Inosine, a bacterial metabolite and agonist of the adenosine A2A receptor, modulates antitumor immunity. However, its precise effects on immune checkpoint inhibitors remain unclear. This study aimed to evaluate the impact of inosine on the efficacy of anti-programmed cell death protein 1 (PD-1) therapy and explore strategies to counteract any potential inhibitory effects. In in vitro co-culture systems, inosine selectively suppressed cancer cell growth without impairing T-cell viability. In a murine subcutaneous tumor model, inosine treatment reduced tumor growth and was associated with elevated interferon-gamma levels in the tumor microenvironment, along with increased infiltration by tumor-infiltrating lymphocytes and enhanced splenic CD4⁺ and CD8⁺ T-cell frequencies. However, the combination of inosine with anti-PD-1 therapy attenuated the antitumor effect and increased cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in splenic T cells compared to levels after anti-PD-1 monotherapy. To overcome this inhibitory effect, we tested whether adding an anti-CTLA-4 antibody could restore antitumor immunity. Notably, the combination of inosine with both anti-PD-1 and anti-CTLA-4 antibodies significantly enhanced antitumor efficacy. These findings suggest that inosine may synergize with dual ICI therapy and represent a promising adjunct to improve immunotherapeutic outcomes.

To investigate the 12-month effectiveness and safety of intravitreal faricimab (IVF) in patients with neovascular age-related macular degeneration (nAMD) resistant to previous anti-VEGF treatment.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options due to its desmoplastic and immunosuppressive tumor microenvironment (TME), which impedes drug delivery and limits T cell infiltration. Immune checkpoint blockade (ICB) has shown poor efficacy in PDAC, partly due to the desmoplastic stroma and low immunogenicity. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) promotes both fibrosis and immune evasion, making it a compelling target for TME remodeling. Here, we develop a dual-action, programmable immunoprobiotic delivery system (EcN@Nbs-NP@API-1) that combines Pin1 inhibition with PD-L1 blockade to enhance immunotherapy. This system uses Escherichia coli Nissle 1917 (EcN) to selectively deliver nanoparticles encapsulating the Pin1 inhibitor API-1 to PDAC, enabling sustained release to degrade the fibrotic stroma and upregulate PD-L1 on tumor cells, promoting immune infiltration. Engineered EcN also produces anti-PD-L1 nanobodies in situ, synergizing with API-1 to boost CD8+ T cell-mediated immunity. In orthotopic PDAC mouse models, this strategy remodels the TME, enhances immune cell infiltration, and improves antitumor response while minimizing systemic toxicity. Moreover, it shows efficacy in other ECM-rich tumors, such as triple-negative breast cancer, highlighting its broader potential. This work presents a promising platform to overcome immunotherapy resistance in solid tumors.

Cyclin-dependent kinase 7 (CDK7) plays a crucial role in cell cycle regulation and transcription, establishing it as a promising target for cancer therapy. Although the covalent inhibitor THZ1 effectively targets CDK7, it presents risks such as a short half-life and potential off-target side effects. To address these limitations, we employed a computational workflow integrating virtual screening, molecular dynamics (MD) simulations, and the free energy perturbation (FEP) method to design noncovalent CDK7 inhibitors with enhanced selectivity and safety profiles. MD simulations elucidated THZ1's inhibitory mechanism and identified key molecular fragments within its structure. By incorporating fragments from known inhibitors, we introduced extensive noncovalent interactions within the binding pocket, leading to the identification of three novel noncovalent inhibitors with binding affinities comparable to or higher than that of THZ1. Our findings not only introduce promising CDK7 inhibitors but also present a robust computational framework that could accelerate the discovery of kinase-targeted therapeutics.

Quinoline, isoxazole, and pyridothiazolopyrimidinone derivatives are novel compounds with significant biological activity, exhibiting anticancer properties and holding promising therapeutic applications.

This study aims to develop a receptor-dependent 4D-QSAR model to overcome key limitations of traditional QSAR, including its dependency on molecular alignment and poor performance with small datasets, by integrating ligand - target interaction information.

Melanoma is a type of aggressive cancer distinguished by its high propensity for recurrence, the development of metastases, and an unfavorable outlook for recovery. Treatment modalities for melanoma encompass surgery, immunotherapy, and targeted therapies. In recent decades, berberine has garnered attention for its significant anticancer properties across various cancer types. This review systematically examines the molecular mechanisms of berberine in melanoma, particularly its modulation of critical signaling pathways, including B-RAF/MEK/ERK, PI3K/AKT, and NF-κB, which are essential for regulating melanoma cell proliferation and promoting apoptosis. Furthermore, berberine activates AMP-activated protein kinase, leading to the inhibition of cyclooxygenase-2, thereby reducing melanoma cell migration and invasion through decreased inflammation and enhanced cellular energy regulation. It also induces mitochondrial dysfunction and oxidative stress, promoting apoptosis while simultaneously inhibiting epithelial-to-mesenchymal transition, a key process in metastasis. Additionally, berberine modulates the immune microenvironment through Toll-like receptors, cytokine networks, and the regulation of various immune cells, thereby enhancing its antitumor effects. Recent studies have shown that the therapeutic effect of berberine is enhanced when used in combination with other therapies, especially immune checkpoint inhibitors, to improve antitumor immune responses. These findings highlight the potential of berberine as a multi-targeted agent for the treatment of melanoma, providing an avenue for further clinical exploration and integration into therapeutic strategies.

This study aimed to investigate the anatomical and functional outcomes of branch retinal vein occlusion (BRVO) eyes treated with anti-vascular endothelial growth factor (anti-VEGF) injections using a novel one and stepped pro re nata protocol. This retrospective case series evaluated the electronic medical records from 22 BRVO patients who were treated with anti-VEGF agents under our novel "One and Stepped PRN" protocol at a single tertiary medical center between January 2016 and October 2022. Outcomes of interest included best-corrected visual acuity and central retinal thickness. Twenty-two treatment-naive BRVO eyes (14 males, 8 females) were included. The mean age was 65.82 ± 10.88 years. Average follow-up was 54.45 ± 7.65 weeks. 7 (31.81%) received mainly Ranibizumab, and 15 (68.18%) received mainly Aflibercept. The baseline average best corrected distance visual acuity was 45.86 ± 19.46 Early Treatment of Diabetic Retinopathy Study letters, and the baseline average central retinal thickness was 562.5 ± 164.02 μm. The mean number of injections received was 3.54 ± 1.74. Average best corrected distance visual acuity improvement was 23.91 ± 17.36 Early Treatment of Diabetic Retinopathy Study letters (P < .0001) and average central retinal thickness improvement was 245.55 ± 153.31 μm (P < .0001). Our results were comparable to the BRAVO and VIBRANT trials while comparatively using fewer anti-VEGF injections. In summary, our novel anti-VEGF protocol applied under real-world conditions achieved good anatomical and visual outcomes among treatment-naive BRVO eyes.

The advent of immune checkpoint inhibitors has introduced innovative therapeutic paradigms for the management of human epidermal growth factor receptor 2 (HER2)-negative advanced gastric or gastroesophageal junction cancer (GC/GEJC). However, the efficacy and safety of programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy versus chemotherapy alone in patients with HER2-negative advanced GC/GEJC remain contentious. The comparability among different subgroups is not fully understood, necessitating the identification of optimal patient demographics and the exploration of potential biomarkers.

However, this study has several limitations that must be acknowledged. First, the non-randomized allocation of treatment duration introduces potential selection bias, particularly as frailer patients were more likely to receive shorter therapeutic cycles, which may have confounded outcome assessments. Background: Although the standard 28-day venetoclax (VEN) regimen combined with azacitidine (AZA) improves outcomes in elderly patients with acute myeloid leukemia, emerging evidence suggests that shorter VEN cycles may maintain efficacy with enhanced safety. We retrospectively analyzed 90 treatment-naive elderly patients with acute myeloid leukemia receiving VEN + AZA (VA): 47 patients (14-day VEN) and 43 patients (28-day VEN). The outcomes included clinical remission rates, hematologic recovery, adverse events, and survival metrics. Both groups achieved comparable clinical remission rates (CRc: 57.4% vs 58.1%, P = .947). The 14-day cohort demonstrated significantly faster neutrophil recovery (median 12.5 vs 26 days, P < .01) and reduced febrile neutropenia (73.3% vs 90.9%, P < .05), with trends toward fewer grade ≥3 infections. At a median follow-up of 494 days, no significant differences in median overall survival (OS: 494 vs 578 days, HR = 1.17, 95%CI 0.64-2.14) or event-free survival (416 vs 454 days, HR = 1.09, 95%CI 0.61-1.96) were observed. A 14-day VA regimen showed antileukemic efficacy comparable to the 28-day protocol while mitigating myelosuppressive sequelae. This abbreviated approach may optimize tolerability in frail elderly patients who are ineligible for prolonged low-intensity chemotherapy. Prospective validation is warranted to refine risk-adapted dosing strategies.

Ferroptosis is a nonapoptotic form of cell death characterized by lethal membrane lipid peroxidation. This mechanism was first characterized in cancer cells well over a decade ago, and there is much enthusiasm for the concept that certain cancers may be treated by inducing ferroptosis. However, therapies that engage ferroptosis have yet to enter clinical testing. In this Review, we highlight the gap between our rapidly expanding knowledge of the ferroptosis mechanism and its translation into cancer therapies. We discuss the known challenges that may be slowing ferroptosis therapies from reaching the clinic.

Objective: To explore the application value of machine learning algorithms in constructing a predictive model for cardiovascular toxicity in breast cancer patients receiving anthracycline-based chemotherapy. Methods: This study was a retrospective cohort study. The female patients with breast cancer who received anthracyclines in the Affiliated Cancer Hospital of Xinjiang Medical University from January 2020 to December 2023 were enrolled. The endpoint event was abnormal electrocardiogram (ECG). According to whether the patients had ECG abnormalities during chemotherapy, they were divided into the ECG abnormal group and the ECG normal group. The dataset was divided into the training set and the test set at a ratio of 8∶2, and logistic regression, random forest, extreme gradient boosting (XGBoost), support vector machine (SVM) and multilayer perceptron (MLP) were used to construct a risk prediction model for cardiovascular toxicity in breast cancer patients, and the receiver operating characteristic curve, calibration curve and clinical decision curve were used to evaluate the model. Results: A total of 731 female patients with breast cancer, aged (51.6±9.4) years, were enrolled. The follow-up time was (130.3±37.1) days. There were 333 cases in the ECG abnormal group and 398 cases in the ECG normal group. Seven factors influencing cardiovascular toxicity were identified, including age, menstrual history, diabetes, combination therapy with trastuzumab, combination therapy with dexrazoxane, creatine kinase isoenzymes, and α-hydroxybutyrate dehydrogenase. In the training set, the area under the curve (AUC) for the logistic regression, random forest, XGBoost, SVM, and MLP models was 0.712, 0.863, 0.774, 0.813, and 0.733, respectively. In the test set, the AUC was 0.671, 0.778, 0.746, 0.771, and 0.705, respectively. Calibration curves and clinical decision curves showed that the random forest model performed the best. Conclusion: Models constructed with machine learning algorithms show promise in predicting cardiovascular toxicity in breast cancer patients receiving anthracycline-based chemotherapy, with the random forest prediction model performing the best.

In colorectal cancer (CRC) treatment, various approaches, including chemotherapy (5-FU, irinotecan, and oxaliplatin), targeted therapy (VEGF inhibitor) and immunotherapy (PD-1/ PD-L1 inhibitor), are employed. However, due to side effects and limited efficacy, more effective novel therapeutic strategies have been required. In this study, we identified the anti-cancer effects of Lactobacillus plantarum DS0709, isolated from infant feces, on CRC. Treatment with the supernatant (Sup) of L. plantarum DS0709 demonstrated growth inhibition of CRC cell lines (HCT116 and SNUC5) by inducing apoptosis. Additionally, using human iPSC-derived intestinal organoids (hIO), we confirmed that L. plantarum DS0709 Sup exhibited no toxicity. Furthermore, in a 3D spheroid model mimicking in vivo conditions, L. plantarum DS0709 Sup showed similar apoptosis induction and growth-inhibitory effects as in 2D cultures. Thus, these findings suggest that L. plantarum DS0709 has the potential to be developed into a novel microbiome-based therapeutic agent for CRC, offering anti-cancer efficacy without side effects.

A significant percentage of melanomas are refractory to immune checkpoint inhibitor (ICI) monotherapies and combinations. As there are currently no effective second-line therapies available for ICI-resistant patients, we sought to identify novel checkpoint inhibitor combinations for future clinical evaluation.

Doxorubicin (DOX), a widely used chemotherapy, suffers from severe cardiotoxicity. Doxil, the first FDA-approved antitumor nanoformulation, mitigates the cardiotoxicity of DOX, but fails to enhance therapeutic efficacy probably due to limited cellular uptake and restricted drug release. To overcome these challenges, this study developed a novel disulfide-acryloyl-modified DOX prodrug (DSSA) for albumin-targeted drug delivery. DSSA could self-assemble into stable nanoassemblies (DSSA NPs) with a high drug-loading capacity (65.46%). DSSA NPs could covalently bind to endogenous albumin, significantly enhancing pharmacokinetics with a nearly 40-fold increase in the area under the curve (AUC) compared to DOX solution (DOX sol) and achieving over twice the tumor accumulation of DOX sol and Doxil. Additionally, the reduction-responsive disulfide bonds enabled selective drug release in tumor microenvironments, minimizing off-target toxicity. These results demonstrate the potential of disulfide-acryloyl modification as a promising prodrug strategy to enhance tumor targeting and safety in chemotherapeutic delivery.

Myeloid Cell Leukemia 1, or MCL-1, is an anti-apoptotic protein belonging to the BCL-2 family of proteins, which regulate the mitochondrial pathway of cellular apoptosis via binding of pro- and anti-apoptotic family members. Genetic amplification and overexpression of MCL-1 is one mechanism cancer cells utilize to avoid death and thus MCL-1 has emerged as an attractive target for cancer treatment. Herein, we describe our strategy and medicinal chemistry efforts to identify best-in-class MCL-1 inhibitors with high cytotoxic potency and improved biorelevant solubility while aiming to maximize therapeutic index versus on-target toxicity via IV dosing. These efforts led to the discovery of JNJ-78394355: a highly efficient anti-tumor agent, as demonstrated by the in vivo studies in human-xenograft mouse models of acute myeloid leukemia (AML) and multiple myeloma (MM).

Designing metabolically stable peptides to target interactions of the tumor suppressor protein p53 with the two oncogenic proteins MDM2 and MDMX represents an attractive approach to harvesting "high-hanging fruits" often inaccessible to traditional anticancer drug discovery and development efforts. Here, we report the design of a proteolysis-resistant d-dodecapeptide, termed DPMI-ω (EFWYVEp-ClFEKLLR), capable of disrupting the p53-MDM2/MDMX complex by antagonizing MDM2 and MDMX. DPMI-ω, upon fabrication on gold nanoparticles, efficiently traversed tumor cells and killed them by reactivating the p53 signaling pathway. Further, DPMI-ω inhibited B16 melanoma growth in vivo and, when combined with an anti-PD1 antibody, powerfully augmented the efficacy of immunotherapy by expanding CD3+/CD8+ cytotoxic T cells and suppressing CD4+/CD25+ regulatory T cells. Our work validates the design of a therapeutically viable anticancer peptide, showcasing its potential in combination therapy to treat patients with tumors that are otherwise resistant or poorly responsive to antitumor immunotherapy.

Cisplatin (DDP) is a typical chemotherapy agent employed in gastric cancer (GC). Resistance development significantly impairs the success of GC therapy, and the essential mechanisms are not yet fully understood. Deubiquitinase enzymes are pivotal in mediating drug resistance across various cancers via ubiquitin-mediated protein degradation. USP44, a deubiquitinase known as ubiquitin-specific peptidase 44, is implicated in the development of tumors, their spread, and resistance to treatment, although its specific role in gastric cancer has yet to be clarified. We found a significant upregulation of USP44 expression in GC tissues compared to normal tissues, and it serves as a potential indicator of chemotherapy response and survival in GC. Through proteomic analysis, ITGB4 was recognized as a new substrate of USP44. Mechanistically, USP44 stabilizes ITGB4 via deubiquitination, thereby mitigating cisplatin resistance in GC cells by modulating ROS and the MAPK/NF-κB pathway. In addition, ITGB4 affects the expression of P-gp and the activity of antioxidant enzymes through the MAPK/NF-κB pathway, thereby promoting cisplatin efflux and chemoresistance. Our research uncovers a novel mechanism behind cisplatin resistance and indicates that USP44 could be a promising therapeutic target for overcoming cisplatin resistance in gastric cancer patients.

This study investigated vascular injury incidence, symptoms, and changes in vascular wall thickness and blood flow in 140 chemotherapy patients. Vascular ultrasound and laboratory tests were conducted at 1 week, 1 month, and 3 months post-chemotherapy. Results showed that vascular injury incidence increased over time (12.9% at 1 week, 25.0% at 1 month, 34.3% at 3 months, P<0.05). Vascular wall thickness (IMT) thickened from 0.61±0.11 mm at baseline to 0.85±0.22 mm at 3 months (P<0.01) and vascular diameter increased from 2.34±0.22 mm to 2.55±0.33 mm at 3 months (P<0.01). Severe phlebitis incidence rose from 2.9% at 1 week to 7.1% at 3 months (P<0.01). Elevated CRP and D-dimer levels correlated with increased vascular wall thickness and thrombosis. Enhanced monitoring and personalized interventions are needed to reduce complications. Combining ultrasound and laboratory markers can improve assessment of chemotherapy-induced vascular injury.

Ovarian cancer (OC) is a highly aggressive malignancy in the reproductive system of women, with a high recurrence rate. The present research was designed to establish a relapse-based RiskScore model to assess the drug sensitivity and prognosis for patients with OC.