The longitudinal patterns of patient-reported outcomes and their association with mortality in routine oncology care are largely unexplored.

Hypoalbuminemia is a common clinical biomarker associated with poor outcomes in cancer patients. While it correlates with resistance to immune checkpoint inhibitors (ICIs), the direct functional role and underlying mechanisms in driving immunotherapy resistance remain unclear. In our study, we demonstrated that hypoalbuminemia directly drives ICIs resistance by orchestrating an immunosuppressive tumor microenvironment (TME) through impaired macrophage arginine metabolism. In a C57/BL model, low-protein diet-induced hypoalbuminemia mice bearing LLC tumors showed poor response to immunotherapy. Comprehensive immune profiling revealed a suppressed TME, characterized by reduced CD8+ T cell infiltration and increased macrophage abundance. Depletion of tumor-associated macrophages (TAMs) alleviated this immunosuppression. Transcriptomic analysis of TAMs from low-protein diet-induced hypoalbuminemia mice revealed a significant downregulation of the arginine biosynthesis pathway, which was consistent with observed reductions in systemic arginine levels. Crucially, dietary arginine supplementation successfully reversed the immunosuppressive phenotype and restored ICIs efficacy. However, this restorative effect of arginine is significantly dependent on its action on macrophages. Our findings establish low-protein diet-induced hypoalbuminemia as a key driver of immunotherapy resistance, unveil a novel metabolic-immune circuit centered on TAM arginine metabolism, and identify arginine replenishment as a potential therapeutic strategy to reverse immune suppression in hypoalbuminemia patients.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. The epigenetic regulator EZH2 is a promising therapeutic target due to its role in tumor progression and therapy resistance. This study combined computational and experimental methods to repurpose FDA-approved drugs as EZH2 inhibitors. Virtual screening and molecular dynamics simulations identified acetyldigitoxin (ADT) as a potent EZH2 inhibitor, demonstrating superior binding affinity (-10.90 kcal/mol) and complex stability compared to the known inhibitor GSK126. ADT formed robust hydrogen bonds and hydrophobic interactions with key residues in the EZH2 binding site, supported by favorable binding free energy calculations (ΔGbinding = -34.73 kcal/mol). In vitro, ADT exhibited selective cytotoxicity against NSCLC A549 cells (IC₅₀ = 32.4 nM) versus normal bronchial epithelial cells (IC₅₀ = 190 nM). Treatment with ADT significantly reduced EZH2 expression and potently inhibited its histone methyltransferase activity, as directly evidenced by decreased global H3K27me3 levels. ADT induced G0/G1 cell cycle arrest and promoted apoptosis, accompanied by upregulation of pro-apoptotic genes (Bax, Caspase-3) and downregulation of anti-apoptotic (Bcl-2) and cell cycle (CyclinD1) genes. Our integrated findings position ADT as a repurposed drug candidate for targeting EZH2 in NSCLC, warranting further preclinical investigation including direct enzyme inhibition assays.

Cyclin-dependent kinase 16 (CDK16), a serine/threonine protein kinase, is a critical regulator of cell cycle progression, vesicle trafficking, and apoptosis. Its dysregulation is implicated in the progression of aggressive cancers, including triple-negative breast, lung, and prostate cancer, where its overexpression correlates with poor prognosis. Despite its therapeutic promise, CDK16 remains an understudied kinase lacking selective inhibitors, underscoring the need for innovative discovery approaches. This study introduces a novel computational framework that leverages multiple docked poses to augment datasets for regression-based machine learning (ML) models targeting CDK16 inhibition. This data augmentation strategy incorporated docking scores, ligand-receptor contact fingerprints (LRCFs), and conformation-sensitive physicochemical descriptors as input features. To our knowledge, this is the first application of docked pose augmentation for a regression-based drug discovery model. A systematic evaluation of eight ML algorithms across multiple docking score consensus levels identified Gradient Boosted Trees as the optimal learner. The Genetic Function Algorithm was integrated to select a minimal set of descriptors, which improved model generalizability. The resulting validated ML-QSAR model guided the generation of a robust pharmacophore model, which was used for virtual screening of the NCI and OpnMe databases. Subsequent in vitro LanthaScreen kinase assays confirmed two novel and potent CDK16 inhibitors: compound H_28 (OpnMe code: BI-831266) with an IC50 of 3.5 µM, and H_33 (OpnMe code: BI-1282) with an IC50 of 5.8 µM. These findings highlight the efficacy of integrating docked pose augmentation with regression modeling and experimental validation, offering a robust framework for accelerating the discovery of targeted anticancer agents.

Interleukin-18 (IL-18) is a pro-inflammatory cytokine, and higher IL-18 expression in pancreatic tumors is associated with poor prognosis. Although 5-fluorouracil (5-FU) has been reported to induce the release of bioactive (mature/cleaved) IL-18 from the pancreatic cancer cell line Capan-2, the underlying mechanism remains unclear. Here, we investigated IL-18 activation in pancreatic cancer cells after 5-FU treatment under low-nutrient conditions that mimic key features of the tumor microenvironment, using a monoclonal antibody we generated that specifically recognizes cleaved, active IL-18. We detected the release of active IL-18 from both Capan-2 and MIA PaCa-2 cells after 5-FU treatment. Analysis of separated attached and detached cell fractions showed that IL-18 cleavage occurred predominantly in detached cells. We also clarified that caspase-8-but not caspase-1/4-was activated in detached cells and was required for IL-18 and GSDMD cleavage that is a hallmark of pyroptosis. Surprisingly, detached cells from only nutrient starvation showed the same phenomenon, and 5-FU contributed to increased pyroptotic cells. On the other hand, the release of active IL-18 was not observed with gemcitabine. These findings suggest that a low-nutrient tumor microenvironment and 5-FU therapy can promote caspase-8-dependent pyroptotic cell death with IL-18 activation, potentially contributing to chronic inflammation in pancreatic tumors.

Immune checkpoint inhibitors (ICPis) are associated with islet function impairment (IFI), manifesting as hyperglycemia, diabetes mellitus (DM), or diabetic ketoacidosis (DKA). Delayed detection and management may lead to irreversible β-cell damage and life-threatening complications. We conducted a systematic review and meta-analysis to assess the risk of IFI associated with ICPis.

In this paper, we report a case of sequential immune-related adverse events induced by envafolimab in a patient with small cell lung cancer (SCLC), including immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM), diabetic ketosis (DK), and pneumonitis (CIP). A 63-year-old male with limited-stage SCLC received 4 cycles of etoposide plus carboplatin chemotherapy followed by radiotherapy, concurrent with maintenance immunotherapy using envafolimab. Eight months after initiating immunotherapy, the patient developed symptoms of dry mouth and excessive thirst. The clinical presentation was consistent with ICI-DM, though all diabetes-associated autoantibodies were negative. After achieving glycemic control with insulin, envafolimab was resumed. At 15 months, metastasis to the left submandibular region was identified and managed with localized iodine-125 seed implantation; envafolimab monotherapy was continued as maintenance treatment. Nineteen months after initiation of immunotherapy, the patient presented with chest tightness, shortness of breath, and dyspnea. Further diagnostic evaluation confirmed CIP and radiation pneumonitis, which improved following glucocorticoid therapy. Envafolimab was consequently suspended, and topotecan therapy was initiated for one month as second-line therapy, but was ultimately discontinued due to financial constraints. Six months after discontinuing topotecan, the patient was readmitted due to a progressively enlarging left submandibular metastases. Laboratory findings upon admission revealed DK, which had occurred due to self-discontinuation of insulin and a switch to oral hypoglycemic agents one week ago. During hospitalization, recurrent syncope of unknown origin occurred. After clinical improvement with supportive care, anti-tumor therapy with anlotinib was initiated as third-line therapy. Following envafolimab immunotherapy, the patient sequentially developed ICI-DM, DK and CIP. With prompt intervention, severe complications such as diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state, and respiratory failure were successfully avoided. This case underscores the importance of early recognition and management of immune-related adverse events (irAEs). The occurrence of DK after self-discontinuation of insulin highlights the necessity for long-term insulin therapy in ICI-DM. The patient remains alive with an overall survival exceeding 27 months, suggesting that ICI-DM may represent a potential prognostic biomarker for favorable outcomes in patients receiving immunotherapy.

The efficacy of immune checkpoint inhibitors (ICI) combined with chemotherapy as a neoadjuvant/adjuvant therapy for locally advanced penile squamous-cell carcinoma (PSCC) remains unclear.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, with its pathogenesis primarily linked to activating mutations in the KIT or platelet derived growth factor receptor alpha (PDGFRA) genes. Surgical resection remains the standard curative treatment for localized GIST; however, ~50% of patients eventually develop recurrence or metastasis. Since the introduction of imatinib in the early 21st century, the management of metastatic GIST has shifted from solely surgical intervention to a systemic, chronic disease management model centered on tyrosine kinase inhibitors (TKIs). However, during the course of treatment, most patients develop drug resistance. Despite the transformative impact of TKIs, some critical clinical challenges remain unresolved. Intratumoral heterogeneity, in particular, poses a significant obstacle, as tumors often comprise diverse populations of cells with varying genetic and molecular profiles. This diversity means that while some subclones may initially respond well to TKI therapy, others harboring inherent or acquired resistance mutations can continue to proliferate, ultimately leading to treatment failure. Additionally, the limited durability of TKIs responses, even in tumors initially sensitive to treatment, remains a pressing concern. Moreover, the lack of curative systemic options for advanced GIST, along with adverse drug reactions, underscores the unmet needs within this patient population. These challenges underscore the necessity of this review, which discusses current standard drug treatment strategies for advanced GIST, including sequential TKIs therapy and investigations into mechanisms of drug resistance. Finally, the review explores precise and actionable future directions for GIST drug development and clinical management, including mutation-stratified therapeutic sequencing, rational TKI-based combination regimens, and circulating tumor DNA (ctDNA)-guided real-time treatment monitoring and resistance surveillance.

To evaluate the efficacy, safety, and treatment burden of intravitreal ranibizumab (RBZ) combined with a dexamethasone (DEX) intravitreal implant compared to ranibizumab monotherapy for macular edema (ME) secondary to non-ischemic retinal vein occlusion (RVO).

Previous research has demonstrated the effectiveness of lenvatinib and programmed death-1 (PD-1) blockades in the treatment of sarcoma. However, there is limited information regarding the efficacy and safety of combining lenvatinib with PD-1 blockades as a re-challenge therapy in patients with metastatic soft tissue sarcoma (STS) following prior treatment failure with tyrosine kinase inhibitors (TKIs).

Skp1 is a potential pharmacological target for cancer treatment. However, the few Skp1 inhibitors reported to date have exhibited limited structural diversity and target specificity. This highlights the need for new chemical scaffolds that could potentially be developed into potent and specific Skp1 inhibitors.

Triple-negative breast cancer (TNBC) is prone to relapse and metastasis due to the immunosuppressive state of the tumor microenvironment and limited exposure to relevant antigens, and chemotherapy alone has poor efficacy. We have developed a novel theranostic nanoplatform to address these problems: multifunctional nanocapsules (NCs) with a PD-L1-mediated gold shell induce immunogenic cell death (ICD) to remodel the immune microenvironment. PD-L1 and NLG919 dual immune checkpoints are programmed to synergistically sensitize photothermal therapy and chemotherapy, and photoacoustic imaging (PAI) is used to visualize and localize TNBC tissues for identification.

breast cancer remains a significant global health burden, with chemotherapy serving as a cornerstone of treatment. However, chemotherapy is associated with a high symptom burden, adversely impacting patients' quality of life. This study assessed the prevalence, severity, and impact of symptom burden among breast cancer patients undergoing chemotherapy in Delta State, Nigeria.

Cisplatin is a widely used chemotherapeutic agent; however, its therapeutic efficacy is often limited by severe cytotoxic side effects, particularly gastrointestinal toxicity, which manifests as intestinal mucositis. MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in both normal physiological and pathological processes by regulating gene expression. However, their role in cisplatin-induced gastrointestinal toxicity remains unclear. In this study, we investigated the regulatory effects of miRNAs on cisplatin-induced inflammation in intestinal epithelial cells (IEC-6). Our results demonstrate that cisplatin significantly decreases cell viability while inducing interleukin-6 (IL-6) expression in a dose-dependent manner. Moreover, we observed that cisplatin activates the phosphorylation of p38 and ERK but does not activate JNK in IEC-6 cells. Using specific inhibitors of p38 and ERK, we confirmed their roles in regulating IL-6 expression. Through analysis of the miRNA database, we identified several miRNAs that potentially target IL-6. Notably, rno-let-7f-5p and rno-let-7g-5p showed significant downregulation following cisplatin treatment. Transfection mimics and inhibitors of rno-let-7f-5p and rno-let-7g-5p further confirmed their regulatory role in IL-6 expression. Importantly, inhibition of the p38 and ERK pathways attenuated the cisplatin-induced reduction of rno-let-7f-5p and rno-let-7g-5p levels, suggesting a potential regulatory link between MAPK signaling and miRNA expression. In conclusion, our findings support a model in which cisplatin promotes inflammation in intestinal epithelial cells by activating the p38 and ERK pathways and is associated with the suppression of rno-let-7f-5p and rno-let-7g-5p. These findings provide mechanistic rationale that may inform future efforts to mitigate cisplatin-associated gastrointestinal toxicity.

The aggregation-caused quenching (ACQ) phenomenon limits the bioimaging application of traditional fluorescent probes. To address this, we developed a novel strategy to convert ACQ-type bioactive Staurosporine analogues into aggregation-induced emission (AIE) luminogens by constructing a donor-acceptor system via the introduction of cyano units as strong electron-withdrawing groups. First, we successfully developed a novel fluorescent scaffold based on the skeleton of Staurosporine, which is a kind of microbial secondary metabolite. Next, we synthesized three derivatives (STY1-3) by introducing a new rotor via one-step structural modification. These three compounds exhibited tunable AIE fluorescence and retained significant bioactivity. Cellular imaging demonstrated their capacity to outline cell contours with low background interference, while cytotoxicity assays revealed potent antitumor activity against NCI-N87 and MCF-7 cell lines. This work provides a design method for developing bioactive AIE probes from natural ACQ scaffolds.

Restoring apoptosis in malignant cells represents a central goal of anticancer therapy. Tumour cells often escape cell death by overexpressing anti-apoptotic members of the BCL-2 protein family, particularly BCL-2, BCL-xL, and MCL1. These proteins inhibit the intrinsic mitochondrial apoptotic pathway through intricate interactions with pro-apoptotic partners and direct modulation of the mitochondrial outer membrane. Their pivotal role in cell survival has established them as attractive therapeutic targets. Over the past two decades, significant efforts have been devoted to developing selective small-molecule inhibitors capable of neutralising these proteins and reactivating apoptosis. A first milestone was the discovery of ABT-263 (navitoclax), a dual BCL-2/BCL-xL inhibitor. Building on this achievement, the development of venetoclax, a highly selective BCL-2 inhibitor, marked a major breakthrough, demonstrating potent pro-apoptotic activity and clinical efficacy in several leukaemia subtypes. Despite these advances, the design of inhibitors of BCL-2 family members remains challenging, largely due to the structural characteristics of the BH3-binding groove, which is both shallow and hydrophobic, complicating the identification of molecules with optimal binding affinity and selectivity. PROTACs targeting BCL-xL may represent a promising future strategy, potentially overcoming the intrinsic limitations of small molecule inhibitors.

Folate-conjugated PLGA-PEG nanocarriers have emerged as a promising strategy for targeted delivery of anticancer agents such as 9-bromo-noscapine (9-Br-Nos) for targeting of folate receptors, which are overexpressed in breast cancer cells. They were synthesized and characterized for their size, morphology, encapsulation efficiency, and drug release profile. In vitro cytotoxicity studies have revealed an enhancement in anticancer efficacy of nano-formulated drugs compared to free drugs. Enhanced cellular uptake, improved mitochondrial membrane potential, and increased reactive oxygen species (ROS) production were observed in treated cells. Additionally, the spheroid disintegration assay was performed to evaluate the effect of the nano-formulation on the three-dimensional (3D) tumor model. Western blot analysis revealed changes in the expression of apoptosis-related proteins, further supporting the enhanced therapeutic potential of the nanocarrier system. In vivo pharmacokinetic studies demonstrated improvement in bioavailability and prolonged circulation of the nano-encapsulated drug. This study underscores the potential of nanocarrier-based drug delivery systems in improving the therapeutic efficacy of anticancer agents.

BACKGROUND Methotrexate-induced encephalopathy is an uncommon but potentially serious neurotoxic complication of high-dose methotrexate therapy. Its clinical and radiological features can closely resemble acute ischemic stroke, leading to diagnostic confusion and unnecessary interventions. Early recognition is crucial to prevent mismanagement and ensure appropriate care. CASE REPORT We report a 16-year-old girl with high-grade osteosarcoma of the distal femur who developed sudden neurological symptoms, beginning with dysphasia and cognitive slowing, progressing within 1 hour to global aphasia and altered consciousness following high-dose methotrexate infusion. Laboratory findings were normal. Magnetic resonance imaging performed 2 hours after symptom onset revealed bilateral diffusion restriction in the centrum semiovale, without corresponding fluid-attenuated ınversion recovery (FLAIR) abnormalities, suggestive of acute ischemia. Intravenous thrombolysis with alteplase (0.9 mg/kg) was administered, but subsequent imaging showed shifting diffusion abnormalities without vascular occlusion, inconsistent with stroke. Methotrexate was withheld, and supportive care alone led to complete neurological recovery within 3 days. The patient resumed chemotherapy 1 week later and remained asymptomatic at 1-year follow-up. CONCLUSIONS Methotrexate-induced encephalopathy is an important stroke mimic in oncology patients. Diffusion restriction without FLAIR changes and a reversible clinical course help distinguish it from true ischemic stroke. Awareness of this condition is essential, as full recovery can occur with supportive care alone, without the need for specific therapeutic interventions.

The excellent biocompatibility and tunable optical properties of carbon dots make them highly promising for applications in photodynamic therapy (PDT). However, effectively enhancing their photodynamic performance remains a significant challenge. This work employed methylene blue and metformin as precursors along with three trace metal elements ion (Fe3+, Zn2+ and Cu2+) to synthesize carbon dots (CDs, FeCDs, ZnCDs and CuCDs) via a one-step hydrothermal method.