Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan-To-Phenylalanine Substitutants in EBV-Positive Gastric Cancer.

Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon-γ (IFN-γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine-2,3-dioxygenase (IDO)- kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan-to-phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV-positive GC continuously secreted IFN-γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV-positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV-positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti-tumor immunotherapy.

Integration of STING activation and COX-2 inhibition via steric-hindrance effect tuned nanoreactors for cancer chemoimmunotherapy.

Integrating immunotherapy with nanomaterials-based chemotherapy presents a promising avenue for amplifying antitumor outcomes. Nevertheless, the suppressive tumor immune microenvironment (TIME) and the upregulation of cyclooxygenase-2 (COX-2) induced by chemotherapy can hinder the efficacy of the chemoimmunotherapy. This study presents a TIME-reshaping strategy by developing a steric-hindrance effect tuned zinc-based metal-organic framework (MOF), designated as CZFNPs. This nanoreactor is engineered by in situ loading of the COX-2 inhibitor, C-phycocyanin (CPC), into the framework building blocks, while simultaneously weakening the stability of the MOF. Consequently, CZFNPs achieve rapid pH-responsive release of zinc ions (Zn2+) and CPC upon specific transport to tumor cells overexpressing folate receptors. Accordingly, Zn2+ can induce reactive oxygen species (ROS)-mediated cytotoxicity therapy while synchronize with mitochondrial DNA (mtDNA) release, which stimulates mtDNA/cGAS-STING pathway-mediated innate immunity. The CPC suppresses the chemotherapy-induced overexpression of COX-2, thus cooperatively reprogramming the suppressive TIME and boosting the antitumor immune response. In xenograft tumor models, the CZFNPs system effectively modulates STING and COX-2 expression, converting "cold" tumors into "hot" tumors, thereby resulting in ≈ 4-fold tumor regression relative to ZIF-8 treatment alone. This approach offers a potent strategy for enhancing the efficacy of combined nanomaterial-based chemotherapy and immunotherapy.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

LncRNA DYNLRB2-AS1 promotes gemcitabine resistance of nasopharyngeal carcinoma by inhibiting the ubiquitination degradation of DHX9 protein.

Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.

PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma.

Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.

Correction: Zhao et al. Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN). Cells 2020, 9, 559.

In the original publication [...].

Tumor-associated macrophage enhances PD-L1-mediated immune escape of bladder cancer through PKM2 dimer-STAT3 complex nuclear translocation.

Tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME) and strongly associated with poor prognosis and drug resistance, including checkpoint blockade immunotherapy in solid tumor patients. However, the mechanism by which TAM affects immune metabolism reprogramming and immune checkpoint signalling pathway in the TME remains elusive. In this study we found that transforming growth factor-beta (TGF-ß) secreted by M2-TAMs increased the level of glycolysis in bladder cancer (BLCA) and played important role in PD-L1-mediated immune evasion through pyruvate kinase isoenzymes M2 (PKM2). Mechanistically, TGF-ß promoted high expression of PKM2 by promoting the nuclear translocation of PKM2 dimer in conjunction with phosphorylated signal transducer and activator of transcription (p-STAT3), which then exerted its kinase activity to promote PD-L1 expression in BLCA. Moreover, SB-431542 (TGF-ß blocker) and shikonin (PKM2 inhibitor) significantly reduced PD-L1 expression and inhibited BLCA growth and organoids by enhancing anti-tumor immune responses. In conclusion, M2-TAM-derived TGF-ß promotes PD-L1-mediated immune evasion in BLCA by increasing the PKM2 dimer-STAT3 complex nuclear translocation. Combined blockade of the TGF-ß receptor and inhibition of PKM2 effectively prevent BLCA progression and immunosuppression, providing a potential targeted therapeutic strategy for BLCA.

Microtubule interacting and trafficking domain containing 1 deficiency leads to poor survival via tissue factor-mediated coagulation in bladder cancer.

BACKGROUND: Patients with cancer are at an increased risk of developing a hypercoagulative phenotype and venous thromboembolism. However, no clinical trial has yet confirmed that anticoagulant therapy improves cancer prognosis, and the mechanism underlying hypercoagulation in patients with bladder cancer is not well understood. OBJECTIVES: We hypothesized that the prognostic genes affect tumor progression via tumor-mediated coagulation. METHODS: We detected the most significant prognostic genes of bladder cancer with The Cancer Genome Atlas dataset and validated them in 2 Gene Expression Omnibus datasets and 1 ArrayExpress dataset. Immunohistochemical tests were performed on a cohort of 80 individuals to further examine the prognostic genes. For the most reliable prognostic gene, its influence on coagulation was evaluated with gene knockdown followed by next-generation sequencing and cellular and animal experiments. RESULTS: Depletion of microtubule interacting and trafficking domain containing 1 (MITD1), a major prognostic gene of bladder cancer, significantly increased the tissue factor (TF) expression. MITD1 deficiency led to cytokinesis arrest, which, in turn, promoted the TF expression via unfolded protein response and c-Jun. The knockdown of IRE1, an essential kinase of unfolded protein response or the inactivation of c-Jun using c-Jun N-terminal kinase inhibitors weakened MITD1 deficiency- or dithiothreitol-induced TF upregulation. Cells lacking MITD1 promoted coagulation and metastasis in the experimental metastasis assay. CONCLUSION: Our findings suggest the novel role of tumor prognostic genes upon the development of hypercoagulative phenotype and venous thromboembolism, thereby underlining the importance of anticoagulant therapy and shedding light on the therapeutic value of targeting MITD1 in bladder cancer.

Toxic effects of combined exposure to homoyessotoxin and nitrite on the survival, antioxidative responses, and apoptosis of the abalone Haliotis discus hannai.

Homoyessotoxin (homo-YTX) and nitrite (NO2-N), released during harmful dinoflagellate cell lysis adversely affect abalones. However, their toxicity mechanisms in shellfish remain unclear. This study investigated the economic abalone species Haliotis discus hannai exposed to varying concentrations of homo-YTX (0, 2, 5, and 10 µg L-1) and NO2-N (0, 3, and 6 mg L-1) on the basis of their 12 h LC50 values (5.05 µg L-1 and 4.25 mg L-1, respectively) and the environmentally relevant dissolved concentrations during severe dinoflagellate blooms, including mixtures. The test abalones were exposed to homo-YTX and NO2-N for 12 h. The mortality rate (D), reactive oxygen species (ROS) levels, antioxidant defense capabilities, and expression levels of antioxidant-related, Hsp-related, and apoptosis-related genes in abalone gills were assessed. Results showed that the combined exposure to homo-YTX and NO2-N increased the D and ROS levels and upregulated B-cell lymphoma-2 (BCL2)-associated X (BAX) and caspase3 (CASP3) expression levels while reducing glutathione peroxidase (GPx) activity and GPx, CuZnSOD, and BCL2 expression levels. High concentrations of homo-YTX (10 µg L-1) and NO2-N (6 mg L-1) solutions and the combinations of these toxicants inhibited the activities of superoxide dismutase (SOD) and catalase (CAT) and downregulated the expression levels of MnSOD, CAT, Hsp70, and Hsp90. The ROS levels were negatively correlated with the activities of SOD, CAT, and GPx and the expression levels of MnSOD, CuZnSOD, CAT, GPx, Hsp70, Hsp90, and BCL2. These results suggest that homo-YTX, in conjunction with NO2-N, induces oxidative stress, disrupts antioxidant defense systems, and triggers caspase-dependent apoptosis in the gills of abalone. ROS-mediated antioxidative and heat-shock responses and apoptosis emerge as potential toxicity mechanisms affecting the survival of H. discus hannai due to homo-YTX and NO2-N exposure.

Presence, Subtypes, and Prognostic Significance of Tertiary Lymphoid Structures in Urothelial Carcinoma of the Bladder.

OBJECTIVE: To evaluate the presence and subtypes of tertiary lymphatic structures (TLSs) in urothelial carcinoma of the bladder (UCB) and to analyze their associated clinicopathological characteristics and prognostic significance. METHODS: The study enrolled 580 patients with surgically treated UCB, including 313 non-muscle invasive bladder cancer (NMIBC) and 267 muscle-invasive bladder cancer (MIBC). The presence and subtypes of TLSs were identified by immunohistochemistry (CD20, CD3, Bcl-6, and CD21). TLSs were classified into non-GC (nGC) TLS and GC TLS subtypes based on germinal center (GC) formation. Disease-free survival (DFS) was used as an endpoint outcome to evaluate the prognostic significance of TLS and its subtypes in UCB. RESULTS: TLSs were more common in MIBC than in NMIBC (67.8% vs 48.2%, P < .001), and the tumor-infiltrating lymphocyte (TIL) mean density was significantly higher in MIBC than in NMIBC (24.0% vs 17.5%, P < .001). Moreover, a positive correlation was found between TLS presence and GC structure formation and TIL infiltration in UCB. Endpoint events occurred in 191 patients. Compared to patients with endpoint events, patients without disease progression exhibited higher TIL density and more TLSs (P < .05). Kaplan-Meier curves showed that TLS was associated with better DFS in NMIBC (P = .041) and MIBC (P = .049). However, the Cox multivariate analysis did not demonstrate the prognostic significance of TLS. CONCLUSIONS: TLS is heterogeneous in UCB, and that TLS and GC structures are related to TIL density and prognostic events. However, TLS as a prognostic indicator remains unclear, warranting further investigation.

A tumor microenvironment-associated circRNA predictor for tumor relapse and chemotherapy vulnerability in nasopharyngeal carcinoma.

Accurate risk stratification for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is crucial for prognosis and treatment decisions. Here, we develop a tumor microenvironment-associated circular RNA (circRNA) signature that can stratify LA-NPC patients with different risks of relapse and vulnerability to induction chemotherapy (IC). Relapsed-related circRNAs are identified by comparing expression profiles between patients with and without relapse, followed by quantitative validation in the training cohort (n = 170). A nine-circRNA signature is constructed to classify patients into high-risk and low-risk groups. Low-risk patients have significantly favorable clinical survivals, which is validated in the internal (n = 170) and external (n = 150) cohorts. They are characterized by an immune-active microenvironment and can derive benefits from IC. Meanwhile, high-risk patients characterized with pro-relapse and DNA repair-associated features, are vulnerable to chemoresistance. Overall, the circRNA-based classifier serves as a reliable prognostic tool and might guide chemotherapy decisions for patients with LA-NPC.

Cancer-associated fibroblasts-derived CXCL12 enhances immune escape of bladder cancer through inhibiting P62-mediated autophagic degradation of PDL1.

BACKGROUND: Cancer-associated fibroblasts (CAFs), the predominant stromal cell of tumor microenvironment (TME), play an important role in tumor progression and immunoregulation by remodeling extracellular matrix (ECM) and secreting cytokines. However, little is known about the details of the underlying mechanism in bladder cancer. METHODS: Bioinformatics analysis was performed to analyze the prognostic value of CAFs and CXCL12 using GEO, TCGA and SRA databases. The effects of CXCL12 on bladder cancer progression were investigated through in vitro and in vivo assays. The biological mechanism of the effect of CXCL12 on PDL1 were investigated using western blotting, immunoprecipitation, RT-PCR, immunofluorescence, mass spectrometry, protein stability, and flow cytometry. RESULTS: The results demonstrated that CAFs-derived CXCL12 promoted cancer cell migration and invasion and upregulated PDL1. Mechanistically, upon binding to its specific receptor, CXCL12 activated the downstream JAK2/STAT3 pathway and rapidly up-regulated the expression of deubiquitinase CYLD. CYLD deubiquitinated P62 causing P62 accumulation, which in turn inhibited the autophagic degradation of PDL1. In vivo experiments demonstrated that blocking CXCL12 inhibited tumor growth, reduced tumor PDL1 expression and increased immune cell infiltration. CONCLUSIONS: This study revealed a novel mechanism for the role of CXCL12 in P62-mediated PDL1 autophagic regulation. Combined application of CXCL12 receptor blocker and PD1/PDL1 blocker can more effectively inhibit PDL1 expression and enhance antitumor immune response. Targeting CAFs-derived CXCL12 may provide an effective strategy for immunotherapy in bladder cancer.

Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression.

ALDH1A1 is one of the classical stem cell markers for bladder cancer. Lysine 2-hydroxyisobutyrylation (Khib) is a newfound modification to modulate the protein expression, and the underlying mechanisms of how ALDH1A1 was regulated by Khib modification in bladder cancer remains unknown. Here, ALDH1A1 showed a decreased K260hib modification, as identified by protein modification omics in bladder cancer. Decreasing ALDH1A1 expression significantly suppressed the proliferation, migration and invasion of bladder cancer cells. Moreover, K260hib modification is responsible for the activity of ALDH1A1 in bladder cancer, which is regulated by HDAC2/3. Higher K260hib modification on ALDH1A1 promotes protein degradation through chaperone-mediated autophagy (CMA), and ALDH1A1 K260hib could sensitize bladder cancer cells to chemotherapeutic drugs. Higher ALDH1A1 expression with a lower K260hib modification indicates a poor prognosis in patients with bladder cancer. Overall, we demonstrated that K260hib of ALDH1A1 can be used as a potential therapeutic target for bladder cancer treatment.

A Nano-Autophagy Inhibitor Triggering Reciprocal Feedback Control of Cholesterol Depletion for Solid Tumor Therapy.

Solid tumors are characterized by enhanced metabolism of lipid, particularly cholesterol, inspiring the exploration of metabolic therapy through cholesterol oxidase (COD)-mediated cholesterol deprivation. However, the therapeutic efficacy of COD is limited due to the hypoxic tumor microenvironment and the protective autophagy triggered by cholesterol deprivation. Herein, a combination therapy for metabolically treating solid tumors through COD in conjunction with molybdenum oxide nanodots (MONDs), which serve as both potent oxygen generators and autophagy inhibitors, is reported. MONDs convert H2 O2 (arising from COD-mediated cholesterol oxidation) into O2 , which is then recycled by COD to form reciprocal feedback for cholesterol depletion. Concurrently, MONDs can overcome autophagy-induced therapeutic resistance frequently occurring in conventional nutrient deprivation therapy by activating AKT/mTOR pathway phosphorylation. Combination therapy in the xenograft model results in an ≈5-fold increase in therapeutic efficiency as compared with COD treatment alone. This functionally cooperative metabolic coupling strategy holds great promise as a novel polytherapy approach that will benefit patients with solid tumors.

Gut microbiome and reproductive endocrine diseases: a Mendelian randomization study.

Background: Observation studies have confirmed the association between the gut microbiome and reproductive endocrine diseases (REDs), namely, polycystic ovary syndrome (PCOS), endometriosis, and female infertility. However, their association has never been confirmed by a two-sample Mendelian randomization (MR) analysis. Methods: We conducted a two-sample MR analysis to evaluate the relationship between the gut microbiome and the three aforementioned REDs. In order to get more comprehensive results, two different thresholds were adopted to select instrumental variables (IVs): one was a locus-wide significance threshold (P <1.0×10-5) and the other was a genome-wide significance level (P< 5×10-8). Summary-level statistics for the gut microbiome and REDs were collected from public databases. Inverse-variance weighted (IVW) was the main method used to estimate causality, and sensitivity analyses were conducted to validate the MR results. Results: At the locus-wide significance level, we identified that the genera Streptococcus (OR=1.52, 95%CI: 1.13-2.06, P=0.006) and RuminococcaceaeUCG005 (OR=1.39, 95%CI: 1.04-1.86, P=0.028) were associated with a high risk of PCOS, while Sellimonas (OR= 0.69, 95%CI: 0.58-0.83, P=0.0001) and RuminococcaceaeUCG011(OR=0.76, 95%CI: 0.60-0.95, P=0.017) were linked to a low PCOS risk. The genus Coprococcus2 (OR=1.20, 95%CI: 1.01-1.43, P=0.039) was correlated with an increased risk of female infertility, while Ruminococcus torques (OR=0.69, 95%CI: 0.54-0.88, P=0.002) were negatively associated with the risk of female infertility. The genera Olsenella (OR= 1.11, 95%CI: 1.01-1.22, P=0.036), Anaerotruncus (OR= 1.25, 95%CI: 1.03-1.53, P=0.025), and Oscillospira (OR= 1.21, 95%CI: 1.01-1.46, P=0.035) were linked to a high risk of endometriosis. However, the results showed that the gut microbiome did not possess a causal link with REDs risk based on the genome-wide significance level. Sensitivity analyses further confirmed the robustness of the MR results. Conclusion: Our study provides evidence that gut microbiome is closely related with REDs. Subsequent studies should be conducted to promote microbiome-orientated therapeutic strategies for managing REDs.

Pentraxin 3 plays a key role in tubular cell senescence and renal fibrosis through inducing ß-catenin signaling.

Renal fibrosis is the common pathological feature of various chronic kidney diseases (CKD). Tubular cell senescence plays a key role in the progression of renal fibrosis. However, the underlying mechanisms are still in mystery. In this study, we identified, Pentraxin 3 (PTX3), belonging to the Pentraxin family, is a new fibrogenic factor. PTX3 was increased in various CKD models. PTX3 was primarily localized in tubular epithelial cells and upregulated, accompanied by mitochondrial dysfunction and cellular senescence. Overexpression of PTX3 aggravated mitochondrial damage and accelerated cell senescence in tubular cells, leading to more severe fibrogenesis in kidneys. However, knockout of PTX3 significantly preserved mitochondrial homeostasis, and blocked cellular senescence in primary cultured tubular cells. Furthermore, KYA1797K, a destabilizer of ß-catenin, greatly inhibited PTX3-induced mitochondrial dysfunction, tubular cell senescence, and renal fibrosis. Overexpression of PTX3 triggered nuclear translocation of ß-catenin, an activating form of ß-catenin. PTX3-induced mitochondrial dysfunction and tubular cell senescence were also significantly inhibited by knockdown of p16INK4A, a senescence-related protein. In a clinical cohort, we found PTX3 was increased in urine and serum in patients with CKD. Urinary PTX3 negatively correlated with eGFR. PTX3 also increased gradually following the severity of diseases, triggering the fibrogenesis. Taken together, our results provide strong evidences that PTX3 is a new fibrogenic factor in the development of renal fibrosis through ß-catenin-induced mitochondrial dysfunction and cell senescence. This study further suggests PTX3 is a new diagnostic factor to renal fibrosis and provides a new therapeutic target against renal fibrosis.

Comparison of the efficacy and safety of total laparoscopic hysterectomy without and with uterine manipulator combined with pelvic lymphadenectomy for early cervical cancer.

OBJECTIVE: Some studies have reported that the prognosis of total laparoscopic hysterectomy (TLH) for early-stage cervical cancer (CC) is worse than that of open surgery. And this was associated with the use of uterine manipulator or not. Therefore, this study retrospectively analyzes the efficacy and safety of TLH without uterine manipulator combined with pelvic lymphadenectomy for early-stage CC. METHODS: Fifty-eight patients with CC (stage IB1-IIA1) who received radical hysterectomy from September 2019 to January 2020 were divided into no uterine manipulator (n = 26) and uterine manipulator group (n = 32). Then, clinical characteristics were collected and intraoperative/postoperative related indicators were compared. RESULTS: Patients in the no uterine manipulator group had significantly higher operation time and blood loss than in the uterine manipulator group. Notably, there was no significant difference in hemoglobin change, blood transfusion rate, number of pelvic nodules, anal exhaust time, complications and recurrence rate between the two groups. Additionally, patients in the uterine manipulator group were prone to urinary retention (15.6%) and lymphocyst (12.5%), while the no uterine manipulator group exhibited high probability of bladder dysfunction (23.1%) and urinary retention (15.4%). Furthermore, the 1-year disease-free survival rate and the 1-year overall survival rate were not significantly different between the two groups. CONCLUSION: There was no significant difference in the efficacy and safety of TLH with or without uterine manipulator combined with pelvic lymphadenectomy in the treatment of patients with early-stage CC. However, the latter requires consideration of the negative effects of high operation time and blood loss.

Synthesis and application of zeolitic imidazolate frameworks-based nucleic acid delivery system in tumor diagnosis and therapy: a review.

Cancer severely threatens human health, which makes it particularly urgent to develop effective strategies for cancer diagnosis and therapy. Gene therapy and nucleic acid-based cancer diagnosis play important roles in cancer theranostic, but their applicability is challenged by the low cellular uptake and enzymatic degradation. In response, safe and efficient carrier metal-organic frameworks (MOFs) have been proposed. Zeolite imidazole frameworks (ZIFs), a promising MOF type, can easily encapsulate negatively charged nucleic acid while offering a high loading efficiency, adjustable structure, and conditional responsiveness (pH, adenosine triphosphate (ATP), or glutathione (GSH)). In this review, we studied recent articles on nucleic acid-loading ZIFs-based nanoplatforms in tumor theranostics on the Pubmed database, with a focus on the synthesis and applications in tumor diagnosis and treatment. The relevant favorable aspects, potential challenges, and future opportunities are also discussed in this review.

m6A-enriched lncRNA LINC00839 promotes tumor progression by enhancing TAF15-mediated transcription of amine oxidase AOC1 in nasopharyngeal carcinoma.

Dysregulation of long noncoding RNAs (lncRNAs) contributes to tumorigenesis by modulating specific cancer-related pathways, but the roles of N6-methyladenosine (m6A)-enriched lncRNAs and underlying mechanisms remain elusive in nasopharyngeal carcinoma (NPC). Here, we reanalyzed the previous genome-wide analysis of lncRNA profiles in 18 pairs of NPC and normal tissues as well as in ten paired samples from NPC with or without post-treatment metastases. We discerned that an oncogenic m6A-enriched lncRNA, LINC00839, which was substantially upregulated in NPC and correlated with poor clinical prognosis, promoted NPC growth and metastasis both in vitro and in vivo. Mechanistically, by using RNA pull-down assay combined with mass spectrometry, we found that LINC00839 interacted directly with the transcription factor, TATA-box binding protein associated factor (TAF15). Besides, chromatin immunoprecipitation and dual-luciferase report assays demonstrated that LINC00839 coordinated the recruitment of TAF15 to the promoter region of amine oxidase copper-containing 1 (AOC1), which encodes a secreted glycoprotein playing vital roles in various cancers, thereby activating AOC1 transcription in trans. In this study, potential effects of AOC1 in NPC progression were first proposed. Moreover, ectopic expression of AOC1 partially rescued the inhibitory effect of downregulation of LINC00839 in NPC. Furthermore, we showed that silencing vir-like m6A methyltransferase-associated (VIRMA) and insulin-like growth factor 2 mRNA-binding proteins 1 (IGF2BP1) attenuated the expression level and RNA stability of LINC00839 in an m6A-dependent manner. Taken together, our study unveils a novel oncogenic VIRMA/IGF2BP1-LINC00839-TAF15-AOC1 axis and highlights the significance and prognostic value of LINC00839 expression in NPC carcinogenesis.