Deciphering fatty acid biosynthesis-driven molecular subtypes in pancreatic ductal adenocarcinoma with prognostic insights.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to its high heterogeneity and aggressiveness. Recognizing the urgency to delineate molecular subtypes, our study focused on the emerging field of lipid metabolism remodeling in PDAC, particularly exploring the prognostic potential and molecular classification associated with fatty acid biosynthesis. METHODS: Gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA) were performed to evaluate the dysregulation of lipid metabolism in PDAC. Univariate cox analysis and the LASSO module were used to build a prognostic risk score signature. The distinction of gene expression in different risk groups was explored by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The biological function of Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5), a pivotal gene within 7-hub gene signature panel, was validated through in vitro assays. RESULTS: Our study identified a 7-hub gene signature associated with fatty acid biosynthesis-related genes (FRGs), providing a robust tool for prognosis prediction. The high-FRGs score group displayed a poorer prognosis, decreased immune cell infiltration, and a higher tumor mutation burden. Interestingly, this group exhibited enhanced responsiveness to various compounds according to the Genomics of Drug Sensitivity in Cancer (GDSC) database. Notably, ACSL5 was upregulated in PDAC and essential for tumor progression. CONCLUSION: In conclusion, our research defined two novel fatty acid biosynthesis-based subtypes in PDAC, characterized by distinct transcriptional profiles. These subtypes not only served as prognostic indicator, but also offered valuable insights into their metastatic propensity and therapeutic potential.

Hybridizing carbonate and ether at molecular scales for high-energy and high-safety lithium metal batteries.

Commonly-used ether and carbonate electrolytes show distinct advantages in active lithium-metal anode and high-voltage cathode, respectively. While these complementary characteristics hold promise for energy-dense lithium metal batteries, such synergy cannot be realized solely through physical blending. Herein, a linear functionalized solvent, bis(2-methoxyethyl) carbonate (BMC), is conceived by intramolecularly hybridizing ethers and carbonates. The integration of the electron-donating ether group with the electron-withdrawing carbonate group can rationalizes the charge distribution, imparting BMC with notable oxidative/reductive stability and relatively weak solvation ability. Furthermore, BMC also offers advantages including the ability to slightly dissolve LiNO3, excellent thermostability and nonflammability. Consequently, the optimized BMC-based electrolyte, even with typical concentrations in the single solvent, demonstrates high-voltage tolerance (4.4 V) and impressive Li plating/stripping Coulombic efficiency (99.4%). Moreover, it fulfills practical lithium metal batteries with satisfactory cycling performance and exceptional tolerance towards thermal/mechanical abuse, showcasing its suitability for safe high-energy lithium metal batteries.

Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells.

Safety and efficacy of radiotherapy combined with chemotherapy for recurrent metastatic renal pelvic and ureteral carcinoma.

PURPOSE: To retrospectively investigate the safety and efficacy of radiotherapy combined with chemotherapy for recurrent metastatic renal pelvic and ureteral carcinoma. METHODS: 109 patients were enrolled in this study, including 44 patients in the radiochemotherapy group and 65 patients in the chemotherapy group. Propensity score matching (PSM) was used to balance the baseline characteristics of the two groups by 1:1 matching. Kaplan-Meier method was used to calculate PFS and OS. Cox regression model was used for multivariate analysis. The side effects were evaluated by CTCAE v5.0 RESULTS: The median follow-up time was 14.5 months. Multivariate analysis showed that radiotherapy was a good independent prognostic factor for OS (HR: 0.327, 95% CI 0.157-0.680, P = 0.003). After matching, there were 40 patients in both groups, and the median PFS and OS in the radiochemotherapy group were longer than those in the chemotherapy group (PFS: 10.4 vs. 6.7 months, P = 0.035; OS: 43.5 vs. 18.8 months, P < 0.001). In addition, in the radiochemotherapy group, patients treated with radiotherapy before first-line chemotherapy failure had a longer PFS than those treated with radiotherapy after chemotherapy failure (median PFS: 15.7 vs. 6 months, P = 0.003). There was no significant difference in the incidence of grade 3-4 toxicities between the two groups (52.3% vs. 50.8%, P = 0.878). CONCLUSION: For patients with recurrent metastatic renal pelvic and ureteral carcinoma, radiotherapy combined with chemotherapy is well tolerable and expected to bring long-term survival benefits, and the benefits of early interventional radiotherapy may be more obvious.

Biomarkers for Prostate Cancer: From Diagnosis to Treatment.

Prostate cancer (PCa) is a widespread malignancy with global significance, which substantially affects cancer-related mortality. Its spectrum varies widely, from slow-progressing cases to aggressive or even lethal forms. Effective patient stratification into risk groups is crucial to therapeutic decisions and clinical trials. This review examines a wide range of diagnostic and prognostic biomarkers, several of which are integrated into clinical guidelines, such as the PHI, the 4K score, PCA3, Decipher, and Prolaris. It also explores the emergence of novel biomarkers supported by robust preclinical evidence, including urinary miRNAs and isoprostanes. Genetic alterations frequently identified in PCa, including BRCA1/BRCA2, ETS gene fusions, and AR changes, are also discussed, offering insights into risk assessment and precision treatment strategies. By evaluating the latest developments and applications of PCa biomarkers, this review contributes to an enhanced understanding of their role in disease management.

Molecular and functional characterization of viperin in golden pompano, Trachinotus ovatus.

The radical S-adenosyl methionine domain-containing protein 2 (RSAD2), also known as viperin, plays a momentous and multifaceted role in antiviral immunity. However, the function of viperin is uninvestigated in golden pompano, Trachinotus ovatus. In the present study, a viperin homolog, named To-viperin, was cloned and characterized from golden pompano, and its role in response to grouper iridovirus (SGIV) and nervous necrosis virus (NNV) infection was investigated. The whole open reading frame (ORF) of To-viperin was composed of 1050 bp and encoded a polypeptide of 349 amino acids with 70.66%-83.51% identity with the known viperin homologs from other fish species. A variable N-terminal domain, a highly conserved C-terminal domain, and a conserved middle radical SAM domain (aa 61-271) with the three-cysteine motif CxxCxxC was found in To-viperin sequence. Expression analysis showed that To-viperin was constitutively expressed in all tested organs and was located mainly in the ER of golden pompano cells. Treatments with SGIV, poly I: C, or NNV could induce the up-regulation of viperin to varying degrees. The ectopic expression of To-viperin in vitro significantly reduced the viral titer of SGIV and NNV. Furthermore, To-viperin overexpression enhanced the expression of IFNc, IRF3, and ISG15 genes as well as, to a lesser extent, the IL-6 gene. In summary, our results suggested that the function of viperin is likely to be conserved in fish specise, as observed in other vertebrates, shedding light on the evolutionary conservation of viperin.

Toward function starch nanogels by self-assembly of polysaccharide and protein: From synthesis to potential for polyphenol delivery.

Nanogels formed by self-assembly of natural proteins and polysaccharides have attracted great interest as potential carriers of bioactive molecules. Herein, we reported that carboxymethyl starch-lysozyme nanogels (CMS-Ly NGs) were prepared using carboxymethyl starch and lysozyme by green and facile electrostatic self-assembly, and the nanogels served as epigallocatechin gallate (EGCG) delivery systems. The dimensions and structure of the prepared starch-based nanogels (i.e., CMS-Ly NGs) were characterized by dynamic light scattering (DLS), ζ-potential, Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and thermal gravimetric analyzer (TGA). FT-IR and 1H NMR spectra together confirmed the formation of CMS; FT-IR spectra confirmed the formation of CMS-Ly NGs; XRD spectra confirmed the disruption of the crystal structure of lysozyme after electrostatic self-assembly with CMS, and further confirmed the formation of nanogels. TGA demonstrated the thermal stability of nanogels. More importantly, the nanogels showed a high EGCG encapsulation rate of 80.0 ± 1.4 %. The CMS-Ly NGs encapsulated with EGCG exhibited regular spherical structure and stable particle size. Under the simulated gastrointestinal environmental conditions, CMS-Ly NGs encapsulated with EGCG showed the controlled release potential, which increased its utilization. Additionally, anthocyanins can also be encapsulated in CMS-Ly NGs and showed slow-release properties during gastrointestinal digestion in the same way. Cytotoxicity assay also demonstrated good biocompatibility between CMS-Ly NGs and CMS-Ly NGs encapsulated with EGCG. The findings of this research suggested the potential application of protein and polysaccharides-based nanogels in the delivery system of bioactive compounds.

Crafting a Personalized Prognostic Model for Malignant Prostate Cancer Patients Using Risk Gene Signatures Discovered through TCGA-PRAD Mining, Machine Learning, and Single-Cell RNA-Sequencing.

BACKGROUND: Prostate cancer is a significant clinical issue, particularly for high Gleason score (GS) malignancy patients. Our study aimed to engineer and validate a risk model based on the profiles of high-GS PCa patients for early identification and the prediction of prognosis. METHODS: We conducted differential gene expression analysis on patient samples from The Cancer Genome Atlas (TCGA) and enriched our understanding of gene functions. Using the least absolute selection and shrinkage operator (LASSO) regression, we established a risk model and validated it using an independent dataset from the International Cancer Genome Consortium (ICGC). Clinical variables were incorporated into a nomogram to predict overall survival (OS), and machine learning was used to explore the risk factor characteristics' impact on PCa prognosis. Our prognostic model was confirmed using various databases, including single-cell RNA-sequencing datasets (scRNA-seq), the Cancer Cell Line Encyclopedia (CCLE), PCa cell lines, and tumor tissues. RESULTS: We identified 83 differentially expressed genes (DEGs). Furthermore, WASIR1, KRTAP5-1, TLX1, KIF4A, and IQGAP3 were determined to be significant risk factors for OS and progression-free survival (PFS). Based on these five risk factors, we developed a risk model and nomogram for predicting OS and PFS, with a C-index of 0.823 (95% CI, 0.766-0.881) and a 10-year area under the curve (AUC) value of 0.788 (95% CI, 0.633-0.943). Additionally, the 3-year AUC was 0.759 when validating using ICGC. KRTAP5-1 and WASIR1 were found to be the most influential prognosis factors when using the optimized machine learning model. Finally, the established model was interrelated with immune cell infiltration, and the signals were found to be differentially expressed in PCa cells when using scRNA-seq datasets and tissues. CONCLUSIONS: We engineered an original and novel prognostic model based on five gene signatures through TCGA and machine learning, providing new insights into the risk of scarification and survival prediction for PCa patients in clinical practice.

Uncovering the Secrets of Prostate Cancer's Radiotherapy Resistance: Advances in Mechanism Research.

Prostate cancer (PCa) is a critical global public health issue with its incidence on the rise. Radiation therapy holds a primary role in PCa treatment; however, radiation resistance has become increasingly challenging as we uncover more about PCa's pathogenesis. Our review aims to investigate the multifaceted mechanisms underlying radiation therapy resistance in PCa. Specifically, we will examine how various factors, such as cell cycle regulation, DNA damage repair, hypoxic conditions, oxidative stress, testosterone levels, epithelial-mesenchymal transition, and tumor stem cells, contribute to radiation therapy resistance. By exploring these mechanisms, we hope to offer new insights and directions towards overcoming the challenges of radiation therapy resistance in PCa. This can also provide a theoretical basis for the clinical application of novel ultra-high-dose-rate (FLASH) radiotherapy in the era of PCa.

Supramolecularly Engineered Reporters with Superoxide Anion-Triggered Chemiluminescence for Early Diagnosis and Efficient Amelioration of Acute Kidney Injury.

We report the "water-in-oil-in-water" preparation of kidney injury molecule-1-targeting supramolecular chemiluminescence (CL) reporters (PCCS), consisting of L-serine-modified poly(lactic-co-glycolic) acid (PLGA)-encapsulated peroxyoxalate (CPPO), chlorin e6 (Ce6) and superoxide dismutase (SOD), for early diagnosis and amelioration of acute kidney injury (AKI). In this system, O2 ⋅- , a biomarker of AKI, triggers the oxidation of CPPO to 1,2-dioxetanedione and subsequent CL emission via CL resonance energy transfer to Ce6. The L-serine-modified PLGA stabilizes CPPO and Ce6 via noncovalent interactions, promoting long-lived CL (half-lives: ≈1000 s). Transcriptomics analysis shows that PCCS reporters reduce the inflammatory response through glutathione metabolism and inhibition of the tumor necrosis factor signaling pathway. The reporters are able to non-invasively detect AKI at least 12 h earlier than current assays, and their antioxidant properties allow simultaneous treatment of AKI.

Genome-wide analysis of RNA-binding proteins co-expression with alternative splicing events in mitral valve prolapse.

Objectives: We investigated the role and molecular mechanisms of RNA-binding proteins (RBPs) and their regulated alternative splicing events (RASEs) in the pathogenesis of mitral valve prolapse (MVP). Methods: For RNA extraction, we obtained peripheral blood mononuclear cells (PBMCs) from five patients with MVP, with or without chordae tendineae rupture, and five healthy individuals. High-throughput sequencing was used for RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) analysis, alternative splicing (AS) analysis, functional enrichment analysis, co-expression of RBPs, and alternative splicing events (ASEs) analysis were conducted. Results: The MVP patients exhibited 306 up-regulated genes and 198 down-regulated genes. All down- and up-regulated genes were enriched in both Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Furthermore, MVP was closely associated with the top 10 enriched terms and pathways. In MVP patients, 2,288 RASEs were found to be significantly different, and four suitable RASEs (CARD11 A3ss, RBM5 ES, NCF1 A5SS, and DAXX A3ss) were tested. We identified 13 RNA-binding proteins (RBPs) from the DEGs and screened out four RBPs (ZFP36, HSPA1A, TRIM21, and P2RX7). We selected four RASEs based on the co-expression analyses of RBPs and RASEs, including exon skipping (ES) of DEDD2, alternative 3' splice site (A3SS) of ETV6, mutually exclusive 3'UTRs (3pMXE) of TNFAIP8L2, and A3SS of HLA-B. Furthermore, the selected four RBPs and four RASEs were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and showed high consistency with RNA sequencing (RNA-seq). Conclusion: Dysregulated RBPs and their associated RASEs may play regulatory roles in MVP development and may therefore be used as therapeutic targets in the future.

The diverse pancreatic tumor cell-intrinsic response to IFNγ is determined by epigenetic heterogeneity.

IFNγ signaling is mainly mediated through the activation of the canonical JAK-STAT signaling pathway, transcription factors, and epigenetic modifications. The activation of IFNγ signaling pathway may provide a novel option for tumor immunotherapy, but the outcomes remain controversial. In fact, recent studies suggest that the resistance to IFNγ-dependent immunotherapies is commonly derived from the tumor cell-intrinsic heterogeneity, the molecular mechanism of which remains elusive. Therefore, elucidating the tumor cell-intrinsic heterogeneity in response to IFNγ would be beneficial to improve the efficacy of immunotherapy. Here, we first delineated the epigenetic redistribution and transcriptome alteration in response to IFNγ stimulation, and demonstrated that ectopic gain of H3K4me3 and H3K27Ac at the promoter region mainly contributed to the enhancement of IFNγ-mediated transcriptional activity of interferon-stimulated genes (ISGs). Furthermore, we found that the cellular heterogeneity of PD-L1 expression in response to IFNγ was mainly attributed to cell-intrinsic H3K27me3 levels. Enhancement of H3K27me3 by GSK-J4 limited PD-L1hi tumor growth by salvaging the intratumoral cytotoxicity of CD8+ T cells, which may provide therapeutic strategies to overcome immune escape and resistance to IFNγ-based immunotherapies in pancreatic cancer.

Antisense Oligonucleotides Selectively Enter Human-Derived Antibiotic-Resistant Bacteria through Bacterial-Specific ATP-Binding Cassette Sugar Transporter.

Current vehicles used to deliver antisense oligonucleotides (ASOs) cannot distinguish between bacterial and mammalian cells, greatly hindering the preclinical or clinical treatment of bacterial infections, especially those caused by antibiotic-resistant bacteria. Herein, bacteria-specific ATP-binding cassette (ABC) sugar transporters are leveraged to selectively internalize ASOs by hitchhiking them on α (1-4)-glucosidically linked glucose polymers. Compared with their cell-penetrating peptide counterparts, which are non-specifically engulfed by mammalian and bacterial cells, the presented therapeutics consisting of glucose polymer and antisense peptide nucleic-acid-modified nanoparticles are selectively internalized into the human-derived multidrug-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus, and they display a much higher uptake rate (i.e., 51.6%). The developed strategy allows specific and efficient killing of nearly 100% of the antibiotic-resistant bacteria. Its significant curative efficacy against bacterial keratitis and endophthalmitis is also shown. This strategy will expand the focus of antisense technology to include bacterial cells other than mammalian cells.

Diagnosis and surgical management strategy for pediatric small bowel obstruction: Experience from a single medical center.

Identifying Bowel strangulation and the approach and timing of surgical intervention for pediatric SBO are still uncertain. In this study, 75 consecutive pediatric patients with surgically confirmed SBO were retrospectively reviewed. The patients were divided into group 1 (n = 48) and group 2 (n = 27) according to the presence of reversible or irreversible bowel ischemia, which was analyzed based on the degree of ischemia at the time of operation. The results demonstrated that the proportion of patients with no prior abdominopelvic surgery was higher, the serum albumin level was lower, and the proportion of patients in which ascites were detected by ultrasonography was higher in group 2 than that in group 1. The serum albumin level was negatively correlated with ultrasonographic findings of the fluid sonolucent area in group 2. There were significant differences in the choice of surgical approach between group 1 and group 2. A symptom duration of >48 h was associated with an increased bowel resection rate. The mean length of hospital stay was shorter in group 1 than that in group 2. In conclusion, immediate surgical intervention should be considered in patients with a symptom duration of >48 h or the presence of free ascites between dilated small bowel loops on ultrasonography. Laparoscopic exploration is recommended as first-line treatment in patients with stable status.

Asymmetric figure-of-eight single-layer suture technique for intestinal anastomosis: A preliminary study.

Background: Anastomotic leakage is a life-threatening complication. Improvement of the anastomosis technique is needed, especially in patients with an inflamed edematous intestine. The aim of our study was to evaluate the safety and efficacy of an asymmetric figure-of-eight single-layer suture technique for intestinal anastomosis in pediatric patients. Methods: A total of 23 patients underwent intestinal anastomosis at the Department of Pediatric Surgery of Binzhou Medical University Hospital. Demographic characteristics, laboratory parameters, anastomosis time, duration of nasogastric tube placement, day of first postoperative bowel movement, complications, and length of hospital stay were statistically analyzed. The follow-up was conducted for 3-6 months after discharge. Results: Patients were divided into two groups: the single-layer asymmetric figure-of-eight suture technique (group 1) and the traditional suture technique (group 2). Body mass index in group 1 was lower than in group 2 (14.43 ± 3.23 vs. 19.38 ± 6.74; P = 0.036). The mean intestine anastomosis time in group 1 (18.83 ± 0.83 min) was less than that in group 2 (22.70 ± 4.11 min; P = 0.005). Patients in group 1 had an earlier first postoperative bowel movement (2.17 ± 0.72 vs. 2.80 ± 0.42; P = 0.023). The duration of nasogastric tube placement in group 1 was shorter than that in group 2 (4.12 ± 1.42 vs. 5.60 ± 1.57; P = 0.043). There was no significant difference in laboratory variables, complication occurrence, and length of hospital stay between the two groups. Conclusion: The asymmetric figure-of-eight single-layer suture technique for intestinal anastomosis was feasible and effective. More studies are needed to compare the novel technique with the traditional single-layer suture.

A computational framework of routine test data for the cost-effective chronic disease prediction.

Chronic diseases, because of insidious onset and long latent period, have become the major global disease burden. However, the current chronic disease diagnosis methods based on genetic markers or imaging analysis are challenging to promote completely due to high costs and cannot reach universality and popularization. This study analyzed massive data from routine blood and biochemical test of 32 448 patients and developed a novel framework for cost-effective chronic disease prediction with high accuracy (AUC 87.32%). Based on the best-performing XGBoost algorithm, 20 classification models were further constructed for 17 types of chronic diseases, including 9 types of cancers, 5 types of cardiovascular diseases and 3 types of mental illness. The highest accuracy of the model was 90.13% for cardia cancer, and the lowest was 76.38% for rectal cancer. The model interpretation with the SHAP algorithm showed that CREA, R-CV, GLU and NEUT% might be important indices to identify the most chronic diseases. PDW and R-CV are also discovered to be crucial indices in classifying the three types of chronic diseases (cardiovascular disease, cancer and mental illness). In addition, R-CV has a higher specificity for cancer, ALP for cardiovascular disease and GLU for mental illness. The association between chronic diseases was further revealed. At last, we build a user-friendly explainable machine-learning-based clinical decision support system (DisPioneer: http://bioinfor.imu.edu.cn/dispioneer) to assist in predicting, classifying and treating chronic diseases. This cost-effective work with simple blood tests will benefit more people and motivate clinical implementation and further investigation of chronic diseases prevention and surveillance program.

Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation.

Emerging evidence shows that the biomechanical environment is required to support cancer stem cells (CSCs), which play a crucial role in drug resistance. However, how mechanotransduction signals regulate CSCs and its clinical significance has remained unclear. Using clinical-practice ultrasound elastography for patients' lesions and atomic force microscopy for surgical samples, we reveal that increased matrix stiffness is associated with poor responses to neoadjuvant chemotherapy, worse prognosis, and CSC enrichment in patients with breast cancer. Mechanically, TAZ activated by biomechanics enhances CSC properties via phase separation with NANOG. TAZ-NANOG phase separation, which is dependent on acidic residues in the N-terminal activation domain of NANOG, promotes the transcription of SOX2 and OCT4. Therapeutically, targeting NANOG or TAZ reduces CSCs and enhances the chemosensitivity in vivo. Collectively, this study demonstrated that the phase separation of a pluripotency transcription factor links mechanical cues in the niche to the fate of CSCs.

The regulatory roles of DDIT4 in TDCIPP-induced autophagy and apoptosis in PC12 cells.

Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a commonly used organophosphate-based flame retardant and can bio-accumulate in human tissues and organs. As its structure is similar to that of neurotoxic organophosphate pesticides, the neurotoxicity of TDCIPP has raised widespread concerns. TDCIPP can increase neuronal apoptosis and induce autophagy. However, its regulatory mechanism remains unclear. In this study, we found that the expression upregulation of the DNA Damage-Inducible Transcript 4 (DDIT4) protein, which might play essential roles in TDCIPP-induced neuronal autophagy and apoptosis, was observed in TDCIPP-treated differentiated rat PC12 cells. Furthermore, we determined the protective effect of the DDIT4 suppression on the autophagy and apoptosis induced by TDCIPP using Western blot (WB) and Flow cytometry (FACS) analysis. We observed that TDCIPP treatment increased the DDIT4, the autophagy marker Beclin-1, and the microtubule-associated protein light chain 3-II (LC3II) expressions and decreased the mTOR phosphorylation levels. Conversely, the suppression of DDIT4 expression increased the p-mTOR expression and decreased cell autophagy and apoptosis. Collectively, our results revealed the function of DDIT4 in cell death mechanisms triggered by TDCIPP through the mTOR signaling axis in differentiated PC12 cells. Thus, this study provided vital evidence necessary to explain the mechanism of TDCIPP-induced neurotoxicity in differentiated PC12 cells.

Tumor Cell-Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis.

Genetic and epigenetic alterations play central roles in shaping the immunosuppressive tumor microenvironment (TME) to evade immune surveillance. The previous study shows that SETD2-H3K36me3 loss promotes KRAS-induced pancreatic tumorigenesis. However, little is known about its role in remodeling the TME and immune evasion. Here, it is shown that SETD2 deficiency can reprogram neutrophils to an immunosuppressive phenotype, thereby promoting immune escape during pancreatic tumor progression. By comprehensive profiling of the intratumoral immune cells, neutrophils are identified as the subset with the most significant changes upon Setd2 loss. Setd2-deficient pancreatic tumor cells directly enhance neutrophil recruitment and reprogramming, thereby inhibiting the cytotoxicity of CD8+ T cells to foster tumor progression. Mechanistically, it is revealed that Setd2-H3K36me3 loss leads to ectopic gain of H3K27me3 to downregulate Cxadr expression, which boosts the PI3K-AKT pathway and excessive expression of CXCL1 and GM-CSF, thereby promoting neutrophil recruitment and reprogramming toward an immunosuppressive phenotype. The study provides mechanistic insights into how tumor cell-intrinsic Setd2 deficiency strengthens the immune escape during pancreatic tumorigenesis, which may offer potential therapeutic implications for pancreatic cancer patients with SETD2 deficiency.