Exploring the clinical and diagnostic value of metagenomic next-generation sequencing for urinary tract infection: a systematic review and meta-analysis.

BACKGROUND: A new pathogen detection tool, metagenomic next-generation sequencing (mNGS), has been widely used for infection diagnosis, but the clinical and diagnostic value of mNGS in urinary tract infection (UTI) remains inconclusive. This systematic review with meta-analysis aimed to investigate the efficacy of mNGS in treating UTIs. METHODS: A comprehensive literature search was performed in PubMed, Web of Science, Embase, and the Cochrane Library, and eligible studies were selected based on the predetermined criteria. The quality of the included studies was assessed via the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool, and the certainty of evidence (CoE) was measured by the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) score. Then, the positive detection rate (PDR), pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve of the summary receiver operating characteristic curve (AUROC) was estimated in Review Manager, Stata, and MetaDisc. Subgroup analysis, meta-regression, and sensitivity analysis were performed to reveal the potential factors that influence internal heterogeneity. RESULTS: A total of 17 studies were selected for further analysis. The PDR of mNGS was markedly greater than that of culture (odds ratio (OR) = 2.87, 95% confidence interval [CI]: 1.72-4.81, p < 0.001, I2 = 90%). The GRADE score presented a very low CoE. Then, the pooled sensitivity was 0.89 (95% CI: 0.86-0.91, I2 = 39.65%, p = 0.06), and the pooled specificity was 0.75 (95% CI: 0.51-0.90, I2 = 88.64%, p < 0.001). The AUROC of the studies analyzed was 0.89 (95% CI: 0.86-0.92). The GRADE score indicated a low CoE. CONCLUSION: The current evidence shows that mNGS has favorable diagnostic performance for UTIs. More high-quality prospective randomized controlled trials (RCTs) are expected to verify these findings and provide more information about mNGS in UTI treatment and prognosis.

Pressure Characteristics and Secondary Ignition Effects of Gas Produced in RDE Using Lignite and Anthracite/CH4 Fuel.

This study aims to address the energy efficiency release and environmental impact of coal dust in rotating detonation engines (RDEs) by monitoring the detonation characteristics of lignite and anthracite in methane gas-solid mixtures using high-precision sensor technology. Experimental results indicate that the peak detonation pressure of anthracite is 1.4% higher than that of lignite, and its detonation wave propagation speed is at least 5.5% faster, suggesting that anthracite exhibits more stable and efficient fuel energy release characteristics during detonation. Additionally, the sensor technology enabled detailed recording of pressure fluctuations and gas composition changes during the detonation process, providing accurate data for assessing and controlling emissions of harmful gases such as carbon monoxide and carbon dioxide. These data are crucial for designing more efficient and environmentally friendly coal dust detonation systems, enhancing mine safety and environmental protection. The outcomes of this research not only advance technological progress in the field of energy science but also address efficiency and environmental issues in industrial applications, offering significant support for achieving safer and more sustainable energy production methods.

Epigenetic modification of Castor zinc finger 1 (CASZ1) is associated with tumor microenvironments and prognosis of clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) represents the predominant and remarkably diverse form of renal cell carcinoma. The involvement of the Castor zinc finger 1 (CASZ1) gene in adverse prognostic outcomes has been observed across different cancer types. Nevertheless, the specific altered activities and associated multi-omics characteristics of CASZ1 in ccRCC remain unelucidated. METHOD: In order to explore the expression of CASZ1, evaluate its prognostic significance, and aid in the therapeutic decision-making process for patients with ccRCC, the The Cancer Genome Atlas(TCGA), Gene expression omnibus (GEO), and The Human Protein Atlas (HPA) databases were utilized to gather data on clinicopathological data, prognostic information, genomic, methylomic and immunomic data. Additionally, the Genomics of drug sensitivity in cancer (GDSC) database provided information on drug sensitivity. RESULTS: CASZ1 expression was found to be significantly reduced in ccRCC and was associated with unfavorable pathological characteristics and a bleak prognosis. Diminished CASZ1 mRNA levels were notably correlated with heightened cytosine-phosphate-guanine (CpG) methylation , indicating a poorer prognosis for patients with increased methylation. Examination of RNA-seq data from TCGA indicated that the CASZ1-high expression subgroup displayed heightened immune cell infiltration and increased expression of immune checkpoint markers, potentially suggesting a more favorable response to immunotherapy. Furthermore, data from the GDSC database indicated that the CASZ1-low expression subgroup might exhibit greater sensitivity to anti-angiogenetic treatments, such as Sunitinib and Axitinib. CONCLUSIONS: These results indicate that CASZ1 may function as a biomarker for distinguishing various tumor microenvironment phenotypes, predicting prognosis, and assisting in treatment decisions for individuals with ccRCC.

Experimental Study and Application Prospects of Coal Dust/Methane/Oxygen Pulse Detonation Performance: Coal Dust Equivalence Ratio and Types.

In order to achieve reliable application of coal in pulse detonation combustion chambers, this study explored the influence mechanism of equivalence ratio and coal type (lignite, anthracite) on the detonation characteristics of coal/methane/oxygen methane-solid two-phase fuel. A high-energy ignition device was used to ignite the preblast methane fuel, and the high-temperature and high-pressure energy generated directly initiated the detonation of coal/methane/oxygen methane-solid two-phase fuel. The experimental results are as follows: (1) The maximum detonation pressure of coal/methane/air fuel is positively correlated with the initial pressure. With the increase of the φglobal, the maximum detonation pressure of the two types of coal gradually increases. To be specific, when the φglobal rises from 0.5 to 1.6, the sensitivity of lignite and anthracite to the maximum detonation pressure with respect to the initial pressure increases from 4.56 to 6.11 and 5.48, respectively; (2) In terms of detonation flame and maximum pressure wave velocity, anthracite shows better dynamic performance than lignite. The maximum velocity of detonation flame and pressure wave is achieved when the φglobal is 1.4. (3) In terms of detonation thrust performance, as the φglobal increases from 0.5 to 1.6, the rate of increase in average thrust of the two types of coal first increases and then decreases. Compared with lignite, anthracite has a wider time domain and higher peak value in the average thrust curve and the generated detonation wave displays a greater impulse. The experimental data and conclusions obtained in this study are of practical significance for realizing the engineering application of pulverized coal detonator power generation.

NAPRT silencing in FH-deficient renal cell carcinoma confers therapeutic vulnerabilities via NAD+ depletion.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. Loss of FH leads to accumulation of fumarate, an oncometabolite that disrupts multiple cellular processes and drives tumor progression. High levels of fumarate inhibit alpha ketoglutarate-dependent dioxygenases, including the ten eleven translocation (TET) enzymes and can lead to global DNA hypermethylation. Here, we report patterns of hypermethylation in FH-mutant cell lines and tumor samples are associated with silencing of nicotinate phosphoribosyl transferase (NAPRT), a rate-limiting enzyme in the Preiss-Handler pathway of NAD+ biosynthesis in a subset of HLRCC cases. NAPRT is hypermethylated at a CpG island in the promoter in cell line models and patient samples, resulting in loss of NAPRT expression. We find that FH-deficient RCC models with loss of NAPRT expression, as well as other oncometabolite-producing cancer models that silence NAPRT, are extremely sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTis). NAPRT silencing was also associated with synergistic tumor cell killing with poly(ADP)-ribose polymerase inhibitors (PARPis) and NAMPTis, which was associated with effects on PAR-mediated DNA repair. Overall, our findings indicate that NAPRT-silencing can be targeted in oncometabolite-producing cancers and elucidates how oncometabolite associated hypermethylation can impact diverse cellular processes and leads to therapeutically relevant vulnerabilities in cancer cells. Implications: NAPRT is a novel biomarker for targeting NAD+ metabolism in FH-deficient HLRCCs with NAMPTis alone and targeting DNA repair processes with the combination of NAMPTis and PARPis.

Effect and Mechanism of 6-Gingerol against Precancerous Lesions of Gastric Cancer Based on Network Pharmacology and In Vitro Experiment.

BACKGROUND: Precancerous Lesions of Gastric Cancer (PLGC) are critical in the secondary prevention of gastric cancer. Despite the notable effects of natural products on PLGC, the specific mechanisms by which compounds, like 6-gingerol, influence these lesions are not fully understood. AIMS: This study aimed to confirm the effect and mechanism of 6-gingerol in the treatment of precancerous lesions of gastric cancer (PLGC). OBJECTIVE: The objective of this study was to elucidate the effects and mechanisms of 6-gingerol against PLGC using network pharmacology and in vitro experiments. METHODS: We employed network pharmacology to identify potential targets and pathways influenced by 6-gingerol, followed by validation through in vitro experiments using a PLGC cell model. RESULTS: Network pharmacology analysis highlighted the PI3K/Akt signaling pathway as significantly influenced by 6-gingerol. In vitro experiments confirmed that 6-gingerol effectively inhibited proliferation, invasion, and metastasis of MC cells, promoted apoptosis, and induced cell cycle arrest, primarily through modulation of the PI3K/Akt pathway. Statistical analysis revealed significant inhibition (p < 0.05) across these cellular processes in a dose-dependent manner. CONCLUSION: This study demonstrated that 6-gingerol acts as an effective agent against PLGC, with clear dose-dependent effects that pave the way for further experimental and clinical exploration.

Epigenetic modification of PHLDA2 is associated with tumor microenvironment and unfavorable outcome of immune checkpoint inhibitor-based therapies in clear cell renal cell carcinoma.

BACKGROUND: A substantial proportion of patients with metastatic clear cell renal cell carcinoma (ccRCC) cannot derive benefit from immune checkpoint inhibitor (ICI) plus anti-angiogenic agent combination therapy, making identification of predictive biomarkers an urgent need. The members of pleckstrin homology-like domain family A (PHLDA) play critical roles in multiple cancers, whereas their roles in ccRCC remain unknown. METHODS: Transcriptomic, clinical, genetic alteration and DNA methylation data were obtained for integrated analyses from TCGA database. RNA sequencing was performed on 117 primary tumors and 79 normal kidney tissues from our center. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis were performed to explore transcriptomic features. Data from three randomized controlled trials (RCT), including CheckMate025, IMmotion151, JAVELIN101, were obtained for validation. RESULTS: Members of PHLDA family were dysregulated in pan-cancer. Elevated PHLDA2 expression was associated with adverse clinicopathologic parameters and worse prognosis in ccRCC. Aberrant DNA hypomethylation contributed to up-regulation of PHLDA2. An immunosuppressive microenvironment featured by high infiltrates of Tregs and cancer-associated fibroblasts, was observed in ccRCC with higher PHLDA2 expression. Utilizing data from three RCTs, the association of elevated PHLDA2 expression with poor therapeutic efficacy of ICI plus anti-angiogenic combination therapy was confirmed. CONCLUSIONS: Our study revealed that elevated PHLDA2 expression regulated by DNA hypomethylation was correlated with poor prognosis and immunosuppressive microenvironment, and highlighted the role of PHLDA2 as a robust biomarker for predicting therapeutic efficacy of ICI plus anti-angiogenic agent combination therapy in ccRCC, which expand the dimension of precision medicine.

Atmosphere-dependent combustion of Ganoderma lucidum biomass toward its enhanced transformability into green energy.

Globally, the circular efficiency of biomass resources has become a priority due to the depletion and negative environmental impacts of fossil fuels. This study aimed to quantify the atmosphere-dependent combustion of Ganoderma lucidum (GL) biomass and its thermodynamic and kinetic parameters toward enhancing its circularity and transformability characteristics. The GL combustion occurred in the three stages of moisture removal, volatile release, and coke combustion. Combustion performance characteristics were more favorable in the N2/O2 atmosphere than in the CO2/O2 atmosphere under the same heating rates. The rising heating rate facilitated the release of volatiles. According to the model-free methods of Ozawa-Flynn-Wall and Kissinger-Akahira-Sunose, the activation energies essential for the primary reaction were 283.09 kJ/mol and 288.28 kJ/mol in the N2/O2 atmosphere and 233.09 kJ/mol and 235.64 kJ/mol in the CO2/O2 atmosphere. The gaseous products of the GL combustion included CH4, H2O, C = O, CO, CO2, NH3, C = C, and C-O(H). Ash prepared in both atmospheres exhibited a tendency for slag formation, with oxy-fuel combustion lowering its risk. This study thus provides a theoretical and practical basis for transforming GL residues into a sustainable energy source.

Patients with ASPSCR1-TFE3 fusion achieve better response to ICI based combination therapy among TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. METHODS: Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. RESULTS: Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. CONCLUSIONS: The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly.

The incidence of immune-related adverse events (irAEs) and their association with clinical outcomes in advanced renal cell carcinoma and urothelial carcinoma patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

BACKGROUND: This study aimed to summarize the occurrence of immune-related adverse events (irAEs) and further evaluate their association with clinical outcomes in patients with advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC) treated with immune checkpoint inhibitors (ICIs). METHODS: A comprehensive search of PubMed, Embase, and the Cochrane Library up to December 2023 was conducted to identify eligible studies. The details of irAEs and data regarding their correlation with clinical outcomes were extracted. R software was used for meta-analysis. RESULTS: A total of 27 studies involving 6148 patients with RCC or UC were included. The pooled overall incidence for any-grade and grade ≥ 3 irAEs was 44.2 % (95 % CI: 38.1 %-50.5 %) and 15.7 % (95 % CI: 11.4 %-21.1 %), respectively. Compared to those without any irAEs, patients with irAEs showed improved PFS (HR = 0.44, 95 % CI: 0.35-0.56, p < 0.01) and OS (HR = 0.47, 95 % CI: 0.42-0.51, p < 0.01), as well as higher ORR (OR = 3.59, 95 % CI: 3.01-4.29, p < 0.01) and DCR (OR = 4.23, 95 % CI: 3.06-5.84, p < 0.01). Subgroup analysis indicated that clinical outcome improvements were associated with the occurrence of irAEs, regardless of tumor type or ICI agent. Notably, patients with cutaneous irAEs, thyroid dysfunction, and grade ≤ 2 irAEs had a higher probability to achieve better survival benefits from ICI-based therapy, while pulmonary irAEs and grade ≥ 3 irAEs seemed to have a negative impact on OS. Additionally, systemic glucocorticoids administration did not affect survival outcomes. CONCLUSION: Our findings suggest that the occurrence of irAEs could be considered as a potential prognostic factor for predicting the efficacy of ICIs in patients with advanced RCC and UC.

Plane-Stress Deformation Behavior of CoCrFeMnNi High-Entropy Alloy Sheet under Low Temperatures.

High-entropy alloys are promising candidates expected to be applied in transportation equipment serving in extreme environments due to their excellent properties. CoCrFeMnNi high-entropy alloy is a typical representative of them, and its low temperature performance is excellent. In this study, to evaluate the feasibility of forming HEA shells, the deformation behavior of CoCrFeMnNi under a plane-stress state at lower temperatures was thoroughly studied. Firstly, a thin-walled HEA tube was fabricated using hot extrusion and further formed into a thin shell for uniaxial tensile and biaxial bulging tests. Subsequently, uniaxial tensile tests at cryogenic temperatures were conducted. Both the strength and the ductility improves as the temperature decreases from -160 °C to -196 °C. Then, a systematic low-temperature bulging test was performed using isothermal dome tests and the thickness uniformity analysis of the bulged specimens was carried out. In addition, grain microstructural observation using EBSD was characterized analyze the possible deformation mechanism at the cryogenic temperature under the biaxial stress state. This study, for the first time, investigated the biaxial deformation behavior of HEA. Considering the plane-stress state deformation is the dominant type in the thin-walled shell deformation, this study enables us to provide direct guidance for various sheet-forming processes of HEAs.

Study on detonation characteristics of pulverized coal and evolution law of detonation residue.

This study explores the detonation characteristics and compositional changes of pulverized coal, focusing on its use in Rotary Detonation Wave (RDW) technologies. While pulverized coal has shown high fuel efficiency in RDW settings, transitioning from theory to practical detonation engineering presents substantial scientific and technical hurdles. A key issue is the reprocessing of detonation byproducts for in-situ coal mine gob filling, a topic that has received little attention. Utilizing advanced methods like X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR), this paper investigates the micro-morphology, composition, and aromatic structures of gas-solid products pre and post-detonation at the Tashan Coal Mine's 2305 working face. Results indicate that coal dust from the underground mining face has enhanced detonation characteristics, with the addition of coal powder fuel extending the gas detonation limits. This benefits economic aspects by reducing reliance on gas fuel and lowering detonation fuel costs. The highest recorded detonation wave velocity was 2450 m/s, 14.8% greater than that of coal dust from external sources, suggesting more effective energy release and pressure gain. Furthermore, the study links detonation combustion intensity to coal's aromatic properties, noting a post-detonation aromaticity index (I) of 0.4941. This indicates an improvement in the aromatic structure under high-temperature conditions, vital for coal's reactivity and energy efficiency in RDW applications. This research not only deepens the understanding of coal dust combustion mechanisms but also advances clean coal utilization and deep coal fluidization mining, addressing significant RDW technological challenges.

Benign metastasizing fumarate hydratase (FH)-deficient uterine leiomyomas: clinicopathological and molecular study with first documentation of multi-organ metastases.

Leiomyoma is the most prevalent benign tumor of the female reproductive system. Benign metastasizing leiomyoma (BML) is a rare phenomenon that presents at distant sites, typically the lungs, exhibiting histopathological features similar to the primary uterine tumor in the absence of malignancy features in both. Fumarate hydratase-deficient uterine leiomyoma (FH-d UL) is an uncommon subtype among uterine smooth muscle tumors (0.5-2%), showing distinctive histomorphology and FH inactivation. The majority of FH-d ULs are sporadic, caused by somatic FH inactivation, while a minority of cases occur in the context of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome caused by germline FH inactivation. Metastasizing FH-d UL has not been well documented and might be under-reported. Here, we present two cases (21- and 34-year-old females) who presented with metastasizing FH-d UL after myomectomy/hysterectomy with histologically proven multiple lung metastases in both, in addition to multi-organ involvement in one case (cervical-thoracic lymph nodes, left kidney, perihepatic region, left zygomatic bone, and soft tissues). Pathological examination confirmed FH-d leiomyomas in the primary/recurrent uterine tumors, multiple lung lesions, and a renal mass. The minimal criteria for diagnosis of leiomyosarcoma were not fulfilled. Genetic testing revealed germline pathogenic FH variants in both cases (c.1256C > T; p.Ser419Leu in Case 1 and c.425A > G; p.Gln142Arg in Case 2). These novel cases highlight a rare but possibly under-recognized presentation of FH-d BML. Our study suggests that FH-d BML cases might be enriched for the HLRCC syndrome.

Predicting abiraterone efficacy in advanced prostate cancer: Insights from marker of proliferation Ki67.

BACKGROUND: KI67 is a well-known biomarker reflecting cell proliferation. We aim to elucidate the predictive role of KI67 in the efficacy of abiraterone for patients with advanced prostate cancer (PCa). METHODS: Clinicopathological data of 152 men with metastatic PCa, who received abiraterone therapy were retrospectively collected. The KI67 positivity was examined by immunohistochemistry using the prostate biopsy specimen. The predictive value of KI67 on the therapeutic efficacy of abiraterone was explored using Kaplan-Meier curve and Cox regression analysis. The endpoints included prostate-specific antigen (PSA) progression-free survival (PSA-PFS), radiographic PFS (rPFS), and overall survival (OS). RESULTS: In total, 85/152 (55.9%) and 67/152 (44.1%) cases, respectively, received abiraterone at metastatic hormone-sensitive (mHSPC) and castration-resistant PCa (mCRPC) stage. The median KI67 positivity was 20% (interquartile range: 10%-30%). Overall, KI67 rate was not correlated with PSA response. Notably, an elevated KI67-positive rate strongly correlated with unfavorable abiraterone efficacy, with KI67 ≥ 30% and KI67 ≥ 20% identified as the optimal cutoffs for prognosis differentiation in mHSPC (median PSA-PFS: 11.43 Mo vs. 26.43 Mo, p < 0.001; median rPFS: 16.63 Mo vs. 31.90 Mo, p = 0.003; median OS: 21.77 Mo vs. not reach, p = 0.005) and mCRPC (median PSA-PFS: 7.17 Mo vs. 12.20 Mo, p = 0.029; median rPFS: 11.67 Mo vs. 16.47 Mo, p = 0.012; median OS: 21.67 Mo vs. not reach, p = 0.073) patients, respectively. Multivariate analysis supported the independent predictive value of KI67 on abiraterone efficacy. In subgroup analysis, an elevated KI67 expression was consistently associated with unfavorable outcomes in the majority of subgroups. Furthermore, data from another cohort of 79 PCa patients with RNA information showed that those with KI67 RNA levels above the median had a significantly shorter OS than those below the median (17.71 vs. 30.72 Mo, p = 0.035). CONCLUSIONS: This study highlights KI67 positivity in prostate biopsy as a strong predictor of abiraterone efficacy in advanced PCa. These insights will assist clinicians in anticipating clinical outcomes and refining treatment decisions for PCa patients.

Memory/Active T-Cell Activation Is Associated with Immunotherapeutic Response in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. EXPERIMENTAL DESIGN: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA-sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients with metastasis. RESULTS: In the localized setting, we found that a cell-cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS, 17.3 vs. 9.6 months, P = 0.016) and OS (median OS, not reached vs. 25.7 months, P = 0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. CONCLUSIONS: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T-cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.

Mechanistic insight into the degradation of sulfadiazine by electro-Fenton system: Role of different reactive species.

Sulfadiazine (SDZ), a widely used effective antibiotic, is resistant to conventional biological treatment, which is concerning since untreated SDZ discharge can pose a significant environmental risk. Electro-Fenton (EF) technology is a promising advanced oxidation technology for efficiently removing SDZ. However, due to the limitations of traditional experimental methods, there is a lack of in-depth study on the mechanism of ·OH-dominated SDZ degradation in EF process. In this study, an EF system was established for SDZ degradation and the transformation products (TPs) were detected by mass spectrometry. Dynamic thermodynamic, kinetic and wave function analysis of reactants, transition states and intermediates were proposed by density functional theory calculations, which was applied to elucidate the underlying mechanism of SDZ degradation. Experimental results showed that amino, benzene, and pyrimidine sites in SDZ were oxidized by ·OH, producing TPs through hydrogen abstraction and addition reactions. ·OH was kinetically more likely to attack SDZ- than SDZ. Fe(IV) dominated the single-electron transfer oxidation reaction of SDZ, and the formed organic radicals can spontaneously generate the de-SO2 product via Smiles rearrangement. Toxicity experiments showed the toxicity of SDZ and TPs can be greatly reduced. The results of this study promote the understanding of SDZ degradation mechanism in-depth. ENVIRONMENTAL IMPLICATION: Sulfadiazine (SDZ) is one of the antibiotics widely used around the world. However, it has posed a significant environmental risk due to its overuse and cannot be efficiently removed by traditional treatment methods. The lack of in-depth study on SDZ degradation mechanism under reactive species limits the improvement of SDZ degradation efficiency. Therefore, this work focused on SDZ degradation mechanism in-depth under electro-Fenton system through reactive species investigation, mass spectrometry analysis, and theoretical calculation. The results in this study can provide a theoretical basis for improving the SDZ degradation efficiency which will contribute to solving SDZ pollution problems.

Long noncoding RNA H19: functions and mechanisms in regulating programmed cell death in cancer.

Long noncoding RNAs (lncRNAs) are a group of noncoding RNAs with transcript lengths of >200 nucleotides. Mounting evidence suggests that lncRNAs are closely associated with tumorigenesis. LncRNA H19 (H19) was the first lncRNA to function as an oncogene in many malignant tumors. Apart from the established role of H19 in promoting cell growth, proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), and metastasis, it has been recently discovered that H19 also inhibits programmed cell death (PCD) of cancer cells. In this review, we summarize the mechanisms by which H19 regulates PCD in cancer cells through various signaling pathways, molecular mechanisms, and epigenetic modifications. H19 regulates PCD through the Wnt/ß-catenin pathway and the PI3K-Akt-mTOR pathway. It also acts as a competitive endogenous RNA (ceRNA) in PCD regulation. The interaction between H19 and RNA-binding proteins (RBP) regulates apoptosis in cancer. Moreover, epigenetic modifications, including DNA and RNA methylation and histone modifications, are also involved in H19-associated PCD regulation. In conclusion, we summarize the role of H19 signaling via PCD in cancer chemoresistance, highlighting the promising research significance of H19 as a therapeutic target. We hope that our study will contribute to a broader understanding of H19 in cancer development and treatment.

Secretory production and characterization of a highly effective chitosanase from Streptomyces coelicolor A3(2) M145 in Pichia pastoris.

In this study, a glycoside hydrolase family 46 chitosanase from Streptomyces coelicolor A3(2) M145 was firstly cloned and expressed in Pichia pastoris GS115 (P. pastoris GS115). The recombinant enzyme (CsnA) showed maximal activity at pH 6.0 and 65°C. Both thermal stability and pH stability of CsnA expressed in P. pastoris GS115 were significantly increased compared with homologous expression in Streptomyces coelicolor A3(2). A stable chitosanase activity of 725.7 ± 9.58 U mL-1 was obtained in fed-batch fermentation. It's the highest level of CsnA from Streptomyces coelicolor expressed in P. pastoris so far. The hydrolytic process of CsnA showed a time-dependent manner. Chitosan oligosaccharides (COSs) generated by CsnA showed antifungal activity against Fusarium oxysporum sp. cucumerinum (F. oxysporum sp. cucumerinum). The secreted expression and hydrolytic performance make the enzyme a desirable biocatalyst for industrial controllable production of chitooligosaccharides with specific degree of polymerization, which have potential to control fungi that cause important crop diseases.

Screening for primary aldosteronism on and off interfering medications.

OBJECTIVE: To determine whether antihypertensives will affect diagnostic accuracy of the aldosterone-to-renin ratio (ARR) to an extent that is clinically relevant. METHODS: Confirmatory tests were used to confirm or exclude PA diagnosis. Area under the receiver operating characteristic curve (AUC), specificity and sensitivity of ARR performance in different conditions were calculated. RESULTS: 208 PA and 78 essential hypertension (EH), and 125 PA and 206 EH patients, were included in the retrospective and prospective cohort, respectively. AUC of ARR on interfering medications was comparable to ARR off interfering medications (retrospective: 0.82 vs. 0.87, p = 0.20; prospective: 0.78 vs. 0.84, p = 0.07). At a threshold of 20 pg/µIU, the sensitivity of ARR on interfering medications was lower (11.1-23.2%) while the specificity was higher (10.2-15.2%) than ARR off interfering medications. However, when the ARR threshold on interfering medications was lowered to 10 pg/µIU, both the sensitivity (retrospective: 0.91 vs. 0.90, p = 0.61; prospective: 0.86 vs. 0.82, p = 0.39) and specificity (retrospective: 0.49 vs. 0.59, p = 0.20; prospective: 0.58 vs. 0.66, p = 0.10) were comparable to the ARR threshold off interfering medications. CONCLUSION: Using ARR to screen for PA whilst taking interfering antihypertensive drugs is feasible in most cases, but the ARR threshold needs to be reduced. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04991961.

Genomic and Evolutionary Characterization of Concurrent Intraductal Carcinoma and Adenocarcinoma of the Prostate.

Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally coexists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared with concomitant adenocarcinoma. In this study, we performed whole-exome, RNA, and DNA-methylation sequencing of IDC-P, concurrent invasive high-grade PAC lesions, and adjacent normal prostate tissues isolated from 22 radical prostatectomy specimens. Three evolutionary patterns of concurrent IDC-P and PAC were identified: early divergent, late divergent, and clonally distant. In contrast to those with a late divergent evolutionary pattern, tumors with clonally distant and early divergent evolutionary patterns showed higher genomic, epigenomic, transcriptional, and pathologic heterogeneity between IDC-P and PAC. Compared with coexisting PAC, IDC-P displayed increased expression of adverse prognosis-associated genes. Survival analysis based on an independent cohort of 505 patients with metastatic prostate cancer revealed that IDC-P carriers with lower risk International Society of Urological Pathology (ISUP) grade 1-4 adenocarcinoma displayed a castration-resistant free survival as poor as those with the highest risk ISUP grade 5 tumors that lacked concurrent IDC-P. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation-associated master regulators and genes involved in intratumoral androgen biosynthesis. Overall, this study provides a molecular groundwork for the aggressive behavior of IDC-P and could help identify potential strategies to improve treatment of IDC-P. SIGNIFICANCE: The genomic, transcriptomic, and epigenomic characterization of concurrent intraductal carcinoma and adenocarcinoma of the prostate deepens the biological understanding of this lethal disease and provides a genetic basis for developing targeted therapies.