Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.

The renal epithelium is sensitive to changes in blood potassium (K+). We identify the basolateral K+ channel, Kir4.2, as a mediator of the proximal tubule response to K+ deficiency. Mice lacking Kir4.2 have a compensated baseline phenotype whereby they increase their distal transport burden to maintain homeostasis. Upon dietary K+ depletion, knockout animals decompensate as evidenced by increased urinary K+ excretion and development of a proximal renal tubular acidosis. Potassium wasting is not proximal in origin but is caused by higher ENaC activity and depends upon increased distal sodium delivery. Three-dimensional imaging reveals Kir4.2 knockouts fail to undergo proximal tubule expansion, while the distal convoluted tubule response is exaggerated. AKT signaling mediates the dietary K+ response, which is blunted in Kir4.2 knockouts. Lastly, we demonstrate in isolated tubules that AKT phosphorylation in response to low K+ depends upon mTORC2 activation by secondary changes in Cl- transport. Data support a proximal role for cell Cl- which, as it does along the distal nephron, responds to K+ changes to activate kinase signaling.

MYTX-011: A pH-Dependent Anti-c-MET Antibody-Drug Conjugate Designed for Enhanced Payload Delivery to c-MET-Expressing Tumor Cells.

Advances in linker payload technology and target selection have been at the forefront of recent improvements in antibody-drug conjugate (ADC) design, leading to several approvals over the last decade. In contrast, the potential of novel ADC technologies to enhance payload delivery to tumors is relatively underexplored. We demonstrate that incorporation of pH-dependent binding in the antibody component of a c-mesenchymal-epithelial transition (MET)-targeting ADC (MYTX-011) can overcome the requirement for high c-MET expression on tumors, an innovation that has the potential to benefit a broader population of patients with lower c-MET levels. MYTX-011 drove fourfold higher net internalization than a non-pH-engineered parent ADC in non-small cell lung cancer (NSCLC) cells and showed increased cytotoxicity against a panel of cell lines from various solid tumors. A single dose of MYTX-011 showed at least threefold higher efficacy than a benchmark ADC in mouse xenograft models of NSCLC ranging from low to high c-MET expression. Moreover, MYTX-011 showed improved pharmacokinetics over parent and benchmark ADCs. In a repeat dose toxicology study, MYTX-011 exhibited a toxicity profile similar to other monomethyl auristatin E-based ADCs. These results highlight the potential of MYTX-011 for treating a broader range of patients with NSCLC with c-MET expression than other c-MET-targeting ADCs. A first-in-human study is ongoing to determine the safety, tolerability, and preliminary efficacy of MYTX-011 in patients with NSCLC (NCT05652868).

Updates in traumatic brain injury management: brain oxygenation, middle meningeal artery embolization and new protocols.

Traumatic brain injury (TBI) confers significant morbidity and mortality, and is a pathology often encountered by trauma surgeons. Several recent trials have evaluated management protocols of patients with severe TBI. The Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II trial (BOOST-II) evaluated efficacy and feasibility of brain oxygen measurement in severe TBI. BOOST phase 3 trial (BOOST-3) and two ongoing trials look to measure functional outcomes in this population. Furthermore, middle meningeal artery embolization has now become standard therapy for adult patients with chronic subdural hematoma (SDH) and has increasing popularity in those with recurrent SDH as an alternative to surgical intervention. In this manuscript, we review the literature, ongoing trials, and discuss current updates in the management of TBI.

MYTX-011: a pH-dependent anti-cMET antibody-drug conjugate designed for enhanced payload delivery to cMET expressing tumor cells.

Advances in linker payload technology and target selection have been at the forefront of recent improvements in antibody-drug conjugate (ADC) design, leading to several approvals over the last decade. In contrast, the potential of novel ADC technologies to enhance payload delivery to tumors is relatively underexplored. We demonstrate that incorporation of pH-dependent binding in the antibody component of a cMET targeting ADC (MYTX-011) can overcome the requirement for high cMET expression on tumors, an innovation that has the potential to benefit a broader population of patients with lower cMET levels. MYTX-011 drove four-fold higher net internalization than a non-pH engineered parent ADC in non-small cell lung cancer (NSCLC) cells and showed increased cytotoxicity against a panel of cell lines from various solid tumors. A single dose of MYTX-011 showed at least three-fold higher efficacy than a benchmark ADC in mouse xenograft models of NSCLC ranging from low to high cMET expression. Moreover, MYTX-011 showed improved pharmacokinetics over parent and benchmark ADCs. In a repeat dose toxicology study, MYTX-011 exhibited a toxicity profile similar to other MMAE-based ADCs. These results highlight the potential of MYTX-011 for treating a broader range of NSCLC patients with cMET expression than other cMET targeting ADCs. A first in human study is ongoing to determine the safety, tolerability, and preliminary efficacy of MYTX-011 in patients with NSCLC (NCT05652868).

Ethics in disaster, mass casualty care, and critical care.

The primary ethical principle guiding general medical practice is autonomy. However, in mass casualty (MASCAL) or disaster scenarios, the principles of beneficence and justice become of foremost concern. Despite multiple reviews, publications, and training courses available to prepare for a MASCAL incident, a minority of physicians and healthcare providers are abreast of these. In this review, we describe several MASCAL scenarios and their associated ethical, moral, and medicolegal quandaries in attempts to curb potential future misadventures.

Failing kidneys: renal replacement therapies in the ICU.

Acute kidney injury (AKI) is one of the most common organ dysfunctions impacting ICU (intensive care unit) patients. Early diagnosis using the various classification systems and interventions that can be aided by use of biomarkers are key in improving outcomes. Once the patient meets criteria of AKI, many patient specific factors determine the optimal timing for and mode of renal replacement therapy. There are several special considerations in surgical ICU patients with AKI including management of intracranial hypertension in those with cerebral edema, anticoagulation in high-risk bleeding patients, and use of contrast imaging. This article provides a focused review of the essential aspects of diagnosis and management of AKI in the critically ill or injured surgical patient.

Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the 'WIN' site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

An 18F-FDG PET/CT and Mean Lung Dose Model to Predict Early Radiation Pneumonitis in Stage III Non-Small Cell Lung Cancer Patients Treated with Chemoradiation and Immunotherapy.

Radiation pneumonitis (RP) that develops early (i.e., within 3 mo) (RPEarly) after completion of concurrent chemoradiation (cCRT) leads to treatment discontinuation and poorer survival for patients with stage III non-small cell lung cancer. Since no RPEarly risk model exists, we explored whether published RP models and pretreatment 18F-FDG PET/CT-derived features predict RPEarly Methods: One hundred sixty patients with stage III non-small cell lung cancer treated with cCRT and consolidative immunotherapy were analyzed for RPEarly Three published RP models that included the mean lung dose (MLD) and patient characteristics were examined. Pretreatment 18F-FDG PET/CT normal-lung SUV featured included the following: 10th percentile of SUV (SUVP10), 90th percentile of SUV (SUVP90), SUVmax, SUVmean, minimum SUV, and SD. Associations between models/features and RPEarly were assessed using area under the receiver-operating characteristic curve (AUC), P values, and the Hosmer-Lemeshow test (pHL). The cohort was randomly split, with similar RPEarly rates, into a 70%/30% derivation/internal validation subset. Results: Twenty (13%) patients developed RPEarly Predictors for RPEarly were MLD alone (AUC, 0.72; P = 0.02; pHL, 0.87), SUVP10, SUVP90, and SUVmean (AUC, 0.70-0.74; P = 0.003-0.006; pHL, 0.67-0.70). The combined MLD and SUVP90 model generalized in the validation subset and was deemed the final RPEarly model (RPEarly risk = 1/[1+e(- x )]; x = -6.08 + [0.17 × MLD] + [1.63 × SUVP90]). The final model refitted in the 160 patients indicated improvement over the published MLD-alone model (AUC, 0.77 vs. 0.72; P = 0.0001 vs. 0.02; pHL, 0.65 vs. 0.87). Conclusion: Patients at risk for RPEarly can be detected with high certainty by combining the normal lung's MLD and pretreatment 18F-FDG PET/CT SUVP90 This refined model can be used to identify patients at an elevated risk for premature immunotherapy discontinuation due to RPEarly and could allow for interventions to improve treatment outcomes.

Morbidity and Length of Stay After Injury Among People Experiencing Homelessness in North America.

Importance: Traumatic injury is a leading cause of hospitalization among people experiencing homelessness. However, hospital course among this population is unknown. Objective: To evaluate whether homelessness was associated with increased morbidity and length of stay (LOS) after hospitalization for traumatic injury and whether associations between homelessness and LOS were moderated by age and/or Injury Severity Score (ISS). Design, Setting, and Participants: This retrospective cohort study of the American College of Surgeons Trauma Quality Programs (TQP) included patients 18 years or older who were hospitalized after an injury and discharged alive from 787 hospitals in North America from January 1, 2017, to December 31, 2018. People experiencing homelessness were propensity matched to housed patients for hospital, sex, insurance type, comorbidity, injury mechanism type, injury body region, and Glasgow Coma Scale score. Data were analyzed from February 1, 2022, to May 31, 2023. Exposures: People experiencing homelessness were identified using the TQP's alternate home residence variable. Main Outcomes and Measures: Morbidity, hemorrhage control surgery, and intensive care unit (ICU) admission were assessed. Associations between homelessness and LOS (in days) were tested with hierarchical multivariable negative bionomial regression. Moderation effects of age and ISS on the association between homelessness and LOS were evaluated with interaction terms. Results: Of 1 441 982 patients (mean [SD] age, 55.1 [21.1] years; (822 491 [57.0%] men, 619 337 [43.0%] women, and 154 [0.01%] missing), 9065 (0.6%) were people experiencing homelessness. Unmatched people experiencing homelessness demonstrated higher rates of morbidity (221 [2.4%] vs 25 134 [1.8%]; P < .001), hemorrhage control surgery (289 [3.2%] vs 20 331 [1.4%]; P < .001), and ICU admission (2353 [26.0%] vs 307 714 [21.5%]; P < .001) compared with housed patients. The matched cohort comprised 8665 pairs at 378 hospitals. Differences in rates of morbidity, hemorrhage control surgery, and ICU admission between people experiencing homelessness and matched housed patients were not statistically significant. The median unadjusted LOS was 5 (IQR, 3-10) days among people experiencing homelessness and 4 (IQR, 2-8) days among matched housed patients (P < .001). People experiencing homelessness experienced a 22.1% longer adjusted LOS (incident rate ratio [IRR], 1.22 [95% CI, 1.19-1.25]). The greatest increase in adjusted LOS was observed among people experiencing homelessness who were 65 years or older (IRR, 1.42 [95% CI, 1.32-1.54]). People experiencing homelessness with minor injury (ISS, 1-8) had the greatest relative increase in adjusted LOS (IRR, 1.30 [95% CI, 1.25-1.35]) compared with people experiencing homelessness with severe injury (ISS ≥16; IRR, 1.14 [95% CI, 1.09-1.20]). Conclusions and Relevance: The findings of this cohort study suggest that challenges in providing safe discharge to people experiencing homelessness after injury may lead to prolonged LOS. These findings underscore the need to reduce disparities in trauma outcomes and improve hospital resource use among people experiencing homelessness.

Trauma surgeons experience compassion fatigue: A major metropolitan area survey.

INTRODUCTION: Compassion fatigue (CF), the physical, emotional, and psychological impact of helping others, is composed of three domains: compassion satisfaction (CS), secondary traumatic stress (STS), and burnout (BO). Trauma surgeons (TSs) experience work-related stress resulting in high rates of CF, which can manifest as physical and psychological disorders. We hypothesized that TSs experience CF and there are potentially modifiable systemic factors to mitigate its symptoms. METHODS: All TSs in a major metropolitan area were eligible. Personal and professional demographic information was obtained. Each participant completed six validated surveys: (1) Professional Quality of Life scale, (2) Perceived Stress Scale, (3) Multidimensional Scale of Perceived Social Support, (4) Adverse Childhood Events Questionnaire, (5) Brief Coping Inventory, and (6) Toronto Empathy Questionnaire. Compassion fatigue subscale risk scores (low, <23; moderate, 23-41; high, >41) were recorded. Linear regression analysis assessed the demographic and environmental factors association with BO, STS, and CS. Variables significant on univariate analysis were included in multivariate models to determine the independent influence on BO, STS, and CS. Significance was p ≤ 0.05. RESULTS: There were 57 TSs (response rate, 75.4% [n = 43]; White, 65% [n = 28]; male, 67% [n = 29]). Trauma surgeons experienced CF (BO, 26 [interquartile range (IQR), 21-32]; STS, 23 [IQR, 19-32]; CS, 39 [IQR, 34-45]). The Perceived Stress Scale score was significantly associated with increased BO (coefficient [coef.], 0.52; 95% confidence interval [CI], 0.28-0.77) and STS (coef., 0.44; 95% CI, 0.15-0.73), and decreased CS (coef., -0.51; 95% CI, -0.80 to -0.23) ( p < 0.01). Night shifts were associated with higher BO (coef., 1.55; 95% CI, 0.07-3.03; p = 0.05); conversely, day shifts were associated with higher STS (coef., 1.94; 95% CI, 0.32-3.56; p = 0.03). Higher Toronto Empathy Questionnaire scores were associated with greater CS (coef., 0.33; 95% CI, 0.12-0.55; p < 0.01). CONCLUSION: Trauma surgeons experience moderate BO and STS associated with modifiable system- and work-related stressors. Efforts to reduce CF should focus on addressing sources of workplace stress and promoting empathic care. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

Racial and Ethnic Disparities in Operative Experience Among General Surgery Residents: A Multi-Institutional Study from the US ROPE Consortium.

OBJECTIVE: To determine the relationship between race/ethnicity and case volume among graduating surgical residents. BACKGROUND: Racial/ethnic minority individuals face barriers to entry and advancement in surgery; however, no large-scale investigations of the operative experience of racial/ethnic minority residents have been performed. METHODS: A multi-institutional retrospective analysis of the Accreditation Council for Graduate Medical Education case logs of categorical general surgery residents at 20 programs in the US Resident OPerative Experience Consortium database was performed. All residents graduating between 2010 and 2020 were included. The total, surgeon chief, surgeon junior, and teaching assistant case volumes were compared between racial/ethnic groups. RESULTS: The cohort included 1343 residents. There were 211 (15.7%) Asian, 65 (4.8%) Black, 73 (5.4%) Hispanic, 71 (5.3%) "Other" (Native American or Multiple Race), and 923 (68.7%) White residents. On adjusted analysis, Black residents performed 76 fewer total cases (95% CI, -109 to -43, P <0.001) and 69 fewer surgeon junior cases (-98 to -40, P <0.001) than White residents. Comparing adjusted total case volume by graduation year, both Black residents and White residents performed more cases over time; however, there was no difference in the rates of annual increase (10 versus 12 cases per year increase, respectively, P =0.769). Thus, differences in total case volume persisted over the study period. CONCLUSIONS: In this multi-institutional study, Black residents graduated with lower case volume than non-minority residents throughout the previous decade. Reduced operative learning opportunities may negatively impact professional advancement. Systemic interventions are needed to promote equitable operative experience and positive culture change.

Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the "WIN" site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small molecule WIN site inhibitors, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anti-cancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anti-cancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

A multi-institutional study from the US ROPE consortium examining factors associated with endocrine surgery exposure for general surgery residents.

BACKGROUND: Prior analyses of general surgery resident case logs have indicated a decline in the number of endocrine procedures performed during residency. This study aimed to identify factors contributing to the endocrine operative experience of general surgery residents and compare those who matched in endocrine surgery fellowship with those who did not. METHODS: We analyzed the case log data of graduates from 18 general surgery residency programs in the US Resident Operative Experience Consortium over an 11-year period. RESULTS: Of the 1,240 residents we included, 17 (1%) matched into endocrine surgery fellowships. Those who matched treated more total endocrine cases, including more thyroid, parathyroid, and adrenal cases, than those who did not (81 vs 37, respectively, P < .01). Program-level factors associated with increased endocrine volume included endocrine-specific rotations (+10, confidence interval 8-12, P < .01), endocrine-trained faculty (+8, confidence interval 7-10, P < .01), and program co-location with otolaryngology residency (+5, confidence interval 2 -8, P < .01) or endocrine surgery fellowship (+4, confidence interval 2-6, P < .01). Factors associated with decreased endocrine volume included bottom 50th percentile in National Institute of Health funding (-10, confidence interval -12 to -8, P < .01) and endocrine-focused otolaryngologists (-3, confidence interval -4 to -1, P < .01). CONCLUSION: Several characteristics are associated with a robust endocrine experience and pursuit of an endocrine surgery fellowship. Modifiable factors include optimizing the recruitment of dedicated endocrine surgeons and the inclusion of endocrine surgery rotations in general surgery residency.

Hinduism.

Death is a universal experience. Regardless of one's culture, religion, race or beliefs, we will all die. Hinduism views death very uniquely. Hindus simultaneously mourn and celebrate the loss of loved ones.

A Multipathway Phosphopeptide Standard for Rapid Phosphoproteomics Assay Development.

Recent advances in methodology have made phosphopeptide analysis a tractable problem for many proteomics researchers. There are now a wide variety of robust and accessible enrichment strategies to generate phosphoproteomes while free or inexpensive software tools for quantitation and site localization have simplified phosphoproteome analysis workflow tremendously. As a research group under the Association for Biomolecular Resource Facilities umbrella, the Proteomics Standards Research Group has worked to develop a multipathway phosphopeptide standard based on a mixture of heavy-labeled phosphopeptides designed to enable researchers to rapidly develop assays. This mixture contains 131 mass spectrometry vetted phosphopeptides specifically chosen to cover as many known biologically interesting phosphosites as possible from seven different signaling networks: AMPK signaling, death and apoptosis signaling, ErbB signaling, insulin/insulin-like growth factor-1 signaling, mTOR signaling, PI3K/AKT signaling, and stress (p38/SAPK/JNK) signaling. Here, we describe a characterization of this mixture spiked into a HeLa tryptic digest stimulated with both epidermal growth factor and insulin-like growth factor-1 to activate the MAPK and PI3K/AKT/mTOR pathways. We further demonstrate a comparison of phosphoproteomic profiling of HeLa performed independently in five labs using this phosphopeptide mixture with data-independent acquisition. Despite different experimental and instrumentation processes, we found that labs could produce reproducible, harmonized datasets by reporting measurements as ratios to the standard, while intensity measurements showed lower consistency between labs even after normalization. Our results suggest that widely available, biologically relevant phosphopeptide standards can act as a quantitative "yardstick" across laboratories and sample preparations enabling experimental designs larger than a single laboratory can perform. Raw data files are publicly available in the MassIVE dataset MSV000090564.

A nationwide analysis of geriatric proximal humerus fractures: trends, outcomes, and cost.

Background: In the USA, proximal humerus fractures (PHF) are the third most common fracture among the elderly. Although most geriatric PHF are treated conservatively, surgical management remains an option. This retrospective study compares annual trends, patient outcomes, and hospital costs between operatively and non-operatively managed geriatric PHF. Methods: The Healthcare Cost and Utilization Project Nationwide Inpatient Sample was queried from 2012 to 2015. Geriatric patients with PHF were identified and those who underwent operative or non-operative management were compared in trends, outcomes and costs. Results: In total, 137 810 patients met inclusion criteria, of which 51 795 (37.6%) underwent operative management. The operative cohort was younger (76.6 vs 80.9, p<0.001) with a greater proportion of females (81.8% vs 77.6%, p<0.001). The operative cohort demonstrated less frailty and lower Elixhauser Comorbidity Scores (both p<0.001). The operative cohort was also more likely to be discharged home (30.4% vs 13.9%, p<0.001). There was no significant linear trend in age-adjusted and sex-adjusted proportions of operative versus non-operative geriatric PHF (p=0.071), but a positive linear trend was statistically significant for total cost of operative geriatric PHF (p<0.001). Multivariable analyses demonstrated similar overall complication rates between cohorts (OR 0.95, 95% CI 0.89 to 1.00; p=0.06), although surgical intervention increased length of stay (LOS) by 0.15 days (95% CI 0.03 to 0.27; p<0.001) and median cost of hospitalization by US$10 684 (95% CI US$10 384 to US$10 984; p<0.001). Conclusions: This study identifies a positive linear trend in total cost of operatively managed geriatric PHF from 2012 to 2015. Operative management of geriatric PHF is associated with a similar overall complication rate and greater likelihood of being discharged home. Although non-operative management is associated with decreased LOS and hospital expenses, providers should consider surgical PHF treatment options when available and appropriate in the context of patient-focused outcomes, particularly long-term disposition after intervention. Level of Evidence: This level IV retrospective study identifies.

Mid-Term Outlook Following Modified Senning's Operation for the Correction of Transposition of the Great Arteries: A Case Series and Review of Literature.

At the time of writing, two patients who underwent modified Senning's operation (MSO) for the treatment of transposition of great arteries (TGAs) were followed up. At the time of surgery, the patients were three months and 15 years old, respectively. The duration of the follow-up was three years, during which there was a good prognosis, and hence no further invasive treatments were required. There was normal functioning of the right ventricle (RV) in both patients, with the exception of a minor baffle leak in the three-month-old patient. At the annual three-year follow-up, the tricuspid regurgitation (systemic atrioventricular valve) status was moderate in the three-year-old child and mild in the 18-year-old girl. Both patients maintained sinus rhythm and are assigned classification as New York Heart Association (NYHA) Classes I and II. This study aims to assess the midterm outlook after MSO in order to identify and manage future long-term complications. Our report shows a positive outcome in terms of survival and functional activities among children with d-TGA; however, there is a strong need for future research to evaluate the prognosis in the long term (LT) and to assess the functioning of RV.

Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism.

Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.