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Health systems resilience is key to learning lessons from country responses to crises such as coronavirus disease 2019 (COVID-19). In this perspective, we review COVID-19 responses in 28 countries using a new health systems resilience framework. Through a combination of literature review, national government submissions and interviews with experts, we conducted a comparative analysis of national responses. We report on domains addressing governance and financing, health workforce, medical products and technologies, public health functions, health service delivery and community engagement to prevent and mitigate the spread of COVID-19. We then synthesize four salient elements that underlie highly effective national responses and offer recommendations toward strengthening health systems resilience globally.

Despite progress on the Millennium and Sustainable Development Goals, significant public health challenges remain to address communicable and non-communicable diseases and health inequities. The Healthier Societies for Healthy Populations initiative convened by WHO’s Alliance for Health Policy and Systems Research; the Government of Sweden; and the Wellcome Trust aims to address these complex challenges. One starting point is to build understanding of the characteristics of successful government-led interventions to support healthier populations. To this end, this project explored five purposefully sampled, successful public health initiatives: front-of-package warnings on food labels containing high sugar, sodium or saturated fat (Chile); healthy food initiatives (trans fats, calorie labelling, cap on beverage size; New York); the alcohol sales and transport ban during COVID-19 (South Africa); the Vision Zero road safety initiative (Sweden) and establishment of the Thai Health Promotion Foundation. For each initiative a qualitative, semistructured one-on-one interview with a key leader was conducted, supplemented by a rapid literature scan with input from an information specialist. Thematic analysis of the five interviews and 169 relevant studies across the five examples identified facilitators of success including political leadership, public education, multifaceted approaches, stable funding and planning for opposition. Barriers included industry opposition, the complex nature of public health challenges and poor interagency and multisector co-ordination. Further examples building on this global portfolio will deepen understanding of success factors or failures over time in this critical area.

R2-like ligand-binding oxidase (R2lox) is a ferritin-like protein that harbours a heterodinuclear manganese–iron active site. Although R2lox function is yet to be established, the enzyme binds a fatty acid ligand coordinating the metal centre and catalyses the formation of a tyrosine–valine ether cross-link in the protein scaffold upon O2 activation. Here, we characterized the ligands copurified with R2lox by mass spectrometry-based metabolomics. Moreover, we present the crystal structures of two new homologs of R2lox, from Saccharopolyspora erythraea and Sulfolobus acidocaldarius, at 1.38 Å and 2.26 Å resolution, respectively, providing the highest resolution structure for R2lox, as well as new insights into putative mechanisms regulating the function of the enzyme.

Victoria Haldane and colleagues delve into the characteristics of national responses to covid-19. They suggest actionable steps at a national level that can guide states to achieve the independent panel’s recommendations for making this the last pandemic

Rohit Ramchandani and colleagues propose a framework to ensure essential public health tools are fairly distributed in future pandemics

Anne-Sophie Jung and colleagues argue that research and policy making must embrace complexity to build sustainable and long term approaches to pandemic preparedness

Shishi Wu and colleagues examine three distinct response strategies for covid-19 in eight countries and argue that aggressive containment is the optimal approach to limiting loss of lives and livelihoods and achievable in the absence of vaccines and effective therapies

Salma M Abdalla and colleagues examine how an atmosphere of misinformation, disinformation, and erosion of trust shaped the early response to covid-19 on both global and national levels

G protein-coupled receptors (GPCRs) are key regulatory proteins of immune cell function inducing signaling in response to extracellular (pathogenic) stimuli. Although unrelated, hydroxycarboxylic acid receptor 3 (HCA3) and GPR84 share signaling via Gαi/o proteins and the agonist 3-hydroxydecanoic acid (3HDec). Both receptors are abundantly expressed in monocytes, macrophages and neutrophils but have opposing functions in these innate immune cells. Detailed insights into the molecular mechanisms and signaling components involved in immune cell regulation by GPR84 and HCA3 are still lacking. Here, we report that GPR84-mediated pro-inflammatory signaling depends on coupling to the hematopoietic cell-specific Gα15 protein in human macrophages, while HCA3 exclusively couples to Gαi protein. We show that activated GPR84 induces Gα15-dependent ERK activation, increases intracellular Ca2+ and IP3 levels as well as ROS production. In contrast, HCA3 activation shifts macrophage metabolism to a less glycolytic phenotype, which is associated with anti-inflammatory responses. This is supported by an increased release of anti-inflammatory IL-10 and a decreased secretion of pro-inflammatory IL-1β. In primary human neutrophils, stimulation with HCA3 agonists counteracts the GPR84-induced neutrophil activation. Our analyses reveal that 3HDec acts solely through GPR84 but not HCA3 activation in macrophages. In summary, this study shows that HCA3 mediates hyporesponsiveness in response to metabolites derived from dietary lactic acid bacteria and uncovers that GPR84, which is already targeted in clinical trials, promotes pro-inflammatory signaling via Gα15 protein in macrophages.

Understanding the spread of SARS-CoV-2, how and when evidence emerged, and the timing of local, national, regional, and global responses is essential to establish how an outbreak became a pandemic and to prepare for future health threats. With that aim, the Independent Panel for Pandemic Preparedness and Response has developed a chronology of events, actions, and recommendations, from December, 2019, when the first cases of COVID-19 were identified in China, to the end of March, 2020, by which time the outbreak had spread extensively worldwide and had been characterised as a pandemic. Datapoints are based on two literature reviews, WHO documents and correspondence, submissions to the Panel, and an expert verification process. The retrospective analysis of the chronology shows a dedicated initial response by WHO and some national governments, but also aspects of the response that could have been quicker, including outbreak notifications under the International Health Regulations (IHR), presumption and confirmation of human-to-human transmission of SARS-CoV-2, declaration of a Public Health Emergency of International Concern, and, most importantly, the public health response of many national governments. The chronology also shows that some countries, largely those with previous experience with similar outbreaks, reacted quickly, even ahead of WHO alerts, and were more successful in initially containing the virus. Mapping actions against IHR obligations, the chronology shows where efficiency and accountability could be improved at local, national, and international levels to more quickly alert and contain health threats in the future. In particular, these improvements include necessary reforms to international law and governance for pandemic preparedness and response, including the IHR and a potential framework convention on pandemic preparedness and response.

Victoria Haldane and colleagues argue that to make covid-19 the last pandemic, public health responses to outbreaks must be strengthened, starting with their most basic functions

Sudhvir Singh and colleagues summarise the recommendations of the Independent Panel for Pandemic Preparedness and Response to try to prevent future pandemics

Considering the physicochemical diversity of the metabolome, untargeted metabolomics will inevitably discriminate against certain compound classes. Efforts are nevertheless made to maximize the metabolome coverage. Contrary to the main steps of a typical liquid chromatography–mass spectrometry (LC–MS) metabolomics workflow, such as metabolite extraction, the sample reconstitution step has not been optimized for maximal metabolome coverage. This sample concentration step typically occurs after metabolite extraction, when dried samples are reconstituted in a solvent for injection on column. The aim of this study was to evaluate the impact of the sample reconstitution solvent composition on metabolome coverage in untargeted LC–MS metabolomics. Lysogeny Broth medium samples reconstituted in MeOH/H2O ratios ranging from 0 to 100% MeOH and analyzed with untargeted reversed phase LC–MS showed that the highest number of metabolite features (n = 1500) was detected in samples reconstituted in 100% H2O. As compared ...

Glutamate-ammonia ligase (GLUL) is important for acid-base homeostasis, ammonia detoxification, cell signaling, and proliferation. Here, we reported that GLUL ablation conferred resistance to several anticancer drugs in specific cancer cell lines while leaving other cell lines non-resistant to the same drugs. To understand the biochemical mechanics supporting this drug resistance, we compared drug-resistant GLUL knockout (KO) A549 non-small-cell lung carcinoma (NSCLC) cells with non-resistant GLUL KO H1299 NSCLC cells and found that the resistant A549 cells, to a larger extent, depended on exogenous glucose for proliferation. As GLUL activity is linked to the tricarboxylic acid (TCA) cycle via reversed glutaminolysis, we probed carbon flux through both glycolysis and TCA pathways by means of 13C5 glutamine, 13C5 glutamate, and 13C6 glucose tracing. We observed increased labeling of malate and aspartate in A549 GLUL KO cells, whereas the non-resistant GLUL KO H1299 cells displayed decreased 13C-labeling. The malate and aspartate shuttle supported cellular NADH production and was associated with cellular metabolic fitness. Inhibition of the malate-aspartate shuttle with aminooxyacetic acid significantly impacted upon cell viability with an IC50 of 11.5 &mu, M in resistant GLUL KO A549 cells compared to 28 &mu, M in control A549 cells, linking resistance to the malate-aspartate shuttle. Additionally, rescuing GLUL expression in A549 KO cells increased drug sensitivity. We proposed a novel metabolic mechanism in cancer drug resistance where the increased capacity of the malate-aspartate shuttle increased metabolic fitness, thereby facilitating cancer cells to escape drug pressure.

Background The Ministry of Health and Sanitation (MOHS) in Sierra Leone partially rolled out the implementation of Integrated Disease Surveillance and Response (IDSR) in 2003. After the Ebola virus disease outbreak in 2014–2015, there was need to strengthen IDSR to ensure prompt detection and response to epidemic-prone diseases. We describe the processes, successes and challenges of revitalizing public health surveillance in a country recovering from a protracted Ebola virus disease outbreak. Methods The revitalization process began with adaptation of the revised IDSR guidelines and development of customized guidelines to suit the health care systems in Sierra Leone. Public health experts defined data flow, system operations, case definitions, frequency and channels of reporting and dissemination. Next, phased training of IDSR focal persons in each health facility and the distribution of data collection and reporting tools was done. Monitoring activities included periodic supportive supervision and data quality assessments. Rapid response teams were formed to investigate and respond to disease outbreak alerts in all districts. Results Submission of reports through the IDSR system began in mid-2015 and by the 35th epidemiologic week, all district health teams were submitting reports. The key performance indicators measuring the functionality of the IDSR system in 2016 and 2017 were achieved (WHO Africa Region target ≥80%); the annual average proportion of timely weekly health facility reports submitted to the next level was 93% in 2016 and 97% in 2017; the proportion of suspected outbreaks and public health events detected through the IDSR system was 96% (n = 87) in 2016 and 100% (n = 85) in 2017. Conclusion With proper planning, phased implementation and adequate investment of resources, it is possible to establish a functional IDSR system in a country recovering from a public health crisis. A functional IDSR system requires well trained workforce, provision of the necessary tools and guidelines, information, communication and technology infrastructure to support data transmission, provision of timely feedback as well as logistical support. Electronic supplementary material The online version of this article (10.1186/s12889-019-6636-1) contains supplementary material, which is available to authorized users.

Tumor cells exhibit a specialized metabolism supporting their superior ability for rapid proliferation, migration, and apoptotic evasion. It is reasonable to assume that the specific metabolic needs of the tumor cells can offer an array of therapeutic windows as pharmacological disturbance may derail the biochemical mechanisms necessary for maintaining the tumor characteristics, while being less important for normally proliferating cells. In addition, the specialized metabolism may leave a unique metabolic signature which could be used clinically for diagnostic or prognostic purposes. Quantitative global metabolic profiling (metabolomics) has evolved over the last two decades. However, despite the technology’s present ability to measure 1000s of endogenous metabolites in various clinical or biological specimens, there are essentially no examples of metabolomics investigations being translated into actual utility in the cancer clinic. This review investigates the current efforts of using metabolomics as a tool for translation of tumor metabolism into the clinic and further seeks to outline paths for increasing the momentum of using tumor metabolism as a biomarker and drug target opportunity.

Untargeted metabolic profiling has generated large activity in the field of clinical biomarker discovery. Yet, no clinically approved metabolite biomarkers have emerged with failure in validation phases often being a reason. To investigate why, we have applied untargeted metabolic profiling in a retrospective cohort of serum samples representing non-related diseases. Age and gender matched samples from patients diagnosed with pneumonia, congestive heart failure, lymphoma and healthy controls were subject to comprehensive metabolic profiling using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The metabolic profile of each diagnosis was compared to the healthy control group and significant metabolites were filtered out using t-test with FDR correction. Metabolites found to be significant between each disease and healthy controls were compared and analyzed for overlap. Results show that despite differences in etiology and clinical disease presentation, the fraction of metabolites with an overlap between two or more diseases was 61%. A majority of these metabolites can be associated with immune responses thus representing non-disease specific events. We show that metabolic serum profiles from patients representing non-related diseases display very similar metabolic differences when compared to healthy controls. Many of the metabolites discovered as disease specific in this study have further been associated with other diseases in the literature. Based on our findings we suggest non-related disease controls in metabolomics biomarker discovery studies to increase the chances of a successful validation and future clinical applications.

Utdragen granskning som institutionaliserad kosmopolitism : PACE:s granskning av demokratier i kris i Sodra Kaukasus

Cancer cells that escape induction therapy are a major cause of relapse. Understanding metabolic alterations associated with drug resistance opens up unexplored opportunities for the development of new therapeutic strategies. Here, we applied a broad spectrum of technologies including RNA sequencing, global untargeted metabolomics, and stable isotope labeling mass spectrometry to identify metabolic changes in P-glycoprotein overexpressing T-cell acute lymphoblastic leukemia (ALL) cells, which escaped a therapeutically relevant daunorubicin treatment. We show that compared with sensitive ALL cells, resistant leukemia cells possess a fundamentally rewired central metabolism characterized by reduced dependence on glutamine despite a lack of expression of glutamate-ammonia ligase (GLUL), a higher demand for glucose and an altered rate of fatty acid β-oxidation, accompanied by a decreased pantothenic acid uptake capacity. We experimentally validate our findings by selectively targeting components of this metabolic switch, using approved drugs and starvation approaches followed by cell viability analyses in both the ALL cells and in an acute myeloid leukemia (AML) sensitive/resistant cell line pair. We demonstrate how comparative metabolomics and RNA expression profiling of drug-sensitive and -resistant cells expose targetable metabolic changes and potential resistance markers. Our results show that drug resistance is associated with significant metabolic costs in cancer cells, which could be exploited using new therapeutic strategies.

Small molecule quantitative tandem mass spectrometry analysis(1) is now widely used in life sciences and medicine. Quantification is usually accomplished by prior fragmentation of standard materials and the use of commercial software to quantitate the resulting peaks(2,3). Despite its widespread application, there is a paucity of public libraries to expedite assay development. Here, we introduce a new library, METLIN-MRM, comprised of more than 15,500 optimized transitions for multiple reaction monitoring of a wide variety of low molecular weight compounds. METLIN-MRM includes (i) transitions optimized following the established protocol with standard materials and (ii) transitions computationally optimized for selectivity. This computational optimization was achieved by the analysis of a large collection of tandem mass spectrometry spectra, where an algorithm selected the most unique transitions for a given compound in comparison with other compounds with a mass within the error of the mass spectrometer. METLIN-MRM streamlines quantitative analyses with minimal resources and development time and also serves as a public repository, allowing the community to upload, share and cite experimental transitions through accession numbers. Additionally, this library has been integrated with XCMS-MRM, a cloud-based data analysis platform that allows for data analysis and sharing across different platforms and laboratories. This platform is publicly accessible at http://metlin.scripps.edu/ and http://xcmsonline-mrm.scripps.edu

Introduction Sierra Leone experienced an unprecedented Ebola virus disease (EVD) outbreak in all its districts. Koinadugu District was the last to report an EVD case. Several outbreak response strategies were implemented. As part of lessons learnt, we conducted an observational study to describe the transmission chain in the district and the impact of the control measures implemented to contain the outbreak. Methods We reconstructed the transmission chain, positioning both confirmed and probable cases, described the distribution of the EVD confirmed cases in the context of the routes of transmission (Community, Funeral or Health facility setting) and assessed the impact of control measures using the surveillance data collected during the outbreak. Results All 142 confirmed and probable EVD cases registered were fully resolved in the transmission chain. 72.5% of all the EVD cases in the district were exposed in the community, 26.1% exposed during funerals, and 1.4% exposed in the health facility setting. Health-care workers contributed little to the EVD outbreak. 71.1% of EVD transmission occurred among family members. Female EVD cases generated more secondary cases than their male counterparts (P = 0.03). With removal of EVD cases from the community and admission to the community care center (CCC), the EVD transmission in the community decreased to substantially lower rates. In addition, transmission due to exposure in health facilities was further reduced with the implementation of full infection and prevention controls. Conclusion This study details the transmission chain of EVD in a rural district setting and the public health interventions implemented to successfully limit the outbreak to just one of 11 chiefdoms. Heightened community-based surveillance for early case detection, swift isolation of suspect cases, efficient contact tracing and monitoring, and good infection prevention and control measures in health facilities were highly effective in limiting transmission and, eventually, breaking the transmission chain. CCCs were also instrumental in achieving early isolation and basic care for suspect cases, while ensuring that their family members who were close contacts remained in the community for easy contact tracing and monitoring. These were very useful lessons learnt that would inform the management of future outbreaks.

Introduction Pancreatic ductal adenocarcinoma (PDAC) is the fifth most common cause of cancer-related death in Europe with a 5-year survival rate of

Christian Lienhardt and colleagues describe the research efforts needed to end the global tuberculosis epidemic by 2035.

Concern that underfunded and weak health systems are impeding the achievement of the health Millennium Development Goals in low-income countries led to the creation of a High Level Taskforce on Innovative International Financing for Health Systems in September, 2008. This report summarises the key challenges faced by the Taskforce and its Working Groups. Working Group 1 examined the constraints to scaling up and costs. Challenges included: difficulty in generalisation because of scarce and context-specific health-systems knowledge; no consensus for optimum service-delivery approaches, leading to wide cost differences; no consensus for health benefits; difficulty in quantification of likely efficiency gains; and challenges in quantification of the financing gap owing to uncertainties about financial commitments for health. Working Group 2 reviewed the different innovative mechanisms for raising and channelling funds. Challenges included: variable definitions of innovative finance; small evidence base for many innovative finance mechanisms; insufficient experience in harmonisation of global health initiatives; and inadequate experience in use of international investments to improve maternal, newborn, and child health. The various mechanisms reviewed and finally recommended all had different characteristics, some focusing on specific problems and some on raising resources generally. Contentious issues included the potential role of the private sector, the rights-based approach to health, and the move to results-based aid. The challenges and disagreements that arose during the work of the Taskforce draw attention to the many issues facing decision makers in low-income countries. International donors and recipient governments should work together to improve the evidence base for strengthening health systems, increase long-term commitments, and improve accountability through transparent and inclusive national approaches.

N(alpha)-tosyl-L-phenylalanine chloromethylketone (TPCK) has been widely used to investigate signal transduction pathways that are involved in gene expression and cell survival/cell death. However, contradictory effects of TPCK on apoptosis have been reported, and the underlying signaling events leading to TPCK-induced promotion or prevention of apoptosis are not fully understood. Here, we show that TPCK induces caspase-dependent apoptosis in Epstein-Barr virus (EBV)-transformed human B cell lines with release of pro-apoptotic proteins from mitochondria. TPCK treatment also results in down-regulation of the anti-apoptotic proteins, cIAP1, cIAP2, and HAX-1, and caspase-dependent cleavage of the anti-apoptotic proteins, Bcl-2 and XIAP. Quantitative PCR analysis confirmed that the TPCK-induced down-regulation of HAX-1 occurred at the transcriptional level, and experiments using the specific pharmacological inhibitor, Bay 11-7082, suggested that HAX-1 expression is subject to regulation by the transcription factor, NF-kappaB. B cell lines derived from patients with homozygous HAX1 mutations were more sensitive to TPCK-induced apoptosis when compared with normal donor cell lines. Furthermore, N-acetylcysteine effectively blocked TPCK-induced apoptosis in EBV-transformed B cell lines and prevented the down-regulation or cleavage of anti-apoptotic proteins. Taken together, our studies demonstrate that TPCK induces apoptosis in human B cell lines and exerts multiple effects on pro- and anti-apoptotic factors.

A multiple ionization mass spectrometry strategy is presented based on the analysis of human serum extracts. Chromatographic separation was interfaced inline with the atmospheric pressure ionization techniques electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) in both positive (+) and negative (-) ionization modes. Furthermore, surface-based matrix-assisted laser desorption/ionization (MALDI) and desorption ionization on silicon (DIOS) mass spectrometry were also integrated with the separation through fraction collection and offline mass spectrometry. Processing of raw data using the XCMS software resulted in time-aligned ion features, which are defined as a unique m/z at a unique retention time. The ion feature lists obtained through LC-MS with ESI and APCI interfaces in both +/- ionization modes were compared, and unique ion tables were generated. Nonredundant, unique ion features, were defined as mass numbers for which no mass numbers corresponding to [M + H](+), [M - H](-), or [M + Na](+) were observed in the other ionization methods at the same retention time. Analysis of the extracted serum using ESI for both (+) and (-) ions resulted in90% additional unique ions being detected in the (-) ESI mode. Complementing the ESI analysis with APCI resulted in an additional approximately 20% increase in unique ions. Finally, ESI/APCI ionization was combined with fraction collection and offline-MALDI and DIOS mass spectrometry. The parts of the total ion current chromatograms in the LC-MS acquired data corresponding to collected fractions were summed, and m/z lists were compiled and compared to the m/z lists obtained from the DIOS/MALDI spectra. It was observed that, for each fraction, DIOS accounted for approximately 50% of the unique ions detected. These results suggest that true global metabolomics will require multiple ionization technologies to address the inherent metabolite diversity and therefore the complexity in and of metabolomics studies.

The surface structure of porous silicon used in desorption/ionization on porous silicon (DIOS) mass analysis is known to play a primary role in the desorption/ionization (D/I) process. In this study, mass spectrometry and scanning electron microscopy (SEM) are used to examine the correlation between intact ion generation with surface ablation and surface morphology. The DIOS process is found to be highly laser energy dependent and correlates directly with the appearance of surface ions (Si(n)(+) and OSiH(+)). A threshold laser energy for DIOS is observed (10 mJ/cm(2)), which supports that DIOS is driven by surface restructuring and is not a strictly thermal process. In addition, three DIOS regimes are observed that correspond to surface restructuring and melting. These results suggest that higher surface area silicon substrates may enhance DIOS performance. A recent example that fits into this mechanism is the surface of silicon nanowires, which has a high surface energy and concomitantly requires lower laser energy for analyte desorption.

The ability of mass spectrometry to generate intact biomolecular ions efficiently in the gas phase has led to its widespread application in metabolomics, proteomics, biological imaging, biomarker discovery and clinical assays (namely neonatal screens). Matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization have been at the forefront of these developments. However, matrix application complicates the use of MALDI for cellular, tissue, biofluid and microarray analysis and can limit the spatial resolution because of the matrix crystal size (typically more than 10 mum), sensitivity and detection of small compounds (less than 500 Da). Secondary-ion mass spectrometry has extremely high lateral resolution (100 nm) and has found biological applications although the energetic desorption/ionization is a limitation owing to molecular fragmentation. Here we introduce nanostructure-initiator mass spectrometry (NIMS), a tool for spatially defined mass analysis. NIMS uses 'initiator' molecules trapped in nanostructured surfaces or 'clathrates' to release and ionize intact molecules adsorbed on the surface. This surface responds to both ion and laser irradiation. The lateral resolution (ion-NIMS about 150 nm), sensitivity, matrix-free and reduced fragmentation of NIMS allows direct characterization of peptide microarrays, direct mass analysis of single cells, tissue imaging, and direct characterization of blood and urine.

The cholesterol metabolism is essential for cancer cell proliferation. We found the expression of genes involved in the cholesterol biosynthesis pathway up-regulated in the daunorubicin-resistant leukemia cell line CEM/R2, which is a daughter cell line to the leukemia cell line CCRF-CEM (CEM). Cellular 2H2O labelling, mass spectrometry, and isotopomer analysis revealed an increase in lanosterol synthesis which was not accompanied by an increase in cholesterol flux or pool size in CEM/R2 cells. Exogenous addition of lanosterol had a negative effect on CEM/R2 and a positive effect on sensitive CEM cell viability. Treatment of CEM and CEM/R2 cells with cholesterol biosynthesis inhibitors acting on the enzymes squalene epoxidase and lanosterol synthase, both also involved in the 24,25-epoxycholesterol shunt pathway, revealed a connection of this pathway to lanosterol turnover. Our data highlight that an increased lanosterol flux poses a metabolic weakness of resistant cells that potentially could be therapeutically exploited. Electronic supplementary material The online version of this article (doi:10.1007/s12032-015-0717-5) contains supplementary material, which is available to authorized users.

Cancer cells that escape induction therapy are a major cause of relapse. Understanding metabolic alterations associated with drug resistance opens up unexplored opportunities for the development of new therapeutic strategies. Here, we applied a broad spectrum of technologies including RNA sequencing, global untargeted metabolomics, and stable isotope labeling mass spectrometry to identify metabolic changes in P-glycoprotein overexpressing T-cell acute lymphoblastic leukemia (ALL) cells, which escaped a therapeutically relevant daunorubicin treatment. We show that compared with sensitive ALL cells, resistant leukemia cells possess a fundamentally rewired central metabolism characterized by reduced dependence on glutamine despite a lack of expression of glutamate-ammonia ligase (GLUL), a higher demand for glucose and an altered rate of fatty acid β-oxidation, accompanied by a decreased pantothenic acid uptake capacity. We experimentally validate our findings by selectively targeting components of this metabolic switch, using approved drugs and starvation approaches followed by cell viability analyses in both the ALL cells and in an acute myeloid leukemia (AML) sensitive/resistant cell line pair. We demonstrate how comparative metabolomics and RNA expression profiling of drug-sensitive and -resistant cells expose targetable metabolic changes and potential resistance markers. Our results show that drug resistance is associated with significant metabolic costs in cancer cells, which could be exploited using new therapeutic strategies.