IntroductionImmune checkpoint inhibitors (ICIs) were introduced at different times across cancer types, but whether early approvals coincided with cancer-specific changes in national mortality remains uncertain.MethodsWe conducted an ecological observational comparative time-series study using CDC WONDER United States Cancer Statistics mortality data from 1999-2019. We analyzed CDC-calculated age-adjusted mortality rates (AAMRs) for melanoma of the skin, lung and bronchus, kidney and renal pelvis, urinary bladder, and Hodgkin lymphoma. Cancer-specific synthetic-control models used each site's first major ICI approval year, preperiod-centered log AAMR trajectories, mutually exclusive solid or hematologic comparison sites, and a common 0-3-year postapproval estimand. Placebo analyses and staggered-adoption difference-in-differences (DiD) were robustness checks.ResultsObserved AAMRs averaged 3.44%, 13.05%, 4.73%, 3.60%, and 3.68% below synthetic estimates for melanoma, lung, kidney, bladder, and Hodgkin lymphoma, respectively. Conditional placebo-rank pseudo-P values were .40, .23, .25, .20, and 1.00. Temporal-placebo models showed earlier divergence for several sites. The balanced 0-3-year DiD estimate was -0.96 deaths per 100,000 (95% pointwise CI, -2.99 to 1.06).ConclusionCancer-specific mortality patterns were directionally compatible with lower mortality during early ICI approval eras, but placebo benchmarking, heterogeneous temporal specificity, and an imprecise DiD estimate precluded firm causal attribution. These ecological findings do not estimate individual treatment effectiveness or current ICI practice.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with a five-year survival rate of approximately 20-25% despite advances in targeted therapy and immunotherapy. There is a continuous need for novel, low-toxicity compounds capable of modulating key oncogenic pathways in non-small cell lung cancer (NSCLC). Mangrove ecosystems are rich reservoirs of bioactive phytochemicals, yet the inhibitory potential of compounds from Rhizophora mucronata against validated lung cancer-associated proteins has not been systematically explored using multi-scale computational approaches. This study employed an integrated computational pipeline to evaluate 14 phytochemicals from R. mucronata. Density Functional Theory (DFT) calculations at the B3LYP/6-31G* level were performed to characterize electronic properties of the ligands. Molecular docking studies were conducted using both AutoDock Vina (PyRx) and Schrödinger Glide against the Keap1 Kelch domain (PDB 1X2J) and the YEATS2 YEATS domain (PDB 5XNV). Top-ranked complexes were subjected to 100-ns molecular dynamics (MD) simulations in Desmond, and pharmacokinetic and toxicity profiles were predicted using SwissADME and pkCSM. Among the screened compounds, ligand L10 (cyclohexane-1,2,3,4,5,6-hexaol) exhibited the smallest HOMO-LUMO energy gap (0.36 eV), favorable binding affinities (Glide score of -7.789 kcal/mol against 1X2J), multiple hydrogen-bonding interactions, and stable complex behavior during MD simulations (Cα RMSD < 3 Å). Several other ligands (L02, L05, and L07) also displayed promising profiles. Most compounds complied with Lipinski's rule of five and showed acceptable predicted ADMET properties. These preliminary findings suggest that Rhizophora mucronate -derived phytochemicals, particularly L10, are promising candidates for further experimental evaluation as modulators of Keap1 and YEATS2 in lung cancer. This study provides a computational framework for prioritizing natural product leads from mangrove species for subsequent in vitro and in vivo validation.

Breast cancer (BC) remains a major global health concern, with rising incidence and mortality rates. Early diagnosis of BC plays an important role in its prevention. However, number of clinically validated biomarkers that enable accurate and minimally invasive diagnosis are still insufficient. Epigenetic modifications, particularly hypermethylation-mediated inactivation of numerous tumor suppressor genes occur early in tumorigenesis and are detectable even before the clinical onset, making them promising candidates for early diagnosis. Therefore, this study aimed to identify breast cancer-associated epigenetically regulated genes with potential diagnostic and biological relevance. A set of forty genes that displayed both hypermethylation and downregulation in BC were initially identified through bioinformatics analysis of publicly available datasets. Based on Gene Ontology (GO) and Reactome pathway enrichment analyses, eight genes were subsequently shortlisted for experimental analysis. Among these eight genes, LHX3 was significantly downregulated in both MCF-7 and MDA-MB-231 cells and in all tested BC tissue samples. LHX3 promoter hypermethylation was found in 80% of tumor tissues, compared to 32% in matched normal tissues. Aberrant LHX3 promoter methylation was significantly associated with metastasis status (P = 0.0002), with higher methylation in non-metastatic tumors, tumor size ≤20 mm (P = 0.002), and advanced tumor stage (P = 0.005). Given the complex pattern of these associations, findings were interpreted cautiously. Treatment with 5-aza-2'-deoxycytidine reversed promoter hypermethylation and restored LHX3 expression in MDA-MB-231 and MCF-7 cells. Additionally, ectopic expression of LHX3 not only reduced migration and proliferation but also induced cell death in BC cells. Our study provided the first evidence of epigenetically induced silencing of LHX3 and its anti-tumor role in BC. Furthermore, our findings support LHX3 as a candidate epigenetically regulated biomarker with tumor-suppressive properties in BC; however, independent cohort validation, quantitative methylation assays, and stage/subtype-stratified analyses are required before its diagnostic or prognostic utility can be established.

Fine-needle aspiration (FNA) is the gold-standard diagnostic procedure for the initial evaluation of thyroid nodules because it is minimally invasive, cost-effective, and highly accurate for distinguishing benign from malignant lesions. However, conventional smear preparation is frequently affected by operator-dependent variability, uneven cell distribution, blood contamination, and air-drying artifacts, all of which may compromise specimen adequacy and diagnostic performance. Liquid-based cytology (LBC) has emerged as an effective alternative, offering standardized specimen processing, improved cellular preservation, and enhanced slide quality. Among the available LBC platforms, the ThinPrep system is one of the most extensively validated technologies for thyroid cytopathology and is increasingly integrated into routine clinical practice and molecular diagnostic workflows. This protocol provides a comprehensive, standardized workflow for processing thyroid FNA specimens using the ThinPrep liquid-based cytology system. The protocol describes specimen collection, transportation, fixation, processing with the ThinPrep 5000 processor, slide preparation, staining, and quality control procedures to ensure optimal cytomorphological evaluation. Recommendations for acceptable specimen preservation, including transport in PreservCyt solution or alternative fixation methods, are also provided. In addition, the protocol includes procedures for recovering the residual cellular material preserved in the ThinPrep vial for paraffin block processing, which allows for complementary studies, e.g., immunohistochemistry, fluorescence in situ hybridization (FISH), DNA and RNA extraction, and next-generation sequencing (NGS), thus expanding the diagnostic utility of thyroid cytology beyond conventional microscopic examination. When properly executed, this protocol generates high-quality monolayer cytology preparations suitable for standardized interpretation according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) while preserving residual material for downstream molecular analyses. Compared with conventional smear cytology, the ThinPrep system improves specimen reproducibility, reduces background artifacts and inadequate samples, facilitates laboratory standardization, and supports precision medicine applications. This protocol provides a practical and reproducible approach for both clinical diagnostic laboratories and translational research. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Simultaneous preparation of ThinPrep cytology slides and cell blocks from thyroid fine-needle aspiration specimens using liquid-based cytology Alternate Protocol: Alternative ThinPrep FNA processing using CytoLyt and PreservCyt.

Lived experience is increasingly recognised as an essential source of expertise in healthcare research, service design, policy and quality improvement. In psycho-oncology, consumer involvement is now widely encouraged in research and service development; however comparatively little attention has been paid to the role of lived experience in educating and training the psycho-oncology workforce. We argue that involving people with lived experience should become a minimum requirement in developing, delivering, and evaluating psycho-oncology education and training. Given that psycho-oncology is fundamentally concerned with understanding and responding to the lived experience of cancer consumer involvement in education and training must be expected. To support meaningful implementation, we provide Principles for Lived Experience-Informed Psycho-Oncology Education and Training: representation, partnership, support, and accountability. Embedding lived experience expertise throughout psycho-oncology workforce development will strengthen the relevance, authenticity, and person-centredness of future education and training initiatives and may improve consumer outcomes.

Chemotherapy commonly induces skeletal muscle dysfunction and cognitive impairment, complications that reduce treatment tolerance and quality of life. Skeletal muscle mass frequently declines during chemotherapy, with cohort studies reporting losses of 3%-10% across treatment courses, while chemotherapy-induced cognitive impairment affects up to one-third of patients. Emerging evidence indicates that chemotherapeutic agents impair mitochondrial function in peripheral tissues, including skeletal muscle, increasing systemic oxidative stress and inflammatory cytokines. These factors may promote oxidative stress and inflammation within the brain, particularly in the hippocampus, contributing to neuronal mitochondrial dysfunction, apoptosis and cognitive decline. Skeletal muscle may therefore represent an important component within a broader muscle-brain axis linking chemotherapy-induced metabolic dysfunction with brain health. Targeted exercise improves skeletal muscle mitochondrial function, reduces systemic inflammation and oxidative stress and modulates multiple exercise-responsive signalling pathways, including myokines such as brain-derived neurotrophic factor and irisin. Collectively, these adaptations may contribute to improved neuronal health, neurogenesis and cognitive function. Understanding these interconnected mechanisms may inform exercise strategies to mitigate chemotherapy-related cognitive impairment.

Conventional CD8+ T cells can acquire natural killer (NK) cell receptors upon persistent antigen exposure, forming antigen-experienced NK-T (AENK-T) cells. Their dual-state plasticity within the tumor immune microenvironment determines cancer immunotherapy outcomes. This narrative review synthesizes recent transcriptomic, epigenomic, and functional data to define the trajectory, regulation, and therapeutic relevance of AENK-T cells. The analysis establishes a "temporal hierarchy" differentiating AENK-T cells from innate-like T cells: activating NK receptors (NKG2C, NKG2D) emerge early, while inhibitory receptors (NKG2A, killer-cell immunoglobulin-like receptors, KLRB1) accumulate under sustained stimulation. Mechanistically, BCL11B downregulation and the T-bet-Zeb2 axis stabilize a cytotoxic Effector AENK-T state. Conversely, the TOX-LAG-3 loop and SOX4-ID3 axis drive transition into a suppressive Exhausted AENK-T state, mirroring terminal exhaustion. The tumor immune microenvironment accelerates this shift via hypoxia, metabolic competition, and TGF-β, contrasting with chronic infection models. Translating these findings, an evaluation of emerging strategies, such as NKG2A blockade, biomarker-guided patient selection, and next-generation chimeric antigen receptor (CAR)-T cell engineering, suggests that temporally informed approaches targeting the AENK-T trajectory may overcome current immune checkpoint therapy limitations.

Cuproptosis is a copper-dependent form of regulated cell death driven by copper binding to lipoylated tricarboxylic acid (TCA) cycle proteins. This interaction triggers aberrant protein aggregation, Fe-S cluster protein degradation, and mitochondrial proteotoxic stress, and its unique metabolic dependency distinguishes cuproptosis from apoptosis and ferroptosis. This review examines the bidirectional regulation between cuproptosis and anti-tumor immunity. Cuproptosis can promote dendritic cell maturation and CD8+ T cell-mediated immunity through immunogenic cell death (ICD), damage-associated molecular pattern release, and cGAS-STING pathway activation. Activated CD8+ T cells may in turn enhance tumor cell cuproptosis sensitivity via IFN-γ-STAT1-IRF1-driven FDX1 upregulation, forming a positive feedback loop. Conversely, direct copper toxicity toward T cells and NK cells, spatial heterogeneity of intratumoral copper distribution, and potential immunosuppressive cytokine release may counterbalance these immunostimulatory effects. We outline core controversies regarding the universality of cuproptosis immunogenicity, the immune activation window of copper ions, and the clinical utility of cuproptosis biomarkers. Translational strategies including copper ionophore-immunotherapy combinations, copper-based nano-delivery systems, and copper metabolism-based patient stratification are discussed. The cuproptosis-immunity intersection remains at an early stage; key mechanistic findings require independent validation before clinical translation.

Gastric cancer remains one of the leading causes of cancer-related death worldwide, with particularly high incidence in East Asia. Despite improvements in surgical resection and perioperative chemotherapy, patients with advanced or metastatic disease face a poor prognosis. The arrival of ICIs, especially anti-PD-1 antibodies such as nivolumab, has offered new treatment options. The landmark CheckMate 649 trial showed that adding nivolumab to chemotherapy significantly improves overall survival in advanced GC, gastroesophageal junction cancer, and esophageal adenocarcinoma. However, longer-term follow-up analyses have made it clear that a substantial proportion of patients either do not respond initially or relapse after an initial response. Thus, there is an urgent need to understand the mechanisms behind immunotherapy resistance.

Cancer cachexia is conventionally viewed as muscle wasting but is increasingly recognized as a tumor-driven immunometabolic syndrome. This systemic disorder is characterized by a vicious cycle of metabolic dysregulation, systemic inflammation, and immune evasion, severely compromising the efficacy of immune checkpoint inhibitors (ICIs). Conventional single-target therapies have largely failed to disrupt this redundant pathological network. Here, we comprehensively review the therapeutic potential of Traditional Chinese Medicine (TCM) as multi-target network modulators acting at the immunometabolic interface. At the micro-level, TCM-derived monomers (such as curcumin, andrographolide, and epigallocatechin gallate (EGCG)) bidirectionally target this interface by concurrently suppressing muscle catabolism (via ubiquitin-proteasome and ferroptosis pathways) and reprogramming the immunosuppressive tumor immune microenvironment (TIME) (downregulating PD-L1 and inhibiting MDSCs/Tregs). At the macro-level, chromatographically characterized multi-herb formulas offer systemic recalibration via the gut-muscle-immune axis, utilizing microbial metabolites to restore intestinal barrier integrity, curb systemic inflammation, and epigenetically reinvigorate exhausted CD8+ T cells. Clinically, integrating TCM with ICIs presents a promising synergistic strategy to restore patient eligibility, optimize immunotherapeutic responses, and mitigate treatment-related adverse events. This review provides a mechanistic framework for positioning TCM as a potential systemic adjuvant to break the cachexia-immunosuppression loop in modern oncology.