ICI-associated myocarditis is an uncommon yet potentially fatal condition, particularly when concomitant with atrioventricular block (AVB) necessitating pacing. The role of pacing therapy for ICI-associated AVB remains unknown.

Glioblastoma (GBM) is among the deadliest cancers, characterized by poor prognosis and median survival of 12-15 months post-diagnosis. Despite aggressive therapeutic regimens, GBM treatment is still an unmet clinical need due to heterogeneity, recurrencies, and resistance. Metabolic reshaping is emerging as a critical mechanism supporting cell proliferation and sustaining chemoresistance. In this study, we explored metabolic changes induced by chemotherapy in temozolomide (TMZ)-sensitive and TMZ-resistant GBM cell lines. We found that purine levels were altered in sensitive versus resistant GBM cells, highlighting a critical role of guanosine and inosine metabolism. By using a mesenchymal-like GBM zebrafish model, we uncovered dysregulated pathways involved in purine metabolism, with a downregulation of catabolic processes. Our data indicate that combined treatment with TMZ plus guanosine and inosine increased cytotoxicity, enhancing chemotherapy effectiveness in TMZ-resistant cells. These effects correlated with alterations in mitochondrial dynamics and activity. Specifically, the combinatorial effectiveness of TMZ with guanosine and inosine was linked to Mitofusin-2 overexpression, enhancing mitochondrial fusion, typically associated with a better prognosis. Therefore, our findings suggest that purine metabolism is involved in the metabolic rewiring of TMZ-resistant cells, suggesting guanosine and inosine as potential adjuvant treatments to improve the cytotoxicity effects of chemotherapy in resistant GBM.

Poly (ADP-ribose) polymerase (PARP) inhibitors are effective in cells with homologous recombination (HR) deficiency, including BRCA1/2 mutation. However, PARP inhibitors remain a therapeutic challenge in breast and ovarian cancer due to inevitably acquired resistance in most cases. Therefore, strategies to overcome PARP inhibitor resistance are unmet clinical need. SRY-box transcription factor 5 (SOX5) plays a crucial role in development of various cancers but the role of SOX5 in PARP inhibitor resistance is poorly understood. This study identified SOX5 as a potential biomarker associated with PARP inhibitor resistance and addressed potential treatment strategies to overcome PARP inhibitor resistance using the olaparib-resistant preclinical model. We observed that SOX5 was significantly upregulated in olaparib-resistant cells and contributed to PARP inhibitor resistance by upregulating DNA repair pathway genes. Ectopic SOX5 overexpression contributed to PARP inhibitor resistance by suppressing DNA double-strand breaks (DSBs) in BRCA-mutated breast and ovarian cancer. SOX5 small interfering RNA combined with olaparib sensitized olaparib-resistant cells and suppressed the growth of olaparib-resistant xenografts in mice via increased DSBs represented by ɣH2AX formation. Mechanistically, SOX5 directly interacted with yes-associated protein 1 (YAP1) and promoted its nuclear translocation by suppressing the Hippo pathway. YAP1, in association with TEA domain family members (TEAD), upregulated HR-related gene expression and conferred PARP inhibitor resistance. Furthermore, the clinical relevance of SOX5 as a therapeutic target was supported by a significant association between SOX5 overexpression and poor prognosis in ovarian cancer on public mRNA microarray data sets. Therefore, we propose SOX5 as a promising therapeutic target for overcoming PARP inhibitor resistance in BRCA1/2-mutated breast and ovarian cancer.

Costunolide (Cos) and dehydrocostus lactone (DhC) are naturally occurring sesquiterpene lactones with potent anticancer properties. Despite their promising bioactivity, limitations such as poor solubility, metabolic instability, and off-target toxicity restrict their clinical application. To overcome these challenges, synthetic derivatives have been developed to enhance cytotoxicity, selectivity, and pharmacokinetics.

Cancer is a major public health problem while liver cancer is the main cause of global cancer-related deaths. The previous study demonstrates that the 5-year survival rate for advanced liver cancer is only 30%. Few of the first-line targeted drugs including sorafenib and lenvatinib are available, which often develop resistance. Drug combination therapy is crucial for improving the efficacy of cancer therapy and overcoming resistance. However, traditional methods for discovering drug synergy are costly and time consuming. In this study, we developed a novel predicting model PathSynergy by integrating drug feature data, cell line data, drug-target interactions, and signaling pathways. PathSynergy combined the advantages of graph neural networks and pathway map mapping. Comparing with other baseline models, PathSynergy showed better performance in model classification, accuracy, and precision. Excitingly, six Food and Drug Administration (FDA)-approved drugs including pimecrolimus, topiramate, nandrolone_decanoate, fluticasone propionate, zanubrutinib, and levonorgestrel were predicted and validated to show synergistic effects with sorafenib or lenvatinib against liver cancer for the first time. In general, the PathSynergy model provides a new perspective to discover synergistic combinations of drugs and has broad application potential in the fields of drug discovery and personalized medicine.

Testicular cancer (TC) is a rare cancer, but due to early age at diagnosis and excellent cure rates, there is a large cohort of survivors. Recent studies have highlighted the late side effects of treatments of TC, especially cisplatin-based chemotherapy. These complications make the survivorship care challenging with detrimental effects on health and prognosis of TC survivors (TCS). In this study, we provide a snapshot of common late side effects in TCS and a possible care pathway with a nurse-led specialised clinic.

To study the stage of presentation, clinical features, and treatment outcomes of patients diagnosed with Coats disease in infants, toddlers, and preschoolers (aged ≤5 years).

The present study assessed the incidence of drug-induced interstitial lung disease (ILD) recurrence among breast cancer patients who underwent rechallenge with cancer-directed therapy.

Prostate cancer (PCa) is the second most common cancer worldwide and the fifth leading cause of cancer-related deaths among men. The emergence of metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) exemplifies the complex disease management for PCa. PARP inhibitors (PARPis) are being tested to treat mCRPC in tumors with defective homologous recombination repair (HRR) to address this complexity. However, increasing resistance towards PARPi in HRR-deficient patients and the low percentage of HRR-defective mCRPC patients requires the identification of new genes whose deficiency can be exploited for PARPi treatment. XRCC1 is a DNA repair protein critical in the base excision repair (BER) and single strand break repair (SSBR) pathways. We analyzed PCa patients' cohorts and found that XRCC1 expression varies widely, with many patients showing low XRCC1 expression. We created XRCC1 deficiency in PCa models to examine PARPi sensitivity. XRCC1 loss conferred hypersensitivity to PARPi by promoting the accumulation of DNA double-strand breaks, increasing cell-cycle arrest, and inducing apoptosis. We confirmed that XRCC1 expression correlated with PARPi sensitivity using a doxycycline-inducible system. Therefore, we conclude that XRCC1 expression level predicts response to PARPi, and the clinical utility of PARPi in PCa can extend to low XRCC1 expressing tumors.

Gemcitabine (GEM), a nucleoside analog chemotherapy agent, has been widely used in the treatment of various cancers. In recent years, there has been growing interest in understanding the immunomodulatory or immunosuppressive effects of GEM. The immunomodulatory roles of GEM could influence the anti-tumor immune responses via several mechanisms, such as modulation of antigen presentation, cytokine production, and immune cell population. Furthermore, there is evidence that GEM enhances the therapeutic efficacy of immunotherapies, including oncolytic viruses, immune checkpoint inhibitors, CAR T-cells, and therapeutic vaccines. On the other hand, accumulating evidence also proposed that GEM may act as an immunosuppressive agent within the tumor microenvironment, resulting in immune evasion of tumor cells and tumor growth. These paradoxical roles of GEM in modifying immune responses highlight the complexity of GEM interaction with immune cells and responses within the tumor microenvironment. This review aims to provide an overview of the immunomodulatory and immunosuppressive effects of GEM within the tumor microenvironment and how GEM affects the efficacy of cancer immunotherapy.

Controlling tumour growth systems presents significant challenges due to the inherent restriction of positive input in biological systems, along with delays in system output and input measurements. Traditional control methods struggle to address these issues effectively, as they rely heavily on real-time feedback from system outputs. The delays in output measurements can lead to instability in closed-loop systems, whereas the inability of conventional approaches to manage the positive input constraint often results in ineffective control. In this study, the authors propose a novel control system designed to overcome these challenges. First, a system state prediction observer that utilises delayed output measurements was developed. Next, a backstepping technique was utilized to develop a feedback controller that ensures the control input stays positive, thereby guaranteeing the system's asymptotic stability. Furthermore, numerical comparisons with previous research validate the effectiveness of the proposed strategy. Overall, the approach offers a promising solution to the issues of delays and positive input constraints in tumour growth control systems.

Progesterone rapidly induces ovarian cancer cell death through non-genomic actions mediated by the membrane progesterone receptor (mPR).

Drug resistance is one of the main reasons for cancer treatment failure, leading to a rapid recurrence/disease progression of the cancer. Recently, artificial intelligence (AI) has empowered physicians to use its powerful data processing and pattern recognition capabilities to extract and mine valuable drug resistance information from large amounts of clinical or omics data, to study drug resistance mechanisms, to evaluate and predict drug resistance, and to develop innovative therapeutic strategies to reduce drug resistance. In this review, we proposed a feasible workflow for incorporating AI into tumor drug resistance research, highlighted current AI-driven tumor drug resistance applications, and discussed the opportunities and challenges encountered in the process. Based on a comprehensive literature analysis, we systematically summarized the role of AI in tumor drug resistance research, including drug development, resistance mechanism elucidation, drug sensitivity prediction, combination therapy optimization, resistance phenotype identification, and clinical biomarker discovery. With the continuous advancement of AI technology and rigorous validation of clinical data, AI models are expected to fuel the development of precision oncology by improving efficacy, guiding therapeutic decisions, and optimizing patient prognosis. In summary, by leveraging clinical and omics data, AI models are expected to pioneer new therapy strategies to mitigate tumor drug resistance, improve efficacy and patient survival, and provide novel perspectives and tools for oncology treatment.

Glioblastoma represents the most prevalent and deadly form of brain tumor with limited therapeutic drugs. The existence of the blood-brain barrier (BBB) hinders drugs permeate to the brain efficiently. Nowadays, nano-formulations, particularly carbon dots, have emerged as promising candidates for targeting and treating brain diseases. In this study, we report the synthesis of a novel carbon dots, PTX-CDs, using a one-step hydrothermal method with paclitaxel (PTX) as the precursor. PTX-CDs shows increased water solubility by about 1000 times in comparison with PTX. Moreover, PTX-CDs effectively penetrates the BBB and exerts significant anticancer effects. In detail, PTX-CDs accumulates in mitochondria of tumor cells without adding extra targeted molecules, resulting in the damage of mitochondrial membrane potential and increased reactive oxygen species (ROS) level. Transcriptome profiling revealed that PTX-CDs disturbs the cell-cycle by inducing arrest at the G2/M phase, thereby inhibiting cell proliferation. PTX-CDs further decreased cell invasion by inhibiting the epithelial-mesenchymal transition (EMT) process in glioblastoma cells. PTX-CDs significantly inhibited the growth of intracranial tumors in orthotopic glioblastoma mice model and prolonged the survival of tumor-bearing mice. This study presents a viable strategy to develop CDs-based therapeutic agent for glioblastoma using the conventional chemotherapeutic drugs.

This study aimed to explore the effect of LIM domain and actin binding 1 (LIMA1) on bladder cancer (BCa) cells and to investigate its underlying molecular mechanisms.

Integration of immune checkpoint inhibitors (ICIs) with non-immune therapies relies on identifying combinatorial biomarkers, which are essential for patient stratification and personalized treatment.

Drug resistance reflects the evolution of tumors and represents the leading factor behind recurrence and death. Lenvatinib is the first-line therapy for hepatocellular carcinoma (HCC), but its effectiveness is limited by rapid development of resistance. Therefore, we aimed to identify lenvatinib resistance-related genes and assess their influence on prognosis and treatment response in HCC.

Cisplatin (DDP) resistance is a key factor hindering esophageal cancer (ESCA) treatment. Exosomes have been reported to confer resistance to DDP in various tumor cells. However, the effects of ESCA cell-derived exosomes and exosomal human antigen R (HuR) on DDP resistance in cancer cells have not been elucidated. In this study, isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. CCK-8 and flow cytometry were employed to assess the functional role of exosomes in ESCA DDP-resistant cells and their parental cells. Bioinformatics analysis was performed to identify molecules that were positively associated with HuR and validated using dual-luciferase reporter analysis and RNA immunoprecipitation assays. We found that exosomes from ESCA cells enhance the resistance of drug-resistant cells to DDP. Importantly, HuR protein, but not mRNA, was directly transferred into DDP-resistant cells via exosomes, thereby increasing the level of HuR protein. Mechanistically, HuR positively correlated with Lamin B2 (LMNB2) in ESCA cells, and ESCA DDP-resistant cells transfected with siRNA targeting LMNB2 exhibited reduced cell viability and elevated apoptosis rates. Moreover, the role of ESCA cell-derived exosomes in the transmission of DDP resistance in vivo was validated using a nude mouse model. Collectively, our results revealed that exosomes exposed to ESCA cells induced greater drug resistance in DDP-resistant ESCA cells via HuR delivery. Targeting HuR or its positively related target LMNB2 may present new therapeutic opportunities for treating patients with DDP-resistant ESCA.

Oxaliplatin (OXA) is widely used for colorectal cancer (CRC) as a first-line chemotherapy. However, drug resistance and peripheral neurotoxicity prevail in colorectal cancer therapy. Salinomycin (SAL) makes cancer cells sensitive to ionizing radiation and chemotherapeutic drugs. Chemotherapy regimens that combine more than two drugs can improve the outcome of patients. In the present study, we detected apoptosis and mitochondrial function in CRC cells through MTT assays, Annexin V-FITC/PI staining, colony-forming assays, intracellular reactive oxygen species (ROS) measurements, western blotting and so on. We used CompuSyn software to calculate combination index (CI). The effect of SAL and OXA was synergistic. The combination treatment inhibited cell proliferation, migration and colony formation but increased the expression of proapoptotic proteins and promoted cell apoptosis of CRC cells. In vitro experiments demonstrated that the SAL and OXA cotreatment increased intracellular ROS levels in CRC cell lines, decreased the MMP and activated the mitogen-activated protein kinase (MAPK) pathway, thus inhibiting the proliferation of CRC cells and promoting the apoptosis of CRC cells. Pretreatment with N-acetylcysteine (NAC) reversed this effect. Cotreatment with SAL and OXA increases the apoptotic effects in OXA-treated CRC cell lines. In vivo, combined treatment of SAL and OXA markedly inhibited the tumor growth compared to either drug alone. SAL enhances OXA-induced antitumor effects in CRC both in vitro and in vivo by ROS-mediated mitochondrial apoptosis and activation of the MAPK pathway. These results may provide a rationale for combining SAL with OXA for CRC treatment.

Cervical cancer (CC) remains a leading cause of cancer-related deaths worldwide and still requires effective interventions to improve patient outcomes. Angiopoietin-like 4 (ANGPTL4) is a multifaceted glycoprotein that plays crucial roles in lipid metabolism and tumor progression. ANGPTL4 exhibits both tumor-promoting and tumor-suppressing effects and has been proposed as a promising target for cancer therapy. This study investigated the role and potential of ANGPTL4 in enhancing therapeutic efficacy in CC using cell line models in vitro. Our analysis revealed a decreased expression of ANGPTL4 in CC samples from the GSE dataset and in the CC cell lines examined. Functional assays demonstrated that ANGPTL4 overexpression suppressed CC cell proliferation, migration, and invasion. Notably, overexpression of ANGPTL4 resulted in decreased cell viability and increased levels of apoptosis, cleaved caspase-3, and cleaved PARP under cisplatin treatment. Furthermore, these analyses were also conducted in ANGPTL4-knockdown cells, and results supporting the tumor-suppressive roles of ANGPTL4 were observed. Taken together, our study elucidates the critical role of ANGPTL4 in modulating progression and chemosensitivity of CC cells, suggesting ANGPTL4 as a potential target for CC treatment.