were carried out over six months, with each cycle lasting for two months each. The participants were divided into three groups, the baseline, written, and audiovisual intervention groups. Anxiety levels were assessed using the State-Trait Anxiety Inventory (STAI) questionnaire. State anxiety is a temporary emotional response, while trait anxiety reflects enduring personality characteristics. ResultsThe mean age of participants was 43.26 years (SD 15.07) in the baseline group, 39.9 years (SD 14.72) in the written group, and 48.59 years (SD 13.54) in the audiovisual group. For state anxiety, the baseline mean was 58.4 (SD 6.9), notably reduced to 43.2 (SD 5.5) with written intervention and to 38.6 (SD 7.7) with audiovisual intervention (p < 0.001). Trait anxiety scores remained relatively stable in all groups (p = 0.31). ConclusionBoth written and audiovisual interventions successfully alleviate pre-imaging anxiety in patients undergoing CT scans. The findings underscore the superior efficacy of audiovisual materials in achieving a more substantial reduction in state anxiety compared to written information. These findings are particularly relevant in resource limited settings where simple interventions show significant improvements.

Transient frequency response test and measurement error prediction of DCTV based on adaptive inertial weight improved ACO

AbstractA temporary frequency response test and measurement error prediction method of direct current voltage transformer (DCTV) based on artificial intelligence (AI) is proposed. Firstly, the frequency characteristic of direct current (DC) side voltage of DCTV is analyzed. On this basis, a DCTV transient Frequency Response testing method based on transient alternating current (AC) &amp; DC superposition was developed. Then, the method of voltage sudden change and phase correction is used to achieve transient process DCTV response time testing. Finally, the ant colony optimization (ACO) algorithm was improved by combining an adaptive inertia weight improvement strategy, achieving accurate prediction of the Measurement Error of DCTV. The proposed AI based DCTV transient Frequency Response testing and Measurement Error prediction method were compared and analyzed with the other three methods through simulation experiments. Compared to the other three comparison methods, the maximum transformation error in the evaluation indicators of mean squared error (MSE), root mean squared error (RMSE), and mean absolute error (MAE) decreased by 0.006, 0.0119, and 0.0085, respectively, while the maximum phase error decreased by 0.2794, 0.3004, and 0.2823, respectively.

Selenomethionine Supplementation Contributes to Reducing Oxidative Stress and Inflammation Markers following Exercise-Induced Muscle Damage

Background. Exercise-induced muscle damage (EIMD) is a temporary response to intense or prolonged exercise that can cause muscle pain, inflammation, and impaired muscle function. Antioxidant supplementation is a proposed strategy to reduce EIMD symptoms by targeting reactive oxygen and nitrogen species (RONS) involved in the process. Objective. The study aimed to investigate the effect of Selenomethionine supplementation on malondialdehyde (MDA) and C-reactive protein (CRP) levels resulting from Exercise-Induced Muscle Damage (EIMD). Materials and methods. This study used a randomized pretest-posttest control group design, involving a total of 32 male recreational students from the State University of Surabaya (Indonesian: Universitas Negeri Surabaya), (age 19.25 ± 0.76 years, body mass 63.16 ± 3.38 kg, height 167.28 ± 4.54 cm, body fat 19.60% ± 4.57%). The participants were randomly assigned to the selenomethionine group (SEM, 100 µg/day) or placebo group (PLA, corn starch 100 mg/day) for a period of 28 days (4 weeks). On days 1 (baseline) and 29, participants underwent a single bout of EIMD. Blood samples were collected 24 hours post-EIMD to measure MDA and CRP concentrations in plasma. The statistical analysis was conducted using paired sample t-test. Results. The placebo group experienced a significant increase in plasma MDA and CRP concentrations after EIMD compared with baseline values (p &lt; 0.05). However, the SeMet group showed lower plasma MDA and CRP levels than the placebo group. Conclusions. Daily Selenomethionine supplementation for 28 days has been found to reduce oxidative stress by lowering MDA levels in the blood and to decrease inflammation by reducing CRP levels post-exercise-induced muscle damage. This indicates a lower risk of EIMD due to reduced oxidative stress and inflammation.

Proteome profiling of Campylobacter jejuni 81–176 at 37 °C and 42 °C by label-free mass spectrometry

BackgroundThe main natural reservoir for Campylobacter jejuni is the avian intestinal tract. There, C. jejuni multiplies optimally at 42 °C – the avian body temperature. After infecting humans through oral intake, the bacterium encounters the lower temperature of 37 °C in the human intestinal tract. Proteome profiling by label-free mass spectrometry (DIA-MS) was performed to examine the processes which enable C. jejuni 81–176 to thrive at 37 °C in comparison to 42 °C. In total, four states were compared with each other: incubation for 12 h at 37 °C, for 24 h at 37 °C, for 12 h at 42 °C and 24 h at 42 °C.ResultsIt was shown that the proteomic changes not only according to the different incubation temperature but also to the length of the incubation period were evident when comparing 37 °C and 42 °C as well as 12 h and 24 h of incubation. Altogether, the expression of 957 proteins was quantifiable. 37.1 − 47.3% of the proteins analyzed showed significant differential regulation, with at least a 1.5-fold change in either direction (i.e. log2 FC ≥ 0.585 or log2 FC ≤ -0.585) and an FDR-adjusted p-value of less than 0.05. The significantly differentially expressed proteins could be arranged in 4 different clusters and 16 functional categories.ConclusionsThe C. jejuni proteome at 42 °C is better adapted to high replication rates than that at 37 °C, which was in particular indicated by the up-regulation of proteins belonging to the functional categories “replication” (e.g. Obg, ParABS, and NapL), “DNA synthesis and repair factors” (e.g. DNA-polymerase III, DnaB, and DnaE), “lipid and carbohydrate biosynthesis” (e.g. capsular biosynthesis sugar kinase, PrsA, AccA, and AccP) and “vitamin synthesis, metabolism, cofactor biosynthesis” (e.g. MobB, BioA, and ThiE). The relative up-regulation of proteins with chaperone function (GroL, DnaK, ClpB, HslU, GroS, DnaJ, DnaJ-1, and NapD) at 37 °C in comparison to 42 °C after 12 h incubation indicates a temporary lower-temperature proteomic response. Additionally the up-regulation of factors for DNA uptake (ComEA and RecA) at 37 °C compared to 42 °C indicate a higher competence for the acquisition of extraneous DNA at human body temperature.

Daflon 500mg is used for the treatment of all grades of hemorrhoids

Background: Hemorrhoidal diseases are very common diseases found in surgical outpatient clinics, affecting populations all over the world. Treatments for the different grades of hemorrhoids include lifestyle changes, conservative medical therapy, and operative interventions. Objective: To assess the conservative treatment response of all grades of hemorrhoidal disease (grades 1-4) to a venotonic agent (Daflon 500mg). Patients and Methods: This is a prospective observational study of 196 patients with hemorrhoids, conducted during the period from January 2015 to January 2020, All treated with the standard dose of a venotonic agent (Daflon 500mg). An observation of the reduction and disappearance of the signs and symptoms of the different grades of the disease was done at 1, 3, and 6 months. Results: The mean age of the patients was 46.6 (range 14–85) years. The majority (41.84%) were diagnosed with grade III hemorrhoidal disease and 30.1% with grade II disease; Grade I and Grade IV constitute 9.69% and 18.37%, respectively. excellent improvement observed in about 72.45%, temporary response seen in 15.82% of cases. Conclusion: Daflon 500 mg is an effective first-line conservative treatment for all four grades of hemorrhoidal diseases, including grade 4, which has a 44.74% permanent response rate. This medical treatment, in turn, reduces the chance of surgical intervention and its complications.

Comparison of physiological markers, behavior monitoring, and clinical illness scoring as indicators of an inflammatory response in beef cattle.

Clinical illness (CI) scoring using visual observation is the most widely applied method of detecting respiratory disease in cattle but has limited effectiveness in practice. In contrast, body-mounted sensor technology effectively facilitates disease detection. To evaluate whether a combination of movement behavior and CI scoring is effective for disease detection, cattle were vaccinated to induce a temporary inflammatory immune response. Cattle were evaluated before and after vaccination to identify the CI variables that are most indicative of sick cattle. Respiratory rate (H2 = 43.08, P < 0.0001), nasal discharge (H2 = 8.35, P = 0.015), and ocular discharge (H2 = 16.38, P = 0.0003) increased after vaccination, and rumen fill decreased (H2 = 20.10, P < 0.0001). Locomotor activity was measured via leg-mounted sensors for the four days preceding and seven days following vaccination. A statistical model that included temperature, steps, lying time, respiratory rate, rumen fill, head position, and excess saliva was developed to distinguish between scores from before and after vaccination with a sensitivity of 0.898 and specificity of 0.915. Several clinical illness signs were difficult to measure in practice. Binoculars were required for scoring respiratory rate and eye-related metrics, and cattle had to be fitted with colored collars for individual identification. Scoring each animal took up to three minutes in a small research pen; therefore, technologies that can automate both behavior monitoring and identification of clinical illness signs are key to improving capacity for BRD detection and treatment.

Transient bending analysis of the graphene nanoplatelets reinforced sandwich concrete building structure validated by machine learning algorithm

This paper demonstrates a thorough examination of the bending behavior of sandwich concrete building structures that are reinforced with graphene nanoplatelets (GPLs). The analysis is confirmed using a machine learning technique. Sandwich structures have notable benefits in terms of strength, longevity, and thermal insulation, making them well-suited for many building applications. Integrating GPLs into the concrete matrix improves the mechanical characteristics and performance of these structures, especially in terms of bending behavior. This study utilizes a machine learning technique to verify the characterization of the temporary bending behavior of a concrete building structure reinforced with graphene nanoplatelets. The approach utilizes a dataset consisting of simulated bending data to create a prediction model that can reliably estimate the temporary bending response of the reinforced structure under different loading situations. The machine learning algorithm’s effectiveness and dependability in optimizing the design and performance of graphene nanoplatelets reinforced sandwich concrete building structures are demonstrated through validation against simulated results. This provides engineers and designers with a powerful tool. This study enhances the comprehension and use of machine learning approaches in analyzing and designing sophisticated structural materials and systems.

Compromised Dynamic Cerebral Autoregulation in Patients with Restless Legs Syndrome.

Restless legs syndrome (RLS) is a prevalent sensorimotor nervous system disorder in patients accompanied with insomnia, blood pressure fluctuation, and sympathetic dysfunction. These symptoms may disrupt cerebral hemodynamics. Dynamic cerebral autoregulation (dCA) describes the temporary response of cerebrovascular system to abrupt fluctuations in blood pressure, which keep cerebral blood flow stable and serve as a marker of cerebrovascular system ability. This research aimed to assess dCA in RLS patients. In this study, RLS patients were recruited and subsequently classified into four groups (mild, moderate, severe, and very severe) based on the International RLS Rating Scale (IRLS). Healthy controls matched for age and sex were enrolled. All participants were evaluated dCA by assessing phase difference (PD). A portion of patients with RLS was reassessed for dCA after one month of medication therapy (pramipexole [0.125 mg/day] and gabapentin [300 mg/day]). There were altogether 120 patients with RLS and 30 controls completed the polysomnography and dCA assessment. PD was lower in the moderate, severe, and very severe RLS groups than that in the controls and mild RLS groups. Periodic limb movement index (PLMI), arousal index, and IRLS all showed a linear correlation with PD in RLS patients. Additionally, PD increased in RLS patients after therapy. The dCA was compromised in moderate, severe, and very severe RLS patients and was negatively correlated with the IRLS, arousal index, and PLMI. After 1 month of therapy, dCA improved in RLS patients.

COVID-19 and Higher Education: Evolving teaching and learning for sustainability - A new era or temporary response?

The COVID-19 pandemic catalysed unprecedented shifts in higher education worldwide, prompting a reevaluation of teaching and learning practices amidst the backdrop of sustainability imperatives. This editorial synthesizes diverse scholarly contributions exploring the intersectionality of COVID-19, sustainability, and higher education. Amidst ongoing global grappling for a "new normal," this special issue poses a central question: How has higher education responded to sustainability amid the pandemic? Reflecting on institutional responses, the collection illuminates both challenges and opportunities in fostering sustainable futures. Themes of technological integration, social sustainability, and policy implications emerge, underlining the need for adaptive pedagogies and community-centered approaches. As higher education navigates this transformative era, the editorial calls for sustained innovation and a commitment to nurturing resilient, inclusive, and environmentally conscious learning environments.

Забезпечення кібербезпеки системи багатофункційних флотів БПЛА для моніторингу критичної інфраструктури: аналіз вразливостей, атак і контрзаходів

The modern world is becoming increasingly dependent on the security of critical infrastructure facilities (CIF), which is monitored by UAVs, their fleets and multifunctional fleet systems (MFS UAVs). The UAV MFS have a complex digital infrastructure (DIS). The DIS is based on new information technologies that have certain security deficiencies and create new cyber threats, in particular, due to specific vulnerabilities that can be exploited externally. The provi-sion of cyber security of the CIS of the MBF of UAVs has been studied thanks to the develop-ment of a sequence of analysis of cyber threats using the IMECA procedure. An overview of existing cyber security assessment methods and their limitations was conducted; developed models of the OKI monitoring system based on the UAV MBF; analyzed cyber threats to its CIS; the criticality of cyber attacks and the impact of countermeasures; formulated recommen-dations for ensuring cyber security and general conclusions based on research results. A method of ensuring cyber security of the CIS of the MBF UAV was created, which consists of determin-ing its specific features as an object of cyber threats, analyzing violators, vulnerabilities, risks of critical violations and choosing countermeasures, the use of which allows you to increase the level of cyber security and reliability of the monitoring system and ensure a temporary response to cyber threats.

Biocompatibility of hydrogel derived from equine tendon extracellular matrix in horses subcutaneous tissue.

Tendinopathies account for a substantial proportion of musculoskeletal injuries. To improve treatment outcomes for partial and total tendon ruptures, new therapies are under investigation. These include the application of mesenchymal stem cells (MSCs) and biocompatible scaffolds derived from the Extracellular Matrix (ECM). Synthetic polymer hydrogels have not demonstrated results as promising as those achieved with ECM hydrogels sourced from the original tissue. This study aimed to evaluate the biocompatibility of a hydrogel formulated from equine tendon ECM. Six horses were administered three subcutaneous doses of the hydrogel, with a saline solution serving as a control. Biopsies were conducted on days 7, 14, and 56 post-application to gauge the hydrogel's impact. Throughout the experiment, the horse's physical condition remained stable. Thermographic analyses revealed a temperature increase in the treated groups compared to the control group within the initial 12h. The von Frey test, used to measure the mechanical nociceptive threshold, also showed significant differences between the treated group and the control group at 6h, 21 days, and 28 days. Histopathological analyses identified an inflammatory response on day 7, which was absent on days 14 and 56. Transmission electron microscopy indicated a decrease in inflammatory cellularity, while immunohistochemistry staining suggested an increased presence of inflammatory factors on day 14. In summary, the hydrogel is easily injectable, triggers a temporary local inflammatory response, and integrates into the adjacent tissue from day 14 onwards.

Isolation of plant-derived exosome-like nanoparticles (PDENs) from Solanum nigrum L. berries and Their Effect on interleukin-6 expression as a potential anti-inflammatory agent.

Inflammation is a temporary response of the immune system that can be treated using common anti-inflammatory drugs. However, prolonged use of these drugs increases the risk of adverse side effects. Accordingly, there is an increasing need for alternative treatments for inflammation with fewer side effects. Exosomes are extracellular vesicles secreted by most eukaryotic cells and have been studied as a candidate for cell-free therapy for inflammatory diseases due to their immunomodulatory and anti-inflammatory properties. In recent years, the focus of exosome research has shifted from animal cell-derived exosomes to plant-derived exosome-like nanoparticles (PDENs). Plant-derived exosome-like nanoparticles (PDENs) are easier to obtain, have minimal safety concerns, and can be produced in higher quantities and lower cost than exosomes derived from animal cells. In this study, the isolation and analysis of the anti-inflammatory potential of PDENs from black nightshade berries (Solanum nigrum L.) were carried out. The results of isolation and characterization showed that PDENs had a spherical morphology, measuring around 107 nm with zeta potential of -0.6 mV, and had a protein concentration of 275.38 μg/mL. PDENs were also shown to be internalized by RAW264.7 macrophage cell line after 2 hours of incubation and had no cytotoxicity effect up to the concentration of 2.5 μg/mL. Furthermore, exposure to several doses of PDENs to the LPS-stimulated RAW264.7 cell significantly decreased the expression of pro-inflammatory cytokine gene IL-6, as well as the expression of IL-6 protein up to 97,28%. GC-MS analysis showed the presence of neral, a monoterpene compound with known anti-inflammatory properties, which may contribute to the anti-inflammatory activity of PDENs isolated from Solanum nigrum L. berries. Taken together, the present study was the first to isolate and characterize PDENs from Solanum nigrum L. berries. The results of this study also demonstrated the anti-inflammatory activity of PDEN by suppressing the production of IL-6 in LPS-stimulated RAW264.7 cells.

Relapsed primary central nervous system lymphoma treated with CD19 chimeric antigen receptor T-cell therapy and allogeneic hematopoietic stem cell transplantation

Relapsed and/or refractory (R/R) primary central nervous system lymphoma (PCNSL) has a poor prognosis. A 57-year-old man diagnosed with PCNSL achieved a complete response by high-dose methotrexate-based chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). The disease was not cured, so he was treated with the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel after the third relapse. However, the disease relapsed again 28 days after CAR T-cell therapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was attempted as curative therapy after bridging with second ASCT and tirabrutinib monotherapy. Although a temporary response was achieved, the disease relapsed 98 days after allo-HSCT. While receiving tirabrutinib for relapse after allo-HSCT, the patient developed acute respiratory failure due to transplant-related toxicity and post-transplant thrombotic microangiopathy. He died 175 days after allo-HSCT. Although various treatments for PCNSL have been investigated in recent years, the treatment strategy for R/R PCNSL has not been established. Further studies are warranted to improve the outcomes of patients with R/R PCNSL.

Handcrafted face shields as a temporary response during COVID-19 pandemic: analyses of variables advocated in nº 356 Resolution by ANVISA

Handcrafted face shields as a temporary response during COVID-19 pandemic: analyses of variables advocated in nº 356 Resolution by ANVISA

A Temporary Frequency Response Strategy Using a Voltage Source-Based Permanent Magnet Synchronous Generator and Energy Storage Systems

A Temporary Frequency Response Strategy Using a Voltage Source-Based Permanent Magnet Synchronous Generator and Energy Storage Systems

Unresectable Ulcerative Colitis Associated Colon Cancer in a Young Japanese Patient: A Case Report.

We herein present the case of a 30-year-old Japanese male patient with ulcerative colitis (UC) who was admitted to our hospital because of significant ascites. Upon evaluation, the patient was diagnosed with unresectable UC-associated cancer (UCAC), localized in the transverse colon. Using gene profiling of the tumor tissue, anti-epidermal growth factor receptor (EGFR) antibody combination chemotherapy was selected. Subsequently, the patient exhibited a temporary response to this regimen, with an enhancement in his quality of life and he was able to survive for 12 months. This case underscores the potential benefits of aggressive chemotherapy tailored to the gene profile in UCAC treatment, offering insights into potential avenues for improving the patient prognosis.

Enhancing operation flexibility of distributed energy systems: A flexible multi-objective optimization planning method considering long-term and temporary objectives

Flexibility is a crucial capability that distributed energy systems need to possess. Flexible distributed energy systems can attain the objectives of daily economic operation for users, temporary demand response for the power grid, and low-carbon operation for environmental benefits. Among these objectives, economy and low-carbon objectives are long-term objectives that need to be met routinely, while grid-friendly interactions only occur temporarily but need to be met as a priority. Current multi-objective optimization planning models disregard the inherent differences in temporal property of these objectives, which may weaken the system's flexibility. Here, a novel multi-objective optimization model is proposed to enhance the flexibility of distributed energy systems. First, a new flexibility index is formulated, in which diverse objectives are evaluated synergistically across different scenarios. Second, a flexible mixed-integer multi-objective programming model is developed, which returns the most flexible system design and its operation strategies for each objective. The application in a real case in Tianjin, China revealed that, compared with the conventional multi-objective planning method, the proposed method could improve the system flexibility by 6%–10 %. The universality of the proposed method was further verified by traversal analysis.

EXTH-36. COMBINING ONC201 AND PAXALISIB FOR THE TREATMENT OF DIFFUSE MIDLINE GLIOMA (DMG); THE PRECLINICAL RESULTS UNDERPINNING THE INTERNATIONAL PHASE II CLINICAL TRIAL (NCT05009992)

Abstract Diffuse midline gliomas (DMGs) diagnosed in the pons (DIPG) are universally fatal central nervous system tumors and are the leading cause of cancer-related death in children. Palliative radiotherapy is the only recognized treatment, with median overall survival just 9-11 months. The brain-penetrant, small molecule, ONC201, shows early-stage clinical trial efficacy, extending survival by ~9-11 months compared to historic controls. However, studies to determine the mechanisms behind the temporary clinical response to ONC201 are needed. Here, we have used a systems-biological approach to investigate whether genomic features influenced ONC201 response. DMGs harboring PIK3CA mutations were more sensitive to ONC201, whereas those harboring TP53 mutations were less sensitive. Quantitative proteogenomics identified that ONC201 elicits potent agonism of the mitochondrial protease, ClpP, driving proteolysis of electron transport chain and tricarboxylic acid proteins, leading to mitochondrial dysfunction. However, metabolic adaptation to ONC201 is promoted by the spare redox-signaling capacity of cells harboring WT-PIK3CA that was counteracted using the brain-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. ONC201 and paxalisib combinations extended survival of orthotopic DIPG xenograft mouse models (SU-DIPG-VI, p=0.0027; SF8626, p=0.0002; HSJD-DIPG-007, p=&amp;lt; 0.0001). The combination in the first three recorded patients; two at progression following re-irradiation, and one at diagnosis following the completion of radiation, resulted in dramatic reductions in tumor area, dramatically extending overall survival for all three patients (25 months, 30 and 31 months continuing). The DIPG patient receiving the combination since diagnosis, remains in progression free survival (MR axial diagnosis scan = 1554 mm2, current tumour area = 306 mm2, ~80% reduction). The patient continuing to receive the combination at progression and following reirradiation also experienced a marked decrease in tumor size (MR axial diagnosis scan = 1248 mm2, current tumour area = 315 mm2, ~75% reduction), 10 months following radiological detection of progression. These data inform the phase II clinical trial (NCT05009992).