Rapid therapeutic monitoring of high-dose methotrexate (MTX) chemotherapy is essential to avoid toxicity. MTX concentrations are commonly monitored using immunoassays that are limited by narrow dynamic range and metabolite cross reactivity. Mass spectrometry may improve the molecular specificity of MTX analysis but is limited by slow throughput and extensive calibration. In this study, we examined the consequences of eliminating LC from MS/MS and foregoing external calibration to enable rapid determination of MTX.

MTX (m/z 455 → 308), was assessed using UPLC-MS/MS or flow-injection MS/MS using a six-point external calibration scheme with a single deuterated internal standard, 4-point internal calibration using 13C5, 13C6, 13C11, and 13C14-MTX, or by single point calibration with the single deuterated internal standard. Accuracy, precision, and resistance to hemolysis, icterus, and lipemia were compared with immunoassay.

Across all six injection/calibration schemes, imprecision ranged from 2.5% to 10% (CV) from 0.05-10 μM. Regardless of calibration scheme, MS/MS ± LC was more resistant to interference from hemolysis and bilirubin than immunoassay. MS/MS ± LC determination of MTX was compared with immunoassay in 81-100 plasma specimens with MTX concentrations ranging from 0.05-81 μM. Intercept estimates all included zero with 95% confidence. Estimates of slopes versus immunoassay for each of the six analytic approaches ranged from 0.88 to 1.09.

Eliminating LC and external calibration enabled rapid, precise, and accurate determination of MTX concentrations in plasma. Minimalist but robust approaches such as these may enable the use of MS for routine MTX determination in time-sensitive clinical circumstances.

Methotrexate (MTX) is an antimetabolite with immunosuppressive and antineoplastic properties extensively used in cancer treatment. It is administered through various routes, including intravenous and intrathecal. MTX inhibits the dihydrofolate reductase, thereby disrupting folic acid metabolism and impending DNA synthesis. Despite its efficacy, MTX administration can result in significant toxicity, affecting multiple organs and leading to potential side effects like myelosuppression, hepatotoxicity, renal failure, mucositis and neurotoxicity. MTX-induced neurotoxicity is a critical problem, with manifestations varying from hours to years post-administration, ranging from transient and reversible to severe presentations. Several risk factors may contribute to MTX-induced neurotoxicity, including genetic predisposition, drug interactions, renal impairment and concurrent radiotherapy. Management strategies in preventing and mitigating neurotoxicity are based on supportive measures such as hydration, leucovorin rescue and the use of glucarpidase. This review focusses on the neurotoxic effects of MTX, a global health issue in the growing cancer population.

Serine hydroxymethyltransferase 2 (SHMT2) is a crucial mitochondrial enzyme in 1-carbon (1C) metabolism. It catalyzes the conversion of serine to glycine, generating 1C units essential for purine and pyrimidine synthesis, thereby supporting DNA replication and repair. Abnormally high expression is associated with malignant progression and treatment tolerance in various cancers. This review systematically summarizes the functions of SHMT2 in different types of cancer, underscoring on its roles in metabolism, immune microenvironment, and key signaling pathways (PI3K/AKT/mTOR, JAK-STAT, etc.) and outlines its epigenetic regulation and posttranslational modification mechanisms. Compared with the existing research, we focused on the latest regulatory mechanisms of SHMT2 and its potential in cancer treatment, such as the development and application of small-molecule inhibitors (SHIN2 and AGF347).

After 75 years of clinical use of folic acid antagonists such as methotrexate, relevant pharmacological data currently important for the effective and safe use of methotrexate were reviewed to see if it is possible to improve outcomes. Specifically, to improve how high-dose methotrexate (HD-MTX) can be given safely, what doses of MTX (methotrexate) are adequate to achieve therapeutic levels, and what is the appropriate folinic acid (FA) dose for effective rescue. This review is based on 50 years of personal experience with the use of HD-MTX in published literature. Many pharmacologic studies were performed over 50 years ago, but are still relevant and stand up to scrutiny today. What should be considered HD-MTX and how it can be given safely and effectively without late toxicity are presented. The variables responsible for effective folinic acid rescue, especially the doses of MTX and folinic acid and the time to start of rescue, are discussed. Understanding these highlighted aspects of therapy could help to prevent acute toxicity, improve treatment results, and prevent late effects.

Ewing sarcoma (EWS) is the second most common primary bone malignancy in adolescents and young adults. Patients who present with localized disease have experienced a steadily improving survival rate over the years, whereas those who present with metastatic disease have the same dismal prognosis as 30 years ago, with long term survival rates less than 20%, despite maximal intensification of chemotherapy. Thus, novel treatment approaches are a significant unmet clinical need. Targeting metabolic differences between EWS and normal cells offers a promising approach to improve outcomes for these patients. One-carbon metabolism utilizes serine and folate to generate glycine and tetrahydrofolate (THF)-bound one-carbon units required for de novo nucleotide biosynthesis. Elevated expression of several one-carbon metabolism genes is significantly associated with reduced survival in EWS patients. We show that both genetic and pharmacological inhibition of a key enzyme of the mitochondrial arm of the one-carbon metabolic pathway, serine hydroxymethyltransferase 2 (SHMT2), leads to substantial inhibition of EWS cell proliferation and colony-forming ability, and that this effect is primarily caused by depletion of glycine and one-carbon units required for synthesis of purine nucleotides. Inhibition of one-carbon metabolism at a different node, using the clinically relevant dihydrofolate reductase inhibitor Pralatrexate, similarly yields a profound growth inhibition, with depletion of thymidylate and purine nucleotides. Genetic depletion of SHMT2 dramatically impairs tumor growth in a xenograft model of EWS. Together, these data establish the upregulation of the one-carbon metabolism as a novel and targetable vulnerability of EWS cells, which can be exploited for therapy.

Using both genetic and pharmacologic approaches, this study identifies Ewing sarcoma's dependence on the mitochondrial arm, but not the cytoplasmic arm, of one-carbon metabolism as a targetable vulnerability that can be effectively harnessed for therapy.

Methotrexate (MTX), a folate antimetabolite, is a cytotoxic drug known to cause cytotoxicity associated with free oxygen radicals. This study investigated the effect of vitamins D3 and K2 on MTX-induced liver cell injury using the zebrafish liver cell line (CRL-2643). Observed effects, levels of antioxidant enzymes, lipid peroxidation marker, and total antioxidant/oxidant status were evaluated by spectrophotometric methods. The mRNA expressions of p53, Bax, and Bcl-2 were measured using RT-PCR. In addition, acridine orange/ethidium bromide staining was performed to analyze the apoptosis status of the cells. The IC50 value of MTX at 48 h was calculated as 442 µg/mL with an MTT assay. The doses of D3&K2 are determined based on the recommended dose to be taken daily. As a result, this study suggests that MTX treatment induced oxidative damage on the liver cell, as assessed by increased reactive oxygen levels, lipid peroxidation, and decreased glutathione levels. In addition, while MTX increased the expression of the p53 and proapoptotic marker Bax, it decreased the expression of the anti-apoptotic factor Bcl-2. In conclusion, D3&K2 treatment protects against MTX-induced liver cell toxicity. It is thought that they can be used as a potential agent in clinical applications with MTX in treatment.

Drug resistance in cancer poses a serious challenge in finding an effective remedy for cancer patients, because of the multitude of contributing factors influencing this complex phenomenon. One way to counter this problem is using a more targeted and dose-limiting approach for drug delivery, rather than relying on conventional therapies that exhibit multiple pernicious side-effects. Stability and specificity have traditionally been the core issues of peptide-based delivery vectors. In this study, we employed a structural regression modelling approach in the design, synthesis and characterization of a series of peptides that belong to approximately same topological cluster, yet with different electrostatic signatures encoded as a result of their differential positioning of amino acids in a given sequence. The peptides tagged with the fluorophore 5(6)-carboxyfluorescein, showed higher uptake in cancer cells with some of them colocalizing in the lysosomes. The peptides tagged with the anti-cancer drug methotrexate have displayed enhanced cytotoxicity and inducing apoptosis in triple-negative breast cancer cells. They also showed comparable uptake in side-population cells of lung cancer with stem-cell like properties. The most-optimized peptide showed accumulation in the tumor resulting in significant reduction of tumor size, compared to the untreated mice in in-vivo studies. Our results point to the following directives; (i) peptides can be design engineered for targeted delivery (ii) stereochemical engineering of peptide main chain can resist proteolytic enzymes and (iii) cellular penetration of peptides into cancer cells can be modulated by varying their electrostatic signatures.

Provide a general historical overview of leukemia, emphasizing the early discoveries that led to its characterization.

Leukemia recognition began in the late 19th century with the advent of the microscope. Leeuwenhoek and Swammerdam described erythrocytes, while Lieutaud first observed globuli albicantes, later identified as lymphocytes by Hewson. Early case studies by Velpeau, Donné, Bennett, Craigie, Virchow, and Fuller suggested that leukocytosis could occur without infection. Virchow coined the term "leukemia," while Bennett proposed "leucocythemia." Neumann identified the bone marrow as the source of blood cells and leukemia, coining the term "myelogenous leukemia," and Ehrlich classified leukemia into myeloid and lymphoid types. In 1914, Boveri linked chromosomal abnormalities to cancer, and in 1960, Nowell and Hungerford discovered the Philadelphia chromosome. The use of mustard gas in WWI led to the development of chemotherapy drugs like chlorambucil and busulfan. The Human Genome Project further advanced leukemia diagnosis and treatment. Leukemia, like many diseases, has evolved due to changes in causative factors such as viruses, bacteria, and genetic mutations, which have impacted its pathogenesis and treatment. It will undoubtedly continue to evolve, with new scientists working towards a cure for this devastating disease.

To discuss the importance of educating healthcare professionals about oncological emergencies linked to novel systemic anticancer therapy (SACT) and the impact on acute oncology (AO) services.

This discussion is based on clinical expertise and informed by current literature.

Novel SACT, such as immune-checkpoint inhibitors, have more complex toxicity profiles and can be challenging to recognize and treat. An increasing prevalence of toxicity is expected as new drugs are developed and the numbers of patients living with and beyond cancer expand; more data are required to capture the full extent of this. There are knowledge gaps within the healthcare workforce, particularly outside oncology-specialist settings. Focused research in this area will provide direction for targeted educational interventions.

Insufficient SACT education is a safety issue; severe toxicities can be fatal but initial symptoms can be subtle and may be missed. We argue that emergency care pathways can help to streamline the appropriate management of patients with SACT toxicity, but awareness of AO issues remains "everyone's business." Continuing clinical education is key to maintaining awareness of newly developed SACT. AO service models may vary, but AO competence assessment passports can provide a standardized method of evidencing AO knowledge and skills.

Oncology nurses, as a highly specialized and knowledgeable part of the healthcare workforce, are key in supporting interprofessional education. By using existing cancer nursing frameworks, this can support the implementation of the AO Passports. The learning and development of AO services in the UK can be transferred internationally.

Pancreatic cancer is highly lethal, and survival chances improve only with early detection at a precancerous stage. However, there remains a significant gap in developing tools for large-scale, rapid screening. To this end, a high-throughput On-Target Array Extraction Platform (OTAEP) by direct sintering of a series of metal-organic frameworks (MOFs) for dual in situ extraction, encompassing both exosomes and their metabolic profiles, is developed. Based on the principle of geometry-dependent photothermal conversion efficiency and standard testing, the appropriate MOF functional unit is identified. This unit enables exosome enrichment within 10 min and metabolic fingerprint extraction in under 1 s of laser irradiation, with over five reuse. To further accelerate and enhance the quality of metabolic profile analysis, the application of Surrogate Variable Analysis to eliminate hidden confounding factors within the profiles is proposed, and five biomarkers demonstrated by MS/MS experiments are identified. These biomarkers enable early diagnosis, risk stratification, and staging of pancreatic cancer simultaneously, with sensitivity of 94.1%, specificity of 98.8%, and precision of 94.9%. This work represents a breakthrough for overcoming throughput challenges in large-scale testing and for addressing confounding factors in big data analysis.

The development of novel therapeutics in neuro-oncology faces significant challenges, often marked by high costs and low success rates. Despite advances in molecular biology and genomics, targeted therapies have had limited impact on improving patient outcomes in brain tumors, particularly gliomas, due to the complex, multigenic nature of these malignancies. While significant efforts have been made to design drugs that target specific signaling pathways and genetic mutations, the clinical success of these rational approaches remains sparse. This review critically examines the landscape of neuro-oncology drug discovery, highlighting instances where serendipity has led to significant breakthroughs, such as the unexpected efficacy of repurposed drugs and off-target effects that proved beneficial. By exploring historical and contemporary cases, we underscore the role of chance in the discovery of impactful therapies, arguing that embracing serendipity alongside rational drug design may enhance future success in neuro-oncology drug development.

Methotrexate (MTX) is a critical antimetabolite drug in treating various pediatric diseases, including acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), brain tumors, osteosarcoma, inflammatory myofibroblastic tumor (IMT), juvenile scleroderma (JS), and juvenile idiopathic arthritis (JIA). MTX acts as a folate antagonist by inhibiting dihydrofolate reductase (DHFR), an enzyme essential for the synthesis of tetrahydrofolate. This disruption impairs DNA synthesis, repair, and cellular replication, particularly affecting rapidly dividing cells. Despite its efficacy, MTX resistance poses significant challenges, particularly in pediatric oncology, where it undermines the ability to achieve sustained therapeutic effects, resulting in reduced therapeutic efficacy and poor prognosis. The mechanisms of MTX resistance encompassed reduced enzyme activity pivotal for MTX metabolism, enhanced expression of efflux transporters, genetic variations, and alterations in signaling pathways. Multifaceted strategies have been explored to overcome MTX resistance. Combination therapies with ginger extract, gold nanoparticles, and arsenic trioxide (ATO) have been investigated to augment MTX's cytotoxic effects. Synergies with mTOR inhibitors and MDM2 inhibitors have demonstrated enhanced outcomes in ALL. In JIA, targeting ATP-binding cassette (ABC) transporters and modulating transforming growth factor‑β (TGF-β) signaling pathways have emerged as promising approaches. For osteosarcoma, emphasis on autophagy pathways and non-coding RNAs influencing chemotherapy sensitivity could enhance MTX effectiveness. This review delineates MTX's therapeutic roles, elucidates its resistance mechanisms, and discusses current and potential strategies for managing MTX resistance to bolster treatment effectiveness in pediatric tumors and other diseases. This knowledge base could underpin further research and development of personalized treatments to optimize MTX's clinical benefits.

Neural tube defects (NTDs) are leading congenital malformations. Its global prevalence is one in 1000 pregnancies and it has high morbidity and mortality. It has multiple risk factors like genetic errors and environmental stressors like maternal malnutrition and in utero exposure to pollutants like chemicals. The genetic program determines neural tube development based on timely expression of many genes involved in developmental signaling pathways like BMP, PCP and SHH. BMP expression defines ectoderm. SOX represses BMP in ectoderm and convertes to the neuroectoderm. Subsequently, PCP molecules define the tissue patterning for convergent-extension, a critical step in neural tube genesis. Further, SHH sets spatial patterning of the neural tube. Nutrients are the essential major environmental input for embryogenesis. But it may also carry risk factors. Malnutrition, especially folate deficiency, during embryogenesis is a major cause for NTDs. Folate is integral in the One Carbon metabolic pathway. Its deficiency and error in the pathway are implicated in NTDs. Folate supplementation alone is insufficient to prevent NTDs. Thus, a comprehensive understanding of the various risk factors is necessary to strategize reduction of NTDs. We review the current knowledge of various risk factors, like genetic, metabolic, nutritional, and drugs causing NTDs and discuss the steps required to identify them in the early embryogenesis to avoid NTDs.

Leukemia is a type of blood cancer characterized by the uncontrolled growth of abnormal cells in the bone marrow, which replace normal blood cells and disrupt normal blood cell function. Timely and personalized interventions are crucial for disease management and improving survival rates. However, many patients experience relapse following conventional chemotherapy, and increasing treatment intensity often fails to improve outcomes due to mutated gene-induced drug resistance in leukemia cells. This article analyzes the association of gene mutations and drug resistance in leukemia. It explores genetic abnormalities in leukemia, highlighting recently identified mutations affecting signaling pathways, cell apoptosis, epigenetic regulation, histone modification, and splicing mechanisms. Additionally, the article discusses therapeutic strategies such as molecular targeting of gene mutations, alternative pathway targeting, and immunotherapy in leukemia. These approaches aim to combat specific drug-resistant mutations, providing potential avenues to mitigate leukemia relapse. Future research with these strategies holds promise for advancing leukemia treatment and addressing the challenges of drug-resistant mutations to improve patient outcomes.

The growing use of measurable residual disease (MRD) assays across haematology-oncology creates an urgent need for clinicians and researchers to reflect on the biological and clinical rationale of this class of biomarkers. In this Viewpoint, we critically examine two premises behind MRD's use in haematology-oncology, focusing on its biological plausibility as a predictive biomarker and surrogate endpoint, and the evidence needed for it to influence decision making in haematological cancers. Examining these premises leads us to advocate for the establishment of more robust biological and clinical evidence to ensure the clinically useful and safe application of MRD. Although achieving the eradication of cancer cells in the form of undetectable MRD seems an attractive goal in haematology-oncology, we highlight the epistemic limitations of this biomarker and need for more clinical evidence to guide its effective use.

Methotrexate (MTX) is an antimetabolite drug that mimics folate and inhibits dihydrofolic acid reductase, resulting in the impairment of malignant growth in actively proliferating tissues. MTX is approved by the FDA for primarily treating non-Hodgkin lymphoma, lymphoblastic leukemia, and osteosarcoma. In addition, MTX is also prescribed as a preferred anti-rheumatic medication for the management of rheumatoid arthritis, including psoriasis, indicating that MTX has a multipronged mechanism of action. MTX is also known to exert anti-inflammatory effects, and interestingly, the role of C5a, a pro-inflammatory glycoprotein of the complement system, is well established in several chronic inflammatory diseases, including rheumatoid arthritis and psoriasis, through the recruitment of C5a receptors (C5aR1/C5aR2) expressed in both immune and non-immune cells. Notably, through drug repurposing studies, we have earlier shown that non-steroidal anti-inflammatory drugs (NSAIDS) can potentially neutralize the function of C5a. Though MTX binds to serum albumin and can affect the immune system, whether its interaction with C5a could be therapeutically beneficial due to the downregulation of both extracellular and intracellular signaling of C5a is not yet established in the literature. In the current study, we have hypothesized and provided preliminary evidence through computational studies that MTX can strongly bind to the hotspot regions on C5a involved in the interactions with its receptors, which is likely to alter the downstream signaling of C5a and contribute to the overall therapeutic efficacy of MTX.

Temporal trends demonstrate improved survival for many types of common pediatric cancer. Studies have not examined improvement in very rare pediatric cancers or compared these improvements to more common cancers. In this cohort study of the Surveillance, Epidemiology, and End Results (SEER) registry, we examined patients from 1975 to 2016 who were 0-19 years of age at the time of diagnosis. Cancers were grouped by decade of diagnosis and 3 cancer frequency groups: Common, Intermediate, and Rare. Trends in mortality across decades and by cancer frequency were compared using Kaplan-Meier curves and adjusted Cox proportional hazards models. A total of 50,222 patients were available for analysis, with the top 10 cancers grouped as Common (67%), 13 cancers grouped with Intermediate (24%), and 37 cancers as Rare (9%). Rare cancers had higher rates of children who were older and Black. 5-year survival increased from 63% to 86% across all cancers from the 1970s to the 2010s. The hazard ratio (HR) for mortality decreased from the reference point of 1 in the 1970s to 0.27 (95% CI: 0.25-0.30) in the 2010s in Common cancers, while the HR only dropped to 0.60 (0.49-0.73) over that same period for rare cancers. Pediatric oncology patients have experienced dramatic improvement in mortality since the 1970s, with mortality falling by nearly 75% in common cancers. Unfortunately, rare pediatric cancers continue to lag behind more common and therefore better studied cancers, highlighting the need for a renewed focus on research efforts for children with these rare diseases.

Relapse continues to limit survival for patients with B-cell acute lymphoblastic leukemia (B-ALL). Previous studies have independently implicated activation of B-cell developmental signaling pathways and increased glucose consumption with chemo-resistance and relapse risk. Here, we connect these observations, demonstrating that B-ALL cells with active signaling, defined by high expression of phosphorylated ribosomal protein S6 ("pS6+ cells"), are metabolically unique and glucose dependent. Isotope tracing and metabolic flux analysis confirm that pS6+ cells are highly glycolytic and notably sensitive to glucose deprivation, relying on glucose for de novo nucleotide synthesis. Uridine, but not purine or pyrimidine, rescues pS6+ cells from glucose deprivation, highlighting uridine is essential for their survival. Active signaling in pS6+ cells drives uridine production through activating phosphorylation of carbamoyl phosphate synthetase (CAD), the enzyme catalyzing the initial steps of uridine synthesis. Inhibition of signaling abolishes glucose dependency and CAD phosphorylation in pS6+ cells. Primary pS6+ cells demonstrate high expression of uridine synthesis proteins, including dihydroorotate dehydrogenase (DHODH), the rate-limiting catalyst of de novo uridine synthesis. Gene expression demonstrates that increased expression of DHODH is associated with relapse and inferior event-free survival after chemotherapy. Further, the majority of B-ALL genomic subtypes demonstrate activity of DHODH. Inhibiting DHODH using BAY2402232 effectively kills pS6+ cells in vitro, with its IC50 correlated with the strength of pS6 signaling across 14 B-ALL cell lines and patient-derived xenografts (PDX). In vivo DHODH inhibition prolongs survival and decreases leukemia burden in pS6+ B-ALL cell line and PDX models. These findings link active signaling to uridine dependency in B-ALL cells and an associated risk of relapse. Targeting uridine synthesis through DHODH inhibition offers a promising therapeutic strategy for chemo-resistant B-ALL as a novel therapeutic approach for resistant disease.

Metabolic reprogramming in both immune and cancer cells plays a crucial role in the antitumor immune response. Recent studies indicate that cancer metabolism not only sustains carcinogenesis and survival via altered signaling but also modulates immune cell function. Metabolic crosstalk within the tumor microenvironment results in nutrient competition and acidosis, thereby hindering immune cell functionality. Interestingly, immune cells also undergo metabolic reprogramming that enables their proliferation, differentiation, and effector functions. This review highlights the regulation of antitumor immune responses through metabolic reprogramming in cancer and immune cells and explores therapeutic strategies that target these metabolic pathways in cancer immunotherapy, including using chimeric antigen receptor (CAR)-T cells. We discuss innovative combinations of immunotherapy, cellular therapies, and metabolic interventions that could optimize the efficacy of existing treatment protocols.

Malignant rhabdoid tumor (MRT) is one of the most aggressive childhood cancers for which no effective treatment options are available. Reprogramming of cellular metabolism is an important hallmark of cancer, with various metabolism-based drugs being approved as a cancer treatment. In this study, we use patient-derived tumor organoids (tumoroids) to map the metabolic landscape of several pediatric cancers. Combining gene expression analyses and metabolite profiling using mass spectrometry, we find nucleotide biosynthesis to be a particular vulnerability of MRT. Treatment of MRT tumoroids with de novo nucleotide synthesis inhibitors methotrexate (MTX) and BAY-2402234 lowers nucleotide levels in MRT tumoroids and induces apoptosis. Lastly, we demonstrate in vivo efficacy of MTX in MRT patient-derived xenograft (PDX) mouse models. Our study reveals nucleotide biosynthesis as an MRT-specific metabolic vulnerability, which can ultimately lead to better treatment options for children suffering from this lethal pediatric malignancy.

PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. Here we show that PAX3-FOXO1 + RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in de novo pyrimidine synthesis, including dihydrofolate reductase (DHFR). Consequently, PAX3-FOXO1 + cells display increased sensitivity to inhibition of DHFR by the chemotherapeutic drug methotrexate, and this dependence is rescued by provision of pyrimidine nucleotides. Methotrexate treatment mimics the metabolic and transcriptional impact of PAX3-FOXO1 silencing, reducing expression of genes related to PAX3-FOXO1-driven malignant cell states. Accordingly, methotrexate treatment slows growth of multiple PAX3-FOXO1 + tumor xenograft models, but not fusion-negative counterparts. Taken together, these data demonstrate that PAX3-FOXO1 induces cell states characterized by altered pyrimidine dependence and nominate methotrexate as an addition to the current therapeutic arsenal for treatment of these malignant pediatric tumors.

Metabolic reprogramming within the tumor microenvironment (TME) is a hallmark of cancer and a crucial determinant of tumor progression. Research indicates that various metabolic regulators form a metabolic network in the TME and interact with immune cells, coordinating the tumor immune response. Metabolic dysregulation creates an immunosuppressive TME, impairing the antitumor immune response. In this review, we discuss how metabolic regulators affect the tumor cell and the crosstalk of TME. We also summarize recent clinical trials involving metabolic regulators and the challenges of metabolism-based tumor therapies in clinical translation. In a word, our review distills key regulatory factors and their mechanisms of action from the complex reprogramming of tumor metabolism, identified as tumor metabolic regulators. These regulators provide a theoretical basis and research direction for the development of new strategies and targets in cancer therapy based on tumor metabolic reprogramming.

In the past decade, evidence for the numerous roles of copper (Cu) in mammalian physiology has grown exponentially. The discoveries of Cu involvement in cell signaling, autophagy, cell motility, differentiation, and regulated cell death (cuproptosis) have markedly extended the list of already known functions of Cu, such as a cofactor of essential metabolic enzymes, a protein structural component, and a regulator of protein trafficking. Novel and unexpected functions of Cu transporting proteins and enzymes have been identified, and new disorders of Cu homeostasis have been described. Significant progress has been made in the mechanistic studies of two classic disorders of Cu metabolism, Menkes disease and Wilson's disease, which paved the way for novel approaches to their treatment. The discovery of cuproptosis and the role of Cu in cell metastatic growth have markedly increased interest in targeting Cu homeostatic pathways to treat cancer. In this review, we summarize the established concepts in the field of mammalian Cu physiology and discuss how new discoveries of the past decade expand and modify these concepts. The roles of Cu in brain metabolism and in cell functional speciation and a recently discovered regulated cell death have attracted significant attention and are highlighted in this review.

The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- and condition-dependent remodeling of certain metabolic pathways. While it has become increasingly clear that tumor cells integrate extracellular and intracellular signals to adapt and proliferate, nutrient and metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, metabolic changes not only support the rapid growth and dissemination of tumor cells but also promote immune evasion by metabolically "educating" immune cells in the tumor microenvironment (TME). Recent studies have highlighted the profound impact of metabolic reprogramming on the TME and the potential of targeting metabolic pathways as a therapeutic strategy, with several enzyme inhibitors showing promising results in clinical trials. Thus, understanding how tumor cells alter their metabolic pathways and metabolically remodel the TME to support their survival and proliferation may offer new strategies for metabolic therapy and immunotherapy.

Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Understanding the metabolic diversities among cancer cells and their surrounding environments is therefore essential in unravelling the complexities of leukaemia and improving therapeutic strategies. Here, we describe the currently available methodologies and approaches to addressing the dynamic heterogeneity of leukaemia progression. In the second section, we focus on metabolic leukaemic vulnerabilities in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Lastly, we provide a comprehensive overview of the most interesting clinical trials designed to target these metabolic dependencies, highlighting their potential to advance therapeutic strategies in leukaemia treatment. The integration of multi-omics data for cancer identification with the metabolic states of tumour cells will enable a comprehensive "micro-to-macro" approach for the refinement of clinical practices and delivery of personalised therapies.

Chikungunya virus (CHIKV) is classified as a pathogen with the potential to cause a pandemic. This situation becomes more alarming since no approved drug exists to combat the virus. The present research aims to demonstrate the anti-CHIKV activity of molecules present in the latex of Euphorbia grandicornis. Therefore, a biodirected assay was carried out to find the molecules with anti-CHIKV activity. Extractions with hexane, dichloromethane, and methanol and subsequent purification by column chromatography were carried out to later evaluate cytotoxic activity by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and antiviral activity by plaque assay. Our findings show that unlike the others, methanolic extract has a low cytotoxic effect and a good anti-CHIKV effect (EC50 = 26.41 µg/mL), which increases when obtaining the purified active fraction (pAFeg1) (EC50 = 0.4835 µg/mL). Time-of-addition suggests that the possible mechanism of action of pAFeg1 could be inhibiting any of the non-structural proteins of CHIKV. In addition, both the cytotoxic and anti-CHIKV activity of pAFeg1 demonstrate selectivity since it killed cancer cells and could not inhibit DENV2.

Cellular resistance can limit the effectiveness of antifolate drugs for the treatment of cancer and autoimmune diseases. We examined the biochemical and cellular effects of a propargyl linked, non-classical antifolate UCP1162 that shows exceptional potency and resilience in the background of methotrexate resistance. UCP1162 inhibited the human DHFR enzyme with affinity and kinetics comparable to methotrexate (MTX). UCP1162 also inhibited cancer cell proliferation and bound cellular DHFR at low nanomolar concentrations. Leucovorin suppressed the cellular effects of UCP1162, consistent with UCP1162 working as an antifolate. Like other antifolates, UCP1162 reduced acute inflammation in mice and inhibited FLS cell growth and motility. Single cell RNA-seq showed that MTX and UCP1162 generated overlapping gene expression changes after a 48-hour exposure. However, while leukemia cells (CCRF-CEM) resistant to MTX could be readily selected, UCP1162-resistant cells could not be obtained. Long-term exposure to UCP1162 resulted in static culture expressing stem cell genes (CD34, ABCG2, ABCB1), adaptive genes (TCN2, CDKN1A), and genes that might serve as therapeutic targets (TPBG/5T4, TNFRSF10A, ACE). These findings suggest that UCP1162 is a unique tool for studying cellular responses to long-term antifolate treatment and holds promise as a lead compound capable of overcoming some forms of antifolate resistance.

The success story of haematology and oncology extends from Virchow's concept of "cellular pathology" to the possibilities of personalized cancer therapy, which molecular oncology offers today. This article highlights the beginnings and developments of chemotherapy, immunotherapy, as well as molecular oncology and psycho-oncology over the past 150 years.

Treating brain tumors requires a nuanced understanding of the brain, a vital and delicate organ. Location, size, tumor type, and surrounding tissue health are crucial in developing treatment plans. This review comprehensively summarizes various treatment options that are available or could be potentially available for brain tumors, including physical therapies (radiotherapy, ablation therapy, photodynamic therapy, tumor-treating field therapy, and cold atmospheric plasma therapy) and non-physical therapies (surgical resection, chemotherapy, targeted therapy, and immunotherapy). Mechanisms of action, potential side effects, indications, and latest developments, as well as their limitations, are highlighted. Furthermore, the requirements for personalized, multi-modal treatment approaches in this rapidly evolving field are discussed, emphasizing the balance between efficacy and patient safety.

One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.

In this perspective, we highlight and reflect on the current knowledge with respect to serine/glycine metabolism in cancer, therapeutic resistance, and precision medicine opportunities for therapeutic targeting and treatment follow-up. Cancer subtypes with high mortality rates include lung cancer and glioblastomas. In order to improve future therapeutic opportunities, patient stratification need to be performed to select patients that might benefit from adjuvant serine/glycine targeting compounds. In an effort to identify the group of patients for stratification purposes, we analyzed publicly available TCGA patient datasets to test associations between serine/glycine metabolism enzyme expression and important cancer drivers in lung cancer and glioblastoma. These patients presenting serine/glycine pathway overexpression might benefit from adjuvant sertraline treatment in the future.

It is well documented that aging is associated with cancer, and likewise, cancer survivors display accelerated aging. As the number of aging individuals and cancer survivors continues to grow, it raises additional concerns across society. Therefore, unraveling the molecular mechanisms of aging in tissues is essential to developing effective therapies to fight the aging and cancer diseases in cancer survivors and cancer patients. Indeed, cellular senescence is a critical response, or a natural barrier to suppress the transition of normal cells into cancer cells, however, hypoxia which is physiologically required to maintain the stem cell niche, is increased by aging and inhibits senescence in tissues. Interestingly, oxygen restriction or hypoxia increases longevity and slows the aging process in humans, but hypoxia can also drive angiogenesis to facilitate cancer progression. In addition, cancer treatment is considered as one of the major reasons that drive cellular senescence, subsequently followed by accelerated aging. Several clinical trials have recently evaluated inhibitors to eliminate senescent cells. However, some mechanisms of aging typically can also retard cancer cell growth and progression, which might require careful strategy for better clinical outcomes. Here we describe the molecular regulation of aging and cancer in crosstalk with DNA damage and hypoxia signaling pathways in cancer patients and cancer survivors. We also update several therapeutic strategies that might be critical in reversing the cancer treatment-associated aging process.

The extracellular matrix (ECM) is present in all tissues and crucial in maintaining normal tissue homeostasis and function. Defects in ECM synthesis and remodeling can lead to various diseases, while overproduction of ECM components can cause severe conditions like organ fibrosis and influence cancer progression and therapy resistance. Collagens are the most abundant core ECM proteins in physiological and pathological conditions and are predominantly synthesized by fibroblasts. Previous efforts to target aberrant collagen synthesis in fibroblasts by inhibiting pro-fibrotic signaling cascades have been ineffective. More recently, metabolic rewiring downstream of pro-fibrotic signaling has emerged as a critical regulator of collagen synthesis in fibroblasts. Here, we propose that targeting the metabolic pathways involved in ECM biomass generation provides a novel avenue for treating conditions characterized by excessive collagen accumulation. This review summarizes the unique metabolic challenges collagen synthesis imposes on fibroblasts and discusses how underlying metabolic networks could be exploited to create therapeutic opportunities in cancer and fibrotic disease. Finally, we provide a perspective on open questions in the field and how conceptual and technical advances will help address them to unlock novel metabolic vulnerabilities of collagen synthesis in fibroblasts and beyond.

One-carbon (1C) metabolism is a complex network of metabolic reactions closely related to producing 1C units (as methyl groups) and utilizing them for different anabolic processes, including nucleotide synthesis, methylation, protein synthesis, and reductive metabolism. These pathways support the high proliferative rate of cancer cells. While drugs that target 1C metabolism (like methotrexate) have been used for cancer treatment, they often have significant side effects. Therefore, developing new drugs with minimal side effects is necessary for effective cancer treatment. Methionine, glycine, and serine are the main three precursors of 1C metabolism. One-carbon metabolism is vital not only for proliferative cells but also for non-proliferative cells in regulating energy homeostasis and the aging process. Understanding the potential role of 1C metabolism in aging is crucial for advancing our knowledge of neoplastic progression. This review provides a comprehensive understanding of the molecular complexities of 1C metabolism in the context of cancer and aging, paving the way for researchers to explore new avenues for developing advanced therapeutic interventions for cancer.

The catalytic activity of most epigenetic enzymes requires a metabolite produced by central carbon metabolism as a cofactor or (co-)substrate. The concentrations of these metabolites undergo dynamic changes in response to nutrient levels and environmental conditions, reprogramming metabolic processes and epigenetic landscapes. Abnormal accumulations of epigenetic modulatory metabolites resulting from mutations in metabolic enzymes contribute to tumorigenesis. In this review, we first present the concept that metabolite regulation of gene expression represents an evolutionarily conserved mechanism from prokaryotes to eukaryotes. We then review how individual metabolites affect epigenetic enzymes and cancer development. Lastly, we discuss the advancement of and opportunity for therapeutic targeting of metabolite-epigenetic regulation in cancer therapy.

Methotrexate is one of the most frequently used medications for the treatment of rheumatic diseases. Although initially developed for use as chemotherapy for both solid and hematologic malignancies, it was used as early as the 1960s with success for rheumatoid arthritis (RA) and psoriatic arthritis, ultimately being approved by the US Food and Drug Administration for the treatment of RA in 1988. Beyond RA and psoriatic arthritis, methotrexate is used in the treatment of systemic lupus erythematosus, idiopathic inflammatory myopathies, and other inflammatory conditions. Methotrexate is cytotoxic to the trophoblast and has been used to treat both ectopic pregnancy and gestational trophoblastic neoplasia, leading to studies in the early 1990s that showed it was effective and safe for early abortion in combination with prostaglandin E1 analog misoprostol. Methotrexate is also a teratogen, causing serious birth defects in 6%-10% of patients taking it while pregnant. Additionally, women are more likely to be affected by both RA at SLE, as compared with males, thus worsening the burden of these adverse effects. Both methotrexate's history of use as an abortifacient and its teratogenic properties make its use more complicated in the current era of abortion policy in the United States following the Dobbs v. Jackson Women's Health Organization ruling. Recently published data suggest that this ruling has affected both provider perspectives and patient experiences as it relates to methotrexate use. In the post-Dobbs era, the role of the rheumatologist as it relates to patients' sexual and reproductive health is likely to expand.

Metabolic rewiring is a defining characteristic of cancer cells, driving their ability to proliferate. Leveraging these metabolic vulnerabilities for therapeutic purposes has a long and impactful history, with the advent of antimetabolites marking a significant breakthrough in cancer treatment. Despite this, only a few in vitro metabolic discoveries have been successfully translated into effective clinical therapies. This limited translatability is partially due to the use of simplistic in vitro models that do not accurately reflect the tumor microenvironment. This Review examines the effects of current cell culture practices on cancer cell metabolism and highlights recent advancements in establishing more physiologically relevant in vitro culture conditions and technologies, such as organoids. Applying these improvements may bridge the gap between in vitro and in vivo findings, facilitating the development of innovative metabolic therapies for cancer.

Cancer research is linked to modern life-sciences, encompassing achievements in virology, yeast-biology, molecular-biology, genetics, systems-biology, bioinformatics, and so on. With these fascinating developments, it's easy to overlook that the fundamental theories and treatment strategies were established in the early 20th century and have remained valid ever since. Therefore, tribute must be paid to the founders of the field. The main hypotheses on carcinogenesis, the genetic model and the metabolic model, and the concept of cancer-treatment with cytotoxic, targeted or metabolic drugs were proposed more than 100 years ago by great minds such as T. Boveri, O. Warburg, and P. Ehrlich. Hence nothing about these cancer concepts is really new. Through development of powerful new technologies, we have been able to decipher the mechanisms of malignant transformation, thus significantly advancing the field. Our own studies have been focused on the cross-talk between cell-growth-signaling and lipid-metabolism in ovarian cancer to find crossover-points for co-targeting in order to achieve synergistic treatment effects. Notably, a side-effect of the application of current methods of molecular-cell-biology is a deeper knowledge of the laws of normal cell-biology and cell-life. Thus we anticipate the field will advance rapidly in the near future.

Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate's impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate's impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. Although multi-kinase inhibitors can prolong the overall survival of late-stage HCC patients, the emergence of drug resistance diminishes these benefits, ultimately resulting in treatment failure. Therefore, there is an urgent need for novel and effective drugs to impede the progression of liver cancer.

This study employed a concentration gradient increment method to establish acquired sorafenib or regorafenib-resistant SNU-449 cells. Cell viability was assessed using the cell counting kit-8 assay. A library of 793 bioactive small molecules related to metabolism screened compounds targeting both parental and drug-resistant cells. The screened compounds will be added to both the HCC parental cells and the drug-resistant cells, followed by a comprehensive assessment. Intracellular adenosine triphosphate (ATP) levels were quantified using kits. Flow cytometry was applied to assess cell apoptosis and reactive oxygen species (ROS). Real-time quantitative PCR studied relative gene expression, and western blot analysis assessed protein expression changes in HCC parental and drug-resistant cells. A xenograft model in vivo evaluated Mito-LND and (E)-Akt inhibitor-IV effects on liver tumors, with hematoxylin and eosin staining for tissue structure and immunohistochemistry staining for endoplasmic reticulum stress protein expression.

From the compound library, we screened out two novel compounds, Mito-LND and (E)-Akt inhibitor-IV, which could potently kill both parental cells and drug-resistant cells. Mito-LND could significantly suppress proliferation and induce apoptosis in HCC parental and drug-resistant cells by upregulating glycolytic intermediates and downregulating those of the tricarboxylic acid (TCA) cycle, thereby decreasing ATP production and increasing ROS. (E)-Akt inhibitor-IV achieved comparable results by reducing glycolytic intermediates, increasing TCA cycle intermediates, and decreasing ATP synthesis and ROS levels. Both compounds trigger apoptosis in HCC cells through the interplay of the AMPK/MAPK pathway and the endoplasmic reticulum stress response. In vivo assays also showed that these two compounds could significantly inhibit the growth of HCC cells and induce endoplasmic reticulum stress.

Through high throughput screening, we identified that Mito-LND and (E)-Akt inhibitor-IV are two novel compounds against both parental and drug-resistant HCC cells, which could offer new strategies for HCC patients.

Autoimmune (or rheumatic) diseases are increasing in prevalence but selecting the best therapy for each patient proceeds in trial-and-error fashion. This strategy can lead to ineffective therapy resulting in irreversible damage and suffering; thus, there is a need to bring the promise of precision medicine to patients with autoimmune disease. While host factors partially determine the therapeutic response to immunosuppressive drugs, these are not routinely used to tailor therapy. Thus, non-host factors likely contribute. Here, we consider the impact of the human gut microbiome in the treatment of autoimmunity. We propose that the gut microbiome can be manipulated to improve therapy and to derive greater benefit from existing therapies. We focus on the mechanisms by which the human gut microbiome impacts treatment response, provide a framework to interrogate these mechanisms, review a case study of a widely-used anti-rheumatic drug, and discuss challenges with studying multiple complex systems: the microbiome, the human immune system, and autoimmune disease. We consider open questions that remain in the field and speculate on the future of drug-microbiome-autoimmune disease interactions. Finally, we present a blue-sky vision for how the microbiome can be used to bring the promise of precision medicine to patients with rheumatic disease.

There is a rich history of cancer treatments which provides a number of important lessons for present and future cancer therapies. We outline this history by looking in the past, reviewing the current landscape of cancer treatments, and by glancing at the potential future cancer therapies.

Dr. Sidney Farber (Farber) was a distinguished pediatric pathologist and widely recognized pioneer of modern chemotherapy. In 1948, his influential study showed that various anti-folates, particularly 4-aminopteroylglutamic acid, also known as aminopterin, induced transient disease control in kids who had acute undifferentiated leukemia. The findings laid the basis for developing and using additional chemotherapies, individually or in combination, for treating pediatric and adult cancers. Farber also introduced actinomycin D to treat Wilms tumor in various stages. Underneath his oversight, the 'Jimmy Fund,' one of the earliest dedicated pediatric oncology centers, and the Children's Cancer Research Foundation, which subsequently evolved into the Dana-Farber Cancer Institute, was established. Farber is known as the "Founder of Pediatric Pathology" and the "Father of Modern Chemotherapy," citing his immense contributions. This article is a tribute to the great scientist Farber for his significant contributions to the scientific field and the countless individuals he has impacted.

The crosstalk between metabolism and epigenetics is an emerging field that is gaining importance in different areas such as cancer and aging, where changes in metabolism significantly impacts the cellular epigenome, in turn dictating changes in chromatin as an adaptive mechanism to bring back metabolic homeostasis. A key metabolic pathway influencing an organism's epigenetic state is one-carbon metabolism (OCM), which includes the folate and methionine cycles. Together, these cycles generate S-adenosylmethionine (SAM), the universal methyl donor essential for DNA and histone methylation. SAM serves as the sole methyl group donor for DNA and histone methyltransferases, making it a crucial metabolite for chromatin modifications. In this review, we will discuss how SAM and its byproduct, S-adenosylhomocysteine (SAH), along with the enzymes and cofactors involved in OCM, may function in the different cellular compartments, particularly in the nucleus, to directly regulate the epigenome in aging and cancer.

Tolerance is the Holy Grail of solid organ transplantation (SOT) and remains its primary challenge since its inception. In this topic, the seminal contributions of Thomas Starzl at Pittsburgh University outlined foundational principles of graft acceptance and tolerance, with chimerism emerging as a pivotal factor. Immunologically, intestinal transplantation (ITx) poses a unique hurdle due to the inherent characteristics and functions of the small bowel, resulting in increased immunogenicity. This necessitates heavy immunosuppression (IS) while IS drugs side effects cause significant morbidity. In addition, current IS therapies fall short of inducing clinical tolerance and their discontinuation has been proven unattainable in most cases. This underscores the unfulfilled need for immunological modulation to safely reduce IS-related burdens. To address this challenge, the Leuven Immunomodulatory Protocol (LIP), introduced in 2000, incorporates various pro-tolerogenic interventions in both the donor to the recipient, with the aim of facilitating graft acceptance and improving outcome. This review seeks to provide an overview of the current understanding of tolerance in ITx and outline recent advances in this domain.