Intravitreal anti-vascular-endothelial growth factor (anti-VEGF) injections have revolutionized the treatment of diabetic macular oedema (DME). The effect of early initiation of anti-VEGF treatment with good baseline visual acuity on treatment outcomes was compared with that of deferred treatment in patients with type 1 diabetes (T1D) and DME.

Bladder cancer (BLCA) remains heavily dependent on bacillus Calmette-Guérin (BCG) therapy due to the profound heterogeneity of its tumor microenvironment (TME) and deregulated metabolic landscapes. Taurine metabolism (TM) is a pivotal axis in BLCA, exhibiting dual roles in tumor progression and immune evasion. Deciphering the molecular mechanisms by which TM reprogramming fosters immunosuppression is imperative for advancing BLCA immunotherapy.

Histone deacetylases (HDACs) are intriguing cancer targets due to their high expression in many tumors. Consequently, inhibition or degradation of HDACs can be beneficial for cancer therapy. Targeted protein degradation using molecular glues represents a promising therapeutic approach, enabling the specific degradation of numerous disease-causing proteins. However, the rational design of molecular glues in a target-based manner remains challenging. A recent study has described the identification of a DCAF16-based covalent linker-less chemical handle for molecular glues. This covalent warhead can be attached to protein of interest ligands to induce the targeted degradation of various protein classes. Inspired by this, we designed and synthesized a new class of DCAF16-based covalent molecular glues utilizing different zinc-binding groups for the targeted degradation of HDACs. This approach led to the discovery of an efficient molecular glue (10a) that reduced HDAC1 levels in multiple myeloma MM.1S cells in a potent and preferential manner.

This retrospective study examines the relationship between negative immune responses and the effectiveness of immune checkpoint inhibitors (ICIs) in the treatment of advanced solid tumors. A total of 59 patients with advanced solid tumors treated with ICIs between August 2020 and May 2022 were included. Based on the presence or absence of immune-related adverse events (irAEs), patients were categorized into 2 cohorts: irAE group (n = 46) and non-irAE group (n = 13). The primary objective was to compare therapeutic efficacy and survival outcomes between these cohorts. Among patients who developed immune-related adverse events (irAEs), the disease control rate (DCR) was 93.48% and the objective response rate (ORR) was 30.43%. In contrast, patients without irAEs exhibited significantly lower rates (DCR: 38.46%; ORR: 7.69%). Kaplan-Meier analysis demonstrated significantly prolonged progression-free survival (PFS) in the irAE group (median: 10.34 months; 95% CI: 9.275-11.401) compared to the non-irAE group (median: 5.82 months; 95% CI: 2.868-8.772; P < .05). Gastrointestinal malignancies (gastric cancer, HCC, and esophageal carcinoma) exhibited the most favorable PFS outcomes. Multivariate Cox regression analysis showed that irAEs, cutaneous irAEs, and endocrine irAEs were significantly associated with prolonged PFS. Multivariate Cox proportional hazards regression analysis identified irAE occurrence (hazard ratio [HR] = 0.542; 95% CI: 0.295-0.971; P = .04), cutaneous irAEs (HR = 0.476; 95% CI: 0.232-0.912; P = .03), and endocrine irAEs (HR = 0.237; 95% CI: 0.037-0.842; P = .02) as independent predictors of prolonged PFS. Among patients with advanced solid tumors treated with ICIs, those who experienced immune side effects had higher DCRs and ORRs and demonstrated superior PFS. The observed benefit was more pronounced in patients with gastric, esophageal, and hepatocellular cancers.

Febrile neutropenia (FN) is a severe complication of chemotherapy, associated with substantial mortality and financial burden. The purpose of this study was to assess the association between hospital length of stay (LOS), supportive therapies, and antibiotic regimens in patients with FN, with a specific focus on the Turkish population. Eighty adult patients with solid tumors were enrolled. Patients received empirical antibiotic therapy within 2 hours of presentation. Data were collected on clinical and demographic variables, including LOS, fever duration, Multinational Association of Supportive Care in Cancer Risk Index scores, and laboratory parameters. The mean hospital LOS was 6.09 ± 3.62 days. Sulperazon use was significantly associated with a shorter LOS compared to meronem and tazocin (P < .001). Patients receiving filgrastim had a longer LOS compared to those who did not (P = .042). Correlation analysis revealed strong positive associations between LOS and febrile days (R = 0.624, P < .001), febrile days during hospitalization (R = 0.711, P < .001), and filgrastim administration days (R = 0.722, P < .001). Multivariate analysis confirmed that sulperazon use reduced LOS by 1.271 days (P = .048), while prolonged filgrastim use was linked to longer stays (P < .001). These findings highlight the critical role of antibiotic selection and supportive care in managing hospitalization duration for patients with FN. The combination of certain treatments and antibiotics plays a significant role in determining the duration of hospital stays, highlighting factors to consider in patient management and treatment planning.

Chemotherapy, as one of the main treatments for patients with colorectal cancer (CRC), brings clinical benefits with varying degrees of gastrointestinal reactions. Post-chemotherapy diarrhea is one of the factors affecting the quality of life of cancer patients. In severe cases, it can cause interruption of the chemotherapy process and even be life-threatening. Probiotics' role in preventing post chemotherapy diarrhea in CRC patients has not been proven.

Characterized by high malignancy and limited treatment efficacy, triple-negative breast cancer (TNBC) remains a clinically challenging subtype within breast cancer classifications, marked by rapid progression and high mortality. Abnormal activation of the transforming growth factor-β (TGFβ) pathway signaling, a pathway integral to tumor progression, metastasis, angiogenesis and immune evasion, is a common feature in a broad spectrum of malignancies. Owing to the restricted effectiveness of first-line interventions including surgical resection, cytotoxic agents, and radiation therapy for TNBC, novel agents that modulate TGFβ activity represent a compelling therapeutic avenue. Herein, we reported the identification and preclinical evaluation of YH395A, a novel tetrahydro-β-carboline derivative derived from the lead compound YR-290 with virtual screening from pseudo molecular library generated by generative deep learning method. In vitro studies demonstrated that YH395A dose-dependently inhibited TNBC cell migration and invasion. In vivo, administration of YH395A not only curtailed metastatic dissemination and prevented the extravasation of breast cancer cells into lung parenchyma in mouse models but also significantly reduced tumor growth in a patient-derived xenograft (PDX) model. Mechanistic analyses indicated that these antitumor effects are mediated via potent inhibition of TGFβ signaling. These cumulative results demonstrate YH395A's viability as a novel therapeutic agent for TNBC, while emphasizing the necessity for expanded preclinical validation studies.

Immunotherapies, particularly immune checkpoint inhibitors (ICIs), have revolutionized cancer clinical management, but low response rates and treatment resistance remain challenging. Protein post-translational modifications (PTMs) are critical for governing protein expression, localization, functions, and interactions with other cellular molecules, which notably build up the diversity and complexity of the proteome. A growing body of evidence supports that PTMs influence immunotherapy efficacy and outcomes by post-translationally modulating the expression and functions of immune checkpoints. Therefore, understanding the PTM mechanisms that govern immune checkpoints is paramount for developing novel treatment strategies to improve immunotherapy efficacy and overcome resistance. This review provides an overview of the current comprehension of the regulatory mechanisms by which PTMs (glycosylation, phosphorylation, ubiquitination, acetylation, succinylation, palmitoylation, lactylation, O-GlcNAcylation, UFMylation, and neddylation) modulate immune checkpoints to unveil potential therapeutic targets. Moreover, this review discusses the potential of therapeutic strategies targeting PTMs of immune checkpoints, providing insights into the combination treatment with ICIs in maximizing the benefits of immunotherapy and overcoming resistance.

Anthracyclines are widely used anticancer agents with a complex mechanism of action involving topoisomerase II inhibition and DNA intercalation. Despite their clinical efficacy, their use is limited by cancer cell resistance, linked to the formation of secondary alcohol metabolites via carbonyl reductase 1 (CBR1)-mediated reduction. These metabolites exhibit reduced anticancer activity, positioning CBR1 as significant factor in determining therapy outcomes. The study aimed to elucidate the role of CBR1 in mediating the differential responses of various anthracyclines in cancer cells. The role of CBR1 in cancer resistance against five anthracyclines: doxorubicin, daunorubicin, epirubicin, idarubicin, and aclarubicin, was examined in A549 lung cancer cells transduced with the CBR1. Anthracyclines were found to present significant differences in activity related to CBR1 overexpression. Surprisingly, aclarubicin was the most dependent on CBR1 among the tested compounds, while it exhibited a low reaction velocity when catalyzed by recombinant CBR1. The findings reveal critical differences in anthracycline susceptibility to CBR1, offering insights into resistance mechanisms.

Aberrant Wnt signaling is a hallmark of many cancers, driving proliferation and disease progression. This review provides a focused overview of recent research (past 10-15 years) into Wnt inhibitors as potential cancer therapeutics, emphasizing their diverse mechanisms of action at the molecular level. We examine the latest findings regarding Wnt ligand blockade, frizzled receptor antagonism, and downstream pathway modulation, assessing each approach's clinical potential and challenges. This includes a discussion of combination therapies and strategies to overcome resistance. Ultimately, this review aims to provide a clear and concise understanding of the current landscape of Wnt inhibition, guiding future research toward more precise and effective cancer treatments.

Human health and the environment are continuously impacted by anthropogenic activities, particularly those involving emerging compounds. As these compounds are newly identified or not yet fully documented in the literature, comprehensive knowledge of their specific toxicities remains limited. Among these, pharmaceutical compounds are of particular concern, as their mechanisms of action and the effects of their pharmaceutical impurities remain insufficiently understood. In this context, this study aimed to evaluate the behavior of the antineoplastic pharmaceutical doxorubicin (DOX) under stress conditions, including acid and base hydrolysis, oxidation, photolysis, and temperature variations. The goal was to identify the major degradation pathways and elucidate the structures of the main degradation products. A stability-indicating HPLC-DAD-MS method was developed and validated for this purpose. Throughout method development, several degradation products were identified, including 7-deoxydehydrodoxorubicinone, formed through acid hydrolysis, and a major thermal degradation product with a mass-to-charge ratio (m/z) of 530. This thermal degradation product was also detected in analyses of expired pharmaceutical formulations. Furthermore, the in vitro toxicity assessment of samples containing degradation products from thermal decomposition revealed cytotoxic effects on mononuclear cells. These findings underscore the importance of not only understanding the degradation pathways of pharmaceutical compounds but also evaluating the potential environmental and human health impacts of these degradation products.

Cisplatin is the primary chemotherapeutic agent for osteosarcoma. However, a significant proportion of patients develop resistance post-treatment, leading to disease recurrence and presenting profound clinical challenges. To understand the mechanisms underlying osteosarcoma recurrence and cisplatin resistance, particularly from the tumor microenvironment perspective, we consolidated numerous single-cell RNA sequencing datasets, offering an encompassing insight into the osteosarcoma microenvironment. When juxtaposing scRNA-seq with bulk RNA-seq data, we observed a strong correlation between high DCUN1D5 expression in osteosarcoma and patient survival. This gene amplifies osteosarcoma's anti-apoptotic, invasive, stem-cell-like traits and PI3K/AKT/GSK3β pathway phosphorylation and fosters cisplatin resistance. Subsequent research revealed that cisplatin-resistant osteosarcoma cells excrete DCUN1D5-rich exosomes, facilitating the maturation of osteoclast precursors. Excessive osteoclast activity is a pivotal contributor to osteosarcoma recurrence and resistance. Given these insights, DCUN1D5 is a promising therapeutic target for osteosarcoma recurrence and drug resistance.

Combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs (AADs) holds promise in cancer treatment. While ICIs block signals that help cancer cells evade the immune system, anti-angiogenic agents target blood vessels, limiting tumor growth by restricting nutrient and oxygen supplies. Additionally, the judicious use of AADs can normalize the tumor vasculature, alleviate hypoxia, and enhance the antitumor immune response. As the shutdown of a single target does not necessarily eradicate cancer, the use of combinations of molecular-targeted agents has been proposed, and some pioneering research has been conducted to examine the efficacy of this strategy. The combination of these two modalities offers a synergistic approach, enhancing the efficacy of tumor eradication. Recent studies have elucidated the rationale behind this combination therapy, but a limited response rate has been achieved with monotherapy. Clinical trials have demonstrated the potential of this combination, with improved outcomes in various solid tumor types. The dual blockade of angiogenesis and immune checkpoints is poised to become a standard of care, with indications expected to expand as more evidence accumulates. The antitumor efficacy of current therapies is limited, most likely because of the high degree of cancer clonal heterogeneity, intratumor genetic heterogeneity, and cell signal complexity. Although numerous studies have been conducted in this area, this review provides a comprehensive analysis of the molecular rationale for ICIs and AADs in cancer therapy. We not only compare the individual properties and mechanisms of both treatments, but also explore their complementary roles, which are essential for optimizing personalized treatment strategies. By addressing key challenges such as tumor heterogeneity, immune evasion, and resistance to monotherapies, we demonstrate how this combination approach can enhance treatment outcomes. Furthermore, we incorporate the latest preclinical and clinical findings and offer future perspectives on optimizing drug selection, dosing, and treatment design to maximize therapeutic efficacy.

Cervical cancer, a common malignant tumor of the female reproductive system, ranks fourth in incidence and mortality among female cancers globally, which highlights the urgent need for new therapeutic agents to improve treatment outcomes. In this study, 16 new erlotinib-1,2,3-triazole derivatives were synthesized via click chemistry and evaluated for their anti-proliferative activities against HeLa cells using the MTT assay. Compound 3h exhibited the most potent antitumor activity, with a half-maximal inhibitory concentration (IC50) value of 1.35 ± 0.74 µM, significantly lower than that of erlotinib (IC50 = 25.91 ± 1.35 µM). Further assays showed that compound 3h reduced cell viability, inhibited colony formation, and suppressed migration. It arrested the cell cycle at the G2/M phase and induced mitochondrial apoptosis, marked by decreased Bcl-2, increased Bax, and downregulated Caspase-9, Caspase-3, and PARP-1. Additionally, compound 3h promoted ROS accumulation, induced γ-H2AX expression, and regulated the phosphorylation of ERK, JNK, and p38. Molecular docking studies suggested direct binding to these MAPKs. Overall, compound 3h inhibited HeLa cell proliferation by inducing ROS-mediated DNA damage and mitochondrial apoptosis via the MAPK pathway. This study provides evidence for the therapeutic potential of erlotinib-1,2,3-triazole derivatives in cervical cancer treatment, offering new strategies for developing effective and low-toxicity drugs.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that urgently needs more effective therapies. Cancer-associated fibroblasts (CAFs) contribute to the aggressive and chemo-resistant nature of the disease by creating a drug-impeding fibrotic microenvironment. We developed novel compounds, the racemate CRO-05 and its active enantiomer CRO-67, which target both pancreatic tumor and CAF cells with robust anti-cancer activity. These compounds were designed using rational medicinal chemistry based on chromans, a class of anti-cancer drugs. Their therapeutic potential and efficacy were assessed in a clinically relevant patient-derived PDAC tumor explant model, which mimics the disease's 3-dimensional complexity. CRO-67 treatment in these explants significantly reduced tumor cell and αSMA+ CAF frequency, decreased cell proliferation and increased cell death. CRO-67 also significantly decreased cell proliferation and enhanced apoptosis by inhibiting cell cycle progression through G2/M phase in PDAC cells and patient-derived CAFs in vitro. CRO-67 treatment of orthotopic PDAC tumors in mice significantly reduced tumor growth in tumors with active growth (> 150% growth at endpoint), and remodeled tumor stroma (reduced αSMA+ CAF frequency, loosened tumor fibrosis and normalized tumor vasculature). Finally, CRO-67 sensitized PDAC cells to multiple standard-of-care chemotherapeutics in vitro, paving the way for future combination therapy development and validation.

The dysfunction of HDACs is closely related to tumorigenesis and development, which has emerged as an attractive target for cancer therapy. In this study, a series of thiazole-containing hydroxamate derivatives were designed and synthesized as novel HDAC inhibitors. Among these inhibitors, compounds 15a and 15d showed excellent inhibitory activities against HDAC1 and HepG2 cancer cell line, these two compounds increased the levels of acetylated histone H3 and H4. Moreover, 15a and 15d significantly arrested HepG2 cells at the G0/G1 phase. Additionally, these two compounds could induce apoptosis and pyroptosis. Moreover, 15a exhibited significant antitumor activity in the HepG2 xenograft model. Molecular docking and molecular dynamics simulation studies revealed the possible interaction mode of compound 15a with HDAC1. Besides, the preliminary pharmacokinetics study of compound 15a in vivo was evaluated. These results suggested that these novel thiazole-based HDAC inhibitors might become a promising scaffold for further structural optimization.

Cancer cells that survive chemotherapy achieve full DNA duplication despite the accumulation of damaged DNA triggered by chemotherapy. This happens because the synthesis of DNA at damaged sites is granted by tolerance events including translesion DNA synthesis (TLS), a process that promotes the use of specialized DNA polymerases (S-Pols) for DNA synthesis. Such a crucial role of S-Pols in the promotion of damaged DNA replication prompted analyses of the cell killing effects of individual S-Pols inhibitors. Because S-Pols can compensate for each other, a global inhibition of S-Pols needs to be designed and tested. Given that S-Pols are recruited to the replisome through their PCNA binding motif, we reasoned that global displacement of S-Pols will occur when delivering a peptide with a strong PCNA binding motif. The cyclin kinase inhibitor p21 contains the strongest PCNA binding motif. Therefore, we designed a peptide representing this C-terminal, PCNA interacting region (PIR) of p21. As hypothesized by us, the PIR peptide achieved global S-Pol displacement from PCNA-associated replication factories and enhanced the cancer cell killing potential of DNA damaging agents including cisplatin, hydroxyurea, olaparib and UV irradiation. Demonstrating strong versatility, the peptide also enhanced the cytotoxicity caused by agents that do not directly provoke DNA damage such as Chk1, ATR and Wee1 inhibitors. In all cases, disrupting the PCNA binding site within the PIR peptide was sufficient to dismantle its cell killing potential. Strengthening the concept, a less potent PIR, namely derived from S-Pol eta, efficiently displaced S-Pols from replication factories exacerbating cell killing by all agents tested. These results collectively indicate that simultaneous displacement of S-Pols from PCNA can be enforced by excess levels of PIR peptides. This strategy is demonstrably valid to enhance the cancer cell killing by different DNA-damaging agents.

Reovirus type 3 Dearing (RT3D) is an oncolytic, double-stranded RNA virus. To identify potential RT3D drug-viral sensitizer, here we use a high-throughput screen of therapeutic agents and find a PARP-1 inhibitor, talazoparib, as a top hit. RT3D interacts with retinoic acid-induced gene-1 (RIG-I) and activates PARP-1, with consequent PARylation of components of the extrinsic apoptosis pathway. Pharmacological or genetic inhibition of PARP-1 abrogates this PARylation and enhances extrinsic apoptosis, NF-kB signalling and pro-inflammatory cell death. Interaction between PARP-1 and RIG-I induced by treating RT3D-infected cells with talazoparib activates downstream IFN-β and TNF/TRAIL production to amplify the therapeutic effect through positive feedback. Furthermore, the effect of RT3D-talazoparib combination is phenocopied by non-viral ds-RNA therapy and RIG-I agonism. In vivo, mouse tumour model results show that RT3D/talazoparib combination regimen induces complete control of inoculated tumour as well as protection from subsequent tumour rechallenge with the, with accompanied innate and adaptive immune activation.

Renal angiomyolipomas (AMLs) are a common renal manifestation in tuberous sclerosis complex (TSC), occurring in 50%-85% of cases. Even in asymptomatic individuals, treatment is often initiated based on AML size, with mTOR inhibitors being the primary medical therapy. AMLs tend to enlarge with age, and treatment during school age is rare. Secondary AML shrinkage in paediatric TSC patients has been reported who received everolimus for subependymal giant cell astrocytomas (SEGA) or epilepsy, but studies on its direct use for AMLs in paediatric cases remain limited. A 9-year-old girl born to a mother with TSC was diagnosed at birth due to cardiac rhabdomyomas, cortical tubers, and Shagreen patches. At the age of 4, ultrasound detected multiple AMLs in both kidneys, with the largest lesions measuring 2.3 cm in the right kidney and 1.6 cm in the left. By the age of 7, MRI showed further growth to 4.8 cm. Despite the absence of symptoms, the risk of haemorrhage led to treatment initiation. Everolimus was started at 1.0 mg/day (1.3 mg/m2/day), significantly lower than the standard 4.5 mg/m2/day. Trough levels remained below the target range, yet AMLs showed a shrinking tendency, with MRI at age 9 revealing a reduction in the largest AML to 2.4 cm. Stomatitis occurred intermittently, but no serious adverse effects were observed. This case suggests that low-dose everolimus can effectively reduce AML size while minimising adverse effects, highlighting its potential as a treatment option for AMLs in paediatric TSC patients.

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption, and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic β-islet cell destruction leading to hyperglycemia and life-long insulin dependence. While prior reports have focused on CD8+ T cells, the role for CD4+ T cells in ICI-T1DM is less understood. We identify expansion of CD4+ T follicular helper (Tfh) cells expressing IL-21 and IFN-γ as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFN-γ are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFN-γ both signal through JAK/STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robust in vivo protection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4+ Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE.