Search Results (7,019)

Glioblastoma (GBM) exhibits profound metabolic reprogramming, among which the balance between unsaturated and saturated fatty acids (UFA/SFA) emerges as a critical determinant of tumor behavior and treatment response. Recent studies have shown that fatty acid metabolic reprogramming is a key mechanism driving GBM progression. Abnormalities in fatty acid uptake, synthesis, desaturation, and oxidation collectively reshape the lipid composition of tumor cells, particularly by altering the unsaturated/saturated fatty acid ratio. Monounsaturated fatty acids mainly promote tumor cell proliferation and membrane biosynthesis, polyunsaturated fatty acids can induce lipid peroxidation and ferroptosis under specific stress conditions, whereas excessive saturated fatty acids can cause lipotoxicity when desaturation is limited. Key enzymes in fatty acid metabolism constitute a regulatory network and provide potential therapeutic targets for GBM. In addition, fatty acid metabolism can remodel the tumor immune microenvironment, especially by affecting the functional state of tumor-associated macrophages. Rather than targeting a single lipid species or isolated metabolic enzyme, therapeutic strategies that recalibrate the UFA/SFA ratio may provide a more integrated approach to restraining GBM progression and improving treatment sensitivity. Full article

This study evaluated the impact of fermented palm kernel meal (FPKM) on the lactation performance, blood biochemical indices, rumen microbiota, and metabolic functions of Holstein dairy cows, aiming to enhance the nutritional value of palm kernel meal (PKM) through solid-state fermentation. A 3 × 3 Latin square design was used, involving 12 multiparous Holstein cows (parity = 3; body weight = 625 ± 25.8 kg; days in milk = 103 ± 19.6 day(s); milk yield = 32.6 ± 1.58 kg/d) over three 28-day periods. Cows were randomly assigned to three isocaloric and isonitrogenous diets: a basal diet with wheat bran (WB group), a diet with wheat bran replaced by PKM (PKM group), and a diet with wheat bran replaced by FPKM (FPKM group). Solid-state fermentation improved PKM’s nutritional profile by reducing fiber and β-mannan content while increasing protein availability and ruminal degradability. Compared to the WB group, the PKM group showed lower dry matter intake, milk yield, and nutrient digestibility. In contrast, the FPKM group had higher DMI and milk yield than the PKM group, improved nutrient digestibility, and the highest energy-corrected milk yield due to increased milk protein and lactose production. The FPKM group also had higher concentrations of total volatile fatty acids, propionate, acetate, and microbial protein synthesis than the PKM group. Pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-8) were elevated in the PKM group but were reduced to levels similar to the WB group in the FPKM group. Plasma immunoglobulin G levels were higher in both the FPKM and WB groups compared to the PKM group. The FPKM group also showed increased relative abundances of Prevotella, Fibrobacterota, and Verrucomicrobiota, while Bacillota and Ruminococcus were reduced compared to the WB group. Metabolomic profiling revealed that FPKM upregulated energy metabolism and inflammation-related pathways, increasing metabolites such as riboflavin and adenine and decreasing succinic acid and guanine compared to the PKM group. In conclusion, FPKM improved the feeding value of PKM-based material and showed more favorable responses than PKM, with generally comparable responses to WB, supporting its potential as an alternative feed ingredient for lactating dairy cows. Full article

Glutamate dehydrogenase (GLUD1) links glutamine metabolism and redox regulation, yet its prognostic and functional relevance across different glioma subtypes warrants further study. Here, we show that GLUD1 expression was inversely associated with tumor grade and positively associated with survival across glioma subtypes, a relationship not fully recapitulated by broader glutaminolysis-related gene signatures. To investigate the consequences of GLUD1 inhibition, we treated endogenous IDH-mutant and IDH-wildtype glioma cell lines with the reported GLUD1 inhibitor R162. GLUD1 inhibition reduced viability in all cell lines tested. This effect was not rescued by α-ketoglutarate (α-KG) supplementation, indicating that impaired tricarboxylic acid (TCA) cycle anaplerosis was not the primary mechanism underlying GLUD1 dependency. Instead, GLUD1 inhibition caused intracellular glutamate accumulation, increased reactive oxygen species (ROS), γ-H2AX induction, and elevated intracellular calcium, while complementary in silico analyses predicted disruption of mitochondrial membrane potential following R162 exposure. Together, these findings indicate that GLUD1 inhibition induces metabolic and redox stress associated with disrupted glutamate and calcium homeostasis and DNA damage. Our findings distinguish the favorable prognostic value of GLUD1 expression from the cellular vulnerability revealed by its inhibition, supporting further investigations of GLUD1 as both a prognostic biomarker and potential therapeutic target in glioma. Full article

Diabetes mellitus (DM) induces significant endocrine disruption and oxidative stress (OS) within the testes, resulting in impaired spermatogenesis, increased sperm abnormalities, and compromised reproductive function. This study aimed to evaluate the combined protective effects of Semaglutide (SEM) combined with Carica papaya (papaya) juice against type 2 diabetes-induced testicular damage in rats. Forty adult male albino rats were divided into four experimental groups: a control group, a Streptozotocin (STZ)-induced diabetic group, a diabetic group treated with SEM (0.3 mg/kg), and a diabetic group treated with SEM (0.3 mg/kg) in combination with 10% papaya juice, administered for eight weeks. Statistically significant superiority over SEM alone was observed for selected endpoints; the findings primarily support the potential of papaya as a dose-sparing adjunct rather than demonstrating uniformly enhanced efficacy. They significantly improved systemic metabolic parameters, as evidenced by reduced fasting blood glucose (FBG) and glycated hemoglobin (HbA_1c) levels and restoration of the lipid profile. Importantly, it also attenuated diabetes-induced testicular injury, as demonstrated by improved reproductive hormone levels, enhanced sperm parameters, restoration of antioxidant defenses, modulation of inflammatory and apoptotic signaling, and marked histopathological recovery of seminiferous tubular architecture. Antioxidant markers revealed a notable reduction in malondialdehyde (MDA) and cytochrome P450 2E1 (CYP2E1), along with significant increases in reduced glutathione, catalase (CAT), and superoxide dismutase (SOD). Furthermore, a marked modulation of key pro-inflammatory and pro-apoptotic mediators was observed, including forkhead box protein O1 (FOXO1), microRNA-155 (miR-155), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B cell subunit 1 (NF-κB1), interleukin-6 (IL-6), caspase-3 (CASP3), and BCL2-Associated X Apoptosis Regulator (Bax), while a significant upregulation of sirtuin-1 (SIRT1), microRNA-34c (miR-34c), and B-cell lymphoma-2 (Bcl-2) was also detected. Histopathological assessments confirmed the restoration of normal testicular architecture in the treated groups. These findings indicate that the combination strategy may have the potential to achieve dose savings while maintaining efficacy comparable to the standard-dose SEM, through the enhancement of the antioxidant defenses, modulation of inflammation, and apoptosis, specifically via the modulation of the miR-34c/miR-155 and SIRT1/FOXO1 signaling. Full article

UDP-glucuronosyltransferases (UGTs) are a key family of phase II metabolic enzymes in humans that play a central role in maintenance of metabolic homeostasis and drug disposition by catalyzing glucuronidation of endogenous and exogenous substances. UGT-mediated metabolism of antitumor drugs plays a dual role in tumor drug resistance, emerging as a hotspot in cancer therapy. This review outlines the structural characteristics, classification system, tissue distribution, and multilevel regulation of UGTs, with a focus on their bidirectional roles in tumor drug resistance, i.e., promotion of resistance through metabolic clearance and inhibition of resistance through metabolic activation. This review also discusses strategies of multidimensional tumor resistance intervention based on UGTs, and we also discussed the challenges in the clinical translation of current UGT-targeting strategies. To date, most data on UGTs were derived from in vitro and preclinical models; clinical validation remains limited, and the dual roles of UGTs are highly context-dependent. This review article provides a perspective for comprehensive understanding of UGT-mediated tumor resistance and offers theoretical foundations and practical directions for development of novel antitumor strategies. Full article

Patients with autoimmune rheumatic diseases, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), experience excess cardiovascular risk that is not fully captured by conventional lipid measurements. In active RA, lower cholesterol may coexist with higher vascular risk, a pattern known as the lipid paradox. We propose that systemic inflammation can uncouple lipid concentration from lipoprotein function and organize the evidence along five mechanistic axes. Inflammatory cytokines, mainly interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1β, IL-17/IL-23 and type I interferons, remodel lipoprotein metabolism. High-density lipoproteins (HDL) lose protective functions and may become pro-inflammatory. Apolipoprotein-B particles are oxidized or otherwise modified, linking lipid metabolism to autoimmunity. Macrophage cholesterol imbalance and cholesterol crystals activate inflammasome pathways in experimental atherosclerosis, while immune-cell metabolic rewiring may amplify cytokine output; these mechanisms are treated as extrapolated when direct rheumatic-disease evidence is limited. The pathways converge on endothelial dysfunction and thrombo-inflammation. RA and SLE are the mechanistic anchors, whereas psoriatic disease, axial spondyloarthritis, systemic sclerosis, vasculitides and antiphospholipid syndrome are weighted by evidence category. Standard lipid panels may therefore underestimate risk in selected contexts, especially during active inflammatory disease. Full article

Clubroot, caused by the obligate biotrophic protist Plasmodiophora brassicae, is a devastating soil-borne disease threatening global cruciferous crop production. To explore non-transgenic control strategies, this study investigated the efficacy of a crude protein extract containing RXLR motif-fused recombinant CRa protein against clubroot in tumorous stem mustard (Brassica juncea var. tumida) and its regulatory mechanisms in the rhizosphere. Mechanistically, fluorescence tracking confirmed that the CRa protein exploits the xylem stream for systemic translocation, colonizing the stele and vascular tissues within 24 h and significantly reducing the disease index. Ecologically, CRa protein reshaped the rhizosphere microbiome by enhancing α-diversity (Shannon and Simpson indices), increasing network complexity, and specifically enriching beneficial genera such as Pseudomonas. Metabolically, CRa protein induced the reprogramming of root exudates, upregulating defensive compounds including jasmonic acid methyl ester, 4-hydroxyglucobrassicin, and (2R)-2-hydroxy-2-phenethylglucosinolate. Overall, exogenous CRa protein activates a coordinated defense response through three key mechanisms: rapid vascular translocation, recruitment of beneficial microbiota, and metabolic reprogramming. This study provides novel insights for developing non-transgenic, microbiome-based green control strategies. Full article

Background/Objectives: Glioblastoma multiforme (GB) is an extremely aggressive tumor of the central nervous system, characterized by rapid growth, high invasiveness, and significant resistance to treatment. A growing body of data indicates that metabolic reprogramming of GB cells may be a therapeutic target, and that the ketogenic diet (KD)—by limiting glucose and inducing ketosis—may modulate tumor metabolism. The aim of this review was to provide a synthetic presentation of the current state of knowledge regarding the use of KD as an adjunctive therapy in the treatment of GB, with a particular focus on the mechanisms of action, safety, feasibility and results of clinical trials. Methods: The review was conducted in accordance with the Joanna Briggs Institute methodology and the PRISMA-ScR guidelines. A systematic search of PubMed, Scopus, EBSCO, Web of Science, Google Scholar, and Cochrane Library (1–10 April 2026) included studies on the use of KD in patients with GB. Full-text observational studies, randomised trials and reviews were included in the analysis. Data extraction was carried out according to the Population–Concept–Context (PCC) model. Results: Of the 26 publications identified, 12 met the inclusion criteria. Preclinical data consistently indicate that KD may reduce glycolysis, lower insulin and IGF-1 levels, increase oxidative stress in cancer cells, and modulate the inflammatory microenvironment. Clinical trials confirm the safety and feasibility of KD, as well as the ability to maintain stable ketosis. Preliminary data suggest potential metabolic benefits and improved quality of life, however, clinical efficacy remains inconclusive due to small trials, heterogeneous dietary protocols, and a lack of randomized trials. The variety of interventions used (classic KD; MCT-KD-Medium-chain triglyceride KD; KD-IF—KD and intermittent fasting) makes it difficult to compare the results. Conclusions: The KD represents a promising, low-toxic strategy to support the treatment of GB, based on biological basis. Available data indicate its safety and feasibility, but there is insufficient evidence to recommend its routine use in clinical practice. Large, multicenter, randomized trials with standardized dietary protocols and objective monitoring of metabolic parameters are needed to unambiguously assess the impact of KD on disease survival and progression. Full article

Objective: Vasculogenic mimicry (VM), characterized by the de novo formation of microvascular-like channels derived from aggressive tumor cells without involving traditional endothelial cells, is a pivotal pathological hallmark driving extreme invasiveness and dismal prognosis in hepatocellular carcinoma (HCC). This study aimed to establish a VM-based molecular subtyping system and systematically characterize its associated biological features, thereby providing a potential framework for individualized prognostic assessment and treatment decision-making in HCC. Methods: We integrated curated VM-associated gene sets with single-cell RNA sequencing data to identify malignant epithelial cell-enriched VM-associated candidate genes. Subsequently, univariate Cox regression, LASSO-Cox regression, and multivariate Cox regression were sequentially performed to identify six prognostic VM-related genes: HSPA9, TGFA, MAD2L1, PROM1, AGXT, and GCGR. HCC patients were stratified into VM, Mixed-VM, and Non-VM subtypes according to VM scores. Kaplan–Meier survival analysis, time-dependent ROC analysis, and Cox regression were used to assess prognostic performance. The biological features of the classification system were evaluated using bulk transcriptomic cohorts, spatial transcriptomics, Cytometry by Time-of-Flight (CyTOF), metabolomics, lipidomics, somatic mutation and copy number alteration analyses, and treatment-related HCC cohorts. Results: The VM score-based classification stratified HCC patients into three molecular subtypes with distinct prognostic and biological characteristics. Patients classified as the VM subtype had significantly poorer overall survival than those classified as Mixed-VM or Non-VM subtypes, and this prognostic pattern was validated across independent cohorts. Multi-omics analyses showed that the VM subtype was associated with YAP-TAZ-TEAD-related transcriptional programs, stemness/proliferation-related features, immunoregulatory and exhaustion-like tumor microenvironmental characteristics, and distinct metabolic and lipidomic alterations involving modified nucleosides, keto acid-related metabolites, cholesteryl esters, and sphingolipid-related species. Spatial transcriptomics revealed focal enrichment of VM-score-high regions and their association with YAP-TAZ-TEAD and immune checkpoint-related signatures. In orthotopic HCC mouse models, YAP1 overexpression increased PAS⁺/CD34⁻ VM-like structures, whereas verteporfin treatment reduced these structures. In two treatment-related cohorts, the Non-VM subtype showed higher response rates to sorafenib and transarterial chemoembolization (TACE) than the VM subtype. Connectivity Map (CMap)-based computational drug prioritization and molecular docking analysis prioritized ivermectin as a candidate compound; however, its antitumor activity requires further experimental validation. Conclusions: This study establishes a VM score-based molecular classification framework for HCC and identifies VM-subtype-associated prognostic, spatial, immune, metabolic, genomic, and therapeutic features. These findings provide a candidate framework for molecular risk stratification and subtype-guided therapeutic exploration in HCC. Full article

Background: Circulating bile acid (BA) profiles are increasingly explored in pancreatic cancer, although their interpretation is often complicated by biliary obstruction and its clinical management. In this study, we characterized plasma BA profiles in pancreatic ductal adenocarcinoma (PDAC) and assessed the relative contributions of tumor localization, histological subtype, cholestasis, and cholestasis-related interventions. Methods: Plasma BAs were quantified by LC-MS/MS in patients with PDAC of the pancreatic head (hPDAC, n = 132), PDAC of the body-tail (tPDAC, n = 42), and non-PDAC tumors of the pancreatic head (hnonPDAC, n = 34). BA concentrations and derived ratios were log-transformed and standardized, and their associations with bilirubin were examined using multivariable linear models, LOESS, and multivariate longitudinal analyses. Results: UDCA therapy was associated with markedly increased circulating UDCA, higher total BA concentrations, and enrichment of secondary BA species. Direct bilirubin explained more variability in BA composition than binary jaundice classification and showed a non-linear association with BA remodeling, with a distinct metabolic profile emerging only at high bilirubin levels. Longitudinally, BA profiles changed substantially over time in hPDAC, largely in parallel with bilirubin, whereas they remained comparatively stable in tPDAC. After adjustment for bilirubin, tumor-related differences were modest and context-dependent. Conclusions: Overall, circulating BA profiles in pancreatic cancer appear to be driven predominantly by cholestasis and its management rather than by tumor-related features alone. Full article

Tumor-associated macrophages (TAMs) are considered to be one of the most attractive targets in cancer therapy but attempts to target them have produced variable and often contradictory results. Their phenotype and function are shaped by developmental origin, spatial niche, metabolic conditions, immune context, and treatment history. For this reason, TAM-directed therapy should not be approached as a simple problem of depletion or repolarization, but as a problem of function and timing. This framework integrates converging evidence from multiple independently reported studies of stage-, sequence-, and context-dependent macrophage targeting into a single decision structure, rather than proposing a new biological mechanism. We discuss here recurrent macrophage functions in solid tumors, including vascular support, matrix remodeling, immune exclusion, tumor-cell survival, antigen presentation, and tissue repair after therapy. We then consider how these functions affect the choice between depletion, recruitment blockade, reprogramming, and activation, and why the same intervention may be beneficial, ineffective, or harmful depending on lesion state and treatment sequence. Particular attention is given to therapeutic windows, biomarker-guided personalization, and adverse consequences of TAM intervention, including toxicity, compensatory myeloid substitution, loss of protective immune functions, repair-driven relapse, and the selection of inflammation-adapted or macrophage-resistant tumor cells. Effective TAM therapy will require functional precision, temporal precision, dynamic reassessment, and explicit attention to macrophage plasticity as both an opportunity and a source of risk. Full article

The advent of cancer immunotherapy opened a transformative era in oncology, shifting the focus from targeting mutated genes through precision oncology to harnessing the body’s immune system via agnostic therapies. This paradigm has demonstrated that a deeper understanding of the tumor immune microenvironment (TIME) can transcend the challenges posed by cancer’s genetic diversity and evolutionary dynamics. In the case of thyroid cancer, progress in immunotherapy has been comparatively slow. Much of the current research still centers on the genetic landscape of thyroid tumors rather than on comprehensive exploration of their TIME. The TIME, composed of immune cells such as macrophages, lymphocytes, natural killer cells, and mast cells, along with a network of signaling molecules, evolves alongside tumor growth and metastasis. It both influences and is influenced by genetic alterations, metabolic conditions, and therapeutic interventions. This dynamic crosstalk defines the clinical and biological heterogeneity of thyroid cancers; from the aggressive anaplastic thyroid carcinoma (ATC) to the more indolent papillary thyroid carcinoma (PTC). Mapping the spatial and temporal changes within the TIME offers the opportunity to design therapies that counter immune evasion and enhance treatment response. As understanding of the tumor microenvironment deepens, thyroid cancer therapy is undergoing a major shift; from strategies aimed merely at genetic mutations to integrated, combinational approaches incorporating personalized immunotherapy. Building on recent findings, which detail immune cell composition and therapeutic implications in thyroid malignancies, this review expands on the molecular and cellular mechanisms shaping the microenvironment. We highlight how oncogenic signaling, stromal remodeling, and metabolic reprogramming coordinate to influence tumor immunity, and we explore emerging strategies that aim to reengineer the tumor microenvironment for improved therapeutic outcomes. Full article

Metabolic syndrome (MetS) is a complex metabolic disorder that includes central fat accumulation and insulin resistance, abnormal lipid levels, high blood pressure, and ongoing mild inflammation as its main symptoms. The global rise in metabolic syndrome parallels the increasing prevalence of male infertility, suggesting a potential association between metabolic health and reproductive function. Male fertility suffers from obesity, which represents a major element of metabolic syndrome because it disrupts hormonal balance, raises scrotal temperatures, and causes oxidative damage and HPG axis malfunction. Excess body fat functions as an endocrine system that induces the body to produce pro-inflammatory cytokines, which include tumor necrosis factor-α and interleukin-6, and various other inflammatory substances that result in ongoing body-wide inflammation. The state of inflammation leads to damaged spermatogenesis, which results in lower testosterone production and impaired semen quality that includes changes in sperm concentration, motility, morphology, and DNA integrity. The combination of insulin resistance and metabolic disturbances that occur in MetS leads to oxidative stress and mitochondrial dysfunction, which harms male reproductive abilities in testicular tissue. Recent research shows that adipokines and endocrine disruptors, together with epigenetic modifications, function as mediators that establish the connection between metabolic syndrome and male infertility. The development of targeted therapeutic strategies and lifestyle interventions requires researchers to study how obesity and chronic inflammation interact with each other to create reproductive dysfunction. This review defines the pathophysiological mechanisms that connect metabolic syndrome to male infertility by focusing on how obesity-related inflammation affects male reproductive health. Full article

Gliomas are the most common group of primary brain tumors, among which glioblastoma multiforme (GBM) is characterized by a particularly poor prognosis and the limited effectiveness of available treatments. Ophiobolin A (OP-A), a natural sesterterpenoid, exhibits promising anticancer properties, including the ability to cross the blood-brain barrier and induce paraptosis-like cell death. However, the molecular mechanisms underlying its action, especially in the early phase of the cellular response, remain not fully understood. The aim of this study was to analyze early changes in the expression of genes associated with apoptosis, ferroptosis, and antioxidant mechanisms in T98G and U118MG glioma cells exposed to OP-A. Gene expression was assessed by RT-qPCR, apoptosis was evaluated using Annexin V/PI staining and flow cytometry, and treatment-induced morphological changes were documented by brightfield microscopy. Statistical analysis was performed using the Mann–Whitney U test. Descriptive Annexin V/PI analysis showed a lower proportion of viable cells and a higher proportion of early apoptotic cells in the analyzed OP-A-treated T98G and U118MG samples compared with the corresponding vehicle-control samples. These preliminary observations were based on technical replicates from a single biological experiment and require confirmation in independent biological replicates. Transcriptional profiling revealed a shift toward a pro-apoptotic phenotype, characterized by increased BAX and FAS expression together with a trend toward reduced BCL2 expression, whereas ferroptosis-associated genes remained largely unchanged. Notably, SLC7A11 upregulation suggested activation of compensatory antioxidant mechanisms in response to OP-A treatment. In T98G cells, OP-A induced a distinct and reproducible transcriptional signature that enabled accurate discrimination from control conditions (AUC = 0.833). Feature importance and SHAP analyses identified BAX as the most informative predictor, followed by SLC7A11 and FAS, with bootstrap validation confirming BAX as a stable marker. Pathway analysis demonstrated selective activation of apoptosis- and cysteine metabolism-related pathways, while hierarchical clustering revealed that OP-A generated a transcriptional profile distinct from oxidative stress-inducing agents. The predictive performance of this molecular signature was cell-line dependent, showing weaker discrimination in U118MG cells.Short-term OP-A exposure in T98G and U118MG cells was associated with exploratory trends in apoptosis- and redox-related gene expression and a higher proportion of Annexin V-positive cells. The machine-learning analyses identified candidate discriminatory features within this limited dataset but should be regarded as hypothesis-generating. Larger studies with independent biological replication, additional GBM models, different exposure conditions, and functional validation are required to confirm these observations and clarify the mechanism of OP-A action. Full article

Reactive oxygen species (ROS) are central regulators of cancer biology and represent a double-edged target in oncology. At physiological levels, ROS support signal transduction, proliferation, differentiation, and immune responses, whereas sustained ROS imbalance promotes DNA damage, genomic instability, metabolic reprogramming, and remodeling of the tumor microenvironment, thereby contributing to tumor initiation, progression, metastasis, and therapy resistance. Conversely, because many cancer cells operate close to the limit of tolerable oxidative stress, further ROS elevation can trigger apoptosis, ferroptosis, immunogenic cell death, and other cytotoxic programs. This review summarizes the major intracellular and microenvironmental sources of ROS, the mechanisms by which redox signaling shapes malignant transformation and tumor adaptation, and the antioxidant systems that buffer oxidative stress in cancer cells. We further discuss current therapeutic approaches based on both ROS suppression and ROS amplification, including redox-modulating small molecules, radiotherapy, photodynamic and sonodynamic therapy, catalytic nanomaterials, and ROS-responsive prodrugs and drug delivery systems. Particular attention is given to the context-dependent effects of ROS, the antioxidant paradox, tumor heterogeneity, hypoxia, off-target toxicity, and the need for robust redox biomarkers. A deeper understanding of tumor-specific redox vulnerabilities will be essential for developing precise and clinically effective ROS-oriented cancer therapies. Full article