BACKGROUND:Colorectal cancer (CRC) exhibits substantial metabolic heterogeneity. This study developed a robust prognostic signature integrating ferroptosis- and lipid metabolism-related genes to investigate the role of CRY2 in CRC progression. METHODS:Transcriptomic and clinical data from the TCGA-COAD and GSE39582 cohorts were analyzed. Weighted gene co-expression network analysis (WGCNA) was performed to identify disease-associated gene modules. A machine learning framework was subsequently applied to construct and optimize the prognostic model, with the combination of forward stepwise Cox regression (StepCox) and Random Survival Forest demonstrating the best predictive performance. The tumor immune microenvironment was characterized using CIBERSORT and TIDE. The biological function of CRY2 was validated through siRNA-mediated knockdown, functional assays, and a murine xenograft model. RESULTS:The ferroptosis- and lipid metabolism-related RiskScore was identified as an independent predictor of overall survival (HR > 1.1, p < 0.001). Patients in the high-risk group showed poorer overall survival and an immunosuppressive tumor microenvironment (TME) characterized by increased regulatory T cells (Tregs) and Th2 cells, reduced CD4+ T-cell infiltration, and higher TIDE scores, suggesting immunotherapy resistance. Among the signature genes, CRY2 was identified as a key regulator associated with CRC progression. In vitro, CRY2 knockdown inhibited CRC cell proliferation and migration while inducing G1-phase cell-cycle arrest. In vivo, silencing CRY2 significantly suppressed xenograft tumor growth and reduced Ki-67 expression. CONCLUSION:This study developed and validated a ferroptosis- and lipid metabolism-related prognostic signature that accurately predicts survival outcomes and immune characteristics in CRC. Furthermore, CRY2 was identified as a critical regulator of tumor growth.

Poly(ADP-ribose) polymerase inhibitors (PARPi) elicit cytotoxicity by trapping PARP1 at DNA lesions, but clinical resistance remains a major challenge. Here, we identify reversible S-palmitoylation as a negative regulator of PARP1 chromatin engagement. Mass spectrometry reveals PARP1 palmitoylation at conserved cysteines within its DNA-binding domains. DNA damage reduces PARP1 palmitoylation, enhancing DNA binding, whereas inhibition of depalmitoylases APT1/2 elevates palmitoylation and suppresses DNA binding. The palmitoyltransferase ZDHHC12 catalyzes PARP1 palmitoylation, and its inhibition, along with the blockade of palmitate synthesis or global palmitoylation, augments PARP1 trapping and sensitizes high-grade ovarian cancer (HGSOC) cells to the PARPi Niraparib. Patient-derived PARP1 variants R138C and R591C display hyper-palmitoylation, impaired trapping, and PARPi resistance through an indirect mechanism independent of palmitoylation at the mutation sites. ZDHHC12 knockdown restores PARP1 trapping and resensitizes resistant cells and xenografts to Niraparib. These findings establish ZDHHC12-mediated PARP1 palmitoylation as a targetable vulnerability to overcome PARPi resistance.

Aberrant phosphatidylinositol 3-kinase (PI3K) activation drives many cancers, but PI3K inhibitors like Pictilisib often induce cytostasis rather than cytotoxicity, limiting their therapeutic potential. Here we demonstrate that PI3K inhibition combined with nutrient stress triggers methuosis, a non-apoptotic form of programmed cell death characterized by dysregulated macropinosomes. This response occurs selectively in PI3K-aberrant cancer cells that maintain macropinocytic uptake despite PI3K inhibition. Methuosis-associated vacuoles originate from macropinosomes that retain endosomal markers but fail to undergo lysosomal fusion. Active macropinocytic uptake is essential for methuosis, as demonstrated by suppression with EIPA and Bafilomycin A1, whereas the AKT inhibitor MK2206 has no effect, establishing that direct PI3K inhibition, rather than AKT signaling, is required. Mechanistically, PI3K blockade prevents conversion of phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) to phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) causing PI(4,5)P2 to accumulate on internalizing macropinosomal membranes. This aberrant PI(4,5)P2 enrichment impairs ion channel function across multiple channel families, disrupting intracellular osmotic balance. Ion dysregulation triggers aquaporin-1-mediated water influx, driving catastrophic vacuolar expansion and cell death. Although Pictilisib activates pro-survival autophagy, this fails to prevent methuosis-mediated cytotoxicity. In xenograft models, dietary restriction synergizes with Pictilisib to suppress tumor growth, correlating with pronounced intratumoral vacuolization. These findings reveal that combining PI3K inhibition with nutrient restriction converts cytostatic responses into methuosis-driven cytotoxicity via PI(4,5)P2-dependent macropinocytic dysregulation, providing a rational pharmacologic-dietary strategy to enhance PI3K-targeted cancer efficacy.

Polycystic ovary syndrome (PCOS) is a complex gynecological endocrinological condition that significantly impacts women’s fertility during their reproductive lifespan. The causes of PCOS are multifaceted, and its pathogenesis is not yet clear. This study established a rat model of PCOS and, in conjunction with clinical samples and database data, analysed the role of claudin 11 (CLDN11) in follicular granulosa cells (GCs) in regulating the proliferation of GCs. Our findings revealed a notable decrease in the protein expression of CLDN11 within the follicular GCs of individuals with PCOS. In vitro rat cell experiments revealed that interference with CLDN11 significantly inhibited viability and increased the apoptosis of GCs. Additional research has illuminated the mechanism by which CLDN11 regulates the expression levels of CCND1 and PCNA through the PI3K/AKT signalling pathway, significantly influencing the proliferation of rat follicular GCs. Furthermore, overexpression of CLDN11 via an adeno-associated virus (AAV) vector was found to reverse the PCOS-like phenotype induced in rats by letrozole. Our findings suggest that CLDN11 stimulates the proliferation of these cells by activating the PI3K/AKT pathway, thereby increasing the expression of CCND1 and PCNA. These discoveries underscore the critical function of CLDN11 in regulating the functionality of follicular GCs, which offers novel insights into the fundamental mechanisms governing PCOS.

The gut microbiota, comprising trillions of bacteria, fungi, and viruses, exists in symbiosis with the host. As the largest microbial ecosystem in the human body. The gut microbiota not only shapes the homeostasis of the intestinal microenvironment through gut-derived metabolites but also exerts regulatory effects on the functions of diverse tissues and organs throughout the body via the intricate “gut-distal organ axis” mechanism. Short chain fatty acids, such as acetic acid, propionic acid and butyric acid are high abundance intestinal metabolites, not only influence the intestinal barrier by regulating tight junction proteins, but also affect intestinal peristalsis by regulating gap junction proteins. These microbial metabolites may also play a important role in the formation and maintenance of the key barriers of the reproductive system, such as the ovarian blood follicle barrier, the testicular blood-testis barrier, and the endometrial epithelial barrier. In reproductive system, Gap junction-mediated intercellular communication, facilitated by connexins, proves essential in germ cell maturation, embryo implantation, and spermatogenesis. The dysregulation of these microbial metabolites leading to abnormal tight junction and gap junction protein functions provides novel perspectives for understanding the pathogenesis of reproductive disorders such as polycystic ovary syndrome and premature ovarian failure. This review systematically elucidates the molecular networks through which short-chain fatty acids regulate tight and gap junction proteins, highlighting their potential roles in reproductive physiology.

Introduction Superior Vena Cava Syndrome (SVCS) is a rare but serious oncologic emergency in pediatric patients, most commonly caused by mediastinal masses such as lymphomas or leukemias. This condition results from the obstruction of the superior vena cava (SVC), leading to impaired venous return and respiratory and cardiovascular complications, progressive exacerbation in a short period, and an extremely high fatality rate. We report the case of a 12-year-old boy with SVCS caused by a mediastinal mass.Main symptoms/findings The patient presented with progressive dyspnea, orthopnea, and swelling of the head and neck. He also exhibited chest tightness, dry cough, and shortness of breath. A chest CT revealed a large anterior mediastinal mass compressing the SVC and main bronchi.Diagnosis, treatment, outcomes The patient was diagnosed with SVCS secondary to T-cell lymphoblastic lymphoma. Treatment began immediately with oxygen therapy and intravenous dexamethasone to reduce mediastinal compression. Significant clinical improvement was observed within 48 h, with a reduction in dyspnea and swelling. A biopsy confirmed T-cell lymphoblastic lymphoma and multidisciplinary care was pivotal to successful management.Conclusion Early recognition and treatment of pediatric SVCS are essential to prevent life-threatening complications. Combined with a multidisciplinary approach, corticosteroid therapy was crucial for the patient's rapid recovery. Further research is needed to optimize treatment protocols and improve outcomes for pediatric SVCS cases.

To develop an automated grading model for rectocele (RC) based on radiomics and evaluate its efficacy. This study retrospectively analyzed a total of 9,392 magnetic resonance imaging (MRI) images obtained from 222 patients who underwent dynamic magnetic resonance defecography (DMRD) over the period from August 2021 to June 2023. The focus was specifically on the defecation phase images of the DMRD, as this phase provides critical information for assessing RC. To develop and evaluate the model, the MRI images from all patients were randomly divided into two groups. 70% of the data were allocated to the training cohort to build the model, and the remaining 30% was reserved as a test cohort to evaluate its performance. First, the severity of RC was assessed using the RC MRI grading criteria by two independent radiologists. To extract and select radiomic features, two additional radiologists independently delineated the regions of interest (ROIs). These features were then dimensionality reduced to retain only the most relevant data for the analysis. The radiomics features were reduced in dimension, and a machine learning model was developed using a Support Vector Machine (SVM). Finally, receiver operating characteristic curve (ROC) and area under the curve (AUC) were used to evaluate the classification efficiency of the model. The AUC (macro/micro) of the model using defecation phase images was 0.794/0.824, and the overall accuracy was 0.754. The radiomics model built using the combination of DMRD defecation phase images is well suited for grading RC and helping clinicians diagnose and treat the disease.

Abstract Background: IL-11 is known as an inflammation-related factor, and it has been proved to be a key driver in fibrotic diseases. Besides, the roles of IL-11 in tumor immunopathology were recognized more in-depth and comprehensively in recent years. IL-11 expression is highly and positively correlated with overall survival in various cancer types, including colorectal cancer, hepatocellular carcinoma and lung cancer. It was reported that IL-11 promoted tumor cell growth and metastasis, mediated partly through its direct effects on macrophages, T cells and cancer-associated fibroblasts. All these studies indicated that blocking IL-11 signaling may be a promising therapeutic approach for the treatment of solid tumors. In this report, 9MW3811, a high-affinity IL-11 blocking antibody was developed to test its anti-tumor activity and synergistic effects with anti-PD-1 antibody in mouse tumor models. Methods: 9MW3811 was generated by mouse hybridoma technology followed by antibody humanization and affinity maturation. Affinity of 9MW3811 was measured by Octet system. Its blocking activity of IL-11/IL11Ra/gp130 protein interaction was detected by ELISA, and the inhibiting effect of IL-11-mediated signaling was assessed with a luciferase reporter cell-based assay. In vivo efficacy of 9MW3811 was tested on A549 xenograft and LUSC PDX models. ScRNA-seq data collection and computational analysis were used to investigate immune cell tumor infiltration and differentiation. The synergistic tumor-suppressing effect of 9MW3811 with anti-PD-1 antibody was evaluated in MC38, CT26 and Hepa1-6 syngeneic models. Results: 9MW3811 showed sub-nanomolar binding affinity to recombinant and membrane bound IL-11 derived from human, mouse, rat and dog. 9MW3811 effectively blocked the formation of IL-11/IL-11R/gp130 protein complex, and inhibited the downstream cell signaling transduction. In the NSCLC A549 xenograft model, as compared with isotype control hIgG, 9MW3811 (2mpk) showed significant tumor growth inhibition (TGI 62%). In two LUSC PDX models, the TGIs for 9MW3811 (10 mpk) were 50% and 28%, respectively. Further, in MC38 and Hepa1-6 syngeneic models, 9MW3811 addition increased the TGI of anti-PD-1 antibody from 45% to 83%, and 34% to 75%, respectively. Interestingly, in an anti-PD-1 non-responsive CT26 model, the combo of 9MW3811/anti-PD-1 antibody exhibited an impressive antitumor activity (TGI 67%). Mechanistic study showed that treatment with 9MW3811 could significantly ameliorate T cell exhaustion, increase CD8+ T cells tumor infiltration and enhance the cytotoxic function of these infiltrated T cells by modulating the expression of a variety of cytokines/chemokines Conclusion: Our results demonstrated profound antitumor activity of 9MW3811 in different tumor models. 9MW3811 is currently in phase I clinical trials in AU, CN and US. Citation Format: Shuang Wang, Chang Zhang, Shasha Jiao, Dadi Zeng, Rongjuan Wang, Min Wang, Weining Lu, Bin Zheng, Xun Gui, Jinchao Zhang. Disrupting IL-11/IL-11R signaling by an efficacious anti-IL-11 antibody 9MW3811 enhances T cell tumor infiltration and synergizes with anti-PD-1 therapies in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2365.

Platinum-based therapies have revolutionized the treatment of high-grade serous ovarian cancer (HGSOC). However, high rates of disease recurrence and progression remain a major clinical concern. Impaired mitochondrial function and dysregulated reactive oxygen species (ROS), hallmarks of cancer, hold potential as therapeutic targets for selectively sensitizing cisplatin treatment. Here, we uncover an oncogenic role of the palmitoyltransferase ZDHHC12 in regulating mitochondrial function and ROS homeostasis in HGSOC cells. Analysis of The Cancer Genome Atlas (TCGA) ovarian cancer data revealed significantly elevated ZDHHC12 expression, demonstrating the strongest positive association with ROS pathways among all ZDHHC enzymes. Transcriptomic analysis of independent ovarian cancer datasets and the SNU119 cell model corroborated this association, highlighting a strong link between ZDHHC12 expression and signature pathways involving mitochondrial oxidative metabolism and ROS regulation. Knockdown of ZDHHC12 disrupted this association, leading to increased cellular complexity, ATP levels, mitochondrial activity, and both mitochondrial and cellular ROS. This dysregulation, achieved by the siRNA knockdown of ZDHHC12 or treatment with the general palmitoylation inhibitor 2BP or the fatty acid synthase inhibitor C75, significantly enhanced cisplatin cytotoxicity in 2D and 3D spheroid models of HGSOC through ROS-mediated mechanisms. Markedly, ZDHHC12 inhibition significantly augmented the anti-tumor activity of cisplatin in an ovarian cancer xenograft tumor model, as well as in an ascites-derived organoid line of platinum-resistant ovarian cancer. Our data suggest the potential of ZDHHC12 as a promising target to improve the outcome of HGSOCs in response to platinum-based chemotherapy.

Colorectal cancer is one of the most common cancers worldwide, and its incidence rates are increasing every year. Treatments for CRC include surgical resection, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Although various agents have been used in the treatment of malignant tumors, they are not as effective as expected. This is primarily owing to the lack of selectivity, poor solubility, and severe side effects of most agents. It is necessary to develop more efficient drug delivery systems for the precise targeting of the tumor site and effective therapeutic effects to meet clinical needs. A hydrogel is a three-dimensional network material composed of crosslinked side chains of hydrophilic or hydrophobic groups and a polymer backbone. Hydrogels possess useful properties including high water content, adjustable physical characteristics, elasticity, flexibility, reversible swelling, and multifunctionality. These properties render them ideal biomaterials with a broad range of applications in biomedicine and bioengineering. In this review, we introduce the pathophysiology and current therapeutic advances in CRC and summarize the applications of hydrogels composed of different materials as well as smart response hydrogels as drug carriers in CRC treatment. We also analyze the unique advantages and challenges of using hydrogels as targeted drug delivery carriers in tumor therapy.

S-nitrosylation (SNO) modification, a nitric oxide (NO)-mediated post-translational modification (PTM) of proteins, plays an important role in protein microstructure, degradation, activity, and stability. Due to the presence of reducing agents, the SNO modification process mediated by NO derivatives is often reversible and unstable. This reversible transformation between SNO modification and denitrification often influences the structure, activity, and function of proteins. The reversibility of SNO modifications also poses a challenge when verifying changes in the biological functions of proteins. Moreover, SNO modification of key signaling pathway proteins, such as caspase-3, NF-κB, and Bcl-2, can affect tumor proliferation, invasion, and apoptosis. The SNO-modified proteins play important roles in both promoting and inhibiting cancer, which indirectly confirms the duality and complexity of SNO modification functions. This article reviews the biological significance of various SNO-modified proteins in different cancers, providing a theoretical basis for determining whether the related changes of SNO-modified proteins are universal in cancers. Additionally, this review presents a comprehensive and detailed summary of the evolution of detection methods for SNO-modified proteins, providing a possible methodological basis for future research on SNO-modified proteins.

Background: Patients with locally advanced rectal cancer (LARC) treated with surgery have a high risk of local recurrence. Intraoperative radiotherapy (IORT) is a promising method for treating locally advanced solid tumors, but there is limited research on the efficacy of IORT in treating LARC. This study aimed to evaluate the long-term efficacy of low-kV X-ray IORT in the treatment of LARC. Methods: In total, 69 LARC patients with stage tumor3-4node0-2metastasis0 (T3-4N0-2M0) treated with radical resection and low-kV X-ray IORT at our center from December 2015 to August 2023 were consecutively included in this retrospective cohort study. Basic patient characteristics, intraoperative and postoperative data, and early and late complications were recorded. A Kaplan-Meier (K-M) survival analysis was performed to analyze the overall survival (OS) and disease-free survival (DFS) of the patients. Results: In total, 69 patients (median age, 64 years; 69.6% male) were enrolled in the study, and the median follow-up time was 47.5 months (range, 6.5-98.5 months). At the time of analysis, 15 patients had died (21.74%), 6 patients (8.70%) had been lost to follow-up, and 48 patients (69.57%) were alive. The 3-year OS and DFS rates were 89.42% and 71.47%, respectively. The local recurrence rate was 26.09%, and the 5-year local control, OS, and DFS rates were 78.90%, 68.59%, and 66.91%, respectively. The T stage of tumors was not predictive of either OS or DFS (P>0.05). However, different N stages and nerve/vascular invasion were found to be positively correlated with OS and DFS (P<0.05). Mortality within 30 days post-surgery was 0%. Early complications included anastomotic leak (5 cases, 7.25%), urinary retention (4 cases, 5.80%), diarrhea (7 cases, 10.14%), and bowel obstruction (4 cases, 5.80%), all of which were cured by conservative 2.90%), sexual dysfunction (5 cases, 7.24%), and bowel obstruction (6 cases, 8.70%). Conclusions: Our findings suggest that low-kV X-ray IORT enhances local control and survival in LARC patients. Further research should be conducted in larger, prospective trials.

Castleman disease (CD), also known as giant lymph node hyperplasia or angiofollicular lymph node hyperplasia, is a rare and indeterminate group of chronic lymphoproliferative disorders. CD is highly heterogeneous, classified into unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD) based on lesion distribution, and further categorized into three pathological types: hyaline vascular type (HV), plasma cell type (PC), and mixed type (Mix). This paper describes a rare case of solitary mediastinal Castleman disease with transparent vessels in the anterior sacrum, presenting as the HV type. Surgical excision of the mass was performed following coccygectomy for treatment. The patient recovered well postoperatively. During a 6-month follow-up period, there were no signs of recurrence, and the patient’s quality of life significantly improved.

Polycystic ovarian syndrome (PCOS) is a common heterogeneous reproductive endocrine metabolic disorder in women of reproductive age characterized by clinical and biochemical hyperandrogenemia, ovulation disorders, and polycystic ovarian morphology. Ferroptosis is a novel type of cell death driven by iron accumulation and lipid peroxidation. Ferroptosis plays a role in maintaining redox balance, iron metabolism, lipid metabolism, amino acid metabolism, mitochondrial activity, and many other signaling pathways linked to diseases. Iron overload is closely related to insulin resistance, decreased glucose tolerance, and the occurrence of diabetes mellitus. There is limited research on the role of ferroptosis in PCOS. Patients with PCOS have elevated levels of ferritin and increased reactive oxygen species in ovarian GCs. Studying ferroptosis in PCOS patients is highly important for achieving personalized treatment. This article reviews the progress of research on ferroptosis in PCOS, introduces the potential connections between iron metabolism abnormalities and oxidative stress-mediated PCOS, and provides a theoretical basis for diagnosing and treating PCOS.

Despite the initial efficacy of enzalutamide in castration-resistant prostate cancer (CRPC), inevitable resistance remains a significant challenge. Here, the synergistic induction of copper-dependent cell death (cuproptosis) in CRPC cells is reported by enzalutamide and copper ionophores (elesclomol/disulfiram). Mechanistically, enzalutamide treatment increases mitochondrial dependence in CRPC cells, rendering them susceptible to cuproptosis, as evidenced by specific reversal with the copper chelator tetrathiomolybdate. This susceptibility is characterized by hallmarks of cuproptosis, including lipoylated protein aggregation and iron-sulfur cluster protein instability. Interestingly, the mitochondrial matrix reductase, FDX1, specifically correlates with elesclomol sensitivity, suggesting a potential mechanistic divergence between the two copper ionophores. Notably, this synergistic effect extends beyond in vitro models, demonstrating efficacy in 22Rv1 xenografts, mouse Pten p53 knockout organoids. Importantly, enzalutamide significantly enhances copper ionophore-mediated cytotoxicity in enzalutamide-resistant cells. Collectively, these findings indicate that enzalutamide and copper ionophores synergistically induce cuproptosis, offering a promising therapeutic avenue for CRPC, potentially including enzalutamide-resistant cases.

Bleeding caused by trauma or surgery is a serious health problem, and uncontrollable bleeding can result in death. Therefore, developing safe, effective, and convenient hemostatic materials is important. Active hemostatic agents currently used to investigate the field of hemostasis are divided into four broad categories: natural polymers, synthetic polymers, inorganic materials, and metal-containing materials. Hemostatic materials are prepared in various forms for wound care applications based on the active ingredients used. These materials include nanofibers, gels, sponges, and nanoparticles. Hemostatic materials find their applications in the field of wound care, and they are also used for hemostasis during malignant tumor surgery. Prompt and effective hemostasis can reduce the possibility of the spread of tumor cells with blood. This review discusses the outcomes of current research conducted in the field and the problems persisting in the field of developing hemostatic materials. The review also presents a platform for the further development of hemostatic materials. Bleeding caused by trauma or surgery is a serious health problem, and uncontrollable bleeding can result in death. Therefore, developing safe, effective, and convenient hemostatic materials is important. Active hemostatic agents currently used to investigate the field of hemostasis are divided into four broad categories: natural polymers, synthetic polymers, inorganic materials, and metal-containing materials. Hemostatic materials are prepared in various forms for wound care applications based on the active ingredients used. These materials include nanofibers, gels, sponges, and nanoparticles. Hemostatic materials find their applications in the field of wound care, and they are also used for hemostasis during malignant tumor surgery. Prompt and effective hemostasis can reduce the possibility of the spread of tumor cells with blood. This review discusses the outcomes of current research conducted in the field and the problems persisting in the field of developing hemostatic materials. The review also presents a platform for the further development of hemostatic materials.