A PSMA PET/CT-based risk model for prediction of concordance between targeted biopsy and combined biopsy in detecting prostate cancer.

PURPOSE: This study is to investigate the diagnostic value of 68Ga-PSMA-11 in improving the concordance between mpMRI-TB and combined biopsy (CB) in detecting PCa. METHODS: 115 consecutive men with 68Ga-PSMA-11 PET/CT prior to prostate biopsy were included for analysis. PSMA intensity, quantified as maximum standard uptake value (SUVmax), minimum apparent diffusion coefficient (ADCmin) and other clinical characteristics were evaluated relative to biopsy concordance using univariate and multivariate logistic regression analyses. A prediction model was developed based on the identified parameters, and a dynamic online diagnostic nomogram was constructed, with its discrimination evaluated through the area under the ROC curve (AUC) and consistency assessed using calibration plots. To assess its clinical applicability, a decision curve analysis (DCA) was performed, while internal validation was conducted using bootstrapping methods. RESULTS: Concordance between mpMRI-TB and CB occurred in 76.5% (88/115) of the patients. Multivariate logistic regression analyses performed that SUVmax (OR= 0.952; 95% CI 0.917-0.988; P= 0.010) and ADCmin (OR= 1.006; 95% CI 1.003-1.010; P= 0.001) were independent risk factors for biopsy concordance. The developed model showed a sensitivity, specificity, accuracy and AUC of 0.67, 0.78, 0.81 and 0.78 in the full sample. The calibration curve demonstrated that the nomogram's predicted outcomes closely resembled the ideal curve, indicating consistency between predicted and actual outcomes. Furthermore, the decision curve analysis (DCA) highlighted the clinical net benefit achievable across various risk thresholds. These findings were reinforced by internal validation. CONCLUSIONS: The developed prediction model based on SUVmax and ADCmin showed practical value in guiding the optimization of prostate biopsy pattern. Lower SUVmax and Higher ADCmin values are associated with greater confidence in implementing mono-TB and safely avoiding SB, effectively balancing benefits and risks.

Long noncoding RNA XIST inhibition promotes Leydig cell apoptosis by acting as a competing endogenous RNA for microRNA-145a-5p that targets SIRT1 in late-onset hypogonadism.

Leydig cell (LCs) apoptosis is responsible for decreased serum testosterone levels during late-onset hypogonadism (LOH). Our study was designed to illustrate the regulatory effect of lncRNA XIST on LCs and to clarify its molecular mechanism of action in LOH. The Leydig cells (TM3) was treated by 300 µM H2O2 for 8 h to establish Leydig cell oxidative stress model in vitro. The expression levels of lncRNA XIST in the testicular tissues of patients with LOH were measured using fluorescence in situ hybridization (FISH). The interaction between lncRNA XIST/SIRT1 and miR-145a-5p was assessed using starBase and dual-luciferase reporter gene assays. Apoptotic cells and Caspase3 activity were determined by flow cytometry (FCM) assay. Testosterone concentration was determined by ELISA. Moreover, histological assessment of testicles in mice was performed by using HE staining and the TUNEL assay was used to determine apoptosis. We found that the lncRNA XIST was downregulated in the testicular tissues of LOH patients and mice and in H2O2-induced TM3 cells. XIST siRNA significantly promoted apoptosis, enhanced Caspase3 activity and reduced testosterone levels in H2O2-stimulated TM3 cells. Further studies showed that the miR-145a-5p inhibitor reversed the effect of XIST-siRNA on H2O2-induced Leydig cell apoptosis. MiR-145a-5p negatively regulated SIRT1 expression, and SIRT1-siRNA reversed the effects of the miR-145a-5p inhibitor on H2O2 stimulated TM3 cells. The in vivo experiments indicated that silencing of the lncRNA XIST aggravated LOH symptoms in mice. Inhibition of lncRNA XIST induces Leydig cell apoptosis through the miR-145a-5p/SIRT1 axis in the progression of LOH.

Robot-assisted Simple Enucleation Versus Standard Robot-assisted Partial Nephrectomy for Low- or Intermediate-complexity, Clinical T1 Renal Tumors: A Randomized Controlled Noninferiority Trial.

BACKGROUND: Although partial nephrectomy has become the gold standard for T1 renal tumors whenever technically feasible, simple enucleation has shown superior results. To the best of our knowledge, no randomized controlled trials comparing these two surgical approaches have been published. OBJECTIVE: To compare the surgical margin status for robot-assisted simple enucleation (RASE) and standard robot-assisted partial nephrectomy (sRAPN) for clinical T1 renal tumors. DESIGN, SETTING, AND PARTICIPANTS: This is a prospective, randomized, controlled, noninferiority trial. A total of 380 patients aged 18-80 yr with newly diagnosed, sporadic, unilateral clinical T1 renal tumors (RENAL score <10) were enrolled and randomized to RASE or sRAPN. The primary endpoint was the positive surgical margin (PSM) rate, with a noninferiority margin of 7.5% set. The study was registered on ClinicalTrials.gov (NCT03624673). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We defined noninferiority for RASE versus standard RAPN as an upper 95% confidence interval (CI) bound of <7.5% for the difference in the proportion of patients with a PSM. RESULTS AND LIMITATIONS: A cohort of 380 patients was enrolled and randomly assigned to RASE (n = 190) or sRAPN (n = 190). On intention-to-treat analysis for patients with malignant tumors, 2.3% of patients in the RASE group and 3.0% in the sRAPN group had a PSM. The RASE group showed noninferiority to the sRAPN group within a 7.5% margin (difference -0.7%, 95% CI -4.0% to 2.7%). Per-protocol analysis also demonstrated noninferiority of RASE. The RASE group had a shorter median operative time (145 vs 155 min; p = 0.018) and a lower rate of tumor bed suturing (8.9% vs 43%; p < 0.001) in comparison to the sRAPN group. Estimated blood loss was considerably lower in the sRAPN group than in the RASE group (p = 0.046). The rate of recurrence did not differ between the groups (p > 0.9). CONCLUSIONS: RASE for the management of low- to intermediate-complexity tumors is noninferior to sRAPN in terms of the PSM rate. Long-term follow-up is needed to draw conclusions regarding oncological outcomes. PATIENT SUMMARY: We carried out a trial to compare simple tumor enucleation versus partial nephrectomy for renal tumors. The outcome we assessed was the proportion of patients with a positive surgical margin. Our results show that simple tumor enucleation is not inferior to partial nephrectomy for this outcome. Longer follow-up is needed to assess other cancer control outcomes.

Antigen-loaded flagellate bacteria for enhanced adaptive immune response by intradermal injection.

Since the skin limits the distribution of intradermal vaccines, a large number of dendritic cells in the skin cannot be fully utilized to elicit a more effective immune response. Here, we loaded the antigen to the surface of the flagellate bacteria that was modified by cationic polymer, thus creating antigen-loaded flagellate bacteria (denoted as 'FB-Ag') to overcome the skin barrier and perform the active delivery of antigen in the skin. The FB-Ag showed fast speed (∼0.2 µm s-1) and strong dendritic cell activation capabilities in the skin model in vitro. In vivo, the FB-Ag promoted the spread of antigen in the skin through active movement, increased the contact between Intradermal dendritic cells and antigen, and effectively activated the internal dendritic cells in the skin. In a mouse of pulmonary metastatic melanoma and in mice bearing subcutaneous melanoma tumor, the FB-Ag effectively increased antigen-specific therapeutic efficacy and produced long-lasting immune memory. More importantly, the FB-Ag also enhanced the level of COVID-19 specific antibodies in the serum and the number of memory B cells in the spleen of mice. The movement of antigen-loaded flagellate bacteria to overcome intradermal constraints may enhance the activation of intradermal dendritic cells, providing new ideas for developing intradermal vaccines.

Impact of operator expertise on transperineal free-hand mpMRI-fusion-targeted biopsies under local anaesthesia for prostate cancer diagnosis: a multicenter prospective learning curve.

PURPOSE: Transperineal mpMRI-targeted fusion prostate biopsies (TPFBx) are recommended for prostate cancer diagnosis, but little is known about their learning curve (LC), especially when performed under local anaesthesia (LA). We investigated how operators' and institutions' experience might affect biopsy results. METHODS: Baseline, procedure and pathology data of consecutive TPFBx under LA were prospectively collected at two academic Institutions, from Sep 2016 to May 2019. Main inclusion criterion was a positive MRI. Endpoints were biopsy duration, clinically significant prostate cancer detection rate on targeted cores (csCDR-T), complications, pain and urinary function. Data were analysed per-centre and per-operator (with ≥ 50 procedures), comparing groups of consecutive patient, and subsequently through regression and CUSUM analyses. Learning curves were plotted using an adjusted lowess smoothing function. RESULTS: We included 1014 patients, with 27.3% csCDR-T and a median duration was 15 min (IQR 12-18). A LC for biopsy duration was detected, with the steeper phase ending after around 50 procedures, in most operators. No reproducible evidence in favour of an impact of experience on csPCa detection was found at operator's level, whilst a possible gentle LC of limited clinical relevance emerged at Institutional level; complications, pain and IPSS variations were not related to operator experience. CONCLUSION: The implementation of TPFBx under LA was feasible, safe and efficient since early phases with a relatively short learning curve for procedure time.

Perfluorotributylamine-Loaded Albumin Nanoparticles Downregulate Platelet-Derived TGFß to Inhibit Tumor Metastasis.

Tumor metastasis contributes to the low overall survival of tumor patients, while transforming growth factor-ß (TGFß) has been recognized as a prominently promoting factor in the development of tumor metastasis. Platelets reserve abundant TGFß, which will be secreted to peripheral blood after activation, and they are the dominant source of circulating TGFß. Therefore, downregulation of platelet-derived TGFß is expected to inhibit the metastasis of circulating tumor cells. Here, unfolded human serum albumin (HSA)-coated perfluorotributylamine (PFTBA) nanoparticles were constructed to display a favorable platelet delivery and an antiplatelet effect to downregulate platelet-derived TGFß in vitro and in blood plasma. PFTBA@HSA-mediated TGFß downregulation impaired epithelial-mesenchymal transition of tumor cells as well as their migration and invasion behaviors and enhanced immune surveillance of NK cells. Intravenous injection of PFTBA@HSA effectively reduced tumor metastasis on the lungs or liver to improve the survival rate of mice on multiple metastatic models, including CT26 colon cancer, B16F10 melanoma, and 4T1 breast cancer. Compared with the clinical antiplatelet drug ticagrelor, PFTBA@HSA reduced bleeding risk when displaying a favorable downregulation on platelet-derived TGFß, thereby obtaining a higher therapy benefit. Together, this study confirmed that downregulation of platelet-derived TGFß by PFTBA@HSA will be a potential approach and therapeutic candidate for the prevention of tumor metastasis.

Animal tissue-derived biomaterials for promoting wound healing.

The skin serves as the primary barrier between the human body and external environment, and is therefore susceptible to damage from various factors. In response to this challenge, animal tissue-derived biomaterials have emerged as promising candidates for wound healing due to their abundant sources, low side-effect profiles, exceptional bioactivity, biocompatibility, and unique extracellular matrix (ECM) mimicry. The evolution of modern engineering technology and therapies has allowed these animal tissue-derived biomaterials to be transformed into various forms and modified to possess the necessary properties for wound repair. This review provides an overview of the wound healing process and the factors that influence it. We then describe the extraction methods, important properties, and recent practical applications of various animal tissue-derived biomaterials. Our focus then shifts to the critical properties of these biomaterials in skin wound healing and their latest research developments. Finally, we critically examine the limitations and future prospects of biomaterials generated from animal tissues in this field.

A probiotic nanozyme hydrogel regulates vaginal microenvironment for Candida vaginitis therapy.

Molecular therapeutics are limited for Candida vaginitis because they damage normal cells and tissues of vagina, aggravating the imbalance of vaginal microbiota and increasing the recurrence. To tackle this limitation, through the combination of peroxidase-like rGO@FeS2 nanozymes [reduced graphene oxide (rGO)] with Lactobacillus-produced lactic acid and H2O2, a responsive hyaluronic acid (HA) hydrogel rGO@FeS2/Lactobacillus@HA (FeLab) is developed. FeLab has simultaneous anti-Candida albicans and vaginal microbiota-modulating activities. In particular, the hydroxyl radical produced from rGO@FeS2 nanozymes and Lactobacillus kills C. albicans isolated from clinical specimens without affecting Lactobacillus. In mice with Candida vaginitis, FeLab has obvious anti-C. albicans activity but hardly damages vaginal mucosa cells, which is beneficial to vaginal mucosa repair. Moreover, a higher proportion of Firmicutes (especially Lactobacillus) and a decrease in Proteobacteria reshape a healthy vaginal microbiota to reduce the recurrence. These results provide a combined therapeutic of nanozymes and probiotics with translational promise for Candida vaginitis therapy.

ROS Scavenging Nanozyme Modulates Immunosuppression for Sensitized Cancer Immunotherapy.

Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), two immunosuppressive myeloid components within the tumor microenvironment (TME), represent fundamental barriers in cancer immunotherapy, whereas current nanomedicines rarely exert dual modulatory roles on these cell types simultaneously. Reactive oxygen species (ROS) not only mediates MDSC-induced immunosuppression but also triggers differentiation and polarization of M2-TAMs. Herein, an ROS scavenging nanozyme, Zr-CeO, with enhanced superoxide dismutase- and catalase-like activities for renal tumor growth inhibition is reported. Mechanistically, intracellular ROS scavenging by Zr-CeO significantly attenuates MDSC immunosuppression via dampening the unfolded protein response, hinders M2-TAM polarization through the ERK and STAT3 pathways, but barely affects neoplastic cells and cancer-associated fibroblasts. Furthermore, Zr-CeO enhances the antitumor effect of PD-1 inhibition in murine renal and breast tumor models, accompanied with substantially decreased MDSC recruitment and reprogrammed phenotype of TAMs in the tumor mass. Upon cell isolation, reversed immunosuppressive phenotypes of MDSCs and TAMs are identified. In addition, Zr-CeO alone or combination therapy enhances T lymphocyte infiltration and IFN-γ production within the TME. Collectively, a promising strategy to impair the quantity and function of immunosuppressive myeloid cells and sensitize immunotherapy in both renal and breast cancers is provided.

Recent advances in bacterial therapeutics based on sense and response.

Intelligent drug delivery is a promising strategy for cancer therapies. In recent years, with the rapid development of synthetic biology, some properties of bacteria, such as gene operability, excellent tumor colonization ability, and host-independent structure, make them ideal intelligent drug carriers and have attracted extensive attention. By implanting condition-responsive elements or gene circuits into bacteria, they can synthesize or release drugs by sensing stimuli. Therefore, compared with traditional drug delivery, the usage of bacteria for drug loading has better targeting ability and controllability, and can cope with the complex delivery environment of the body to achieve the intelligent delivery of drugs. This review mainly introduces the development of bacterial-based drug delivery carriers, including mechanisms of bacterial targeting to tumor colonization, gene deletions or mutations, environment-responsive elements, and gene circuits. Meanwhile, we summarize the challenges and prospects faced by bacteria in clinical research, and hope to provide ideas for clinical translation.

Effect of extensive artery isolation during robotic-assisted partial nephrectomy on blood pressure of patients with poorly controlled hypertension: a preliminary study.

PURPOSE: To investigate whether extensive renal artery isolation during robotic-assisted partial nephrectomy (RAPN) for renal cell carcinoma (RCC) affects blood pressure (BP) of patients with poorly controlled hypertension. METHODS: We included 60 patients diagnosed with poorly controlled hypertension who underwent RAPN by an experienced surgeon. The renal artery of the treated kidney was sufficiently isolated. Systolic BP (SBP), diastolic BP (DBP) and antihypertensive medication information were obtained at baseline and 3- and 6-month follow-up after surgery. Primary endpoints were changes in BP, and medications. Predictors of SBP reduction at 3 months were assessed by multivariable logistic regression. RESULTS: All 60 RAPN procedures were successful, with no major intra- or postoperative complications. Mean SBP and DBP decreased significantly at 3 months after surgery (SBP, -7.8 ± 6.3 mmHg, P < 0.001; DBP, -4.2 ± 6.4 mmHg, P = 0.01). SBP and DBP did not differ between 3- and 6-month follow-up. The mean number of BP medications prescribed was lower at 3 months than baseline (1.7 ± 1.0 vs 2.1 ± 1.0, P = 0.016). The only significant predictor of SBP reduction at 3 months was baseline SBP. CONCLUSIONS: Renal denervation with extensive renal artery isolation during RAPN may improve BP control among patients with poorly controlled hypertension in short term.

Reactive Oxygen Species- and Cell-Free DNA-Scavenging Mn3O4 Nanozymes for Acute Kidney Injury Therapy.

Reactive oxygen species (ROS) scavenging therapy toward acute kidney injury (AKI) is promising, but no effective ROS scavenging drug has been developed yet. Moreover, cell-free DNA (cfDNA) is also involved in AKI, but the corresponding therapies have not been well developed. To tackle these challenges, Mn3O4 nanoflowers (Nfs) possessing both ROS and cfDNA scavenging activities were developed for better AKI protection as follows. First, Mn3O4 Nfs could protect HK2 cells through cascade ROS scavenging (dismutating ·O2- into H2O2 by superoxide dismutase-like activity and then decomposing H2O2 by catalase-like activity). Second, Mn3O4 Nfs could efficiently adsorb cfDNA and then decrease the inflammation caused by cfDNA. Combined, remarkable therapeutic efficacy was achieved in both cisplatin-induced and ischemia-reperfusion AKI murine models. Furthermore, Mn3O4 Nfs could be used for the T1-MRI real-time imaging of AKI. This study not only offered a promising treatment for AKI but also showed the translational potential of nanozymes.

Cancer-associated fibroblasts promote the stemness and progression of renal cell carcinoma via exosomal miR-181d-5p.

The mechanisms underlying the effects of cancer-associated fibroblasts (CAFs) on cancer stemness and tumor progression in renal cell carcinoma (RCC) have not been elucidated yet. In the present study, we found that the enrichment of CAFs was positively associated with tumor progression and cancer stemness in RCC. Further investigation revealed that CAFs could enhance cancer stemness through delivering exosomes to RCC cells, and miR-181d-5p was identified as the critical exosomal miRNA in CAF-secreted exosomes by small RNA sequencing and subsequent screening assays. Mechanistically, exosomal miR-181d-5p transferred from CAFs to RCC cells directly suppressed the expression of ring finger protein 43 (RNF43) and activated Wnt/ß-catenin signaling pathway, thus promoted cancer stemness and tumor progression. Overexpression of RNF43 strongly suppressed stemness properties and the effects could be reverted by miR-181d-5p. Overall, our findings revealed a crucial mechanism by which CAF-secreted exosomal miRNAs to enhance cancer stemness and thus promote RCC progression, suggesting a new avenue based on CAF-secreted miRNAs for more effective targeted therapies.

Hijacking Self-Assembly to Establish Intracellular Functional Nanoparticles.

The targeted transport of nanomedicines is often impeded by various biological events in the body. Viruses can hijack host cells and utilize intracellular transcription and translation biological events to achieve their replication. Inspired by this, a strategy to hijack endogenous products of biological events to assemble into intracellular functional nanoparticles is established. It has been shown that, following tumor vessel destruction therapy, injected cell permeable small molecule drugs bisphosphonate can hijack the hemorrhagic product iron and self-assemble into peroxidase-like nanoparticles within tumor-infiltrating macrophages. Unlike free drugs, the generated intercellular nanoparticles can specifically stress mitochondria, resulting in immune activation of macrophages in vitro and polarizing tumor-associated macrophages (TAMs) from immunosuppressive to tumoricidal and increasing the recruitment of T cells deep within tumor. The hijacking self-assembly strategy significantly inhibits tumor growth compared with the treatment of vascular-disrupting agents alone. Using bisphosphonate to hijack the metabolite associated with hemorrhage, iron, to fabricate functional nanoparticles within specific cells, which may open up new nanotechnology for drug delivery and small molecular drug development.

Lysosomal protein transmembrane 5 promotes lung-specific metastasis by regulating BMPR1A lysosomal degradation.

Organotropism during cancer metastasis occurs frequently but the underlying mechanism remains poorly understood. Here, we show that lysosomal protein transmembrane 5 (LAPTM5) promotes lung-specific metastasis in renal cancer. LAPTM5 sustains self-renewal and cancer stem cell-like traits of renal cancer cells by blocking the function of lung-derived bone morphogenetic proteins (BMPs). Mechanistic investigations showed that LAPTM5 recruits WWP2, which binds to the BMP receptor BMPR1A and mediates its lysosomal sorting, ubiquitination and ultimate degradation. BMPR1A expression was restored by the lysosomal inhibitor chloroquine. LAPTM5 expression could also serve as an independent predictor of lung metastasis in renal cancer. Lastly, elevation of LAPTM5 expression in lung metastases is a common phenomenon in multiple cancer types. Our results reveal a molecular mechanism underlying lung-specific metastasis and identify LAPTM5 as a potential therapeutic target for cancers with lung metastasis.

circDHTKD1 promotes lymphatic metastasis of bladder cancer by upregulating CXCL5.

Lymph node (LN) metastasis is associated with unfavorable prognosis of bladder cancer (BCa). Although lymphangiogenesis is functionally important in LN metastasis of tumors, the potential mechanism in BCa remains unclear. Here, we clarified a regulatory mechanism of circRNA-mediated lymphangiogenesis and LN metastasis in BCa based on next-generation sequencing data. We revealed that circDHTKD1 was positively associated with LN metastasis and significantly upregulated in BCa. By analyzing the co-expression patterns of circDHTKD1 and differentially expressed mRNAs, we identified that circDHTKD1 facilitated lymphangiogenesis by upregulating CXCL5. Mechanistically, circDHTKD1 directly interacted with miR-149-5p, and antagonized the repression of miR-149-5p on CXCL5. Furthermore, circDHTKD1-induced CXCL5 expression recruited and activated neutrophils, which participated in lymphangiogenesis by secreting VEGF-C. Our study supports circDHTKD1 as a promising diagnostic and therapeutic target for LN metastasis in BCa.

68Ga-PSMA-11 PET/CT Parameter Correlates with Pathological VEGFR-2/PDGFR-ß Expression in Renal Cell Carcinoma Patients.

BACKGROUND: Response prediction is necessary for renal cell carcinoma (RCC) tumors. We aim to evaluate parameters derived from 68 Ga-PSMA-11 PET/CT images for prediction of pathological VEGFR-2/PDGFR-ß expression of primary RCC tumors. METHODS: Forty-eight RCC patients were retrospectively enrolled with preoperative 68 Ga-PSMA-11 PET/CT scan and surgical specimen. Radiological parameters including tumor diameter, mean CT value, and maximal standard uptake value (SUVmax) were derived from PET/CT images and pathological VEGFR-2/PDGFR-ß/PSMA expression were identified with immunohistochemistry. Mann-Whitney U test was performed for continuous variables and the chi-square test for categorical variables. ROC was used for determining the effectiveness of preoperative parameters in differentiating VEGFR-2/PDGFR-ß expression. Univariate and multivariate logistic regression analyses were performed for significant parameters to predict VEGFR-2 & PDGFR-ß co-expression. RESULTS: Of the 48 tumors, 25 (52.1%) harbored positive VEGFR-2 expression, 28 (58.3%) harbored positive PDGFR-ß expression, and 24 (50%) were both VEGFR-2 positive and PDGFR-ß positive. SUVmax significantly differed by subgroups of VEGFR-2/PDGFR-ß expression (both P < 0.001). SUVmax demonstrated superior performance for differentiating VEGFR-2 & PDGFR-ß co-expression (positive vs. negative), with area under the curve 0.87 (95% CI 0.78-0.96, P < 0.001), sensitivity 93% and specificity 78%. Moreover, SUVmax was identified as the significant predictor for VEGFR-2 & PDGFR-ß co-expression (odds ratio 4.01, 95% CI 1.99-8.08, P < 0.001). Concordant with radiological findings with 68 Ga-PSMA-11 PET/CT, pathological PSMA staining intensity was significantly higher in both VEGFR-2-positive tumor and PDGFR-ß-positive tumor (P = 0.009 and P < 0.001, respectively). CONCLUSION: 68 Ga-PSMA-11 PET/CT could effectively identify pathological VEGFR-2/PDGFR-ß expression of primary RCC tumors, which may help with selection of mRCC patients suitable for TKIs treatment.

A Valence-Engineered Self-Cascading Antioxidant Nanozyme for the Therapy of Inflammatory Bowel Disease.

Antioxidant treatment strategy by scavenging reactive oxygen species (ROS) is a highly effective disease treatment option. Nanozymes with multiple antioxidant activities can cope with the diverse ROS environment. However, lack of design strategies and limitation of negative correlation for nanozymes with multiple antioxidant activities hindered their development. To overcome these difficulties, here we used ZnMn2 O4 as a model to explore the role of Mn valency at the octahedral site via a valence-engineered strategy, and found that its multiple antioxidant activities are positively correlated with the content of Mn4+ . Therefore, through this strategy, a self-cascading antioxidant nanozyme LiMn2 O4 was constructed, and its efficacy was verified at the cellular level and in an inflammatory bowel disease model. This work not only provides guidance for the design of multiple antioxidant nanozymes, but also broadens the biomedical application potential of multiple antioxidant nanozymes.

Pan-cancer analysis identifies LMNB1 as a target to redress Th1/Th2 imbalance and enhance PARP inhibitor response in human cancers.

BACKGROUND: Emerging evidence suggests that LMNB1 is involved in the development of multiple cancer types. However, there is no study reporting the potential role of LMNB1 in a systematic pan-cancer manner. METHODS: The gene expression level and potential oncogenic roles of LMNB1 in The Cancer Genome Atlas (TCGA) database were analyzed with Tumor Immune Estimation Resource version 2 (TIMER2.0), Gene Expression Profiling Interactive Analysis version 2 (GEPIA2), UALCAN and Sangerbox tools. Pathway enrichment analysis was carried out to explore the possible mechanism of LMNB1 on tumorigenesis and tumor progression. The therapeutic effects of LMNB1 knockdown combined with PARP inhibition on human cancers were further investigated in vitro. RESULTS: LMNB1 upregulation is generally observed in the tumor tissues of most TCGA cancer types, and is verified in kidney renal clear cell carcinoma using clinical specimens of our institute. High level of LMNB1 expression usually predicts poor overall survival and disease free survival for patients with tumors. Mechanically, LMNB1 level is positively correlated with CD4+ Th2 cell infiltration and DNA homologous recombination repair gene expression. In vitro experiments reveal that targeting LMNB1 has a synergistic effect on prostate cancer with PARP inhibitor treatment. CONCLUSIONS: LMNB1 is a biomarker of CD4+ Th2 cell infiltration and DNA homologous recombination repair in human cancers. Blockage of LMNB1 combined with PARP inhibitor treatment could be a promising therapeutic strategy for patients with cancers.

Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma.

Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy.