The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. The NCI conducts and supports research, training, health information dissemination, and other activities related to the causes, prevention, diagnosis, and treatment of cancer; the supportive care of cancer patients and their families; and cancer survivorship.NCI is the oldest and has the largest budget and research program of the 27 institutes and centers of the NIH ($6.9 billion in 2020). It fulfills the majority of its mission via an extramural program that provides grants for cancer research. Additionally, the National Cancer Institute has intramural research programs in Bethesda, Maryland, and at the Frederick National Laboratory for Cancer Research at Fort Detrick, in Frederick, Maryland. The NCI receives more than US$5 billion in funding each year.The NCI supports a nationwide network of 71 NCI-designated Cancer Centers with a dedicated focus on cancer research and treatment and maintains the National Clinical Trials Network.
Membrane-active peptides (MAPs) have garnered significant attention as potential alternatives to conventional cancer therapies, which are frequently limited by severe side effects. Among them, antimicrobial peptides (AMPs) that leverage differences between the plasma membranes of cancer cells and healthy cells are particularly attractive. While several AMPs have demonstrated anticancer potency, structure-function relationship studies are lacking to explain the molecular basis of their selectivity and to help design improved analogs. Here, we contribute to filling this gap by investigating Nile tilapia piscidin 4 (TP4), an AMP with demonstrated activity against several solid organ cancers. First, we discover through biological assays that the anticancer activity of the peptide, which underscores a promising therapeutic window, is associated with increased plasma membrane permeability in cancer cells compared to normal cells and positively (negatively) correlated with enzymes that enrich (deplete) anionic PS in the outer leaflet. Next, we utilize a suite of complementary techniques on model membranes to investigate the interactions of TP4 with membranes, uncovering behaviors not previously observed in related AMPs. Circular dichroism experiments reveal that TP4 preferentially binds to zwitterionic phosphatidylcholine (PC) membranes enriched in anionic PS, while cholesterol markedly impairs binding. X-ray diffraction demonstrates that TP4 disrupts PC-PS membranes by inducing lipid segregation. Covering a range of biologically relevant peptide concentrations with neutron diffraction and reflectometry measurements in fluid bilayers and MD simulations, we unveil how TP4 and associated water gradually insert into the hydrocarbon region and cause convoluted membrane deformations to breach the membrane barriers. These studies highlight the pivotal role of the TP4 polyarginine tail in driving selective membrane binding and disruption on membranes enriched with the anionic lipid PS. Together, our results elucidate the molecular determinants underpinning the selective anticancer effects of TP4, providing a strategic framework for the rational design of advanced membrane-active therapeutics.
Triapine is a potent small-molecule ribonucleotide reductase inhibitor investigated in combination with radiation and/or chemotherapy for the treatment of advanced stage solid cancers. The aim of this study is to develop a population pharmacokinetic-pharmacodynamic (PK/PD) model for triapine to describe the PK parameters, the effect of smoking on exposure, and the relationship between methemoglobin concentrations and exposure. A total of 36 patients with advanced stage cervical or neuroendocrine cancers from two phase I studies were included in the population PK/PD model building. Triapine and methemoblogin plasma concentrations were sampled over an 8-hr or 24-hour period. Data were analyzed by a nonlinear mixed-effects modelling approach. Simulations were performed to optimize the dosing strategy for oral triapine. A two-compartment model with two-transit compartment Erlang absorption and first-order elimination best described the PK of triapine, and an effect compartment model best described the PD effect of triapine on methemoglobin concentrations. The final model described triapine PK/PD well, and a 38
Radiotherapy is a key foundation of oncologic treatment that is used across the spectrum of cancer indications. Advances in imaging, treatment planning, and dose delivery have led to increasingly conformal and even ablative treatments, which have resulted in improved tumor control with no increase in the risk of side effects (or with a decrease in risk) as compared with previous treatments. These advances have facilitated the combined use of radiotherapy with efficacious systemic therapies, including targeted treatments and immunotherapies. Radiation-induced changes in normal tissue occur as a result of stem-cell senescence, inflammation, vascular changes, fibroblast activation, and loss of parenchymal cells. Research into the biologic underpinnings of radiation-induced changes in normal tissue, biomarkers of side effects of various irradiation regimens, and new treatment methods offers great promise for further increasing the efficacy of radiotherapy and improving the side-effect profile through personalized approaches.
Background: Immune checkpoint inhibitors (ICIs), such as anti-programmed death (PD)-1 and anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 agents, have revolutionized oncology but are associated with immune-related adverse events (irAEs). Among these, ICI-associated myocarditis (ICI-M) is a rare but life-threatening complication, with mortality rates ranging from 27% to 50%. Objective: This narrative review summarizes the pathogenesis, epidemiology, clinical presentation, diagnostic methods, and management strategies for ICI-induced myocarditis, specifically highlighting emerging biomarkers and immunosuppressive therapeutic approaches. Results and Discussion: ICI-M typically presents within the first 65 days of treatment and is significantly more frequent with combination therapies. Pathologically, it is characterized by myocyte necrosis and massive infiltration of cluster of differentiation (CD)4+ and CD8+ T-cells, often overlapping with myositis (irM/M). Diagnosis relies on a multimodal approach. Management requires immediate ICI cessation and initiation of high-dose corticosteroids as first-line therapy. For steroid-refractory cases, second-line options include mycophenolate mofetil (MMF), intravenous immunoglobulin (IVIG), and emerging therapies like abatacept and ruxolitinib. Rechallenge with ICIs after high-grade ICI-M must be approached with extreme caution by the multidisciplinary team (MDT). Emerging biomarkers and omics techniques hold promise for earlier diagnosis and risk stratification. Conclusions: ICI-M is a rare yet highly lethal cardiac complication demanding high clinical vigilance and timely diagnosis. Management hinges on an aggressive multidisciplinary approach, aiming to minimize toxicity while balancing oncological efficacy.
Mycotoxin contamination represents a major public health and economic burden worldwide. Aflatoxins, particularly aflatoxin B1, are the most detrimental for human health. In this review, we discuss the sources of exposure and geographic distribution. The prevalence of aflatoxin–albumin/lysine adduct detection in humans varies dramatically across the world, from 0% reported in two European studies to up to 100% reported in studies from parts of Africa and Asia. We also summarize the disease outcomes that aflatoxins are associated with in humans. We focus particularly on cancer outcomes, which aflatoxins can cause through mutagenic DNA adducts, oxidative stress, mitochondrial dysfunction, immune effects, and epigenetic changes. Synergy with hepatitis B virus and potentially with other mycotoxins can also increase risk. Minimization of aflatoxin exposure requires an integrative approach, beginning at the farm level and continuing through pre-harvest, post-harvest, storage, and the consumer level. New developments in technology, such as electrochemical biosensors and artificial intelligence algorithms, are being piloted and could help improve detection and decontamination efforts. Further, new tests for aflatoxin exposure in humans (e.g., blood spot assays) could assist biomonitoring efforts. Despite regulatory standards in most countries for the maximum allowable level of aflatoxins in food products and animal feed, exposure remains high in many parts of the world and might be increasing even in countries with historically low exposure. Integration of these tools in a One Health framework is essential to reduce the current and future burden of aflatoxin-related disease.
