搜索结果：Cancer biology & medicine

BRCA1 c.181T>G (p.Cys61Gly) is a pathogenic founder genetic variant prevalent in Central and Eastern Europe. The data on its clinicopathological manifestations in Ukrainian patients remain limited. This study aimed to characterize clinical presentation, tumor biology, and family history in Ukrainian women with BRCA1 c.181T>G variant. We conducted a single-centre case series of women with primary breast cancer (BC) and/or ovarian cancer (OC) harbouring BRCA1 c.181T>G genetic variant and treated at Lviv Regional Oncology Treatment and Diagnostic Center (Ukraine) between January 2024 and August 2025. Clinical presentation, tumor pathology, biomarker status, family history, treatment, and outcomes were analysed. Thirteen women aged 29-81 years (median 35 years) were included in this case series. Early-onset BC was recorded in 10 (76.9%) of patients diagnosed before 40 years. BC was the initial malignancy in 12 (92.3%) patients. OC occurred as a first tumor in 1 (7.7%) and as a subsequent cancer in 4 (30.8%) patients. Multiple malignancies were observed in 61.5% of patients, with intervals of 5-21 years between diagnoses. Family history revealed strong clustering of BC and OC across generations, often involving multiple affected relatives, consistent with hereditary breast and ovarian cancer syndrome phenotype. Among cases with known biomarker status (10/13), 2 were HER2-positive, 4 belonged to luminal-like type, and 4 cases represented triple negative BC. Most cases (10/13, 76.9%) were diagnosed at early tumor growth stage (pT1-2). However, more than half of primary tumors (8 of 13; 61.5%) had positive nodal status (pN1-2) reflecting invasive behaviour of cancer cells. This Ukrainian case series demonstrates that the BRCA1 c.181T>G genetic variant is associated with early-onset breast cancer, variable tumor biology, frequent multiple primary cancers, and strong familial clustering. These observations support the need for expanded genetic testing, targeted surveillance, and corresponding risk reduction strategies tailored to Ukraine's BRCA1 founder pathogenic variant landscape.

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer.

Radiotherapy-associated pain is among the most common and debilitating complications in head and neck cancer. Although historically viewed primarily as a treatment-related adverse effect, growing evidence suggests that pain is deeply intertwined with tumor biology, immune remodeling, and therapeutic outcomes. At the same time, recent advances in cancer neuroscience have identified sensory nerves as active components of the tumor microenvironment (TME), capable of influencing antitumor immunity through complex neuroimmune crosstalk. These observations raise the possibility that radiotherapy-associated pain is not merely a clinical symptom but also a biological indicator of dynamic changes within the tumor immune microenvironment (TIME). In this review, we outline the major clinical manifestations of radiotherapy-associated pain in head and neck cancer, including inflammatory or mucositis-related pain, neuropathic pain, and long-term chronic pain, with emphasis on their underlying biological features and potential therapeutic relevance. Given that oral mucositis is the dominant source of acute radiotherapy-associated pain in head and neck cancer, we further summarize evidence-based preventive and supportive strategies, including photobiomodulation, mucosal barrier-forming agents, anti-inflammatory mouthwashes, nutritional interventions, pain control, and multidisciplinary oral care. We further discuss how radiotherapy reshapes the TIME through mechanisms such as immunogenic cell death, activation of the cGAS-STING pathway, vascular and stromal remodeling, and regulation of lymphoid compartments, while also triggering compensatory immunosuppressive responses. Preclinical and translational studies suggest that nociceptive signaling pathways may modulate T-cell function, myeloid-cell activity, and immune-evasive programs. Through these neuroimmune interactions, radiotherapy-induced neural injury and persistent pain may contribute to the establishment of an immunosuppressive, wound-like microenvironment that ultimately affects treatment response and tumor progression. Finally, we discuss the translational significance of incorporating pain phenotyping into combined radiotherapy and immunotherapy strategies for head and neck cancer. Opioid-sparing multimodal analgesia, neuromodulation, and neuroimmune-targeted interventions may represent promising approaches to simultaneously improve symptom control and antitumor immunity. We propose that radiotherapy-associated pain may be considered a candidate neuroimmune phenotype rather than a passive adverse event, providing a new conceptual framework for precision management and translational research in head and neck cancer.

Prostate cancer (PCa) is one of the most common causes of cancer-related mortality in men globally. Although current therapies can control early-stage disease, advanced PCa remains difficult to treat because of therapeutic resistance and adverse side effects, highlighting the need for new treatment strategies. Syzygium nervosum (SN), a medicinal plant rich in bioactive compounds such as gallic acid and ellagic acid, has demonstrated anticancer properties in several malignancies; however, its effects on PCa remain unclear. This study investigated the anticancer potential of SN using integrated computational and in vitro approaches. DU145 and PC-3 prostate cancer cells were treated with SN extract at concentrations of 25-400 µg/mL for 24 and 48 h. Cell viability, colony formation, and cell-cycle progression were evaluated to determine antiproliferative activity. In parallel, computational analyses were performed to predict molecular targets of SN-derived compounds. Our results displayed that SN extract reduced cell viability, suppressed clonogenic growth, and disrupted cell-cycle progression in both cell lines. Computational findings suggested that gallic and ellagic acids may interact with key regulatory proteins related to cell proliferation and survival, including AKT and CDK2. Overall, SN demonstrates promising anticancer activity and may represent a potential therapeutic source for prostate cancer treatment.

Prostate cancer remains one of the most biologically heterogeneous malignancies in men and continues to present major therapeutic challenges despite advances in androgen receptor-targeted therapy and molecular stratification. Increasing evidence suggests that prostate cancer progression is influenced not only by tumor-intrinsic genetic alterations but also by complex interactions involving androgen receptor signaling, inflammatory pathways, metabolic reprogramming, oxidative stress, epigenetic remodeling, immune dysregulation, and gut microbiome-associated signaling. Within this evolving systems-level framework, natural products have attracted increasing attention because of their ability to modulate multiple interconnected molecular pathways. This review examines the molecular basis of prostate cancer progression with particular emphasis on crosstalk among androgen receptor signaling, microbiome-associated regulation, epigenetic adaptation, inflammatory signaling, and tumor microenvironment remodeling. The emerging role of the gut microbiome in androgen metabolism, microbial metabolite production, immune regulation, and endocrine resistance is critically discussed, together with current evidence describing the biological effects of selected phytochemicals including curcumin, epigallocatechin-3-gallate, resveratrol, sulforaphane, quercetin, and genistein. These compounds may influence prostate cancer-associated pathways through modulation of inflammatory signaling, oxidative stress, metabolic adaptation, chromatin remodeling, and microbiome dynamics. Major translational limitations including poor bioavailability, pharmacokinetic variability, microbiome heterogeneity, inconsistent clinical evidence, and incomplete mechanistic understanding are additionally discussed. Rather than considering natural products as isolated anticancer agents, this review adopts a systems-level perspective in which dietary bioactive compounds may function as modulators of interconnected regulatory networks relevant to prostate cancer biology and therapeutic responsiveness.

Testicular cancer is the most common cancer in young adult men, and its incidence is increasing globally, with testicular germ cell tumors (TGCT) being the most frequent subtype. These tumors show remarkable sensitivity to cisplatin, but there is a small subset of patients that develop resistance to the therapy, experiencing low quality of life and having no treatment options. Nowadays, there are a number of models that are useful for studying TGCT tumorigenesis and identifying novel targeted therapies for these patients. Thus, in this review, we aim to provide a comprehensive overview of the in vitro and in vivo TGCT models that are currently available, and also to summarize the main findings that have been made in the last years regarding preclinical and clinical studies of novel targeted therapies in TGCT patients. Available preclinical models and clinical targeted approaches for the treatment of testicular cancer Testicular cancer is the most common type of cancer in young adult men. Most patients have a good prognosis due to the effectiveness of chemotherapy, which usually eliminates these cancer cells efficiently. However, there is a small percentage of patients that develop resistance to chemotherapy, and there are no effective alternative treatment options for such cases. Thus, there is a need for new therapies for those patients. In this review, the authors describe the laboratory models currently available to study this disease and how they can be used to test new drugs. Also, novel therapies that are being tested in testicular cancer patients are also discussed, to provide a comprehensive summary of both laboratory and clinical research being performed worldwide.

Survivin (BIRC5) is a key inhibitor of apoptosis that is highly overexpressed in many cancers, where it promotes tumour cell survival, mitotic progression, and resistance to therapy. Because survivin is largely absent from normal adult tissues, it represents a selective and promising target for cancer treatment. Antisense oligonucleotides (ASOs) provide a precise approach to silence survivin by targeting its transcripts. Preclinical studies have shown that ASO-mediated reduction of survivin is associated with increased cancer cell death, inhibition of tumour growth, and enhanced sensitivity to other treatments. Early-phase clinical trials of survivin-targeting ASOs have shown evidence of target engagement but ultimately failed to demonstrate consistent clinical benefit and/or encountered dose-limiting toxicities, which hindered their further development. This review outlines survivin's central role in cancer biology, the principles of ASO therapeutics (sequence design, mechanisms of action, chemical modifications, and delivery strategies), and the progress in preclinical and clinical development of survivin-targeting ASOs, while also discussing key challenges that may contribute to their clinical limitations, including inefficient delivery, off-target effects, and systemic toxicities. Collectively, the current status of survivin-targeting ASOs underscores the need for synergistic optimization of delivery platforms and molecular chemistry to improve efficacy and safety, thereby enabling their use in personalised and combination cancer treatment approaches.

The design, synthesis, and biological assessment of new heterocyclic compounds containing the 1,3,4-thiadiazole moiety, a well-known pharmacophore with substantial medicinal significance, are the main topics of this study. To create a variety of thiadiazole-based heterocyclic systems, such as pyrazoles, triazoles, pyrimidines, and thiophenes, a novel cyanoacetohydrazide derivative was created and used as a crucial intermediate. IR, 1H-NMR, 13C-NMR, and mass spectrometry were the spectroscopic methods used to confirm the structures of produced compounds. The synthesized compounds' biological properties were assessed for their potential as antioxidants and anticancer agents. Several derivatives showed impressive activity in cytotoxicity tests against HePG-2 and MCF-7 cancer cell lines, with several compounds showing greater potency than the reference medication 5-fluorouracil. Compounds 17, 18, and 13 exhibited the strongest anticancer activity, highlighting the significance of structural and electronic properties in improving biological performance. Furthermore, an assessment of the synthesized compounds' antioxidant activity revealed that they have differing levels of free radical scavenging activity, with compounds 17 and 18 exhibiting the most notable benefits, albeit still less than ascorbic acid. Electron-donating and electron-withdrawing groups, molecular conjugation, and lipophilicity all play a part in regulating antioxidant and anticancer actions, according to structure-activity relationship (SAR) studies. Additionally, substantial interactions between specific drugs and the EGFR tyrosine kinase domain were suggested by molecular docking studies, indicating their possible mode of action. All things considered, our work shows that thiadiazole-based heterocycles are attractive candidates for the creation of novel antioxidants and anticancer medicines and offers insightful information for future drug design.

While traditional transcriptomics and single-cell RNA sequencing can reveal differences in cell type and gene expression, they cannot provide spatial information within tissues. Spatial transcriptomics (ST), as an emerging technology in recent years, has achieved significant progress in resolving gene expression along the spatial dimension. This technology quantifies gene expression at defined spatial coordinates and describes the spatial distribution of transcripts and the co-localization patterns between cells within intact tissue, allowing for an integrated analysis of molecular and spatial information. This review aims to systematically trace the development of ST and highlight its application value in breast cancer research. We systematically reviewed the recent literature on ST platforms, on combined analyses of single-cell RNA sequencing (scRNA-seq) and ST, and on integrated spatial multi-omics in breast cancer. Key topics include tumor microenvironment organization, intra-tumor heterogeneity, the spatial distribution of immune cells, cancer-associated fibroblast function, treatment-response prediction, and personalized-treatment strategy development. ST can characterize the spatial organization of interactions between breast cancer cells and the tumor microenvironment, describe the spatial dimensions of tumor heterogeneity, and provide multi-dimensional information that may support refined subtype classification and prognostic assessment. Existing studies indicate that ST shows significant potential to inform personalized treatment strategies, but the technology also faces bottlenecks in data integration, spatial resolution, standardization, and the need for functional validation. ST provides an important tool for an in-depth description of the complex spatial organization within breast cancer tumors. When integrated with functional perturbation, longitudinal cohorts, and orthogonal omics, it has the potential to ultimately improve clinical outcomes for breast cancer patients.

Solid organ transplant recipients (SOTRs) face a markedly elevated risk of post-transplant skin cancer, particularly cutaneous squamous cell carcinoma (cSCC), driven by chronic immunosuppression, including the direct oncogenic effects of some immunosuppressive drugs, and cumulative carcinogenic risk factors including ultraviolet radiation exposure. Retransplanted solid organ transplant recipients (R-SOTRs) represent a growing yet under-recognised subgroup, carrying additional vulnerability as the second or third transplant will often require more profound immunosuppression. Despite this, no retransplant-specific dermatologic surveillance guidelines currently exist. Risk stratification tools, including the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator (SUNTRAC), do not incorporate retransplant status or cumulative immunosuppressive burden. Given the plausibly amplified risk profile of this population, a conceptual framework for skin cancer risk stratification in the context of retransplantation remains an unmet clinical need. To address this, we conducted a narrative review of studies published between January 2000 and February 2026, synthesising primary studies alongside relevant guidelines and consensus statements. Kidney and heart registry data identify retransplantation as a risk indicator for post-transplant skin cancer outcomes, while the only cohort reporting cutaneous outcomes after retransplantation, comprising highly selected kidney recipients with prior cSCC, demonstrated higher rates of aggressive cSCC after retransplantation. We therefore propose a conceptual framework stratifying R-SOTRs into five risk categories according to prior skin cancer history, acknowledging the limited direct evidence currently available: no prior skin cancer, prior single non-aggressive cSCC, prior multiple cSCC, prior histologically aggressive cSCC, and prior metastatic cSCC. This framework is intended to support individualised risk assessment and to identify patients likely to warrant closer dermatologic follow-up, rather than to prescribe specific surveillance intervals. Prospective studies evaluating the impact of risk-stratified surveillance on skin cancer outcomes in this population are urgently needed.

Cancer remains one of the most complex diseases to study and treat, with tumour microenvironment heterogeneity and therapeutic resistance continuing to limit clinical progress. Biomaterials-based nanoparticles have emerged as versatile platforms that not only advance understanding of cancer biology but also enable innovative therapeutic strategies. As mechanistic tools, nanoparticles can be used to investigate extracellular matrix interactions, mechanotransduction pathways, drug resistance, and tumour-immune crosstalk, providing insights into how physical and biochemical cues influence disease progression. Therapeutically, engineered nanoparticle systems have been developed for the targeted delivery of chemotherapeutics, nucleic acids, and immunomodulatory agents, incorporating features such as stimuli-responsive release, multifunctionality, and theranostic capabilities. Recent advances in patient-derived tumour models, high-throughput screening platforms, and artificial intelligence-assisted design are further driving the development of precision nanomedicine. Despite ongoing challenges related to biodistribution, safety, manufacturing scalability, and regulatory approval, nanoparticle-based biomaterials offer significant opportunities to bridge fundamental cancer research and clinical translation. This review highlights recent mechanistic and therapeutic advances, discusses key translational barriers, and outlines future directions at the interface of biomaterials, nanotechnology, and oncology.

Rosmarinic acid (RA), a naturally occurring polyphenolic compound, has demonstrated promising anticancer activity; however, its combinatorial potential with conventional chemotherapeutic agents remains incompletely characterized. This study investigated the cytotoxic, pro-apoptotic, oxidative stress-associated, and cytokine-associated effects of RA alone and in combination with doxorubicin (DOX) in 4T1 murine breast cancer cells and HaCaT human keratinocyte cells as a non-cancerous control model. Cellular viability, apoptosis, cell cycle progression, oxidative stress, mitochondrial function, cytokine responses, and apoptosis-associated molecular alterations were evaluated using complementary cellular and molecular approaches. In addition, three-dimensional (3D) tumor spheroid experiments were performed to assess treatment responses under physiologically relevant tumor-like conditions. Results demonstrated that RA synergistically enhanced DOX-induced cytotoxicity in 4T1 cells while exhibiting comparatively lower toxicity toward HaCaT cells. Combination treatment significantly increased apoptotic cell death, mitochondrial depolarization, intracellular reactive oxygen species (ROS) accumulation, apoptotic DNA fragmentation, and G2/M-phase accumulation. N-acetylcysteine (NAC)-mediated rescue experiments partially reversed ROS elevation and treatment-associated cytotoxicity in both monolayer and 3D spheroid models. Furthermore, the RA+DOX combination markedly disrupted spheroid integrity and reduced spheroid viability compared with monotherapies. Collectively, these findings indicate that RA enhances the anticancer activity of DOX and support further investigation of this combination strategy in breast cancer models.

Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide, highlighting the need for safer and more effective chemopreventive strategies. Although many phytochemicals can modulate key molecular processes involved in breast carcinogenesis, their chemopreventive potential largely depends on delivery strategies that preserve their biological activity and enable efficient accumulation at the target site. Protein-based nanocarriers have emerged as promising delivery systems capable of improving the protection, solubility, cellular uptake, targeted delivery, and controlled release of bioactive compounds in tumor tissues. This review summarizes recent advances in selected animal- and plant-derived protein nanocarriers used for the encapsulation and delivery of natural compounds in breast cancer chemoprevention. Particular attention is given to their physicochemical properties, encapsulation performance, release behavior, biological activity, targeting potential, and translational limitations. Furthermore, the mechanisms underlying the enhanced anticancer activity of encapsulated phytochemicals, including improved stability, receptor-mediated uptake, pH-responsive release, apoptosis induction, oxidative stress modulation, and inhibition of tumor growth and metastasis, are highlighted. Current challenges, including enzymatic degradation, formulation instability, immunogenicity concerns, manufacturing scalability, and limited clinical evidence, remain important barriers to translation. Overall, selected protein-based nanocarriers represent promising multifunctional platforms for improving the chemopreventive potential of natural compounds in breast cancer.

Background and Objectives: A subset of cancer patients treated with immune checkpoint inhibitors may experience rapid tumor progression rather than therapeutic benefit, a phenomenon described as hyperprogressive disease (HPD), which is linked to poor prognosis and shortened survival. Reliable biomarkers capable of predicting HPD remain lacking. To better understand the molecular background of HPD, we analyzed promoter region methylation and somatic mutation profiles in cancer-related genes in patients with malignant melanoma (MM) and renal cell carcinoma (RCC) undergoing anti-PD-1/PD-L1 treatment. Methods: Patients diagnosed with MM or RCC and treated with anti-PD-1/PD-L1 agents between 2011 and 2020 were included, and FFPE tumor samples along with paired normal tissues were analyzed. A diagnosis of HPD was assigned to patients with RECIST 1.1-defined progressive disease who demonstrated a ≥2-fold acceleration in tumor growth kinetics after initiation of immune checkpoint inhibitor therapy. Methylation-specific real-time PCR was performed on 54 samples (15 MM tumors, 22 RCC tumors, 17 RCC-matched adjacent normal samples) to assess promoter methylation of PIK3CA, BAP1, PTEN, and TP53. Next-generation sequencing (NGS) with an 86-gene pan-cancer panel was conducted on 9 HPD samples. Results: Promoter hypermethylation involving PIK3CA, BAP1, PTEN, and TP53 was more pronounced in HPD-associated tumor samples (n = 16) than in tumors without HPD (n = 21). Within the MM cohort, PTEN and TP53 methylation levels demonstrated statistically significant differences between the two groups (p = 0.005 and p = 0.028, respectively), while no comparable associations were observed in RCC patients. NGS analysis detected missense mutations classified as pathogenic or likely pathogenic in 5 of 9 HPD patients (55.6%), involving KIT, PTEN, and VHL. Conclusions: Promoter region hypermethylation in cancer-related genes may contribute to the aggressive tumor behavior observed in HPD. The somatic variants identified in HPD patients are consistent with known oncogenic pathways. These findings support further investigation of epigenetic and genomic biomarkers for HPD risk stratification in larger, prospective cohorts.

Triple negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer characterized by the absence of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), resulting in limited options for targeted therapy and high rates of metastasis, recurrence and death. Extracellular vesicles (EVs) have emerged as central mediators of TNBC pathophysiology, functioning as key intercellular communication vehicles transporting oncogenic proteins, nucleic acids, lipids, and metabolites. These EV-mediated interactions promote tumor microenvironment (TME) remodeling, immune evasion, metastatic niche formation, and therapeutic resistance. Given their stability, accessibility, and molecular complexity, EVs also represent promising diagnostic and prognostic biomarkers for TNBC. Advances in isolation and molecular profiling technologies have enabled the identification of EV-associated signatures that predict therapeutic response and stratify patient risk. Beyond their utility as biomarkers, EVs are rapidly emerging as therapeutic targets and delivery platforms, demonstrating efficacy in transporting chemotherapeutics, RNA-based therapeutics, immune modulators, and photosensitizers with enhanced targeting specificity and therapeutic efficiency. Collectively, EVs play a multifaceted role in TNBC biology, serving simultaneously as drivers of disease progression, minimally invasive biomarkers, and versatile therapeutic vehicles. The integration of EV-centered diagnostics, multi-omic profiling, and engineered therapeutics holds significant potential to transform TNBC management and advance precision oncology for this challenging breast cancer subtype.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States, driven by its aggressive biology and high metastatic incidence at diagnosis. With a 5-year survival rate of just 8%, PDAC remains one of the most lethal cancers. Mutant KRAS, present in more than 90% of cases, serves as a key driver of tumorigenesis and metabolic reprogramming. In this issue of Cancer Research, Thakur and colleagues uncover a novel metabolic adaptation that PDAC cells use to survive therapeutic stress. Their integrated metabolomic and lipidomic analyses show that ERK inhibition-targeting a key KRAS pathway effector-not only disrupts glycolysis and glutamine metabolism but also triggers a compensatory increase in fatty acid oxidation (FAO). This shift occurs through lipophagy, a lysosome-mediated lipid degradation process, rather than cytosolic lipolysis. Mechanistically, ERK inhibition promotes the nuclear translocation of TFEB, which drives the upregulation of FAO and lipophagy genes. This metabolic reprogramming enables PDAC cells to survive KRAS pathway blockade. Importantly, cotargeting FAO alongside ERK or KRAS inhibitors elicits a potent synergistic antitumor effect in vivo. This dual-target strategy holds promise for overcoming PDAC resistance to KRAS-targeted therapies, laying the groundwork for novel combination treatments. See related article by Thakur et al., p. 3519.

Papillary thyroid carcinoma (PTC) is among the most common endocrine malignancies worldwide, and although generally associated with a favorable prognosis, a subset of patients develops aggressive disease with higher recurrence risk. This highlights the need for improved molecular characterization. Data integration approaches combined with computational methods offer new opportunities to refine diagnosis and uncover disease mechanisms. This study aims to integrate omics data and apply machine learning (ML) to identify clinically relevant biomarkers in papillary thyroid carcinoma. We selected 11 genes from the differentially expressed genes (DEGs)-LASSO intersection approach. Genes were validated using an independent external dataset (AUC = 91%, Sens. = 92%, Spec. = 97%, and Acc. = 95%). DEGs were integrated with metabolomics data from the literature, enabling the construction of a metabolite-gene interaction network, highlighting norepinephrine, arachidonic acid, and glutamic acid as representative metabolites, while the main genes were SLC6A14, ADK, ATIC, NT5E, and AR. We identified potential drug-gene interactions and performed survival analysis to assess the relevance of the possible biomarkers. This novel pipeline combining integration and machine learning provides new insights into thyroid cancer biology and identifies promising diagnostic markers, supporting advances in precision medicine.

The purpose of this trial was to assess the feasibility, acceptability and safety of a 10-week hybrid (in-clinic and virtual) resistance exercise training RET program with or without CrM in individuals treated for colorectal cancer. Twenty-seven participants were randomized to RET plus 5 grams/day of CrM (EXSUPP; n = 13) or 5 grams/day corn-starch maltodextrin placebo (EXPLA; n = 14). RET was performed three times per week. Feasibility was assessed through recruitment, retention and fidelity (percentage of prescribed RET and supplementation completed). Acceptability was evaluated using a 5-point Likert scale, and safety was monitored through adverse event reporting. Secondary outcomes (body composition, muscular strength, physical function) were assessed pre- and post-intervention using baseline-adjusted ANCOVA models and focus group interviews. Registry-based recruitment identified 1378 potentially eligible individuals and 27 of 410 assessed (6.6%) enrolled, highlighting recruitment challenges. Retention was high (24/27; 88.9%). Adherence to RET and supplementation was strong (both > 85%) with no serious adverse events reported. Participants reported high acceptability for both in person and virtual components. No significant between group differences were observed for secondary outcomes; however, both groups demonstrated modest improvements in muscular strength and short physical performance battery (SPPB) scores. A hybrid RET program with CrM was feasible, acceptable and well tolerated in individuals with colorectal cancer who were previously treated with chemotherapy. Hybrid supervised RET is safe, acceptable, and associated with modest improvements in strength and physical function among individuals treated for colorectal cancer. While creatine supplementation did not demonstrate clear additive effects in this pilot trial, further adequately powered studies are warranted. Trial Registration: NCT06420726.

PSMA PET/CT has become widely incorporated into restaging algorithms for patients with biochemical recurrence (BCR) of prostate cancer, defined as a rising PSA level after attempted curative therapy. A substantial proportion of patients with BCR demonstrate no detectable disease on PSMA PET/CT. In these patients, management remains challenging as clinicians must balance risks of undertreatment of occult disease and potential morbidity of empiric salvage therapies with a potential missed therapeutic window from further diagnostic workup. Guidelines recommend not withholding salvage radiation therapy based on negative PSMA PET/CT results. In practice, additional imaging is frequently pursued to attempt to localize disease before salvage treatment. This AJR Expert Panel Narrative Review examines the available evidence addressing the ongoing uncertainty surrounding optimal imaging strategies and related management after a negative PSMA PET/CT examination in patients with BCR. We review performance characteristics of initial and repeat PSMA PET/CT examinations, explore prognostic factors that may guide imaging timing and selection, and evaluate the role of radiotracers other than PSMA and modalities other than PET. Based on the presented information, we provide consensus statements for imaging strategies emphasizing PSA kinetics and tumor biology while acknowledging areas where additional data are needed for informed clinical decision-making.