Pharmacology of Hydrogen Sulfide and Its Donors in Cardiometabolic Diseases.

Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H2S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H2S in regulating proteins via persulfidation, a well known modification intricately associated with the pathogenesis of CMDs. This review seeks to investigate recent updates on the physiological actions of endogenous H2S and the pharmacological roles of various H2S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies, including multiomics, intestinal microflora analysis, organoid, and single-cell sequencing techniques, are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H2S in health and diseases. We will critically assess the current literature to clarify the roles of H2S in diseases while also delineating the opportunities and challenges they present in H2S-based pharmacotherapy for CMDs. SIGNIFICANCE STATEMENT: This comprehensive review covers recent developments in H2S biology and pharmacology in cardiometabolic diseases CMDs. Endogenous H2S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H2S.

The functional specificity of ERECTA-family receptors in Arabidopsis stomatal development is ensured by molecular chaperones in the endoplasmic reticulum.

Stomata are epidermal pores that control gas exchange between plants and the atmosphere. In Arabidopsis, the ERECTA family (ERECTAf) receptors, including ERECTA, ERECTA-LIKE 1 (ERL1) and ERL2, redundantly play pivotal roles in enforcing the 'one-cell-spacing' rule. Accumulating evidence has demonstrated that the functional specificities of receptors are likely associated with their differential subcellular dynamics. The endoplasmic reticulum (ER)-resident chaperone complex SDF2-ERdj3B-BiP functions in many aspects of plant development. We employed pharmacological treatments combined with cell biological and biochemical approaches to demonstrate that the abundance of ERECTA was reduced in the erdj3b-1 mutant, but the localization and dynamics of ERECTA were not noticeably affected. By contrast, the erdj3b mutation caused the retention of ERL1/ERL2 in the ER. Furthermore, we found that the function of SDF2-ERdj3B-BiP is implicated with the distinct roles of ERECTAf receptors. Our findings establish that the ERECTAf receptor-mediated signaling in stomatal development is ensured by the activities of the ER quality control system, which preferentially maintains the protein abundance of ERECTA and proper subcellular dynamics of ERL1/ERL2, prior to the receptors reaching their destination - the plasma membrane - to execute their functions.

Dynamic Assembly of DNA Nanostructures in Cancer Cells Enables the Coupling of Autophagy Activating and Real-Time Tracking.

Developing dynamic nanostructures for in situ regulation of biological processes inside living cells is of great importance in biomedical research. Herein we report the cascaded assembly of Y-shaped branched DNA nanostructure (YDN) during intracellular autophagy. YDN contains one arm with semi-i-motif sequence and Cy3-BHQ2, and another arm with an apurinic/apyrimidinic (AP) site and Cy5-BHQ3. Upon uptake by cancer cells, intermolecular i-motif structures are formed in response to lysosomal H+, causing the formation of YDN-dimer and the recovery of Cy3 fluorescence; when escapes occur from the lysosome to the cytoplasm, the YDN-dimer responds to the overexpressed APE1, leading to the assembly of YDN into the DNA network and the fluorescence recovery of Cy5. Simultaneously, the cascaded assembly activates autophagy, and thus the process of assembly of YDN and autophagy flux can be spatiotemporally coupled. This work illustrates the potential of DNA nanostructures for the in situ regulation of intracellular dynamic events with spatiotemporal control.

Identification macrophage signatures in prostate cancer by single-cell sequencing and machine learning.

BACKGROUND: The tumor microenvironment (TME) encompasses a variety of cells that influence immune responses and tumor growth, with tumor-associated macrophages (TAM) being a crucial component of the TME. TAM can guide prostate cancer in different directions in response to various external stimuli. METHODS: First, we downloaded prostate cancer single-cell sequencing data and second-generation sequencing data from multiple public databases. From these data, we identified characteristic genes associated with TAM clusters. We then employed machine learning techniques to select the most accurate TAM gene set and developed a TAM-related risk label for prostate cancer. We analyzed the tumor-relatedness of the TAM-related risk label and different risk groups within the population. Finally, we validated the accuracy of the prognostic label using single-cell sequencing data, qPCR, and WB assays, among other methods. RESULTS: In this study, the TAM_2 cell cluster has been identified as promoting the progression of prostate cancer, possibly representing M2 macrophages. The 9 TAM feature genes selected through ten machine learning methods and demonstrated their effectiveness in predicting the progression of prostate cancer patients. Additionally, we have linked these TAM feature genes to clinical pathological characteristics, allowing us to construct a nomogram. This nomogram provides clinical practitioners with a quantitative tool for assessing the prognosis of prostate cancer patients. CONCLUSION: This study has analyzed the potential relationship between TAM and PCa and established a TAM-related prognostic model. It holds promise as a valuable tool for the management and treatment of PCa patients.

A Novel Classification System of Renal Hilar Tumors for Surgical Guidance: Technique, Outcome, and Safety.

BACKGROUND: This study was designed to develop an innovative classification and guidance system for renal hilar tumors and to assess the safety and effectiveness of robot-assisted partial nephrectomy (RAPN) for managing such tumors. METHODS: A total of 179 patients undergoing RAPN for renal hilar tumors were retrospectively reviewed. A novel classification system with surgical techniques was introduced and the perioperative features, tumor characteristics, and the efficacy and safety of RAPN were compared within subgroups. RESULTS: We classified the tumors according to our novel system as follows: 131 Type I, 35 Type II, and 13 Type III. However, Type III had higher median R.E.N.A.L., PADUA, and ROADS scores compared with the others (all p < 0.001), indicating increased operative complexity and higher estimated blood loss [180.00 (115.00-215.00) ml]. Operative outcomes revealed significant disparities between Type III and the others, with longer operative times [165.00 (145.00-200.50) min], warm ischemia times [24.00 (21.50-30.50) min], tumor resection times [13.00 (12.00-15.50) min], and incision closure times [22.00 (20.00-23.50) min] (all p < 0.005). Postoperative outcomes also showed significant differences, with longer durations of drain removal (77.08 ± 18.16 h) and hospitalization for Type III [5.00 (5.00-6.00) d] (all p < 0.05). Additionally, Type I had a larger tumor diameter than the others (p = 0.009) and pT stage differed significantly between the subtypes (p = 0.020). CONCLUSIONS: The novel renal hilar tumor classification system is capable of differentiating the surgical difficulty of RAPN and further offers personalized surgical steps tailored to each specific classification. It provides a meaningful tool for clinical practice.

Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice.

BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. METHODS: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. RESULTS: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. CONCLUSIONS: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.

Klotho Stabilizes the Podocyte Actin Cytoskeleton in Idiopathic Membranous Nephropathy through Regulating the TRPC6/CatL Pathway.

INTRODUCTION: The aim of this study was to explore the renoprotective effects of Klotho on podocyte injury mediated by complement activation and autoantibodies in idiopathic membranous nephropathy (IMN). METHODS: Rat passive Heymann nephritis (PHN) was induced as an IMN model. Urine protein levels, serum biochemistry, kidney histology, and podocyte marker levels were assessed. In vitro, sublytic podocyte injury was induced by C5b-9. The expression of Klotho, transient receptor potential channel 6 (TRPC6), and cathepsin L (CatL); its substrate synaptopodin; and the intracellular Ca2+ concentration were detected via immunofluorescence. RhoA/ROCK pathway activity was measured by an activity quantitative detection kit, and the protein expression of phosphorylated-LIMK1 (p-LIMK1) and p-cofilin in podocytes was detected via Western blotting. Klotho knockdown and overexpression were performed to evaluate its role in regulating the TRPC6/CatL pathway. RESULTS: PHN rats exhibited proteinuria, podocyte foot process effacement, decreased Klotho and Synaptopodin levels, and increased TRPC6 and CatL expression. The RhoA/ROCK pathway was activated by the increased phosphorylation of LIMK1 and cofilin. Similar changes were observed in C5b-9-injured podocytes. Klotho knockdown exacerbated podocyte injury, while Klotho overexpression partially ameliorated podocyte injury. CONCLUSION: Klotho may protect against podocyte injury in IMN patients by inhibiting the TRPC6/CatL pathway. Klotho is a potential target for reducing proteinuria in IMN patients.

Nesfatin-1 enhances vascular smooth muscle calcification through facilitating BMP-2 osteogenic signaling.

Vascular calcification (VC) arises from the accumulation of calcium salts in the intimal or tunica media layer of the aorta, contributing to higher risk of cardiovascular events and mortality. Despite this, the mechanisms driving VC remain incompletely understood. We previously described that nesfatin-1 functioned as a switch for vascular smooth muscle cells (VSMCs) plasticity in hypertension and neointimal hyperplasia. In this study, we sought to investigate the role and mechanism of nesfatin-1 in VC. The expression of nesfatin-1 was measured in calcified VSMCs and aortas, as well as in patients. Loss- and gain-of-function experiments were evaluated the roles of nesfatin-1 in VC pathogenesis. The transcription activation of nesfatin-1 was detected using a mass spectrometry. We found higher levels of nesfatin-1 in both calcified VSMCs and aortas, as well as in patients with coronary calcification. Loss-of-function and gain-of-function experiments revealed that nesfatin-1 was a key regulator of VC by facilitating the osteogenic transformation of VSMCs. Mechanistically, nesfatin-1 promoted the de-ubiquitination and stability of BMP-2 via inhibiting the E3 ligase SYTL4, and the interaction of nesfatin-1 with BMP-2 potentiated BMP-2 signaling and induced phosphorylation of Smad, followed by HDAC4 phosphorylation and nuclear exclusion. The dissociation of HDAC4 from RUNX2 elicited RUNX2 acetylation and subsequent nuclear translocation, leading to the transcription upregulation of OPN, a critical player in VC. From a small library of natural compounds, we identified that Curculigoside and Chebulagic acid reduced VC development via binding to and inhibiting nesfatin-1. Eventually, we designed a mass spectrometry-based DNA-protein interaction screening to identify that STAT3 mediated the transcription activation of nesfatin-1 in the context of VC. Overall, our study demonstrates that nesfatin-1 enhances BMP-2 signaling by inhibiting the E3 ligase SYTL4, thereby stabilizing BMP-2 and facilitating the downstream phosphorylation of SMAD1/5/9 and HDAC4. This signaling cascade leads to RUNX2 activation and the transcriptional upregulation of MSX2, driving VC. These insights position nesfatin-1 as a potential therapeutic target for preventing or treating VC, advancing our understanding of the molecular mechanisms underlying this critical cardiovascular condition.

Excellent ratiometric two-photon fluorescent probes for hydrogen sulfide detection based on the fluorescence resonance energy transfer mechanism.

Fluorescence resonance energy transfer (FRET) is an important mechanism to design ratiometric fluorescent probes that are able to detect analytes quantitatively according to the ratio of two well-resolved emission signals. Two-photon (TP) fluorescent probes can realize the detection in living cells and tissues with deeper penetration depth, higher resolution, and lower photodamage in contrast to one-photon fluorescent probes. However, to date, fabricating TP-FRET ratiometric fluorescent probes possessing large two-photon absorption (TPA), high fluorescence quantum yield and perfect FRET efficiency is still challenging. Consequently, to develop excellent TP-FRET ratiometric probes and explore the relationship between their molecular structures and TP fluorescence properties, in this paper, we designed a series of H2S-detecting TP fluorescent probes employing the FRET mechanism based on an experimental probe BCD. Thereafter, we comprehensively evaluated the TP sensing performance of these probes by means of time-dependent density functional theory and quadratic response theory. Furthermore, we determined energy transfer efficiency and fluorescence quantum yield. Significantly, through regulating benzene-fused positions, we successfully improved fluorescence quantum yield and TPA cross-section simultaneously. Large spectral overlap between energy donor emission and acceptor absorption was achieved and near perfect energy transfer efficiency was acquired for all the studied probes. We revealed that these probes exhibit two well-resolved TPA bands, which are contributed by FRET donors and acceptors, respectively. Especially, both the wavelengths and the cross-sections of the two TPA bands agree well with those of energy donors and acceptors, which is the unique TPA spectral profile of FRET probes and has never been previously reported. Moreover, we proposed an excellent TP-FRET probe BCD3 and its product molecule BCD3-H2S, which exhibit large Stokes (141 nm and 88 nm) and emission shifts (5931 cm-1), as well as greatly increased TP action cross-sections (24-fold and 60-fold) in the near-infrared region with respect to BCD and BCD-H2S. Our detailed study can give an insight into the efficient design of novel TP-FRET fluorescent probes.

The Vici Syndrome Protein EPG5 Is a Rab7 Effector that Determines the Fusion Specificity of Autophagosomes with Late Endosomes/Lysosomes.

Mutations in the human autophagy gene EPG5 cause the multisystem disorder Vici syndrome. Here we demonstrated that EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. EPG5 is recruited to late endosomes/lysosomes by direct interaction with Rab7 and the late endosomal/lysosomal R-SNARE VAMP7/8. EPG5 also binds to LC3/LGG-1 (mammalian and C. elegans Atg8 homolog, respectively) and to assembled STX17-SNAP29 Qabc SNARE complexes on autophagosomes. EPG5 stabilizes and facilitates the assembly of STX17-SNAP29-VAMP7/8 trans-SNARE complexes, and promotes STX17-SNAP29-VAMP7-mediated fusion of reconstituted proteoliposomes. Loss of EPG5 activity causes abnormal fusion of autophagosomes with various endocytic vesicles, in part due to elevated assembly of STX17-SNAP25-VAMP8 complexes. SNAP25 knockdown partially suppresses the autophagy defect caused by EPG5 depletion. Our study reveals that EPG5 is a Rab7 effector involved in autophagosome maturation, providing insight into the molecular mechanism underlying Vici syndrome.

Membrane P-glycoprotein expression in lymphocytes from adult patients with refractory glomerulonephritis.

OBJECTIVES: To investigate the expression of P-glycoprotein in T-cell subpopulations of lymphocytes from adult patients with refractory glomerulonephritis (GN). MATERIALS AND METHODS: Flow cytometry was used to analyze the T-cell subpopulations of lymphocytes from adult patients with refractory GN and healthy individuals. The CD243 antibody marked the membrane P-glycoprotein of immune cells. RESULTS: The mean ± standard deviation (SD) values of percentages of CD3+, CD3+CD4+, CD3+CD8+ cells in lymphocytes from patients with refractory GN were 63.94 ± 26.98, 55.16 ± 4.78, and 37.79 ± 6.01%, respectively. These values in healthy individuals were 74.88 ± 3.75, 56.60 ± 9.22, and 34.20 ± 5.21%, respectively. No significant differences were observed between the patients with refractory GN and healthy individuals. The mean ± SD values of percentages of CD3+CD4+CD243+ and CD3+CD8+CD243+ cells in the lymphocytes of patients with refractory GN were 0.14 ± 0.11 and 0.11 ± 0.07%, respectively. These values in healthy individuals were 0.05 ± 0.02 and 0.04 ± 0.02%, respectively. The difference in CD3+CD8+CD243+ percentage between patients with refractory GN and healthy individuals was significant (p = 0.0216). CONCLUSION: These findings suggest that P-glycoprotein expression on CD3+CD8+ T cells is a promising marker and a suitable target of drug resistance in patients with refractory GN.

A tumor-associated macrophages related model for predicting biochemical recurrence and tumor immune environment in prostate cancer.

OBJECTIVE: To identify tumor-associated macrophages (TAMs) related molecular subtypes and develop a TAMs related prognostic model for prostate cancer (PCa). METHODS: Consensus clustering analysis was used to identify TAMs related molecular clusters. A TAMs related prognostic model was developed using univariate and multivariate Cox analysis. RESULTS: Three TAMs related molecular clusters were identified and were confirmed to be associated with prognosis, clinicopathological characteristics, PD-L1 expression levels and tumor microenvironment. A TAMs related prognostic model was constructed. Patients in low-risk group all showed a more appreciable biochemical recurrence-free survival (BCRFS) than patients in high-risk group in train cohort, test cohort, entire TCGA cohort and validation cohort. SLC26A3 attenuated progression of PCa and prevented macrophage polarizing to TAMs phenotype, which was initially verified. CONCLUSIONS: We successfully identified molecular clusters related to TAMs. Additionally, we developed a prognostic model involving TAMs that exhibits excellent predictive performance for biochemical recurrence-free survival in PCa.

ND630 controls ACACA and lipid reprogramming in prostate cancer by regulating the expression of circKIF18B_003.

BACKGROUND: ND630 is believed to be a new therapy pharmacologic molecule in targeting the expression of ACACA and regulating the lipid metabolism. However, the function of ND630 in prostate cancer remains unknown. KIF18B, as an oncogene, plays a vital role in prostate cancer progression. circKIF18B_003 was derived from oncogene KIF18B and was markedly overexpressed in prostate cancer tissues. We speculated that oncoprotein KIF18B-derived circRNA circKIF18B_003 might have roles in prostate cancer promotion. The aim of this study was to validate whether ND630 could control ACACA and lipid reprogramming in prostate cancer by regulating the expression of circKIF18B_003. METHODS: RT-qPCR was used to analyze the expression of circKIF18B_003 in prostate cancer cell lines and prostate cancer samples. circKIF18B_003 expression was modulated in prostate cancer cells using circKIF18B_003 interference or overexpression plasmid. We examined the function and effects of circKIF18B_003 in prostate cancer cells using CCK-8, colony formation, wound healing, and Transwell invasion assays and xenograft models. Fluorescence in situ hybridization (FISH) was performed to evaluate the localization of circKIF18B_003. RNA immunoprecipitation (RIP), RNA pull down, and luciferase reporter assay were performed to explore the potential mechanism of circKIF18B_003. RESULTS: The function of ND630 was determined in this study. circKIF18B_003 was overexpressed in prostate cancer tissues, and overexpression of circKIF18B_003 was associated with poor survival outcome of prostate cancer patients. The proliferation, migration, and invasion of prostate cancer cells were enhanced after up-regulation of circKIF18B_003. circKIF18B_003 is mainly located in the cytoplasm of prostate cancer cells, and the RIP and RNA pull down assays confirmed that circKIF18B_003 could act as a sponge for miR-370-3p. Further study demonstrated that up-regulation of circKIF18B_003 increased the expression of ACACA by sponging miR-370-3p. The malignant ability of prostate cancer cells enhanced by overexpression of circKIF18B_003 was reversed by the down-regulation of ACACA. We found that overexpression of circKIF18B_003 was associated with lipid metabolism, and a combination of ND-630 and docetaxel markedly attenuated tumor growth. CONCLUSION: ND630 could control ACACA and lipid reprogramming in prostate cancer by regulating the expression of circKIF18B_003. ND630 and circKIF18B_003 may represent a novel target for prostate cancer.

Integrative Analysis Developing and Validating Potential Candidate Biomarkers for Cancer Stemness Features of Pan-Renal Cell Carcinoma.

In our study, 49 key genes significantly associated with renal cell carcinoma (RCC) stemness were obtained. Next, we developed a molecular prognostic signature associated with stemness features of pan-RCC. The difference in overall survival (OS) between the high- and low-risk groups was statistically significant (p < .05). The area under the receiver operating characteristic curve for 1-year OS, 5-year OS, and 10-year OS was 0.759, 0.712, and 0.918, respectively. The results of validation in The Cancer Genome Atlas cohort and International Cancer Genome Consortium cohort revealed the predictive capability of this signature. Furthermore, we selected three genes and further validation showed that these three hub genes were potential hub biomarkers for pan-RCC stemness features.

Head-to-head comparisons of [68Ga]Ga-PSMA-11 PET/CT, multiparametric MRI, and prostate-specific antigen for the evaluation of therapeutic responses to neoadjuvant chemohormonal therapy in high-risk non-metastatic prostate cancer patients: a prospective study.

PURPOSE: The optimal tool to evaluate the tumour therapeutic responses to neoadjuvant chemohormonal therapy (NCHT) in patients with high-risk non-metastatic prostate cancer (PCa) remains uncertain. We compared the role of [68Ga]-labeled prostate-specific membrane antigen (PSMA)-11 positron emission tomography/computerized tomography ([68Ga]Ga-PSMA-11 PET/CT), multiparametric MRI (mpMRI), and prostate-specific antigen (PSA) and assessed the practical value of the recent European Association of Urology and European Association of Nuclear Medicine (EAU/EANM) recommended criteria of PSMA PET/CT to evaluate the therapeutic responses to NCHT in patients with high-risk non-metastatic PCa. METHODS: This prospective study included 72 high-risk non-metastatic PCa patients receiving NCHT followed by radical prostatectomy from June 2021 to March 2022. PSA testing, [68Ga]Ga-PSMA-11 PET/CT, and mpMRI scanning were conducted in all patients before and after NCHT. Therapeutic responses to NCHT were evaluated with PSA, RECIST 1.1, PERCIST 1.0, and EAU/EANM recommended criteria. Postoperative pathological results were considered the reference standard. A favourable pathological response was defined as pathologic complete remission (pCR) or minimal residual disease (MRD). Diagnostic accuracy was assessed by sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), positive predictive value (PPV), negative predictive value (NPV), and Cohen's kappa index. Logistic regression analysis was used to determine the independent predictive value of [68Ga]Ga-PSMA-11 PET/CT-derived parameters. RESULTS: All cases experienced a marked decrease in PSA levels after NCHT. Twenty-four (33.33%) cases experienced a favourable pathological response, including five (6.94%) cases of pCR and 19 (26.39%) cases of MRD. According to the results of [68Ga]Ga-PSMA-11 PET/CT, EAU/EANM recommended criteria indicated that 20 (27.78%) cases had a CR, whereas PERCIST 1.0 criteria indicated that 23 (31.94%) cases had a CR. There was a strong association between EAU/EANM recommended criteria and PERCIST 1.0 criteria (Pearson's R=0.857). The sensitivity (75.00%, 79.17% vs. 58.33%, 58.33%), specificity (95.83%, 91.67% vs. 83.33%, 68.75%), PLR (18.00, 9.50 vs. 3.50, 1.87), NLR (0.26, 0.23 vs. 0.50, 0.61), PPV (90.0%, 82.6% vs. 63.6%, 48.3%), and NPV (88.5%, 89.8% vs. 80.0%, 76.7%) of [68Ga]Ga-PSMA-11 PET/CT (including EAU/EANM recommended criteria and PERCIST 1.0 criteria) to predict favourable pathological responses were all superior to those of mpMRI and nadir PSA. The kappa index to predict a favourable pathological response was 0.257 for PSA, 0.426 for RECIST 1.1, 0.716 for PERCIST 1.0, and 0.739 for EAU/EANM recommended criteria. Multivariate logistic analysis revealed that the post-NCHT maximum standardized uptake value (SUVmax) before radical prostatectomy was an independent predictor of a favourable pathological response to NCHT. CONCLUSIONS: [68Ga]Ga-PSMA-11 PET/CT had a better concordance with a favourable pathological response to NCHT compared with nadir PSA and mpMRI. EAU/EANM recommended criteria and PERCIST 1.0 criteria performed equally to identify pathological responders when [68Ga]Ga-PSMA-11 PET/CT was used as a therapeutic response assessment tool.

Thermal Reactivity of High-Density Hybrid Hexahydro-1,3,5-trinitro-1,3,5-triazine Crystals Prepared by a Microfluidic Crystallization Method.

In this paper, the two-dimensional (2D) high nitrogen triaminoguanidine-glyoxal polymer (TAGP) has been used to dope hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) crystals using a microfluidic crystallization method. A series of constraint TAGP-doped RDX crystals using a microfluidic mixer (so-called controlled qy-RDX) with higher bulk density and better thermal stability have been obtained as a result of the granulometric gradation. The crystal structure and thermal reactivity properties of qy-RDX are largely affected by the mixing speed of the solvent and antisolvent. In particular, the bulk density of qy-RDX could be slightly changed in the range from 1.78 to 1.85 g cm-3 as a result of varied mixing states. The obtained qy-RDX crystals have better thermal stability than pristine RDX, showing a higher exothermic peak temperature and an endothermic peak temperature with a higher heat release. Ea for thermal decomposition of controlled qy-RDX is 105.3 kJ mol-1, which is 20 kJ mol-1 lower than that of pure RDX. The controlled qy-RDX samples with lower Ea followed the random 2D nucleation and nucleus growth (A2) model, whereas controlled qy-RDX with higher Ea (122.8 and 122.7 kJ mol-1) following some complex model between A2 and the random chain scission (L2) model.

Precise Regulation of Combustion Characteristics of High-Energy Composite Propellants by Incorporation of CL-20 Crystals Intercalated with Energetic Burn Rate Modifiers.

In this study, a 2D structured triaminoguanidine-glyoxal polymer with a high nitrogen content has been coordinated with metal ions to produce energetic metal complexes (TAGP-Ms) employed as energetic burn rate inhibitors. The metal ions (Ba2+, K+, and Ca2+) are elaborately selected based on their ability of suppressing the burn rate of composite propellants. The CL-20 crystals were intercalated with prepared TAGP-Ms materials via a solvent-antisolvent method for realization of the precise control on burning behaviors of studied propellants. The influence of TAGP-Ms inhibitors on thermal decomposition and combustion characteristics of high-energy composite propellants was evaluated using thermal analysis and a combustion diagnostic method. Results of TGA/DSC-FTIR measurements suggest that the thermal decomposition of CL-20-containing composite propellants was found to be constrained by varied degrees as a result of TAGP-Ms additions, in which the TAGP-K displays a stronger effect on suppressing the thermal decomposition of CL-20 compared with that of other TAGP-Ms. The FTIR spectra indicate that the primary gaseous phase products are composed of N2O, H2O, and CO2 in CL-20 decomposition, as well as by HCl, H2O, NO2, and N2O in the decomposition of AP for all studied composite propellants. The combustion characterizations show that the TAGP-K-containing composite propellant exhibits a significantly reduced rate of heat release but is associated with a higher flame radiation intensity increased by 4.2% compared with that of the reference propellant, which clearly implies that the TAGP-K is capable of suppressing the energy release rate while ensuring the high energetic features of propellants to be well maintained. Moreover, the burn rate pressure exponents are considerably decreased by ∼10% for the TAGP-K-containing propellants in comparison with those of propellants with the typical formulation, which strongly suggests that TGAP-Ms are promising candidates for tuning the combustion behaviors of composite propellants by influencing the decomposition processes of CL-20 and AP collectively.

Risk factors for lymphorrhea and lymphocele after radical prostatectomy: a retrospective case-control study.

PURPOSE: To investigate the risk factors for postoperative lymphorrhea or/and lymphocele (PLL) in patients undergoing radical prostatectomy (RP). MATERIALS AND METHODS: The clinical data of 606 patients were retrospectively collected. The receiver operating characteristic (ROC) curve was utilized to identify the optimal cutoff value. Multivariable logistic regression analysis was used to screen the independent predictors of PLL. RESULTS: Univariate analysis showed that nine factors differed between the PLL and non-PLL group. Multivariable logistic regression analysis showed that low preoperative fibrinogen level, extraperitoneal surgery, robot-assisted laparoscopic radical prostatectomy (RALRP), and hypoalbuminemia were risk factors and the use of fibrin glue was a protective factor. Correlation analysis showed that the scope of LN dissection (LND) and number of lymph nodes (LNs) dissected were positively correlated with PLL in the extraperitoneal approach, but were not significantly correlated with PLL in the transperitoneal approach. The use of fibrin glue was negatively associated with PLL in the overall procedure and the extraperitoneal approach, but not significantly so in the transperitoneal approach. Comparison of LNs clearance between the two surgical approaches revealed that the extent of LND and number of LNs dissected in the extraperitoneal approach were less than in the transperitoneal approach. CONCLUSION: During RALRP, more attention should be paid to fully clotting the broken end of lymphatic vessels. The use of fibrin glue could reduce the probability of PLL. The extent of LND or number of LNs dissected were positively correlated with PLL in the extraperitoneal approach.

A novel CD8+ T cell-related gene signature for predicting the prognosis and immunotherapy efficacy in bladder cancer.

OBJECTIVE: To identify CD8+ T cell-related molecular clusters and establish a novel gene signature for predicting the prognosis and efficacy of immunotherapy in bladder cancer (BCa). METHODS: Transcriptome and clinical data of BCa samples were obtained from the Cancer Genome Atlas (TCGA) and GEO databases. The CD8+ T cell-related genes were screened through the CIBERSORT algorithm and correlation analysis. Consensus clustering analysis was utilized to identified CD8+ T cell-related molecular clusters. A novel CD8+ T cell-related prognostic model was developed using univariate Cox regression analysis and Lasso regression analysis. Internal and external validations were performed and the validity of the model was validated in a real-world cohort. Finally, preliminary experimental verifications were carried out to verify the biological functions of SH2D2A in bladder cancer. RESULTS: A total of 52 CD8+ T cell-related prognostic genes were screened and two molecular clusters with notably diverse immune cell infiltration, prognosis and clinical features were developed. Then, a novel CD8+ T cell-related prognostic model was constructed. The patients with high-risk scores exhibited a significantly worse overall survival in training, test, whole TCGA and validating cohort. The AUC was 0.766, 0.725, 0.739 and 0.658 in the four cohorts sequentially. Subgroup analysis suggested that the novel prognostic model has a robust clinical application for selecting high-risk patients. Finally, we confirmed that patients in the low-risk group might benefit more from immunotherapy or chemotherapy, and validated the prognostic model in a real-world immunotherapy cohort. Preliminary experiment showed that SH2D2A was capable of attenuating proliferation, migration and invasion of BCa cells. CONCLUSIONS: CD8+ T cell-related molecular clusters were successfully identified. Besides, a novel CD8+ T cell-related prognostic model with an excellent predictive performance in predicting survival rates and immunotherapy efficacy of BCa was developed.

Exosomal MiR-381 from M2-polarized macrophages attenuates urethral fibroblasts activation through YAP/GLS1-regulated glutaminolysis.

OBJECTIVE AND DESIGN: Post-traumatic urethral stricture is a clinical challenge for both patients and clinicians. Targeting glutamine metabolism to suppress excessive activation of urethral fibroblasts (UFBs) is assumed to be a potent and attractive strategy for preventing urethral scarring and stricture. MATERIAL OR SUBJECTS: In cellular experiments, we explored whether glutaminolysis meets the bioenergetic and biosynthetic demands of quiescent UFBs converted into myofibroblasts. At the same time, we examined the specific effects of M2-polarized macrophages on glutaminolysis and activation of UFBs, as well as the mechanism of intercellular signaling. In addition, findings were further verified in vivo in New Zealand rabbits. RESULTS: It revealed that glutamine deprivation or knockdown of glutaminase 1 (GLS1) significantly inhibited UFB activation, proliferation, biosynthesis, and energy metabolism; however, these effects were rescued by cell-permeable dimethyl α-ketoglutarate. Moreover, we found that exosomal miR-381 derived from M2-polarized macrophages could be ingested by UFBs and inhibited GLS1-dependent glutaminolysis, thereby preventing excessive activation of UFBs. Mechanistically, miR-381 directly targets the 3'UTR of Yes-associated protein (YAP) mRNA to reduce its stability at the transcriptional level, ultimately downregulating expression of YAP, and GLS1. In vivo experiments revealed that treatment with either verteporfin or exosomes derived from M2-polarized macrophages significantly reduced urethral stricture in New Zealand rabbits after urethral trauma. CONCLUSION: Collectively, this study demonstrates that exosomal miR-381 from M2-polarized macrophages reduces myofibroblast formation of UFBs and urethral scarring and stricture by inhibiting YAP/GLS1-dependent glutaminolysis.