Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer.

Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation.

Multidimensionally ordered mesoporous intermetallics: Frontier nanoarchitectonics for advanced catalysis.

Ordered intermetallics contribute to a unique class of catalyst materials due to their rich atomic features. Further engineering of ordered intermetallics at a mesoscopic scale is of great importance to expose more active sites and introduce new functions. Recently, multidimensionally ordered mesoporous intermetallic (MOMI) nanoarchitectonics, which subtly integrate atomically ordered intermetallics and mesoscopically ordered mesoporous structures, have held add-in synergies that not only enhance catalytic activity and stability but also optimize catalytic selectivity. In this tutorial review, we have summarized the latest progress in the rational design, targeted synthesis, and catalytic applications of MOMIs, with a special focus on the findings of our group. Three strategies, including concurrent template route, self-template route, and dealloying route, are discussed in detail. Furthermore, physicochemical properties and catalytic performances for several important reactions are also described to highlight the remarkable activity, high stability, and controllable selectivity of MOMI nanoarchitectonics. Finally, we conclude with a summary and explore future perspectives in the field to contribute to wider applications.

Highly Efficient Iridium-Iron-Molybdenum Catalysts Condensed on Boron Nitride for Biomass-Derived Diols' Hydrogenolysis to Secondary Monoalcohols.

A trade-off of activity-selectivity exists in primary C-O hydrogenolysis of biomass-derived diols to secondary alcohols over bimetallic catalysts, especially the combination of noble metal and early transition metal in the metallic state and metal oxide state, respectively. Herein, the combination of high surface concentration of boron nitride (BN)-supported metals and the addition of Mo as third metal broke the trade-off. High yields (>50%) of secondary alcohols were obtained with robust productivity up to 25-fold based on Ir over Ir-Fe0.13-Mo0.08/BN (Ir = 20 wt %, Fe/Ir = 0.13, Mo/Ir = 0.08) than previously reported Ir-Fe catalysts. In contrast, simply increasing the loading amount of Ir-Fe catalysts or the addition of Mo species only enhanced the productivity by <2-4-fold. Various characterizations showed that large Ir loading enables the formation of condensed nanostructures (∼2 nm) on the BN support, which further alloy with Mo and Fe to form an face centred cubic (fcc)-type trimetallic alloy with surface enrichment of Fe. On the other hand, in Ir-Fe0.25-Mo0.08/BN with lower Ir (5 wt %) and lower Ir-based activity, the Mo species were rather bound on the support surface possibly as the MoBx state. These structures were formed by simple impregnation and reduction with H2 at the reaction temperature (453 K). The high activity of Ir-Fe0.13-Mo0.08/BN (20 wt % Ir) is derived from two aspects: (1) the formation of condensed nanostructures (∼2 nm) exposing more active sites and (2) alloying with Mo to modify the electronic state of Ir to enhance the H2 activation ability, as shown by the decreased Ea (82-84 → 67 kJ mol-1).

Co-transcriptional R-loops-mediated epigenetic regulation drives growth retardation and docetaxel chemosensitivity enhancement in advanced prostate cancer.

R-loops are prevalent three-stranded nucleic acid structures, comprising a DNA-RNA hybrid and a displaced single-stranded DNA, that frequently form during transcription and may be attributed to genomic stability and gene expression regulation. It was recently discovered that RNA modification contributes to maintain the stability of R-loops such as N6-methyladenosine (m6A). Yet, m6A-modified R-loops in regulating gene transcription remains poorly understood. Here, we demonstrated that insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) recognize R-loops in an m6A-dependent way. Consequently, IGF2BPs overexpression leads to increased overall R-loop levels, cell migration inhibition, and cell growth retardation in prostate cancer (PCa) via precluding the binding of DNA methyltransferase 1(DNMT1) to semaphorin 3 F (SEMA3F) promoters. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A-containing R-loops and are required for tumor suppressor functions. Overexpression of SEMA3F markedly enhanced docetaxel chemosensitivity in prostate cancer via regulating Hippo pathway. Our findings point to a distinct R-loop resolution pathway mediated by IGF2BPs, emphasizing the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology.The manuscript summarizes the new role of N6-methyladenosine in epigenetic regulation, we introduce the distinct R-loop resolution mediated by IGF2BP proteins in an m6A-dependent way, which probably lead to the growth retardation and docetaxel chemotherapy resistance in prostate cancer. Moreover, our findings first emphasized the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology. In addition, our research provides a novel RBM15/IGF2BPs/DNMT1 trans-omics regulation m6A axis, indicating the new crosstalk between RNA m6A methylation and DNA methylation in prostate cancer.

Self-Enhanced Electrochemiluminesence of Dye-Doped Polymer Dots for Coreactant-Free Visualized Detection of Iodide Ions.

The monitoring of radioactive iodide levels is of great significance in environmental science and cancer radiotherapy. In this work, a high-throughput, radiation-resistant, and visualized electrochemiluminescence (ECL) strategy was developed for detection of iodide ions. Herein, the hydrophobic ruthenium derivative (Ru(bpy)3[B(C6F5)4]2) (bpy = bipyridyl) was doped in tertiary amine-coupled polymer dots (N-PFO Pdots) to synthesize self-enhanced Pdots (Ru@Pdots), which showed extremely high ECL intensity in absence of coreactant. Due to the efficient ECL resonance energy transfer between Ru(bpy)3[B(C6F5)4]2 and N-PFO, the Ru@Pdots exhibited 18 times higher ECL intensity compared with bare N-PFO Pdots. Besides, Ru@Pdots also showed 220-times higher ECL intensity compared with Ru(bpy)3[B(C6F5)4]2 doped coreactant-dependent Pdots (Ru@PFO Pdots). Using Ru@Pdots as ECL emitters, an ECL imaging array was designed for iodide ion detection, which exhibited a detection range of 0.8 nM-4 µM and a limit of detection of 0.1 nM. In this strategy, iodide ions were oxidized as iodide free radicals on the surface of the electrode, which could further consume the nitrogen radical of Ru@Pdots and effectively quench the ECL signal. This method also showed good specificity, radiation-resistant performance, and accuracy in actual seawater sample testing, which indicated its value in marine environmental monitoring, nuclear security, and cancer radiotherapy.

Photoinduced carrier transfer dynamics in a monolayer MoS2/PbS quantum dots heterostructure.

Two-dimensional molybdenum disulfide (MoS2) has been proven to be a candidate in photodetectors, and MoS2/lead sulfide (PbS) quantum dots (QDs) heterostructure has been used to expand the optical response wavelength of MoS2. Time-resolved pump-probe transient absorption measurements are performed to clarify the carrier transfer dynamics in the MoS2/PbS heterostructure. By comparing the carrier dynamics in MoS2 and MoS2/PbS under different pump wavelengths, we found that the excited electrons in PbS QDs can transfer rapidly (<100 fs) to MoS2, inducing its optical response in the near-infrared region, although the pump light energy is lower than the bandgap of MoS2. Besides, interfacial excitons can be formed in the heterostructure, prolonging the lifetime of the excited carriers, which could be beneficial for the extraction of the carriers in devices.

Construction of Cyclodextrin-Based Covalent Organic Frameworks for Efficient Encapsulation of Menthol.

The application of flavoring ingredients like menthol in the food industry is hindered by their high volatility and poor thermal stability, which lead to significant losses during processing and storage. Encapsulation of flavors into porous materials to obtain inclusion complexes (ICs) has proved to be an efficient strategy. In the present study, we synthesized a series of relatively food-safe three-dimensional anionic cyclodextrin-based covalent organic frameworks (CD-COFs) with spiroborate linkages using a facile microwave-assisted method. The high surface area and newly formed cavities of COFs significantly enhanced the encapsulation efficiency of menthol compared to native CD materials. Our findings revealed that γ-CD-COF-Li, with Li+ as the counterion, achieved superior encapsulation efficiency of 25.9 %, outperforming γ-CD-COF-Na, γ-CD-COF-K and α-CD-COF-Li under the same conditions. Thermal stability measurements show that the menthol/γ-CD-COF-Li-ICs effectively stabilize menthol against heat evaporation at elevated temperatures due to the strengthened interaction between menthol and γ-CD-COF-Li. The promising results of this research suggest that rapid advancements in COF technology will provide new opportunities for enhancing the stability of flavoring ingredients in the food industry.

Characteristics of Nocturnal Boundary Layer over a Subtropical Forest: Implications for the Dispersion and Fate of Atmospheric Species.

The nocturnal boundary layer (NBL) significantly influences the dispersion and fate of atmospheric species at night. Subtropical forests are crucial in carbon and water exchange between the biosphere and the atmosphere. However, the NBL characteristics and their impact on atmospheric species over these forests remain unknown. This study conducted vertical measurements of atmospheric species such as O3 and volatile organic compounds (VOCs), along with meteorological variables, over a national forest reserve in Southern China. Results reveal that the NBL height ranged from 180 to 300 m in the summer and from 80 to 160 m in the winter. The vertical distribution of chemical species varied by time and season, with greater concentration gradients observed in the summer. Over 90% of VOCs above the NBL were anthropogenic, while biogenic VOCs were mainly found within the NBL. Higher O3 concentration and VOC product-to-reactant ratios were observed in the residual layer, suggesting enhanced oxidation levels. This unique vertical distribution of atmospheric species at night is driven by factors, such as emission, deposition, turbulence, and atmospheric chemistry, potentially affecting ecosystem functions. Results from this study highlight the importance of incorporating NBL dynamics into atmospheric models to better understand the evolution of chemical species and their ecological effects over forests.

BRCA1/FANCD2/BRG1-Driven DNA Repair Stabilizes the Differentiation State of Human Mammary Epithelial Cells.

An abnormal differentiation state is common in BRCA1-deficient mammary epithelial cells, but the underlying mechanism is unclear. Here, we report a convergence between DNA repair and normal, cultured human mammary epithelial (HME) cell differentiation. Surprisingly, depleting BRCA1 or FANCD2 (Fanconi anemia [FA] proteins) or BRG1, a mSWI/SNF subunit, caused HME cells to undergo spontaneous epithelial-to-mesenchymal transition (EMT) and aberrant differentiation. This also occurred when wild-type HMEs were exposed to chemicals that generate DNA interstrand crosslinks (repaired by FA proteins), but not in response to double-strand breaks. Suppressed expression of ΔNP63 also occurred in each of these settings, an effect that links DNA damage to the aberrant differentiation outcome. Taken together with somatic breast cancer genome data, these results point to a breakdown in a BRCA/FA-mSWI/SNF-ΔNP63-mediated DNA repair and differentiation maintenance process in mammary epithelial cells that may contribute to sporadic breast cancer development.

Analysis of Xp22.31q27.1 Region Variation Detection based on SNP Array Technology.

BACKGROUND: The aim of the study was to investigate the value of single nucleotide polymorphism array (SNP array) technology in the prenatal diagnosis. METHODS: The variants in Xp22.31q27.1 region of 13 fetuses were analyzed by SNP array technology. Chromosome karyotype analysis was also performed for these fetuses and their parents. RESULTS: Chromosome karyotype analysis found no obvious chromosomal abnormality at 400 bands resolution. Using SNP array technology, we found that all fetuses had mutations in Xp22.31q27.1 region, which was mainly Xp22.31 lesion (61.5%, 8/13) that contained 2 to 5 OMIM genes. Moreover, these mutations consisted of 7 cases of repetition and 6 cases of deletion. In addition, 9 variants were inherited from their mothers, 3 mutations were inherited from the father, and 1 variant was de novo. CONCLUSIONS: Compared to traditional analysis of chromosome karyotype, SNP-array technology can detect more chromosomal microdeletions and microduplications. SNP-array technology can act as a supplementary diagnostic method in clinical cytogenetic diagnosis.

Correlation between gene polymorphism and adverse reactions of high-dose methotrexate in osteosarcoma patients: a systematic review and meta-analysis.

OBJECTIVE: We aimed to provide a reference based on evidence for an individualized clinical medication of high-dose methotrexate (HD-MTX) in osteosarcoma patients by evaluating the effect of gene polymorphism on adverse reactions of HD-MTX usage. METHODS: Several databases were combed for research on the association between gene polymorphisms and adverse reactions to HD-MTX up to January 2023. A meta-analysis and/or descriptive analysis on the incidence of HD-MTX-related adverse reactions were conducted by using clinical studies meeting inclusion criteria. RESULTS: Twelve studies involving 889 patients were included. There were 8, 6, 5, and 4 studies related to MTHFR C677T, MTHFR A1298C, RFC1 G80A, and MDR1 C3435T polymorphisms, respectively. The results of the meta-analysis showed that the MTHFR C677T polymorphism was associated with G3-4 hepatotoxicity, G3-4 nephrotoxicity, G3-4 gastrointestinal toxicity, and G3-4 mucositis under the recessive genetic model (MM vs. Mm/mm). Limited research showed that MTHFR C677T was associated with G3-4 nephrotoxicity in the allelic genetic model (M vs. m). MTHFR A1298C polymorphism was associated with a decreased risk of adverse reactions to HD-MTX usage, without statistical significance. This review's descriptive analysis showed no significant correlation between the RFC1 G80A, and MDR1 C3435T polymorphism and adverse reactions of HD-MTX. CONCLUSION: The MTHFR C677T mutation may enhance the risk of HD-MTX adverse reactions in osteosarcoma patients. Existing studies have not found a significant correlation between the MTHFR A1298C, RFC1 G80A, and MDR1 C3435T polymorphism and adverse reactions caused by HD-MTX. Lastly, this conclusion was limited because of few studies.

Influence of preoperative antituberculosis chemotherapy duration on perioperative complications in patients treated with epididymectomy for epididymal tuberculosis.

OBJECTIVES: We aimed to investigate the influence of preoperative antituberculosis chemotherapy duration on perioperative epididymectomy complications in patients with epididymal tuberculosis (ETB). METHODS: This retrospective study examined patients with ETB between January 1, 2013, and March 31, 2023, who underwent unilateral epididymectomy at our hospital. We selected preoperative antituberculosis chemotherapy duration of 2, 4, and 8 weeks as the cutoffs for this study, to explore whether there are differences in the incidence of intraoperative and 30-day postoperative complications among the patients with different preoperative antituberculosis chemotherapy durations. Intraoperative complications were graded according to the Satava classification, and 30-day postoperative complications were defined according to the Clavien-Dindo classification. The study groups were compared using the unpaired t-test, Wilcoxon rank-sum test, Pearson's chi-square test, or Fisher's exact test, as appropriate. RESULTS: Overall, 155 patients were included. Statistical analysis revealed that there were no significant differences in the incidence of intraoperative and 30-day postoperative complications between patients with shorter preoperative antituberculosis chemotherapy duration and those with longer preoperative antituberculosis chemotherapy duration. CONCLUSIONS: In patients with ETB, preoperative antituberculosis chemotherapy duration did not significantly affect the incidence of perioperative complications after epididymectomy.

Stabilizing Hydrogen Radicals in Two-Dimensional Cobalt-Copper Mesoporous Nanoplates for Complete Nitrate Reduction Electrocatalysis to Ammonia.

Ambient electrochemical reduction of waste nitrate (NO3-) represents an alternative green route for sustainable ammonia (NH3) electrosynthesis in water. Despites some encouraged achievements, sluggish eight electron and nine proton reduction routes that involve multi-step hydrogenation pathways have severely hindered their NH3 Faradaic efficiency (FENH3) and yield rate. Herein, we develop a robust two-dimensional mesoporous cobalt-copper (meso-CoCu) nanoplate electrocatalyst that delivers excellent performance of complete NO3- reduction reaction (NO3RR), including superior FENH3 of 98.8%, high NH3 yield rate of 3.39 mol h-1 g-1 and energy efficiency of 49.8%, and good cycling stability. Mechanism investigations unveil that active hydrogen (*H) radicals produced from water splitting on Co sites spillover to adjacent Cu sites and further stabilize within confined mesopores, which kinetically promote its coupling hydrogenation reactions of nitrogen intermediates and thus facilitate complete NO3RR for favorable NH3 electrosynthesis. Moreover, meso-CoCu nanoplates perform well as a bifunctional electrocatalyst in the two-electrode coupling system that concurrently synthesizes NH3 from NO3- at cathode and 2,5-furanedicarboxylic acid from 5-hydroxymethylfurfural at anode. This work in stabilizing *H radicals in mesoporous microenvironment provides some insights applied to various hydrogenation reactions for selective electrosynthesis of highly value-added chemicals in water.

Intrarenal pH-Responsive Self-Assembly of Luminescent Gold Nanoparticles for Diagnosis of Early Kidney Injury.

Metabolic acidosis-induced kidney injury (MAKI) is asymptomatic and lack of clinical biomarkers in early stage, but rapidly progresses to severe renal fibrosis and ultimately results in end-stage kidney failure. Therefore, developing rapid and noninvasive strategies direct responsive to renal tubular acidic microenvironment rather than delayed biomarkers are essential for timely renoprotective interventions. Herein, we develop pH-responsive luminescent gold nanoparticles (p-AuNPs) in the second near-infrared emission co-coated with 2,3-dimethylaleic anhydride conjugated ß-mercaptoethylamine and cationic 2-diethylaminoethanethiol hydrochloride, which showed sensitive pH-induced charge reversal and intrarenal self-assembly for highly sensitive and long-time (~24 h) imaging of different stages of MAKI. By integrating advantages of pH-induced intrarenal self-assembly and enhanced interactions between pH-triggered positively charged p-AuNPs and renal tubular cells, the early- and late-stage MAKI could be differentiated rapidly within 10 min post-injection (p.i.) with contrast index (CI) of 3.5 and 4.3, respectively. The corresponding maximum CI could reach 5.1 and 9.2 at 12 h p.i., respectively. Furthermore, p-AuNPs were demonstrated to effectively real-time monitor progressive recovery of kidney injury in MAKI mice after therapy, and also exhibit outstanding capabilities for drug screening. This pH-responsive strategy showed great promise for feedback on kidney dysfunction progression, opening new possibilities for early-stage diagnosis of pH-related diseases.

Ir-Doped CuPd Single-Crystalline Mesoporous Nanotetrahedrons for Ethylene Glycol Oxidation Electrocatalysis: Enhanced Selective Cleavage of C-C Bond.

The development of highly efficient electrocatalysts for complete oxidation of ethylene glycol (EG) in direct EG fuel cells is of decisive importance to hold higher energy efficiency. Despite some achievements, their progress, especially electrocatalytic selectivity to complete oxidated C1 products, is remarkably slower than expected. In this work, we developed a facile aqueous synthesis of Ir-doped CuPd single-crystalline mesoporous nanotetrahedrons (Ir-CuPd SMTs) as high-performance electrocatalyst for promoting oxidation cleavage of C-C bond in alkaline EG oxidation reaction (EGOR) electrocatalysis. The synthesis relied on precise reduction/co-nucleation and epitaxial growth of Ir, Cu and Pd precursors with cetyltrimethylammonium chloride as the mesopore-forming surfactant and extra Br- as the facet-selective agent under ambient conditions. The products featured concave nanotetrahedron morphology enclosed by well-defined (111) facets, single-crystalline and mesoporous structure radiated from the center, and uniform elemental composition without any phase separation. Ir-CuPd SMTs disclosed remarkably enhanced electrocatalytic activity and excellent stability as well as superior selectivity of C1 products for alkaline EGOR electrocatalysis. Detailed mechanism studies demonstrated that performance improvement came from structural and compositional synergies, which kinetically accelerated transports of electrons/reactants within active sites of penetrated mesopores and facilitated oxidation cleavage of high-energy-barrier C-C bond of EG for desired C1 products. More interestingly, Ir-CuPd SMTs performed well in coupled electrocatalysis of anode EGOR and cathode nitrate reduction, highlighting its high potential as bifunctional electrocatalyst in various applications.

Proxalutamide in metastatic castration-resistant prostate cancer: Primary analysis of a multicenter, randomized, open-label, phase 2 trial.

We aim to assess the safety and efficacy of proxalutamide, a novel androgen receptor antagonist, for men with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter, randomized, open-label, phase 2 trial. In our study, the enrolled mCRPC patients were randomized to 100, 200 and 300 mg dose groups at 1:1:1. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and time to PSA and radiographic progression. Safety and pharmacokinetics were also assessed. Finally, there were 108 patients from 17 centers being enrolled. By week 16, there were 13 (35.1%), 12 (36.4%) and 15 (42.9%) patients with confirmed 50% or greater PSA decline in 100 mg (n = 37), 200 mg (n = 33) and 300 mg (n = 35) groups, respectively. Among the 19 patients with target lesions at study entry, three (15.8%) had a partial response and 12 (63.2%) had stable disease. The ORRs of 20.0%, 22.2%, 0% and DCRs of 80.0%, 88.9%, 60.0% were, respectively, achieved in 100, 200 and 300 mg groups. By the maximum follow-up time of 24 weeks, there were 42.6% and 10.2% of cases experiencing PSA progression and radiographic progression, respectively. Overall, adverse events (AEs) were experienced by 94.4% of patients, most of which were mild or moderate. There were 28 patients experiencing ≥grade 3 AEs. The most common AEs were fatigue (17.6%), anemia (14.8%), elevated AST (14.8%) and ALT (13.0%), decreased appetite (13.0%). These findings preliminarily showed the promising antitumor activity of proxalutamide in patients with mCRPC with a manageable safety profile. The proxalutamide dose of 200 mg daily is recommended for future phase 3 trial (Clinical trial registration no. CTR20170177).

Microenvironment Engineering to Promote Selective Ammonia Electrosynthesis from Nitrate over a PdCu Hollow Catalyst.

The electrosynthesis of recyclable ammonia (NH3 ) from nitrate under ambient conditions is of great importance but still full of challenges for practical application. Herein, an efficient catalyst design strategy is developed that can engineer the surface microenvironment of a PdCu hollow (PdCu-H) catalyst to confine the intermediates and thus promote selective NH3 electrosynthesis from nitrate. The hollow nanoparticles are synthesized by in situ reduction and nucleation of PdCu nanocrystals along a self-assembled micelle of a well-designed surfactant. The PdCu-H catalyst shows a structure-dependent selectivity toward the NH3 product during the nitrate reduction reaction (NO3 - RR) electrocatalysis, enabling a high NH3 Faradaic efficiency of 87.3% and a remarkable NH3 yield rate of 0.551 mmol h-1 mg-1 at -0.30 V (vs reversible hydrogen electrode). Moreover, this PdCu-H catalyst delivers high electrochemical performance in the rechargeable zinc-NO3 - battery. These results provide a promising design strategy to tune catalytic selectivity for efficient electrosynthesis of renewable NH3 and feedstocks.

Oxygen therapy accelerates apoptosis induced by selenium compounds via regulating Nrf2/MAPK signaling pathway in hepatocellular carcinoma.

Selenium has good antitumor effects in vitro, but the hypoxic microenvironment in solid tumors makes its clinical efficacy unsatisfactory. We hypothesized that the combination with oxygen therapy might improve the treatment efficacy of selenium in hypoxic tumors through the changes of redox environment. In this work, two selenium compounds, Na2SeO3 and CysSeSeCys, were selected to interrogate their therapeutic effects on hepatocellular carcinoma (HCC) under different oxygen levels. In tumor-bearing mice, both selenium compounds significantly inhibited the tumor growth, and combined with oxygen therapy further reduced the tumor volume about 50 %. In vitro HepG2 cell experiments, selenium induced autophagy and delayed apoptosis under hypoxia (1 % O2), while inhibited autophagy and accelerated apoptosis under hyperoxia (60 % O2). We found that, in contrast to hypoxia, the hyperoxic environment facilitated the H2Se, produced by the selenium metabolism in cells, to be rapidly oxidized to generate H2O2, leading to inhibit the expression level of Nrf2 and to increase that of phosphorylation of p38 and MKK4, resulting in inhibiting autophagy and accelerating apoptosis. Once the Nrf2 gene was knocked down, selenium compounds combined with hyperoxia treatment would further activate the MAPK signaling pathway and further increase apoptosis. These findings highlight oxygen can significantly enhance the anti-HCC effect of selenium compounds through regulating the Nrf2 and MAPK signaling pathways, thus providing novel therapeutic strategy for the hypoxic tumors and pave the way for the application of selenium in clinical treatment.

A prospective multi-center randomized comparative trial evaluating outcomes of transrectal ultrasound (TRUS)-guided 12-core systematic biopsy, mpMRI-targeted 12-core biopsy, and artificial intelligence ultrasound of prostate (AIUSP) 6-core targeted biopsy for prostate cancer diagnosis.

BACKGROUND: Artificial intelligence ultrasound of prostate (AIUSP)-targeted biopsy has been used for prostate cancer (PCa) diagnosis. The objective of this prospective multi-center head-to-head clinical randomized comparative trail (RCT) is to compare PCa detection rate in the TRUS-guided 12-core standard systematic biopsy (TRUS-SB) group and cognitive fused mpMRI-guided 12-core biopsy (mpMRI) group against AIUSP group. METHODS: Four hundred patients were randomized to three arms and underwent biopsies by TRUS-SB (n = 133), mpMRI (n = 134), and AIUSP (n = 133) between January 2015 and December 2017. In TRUS-SB group, a standard 12-core systematic biopsy was performed. In mpMRI group, mpMRI-suspicious lesions (PI-RADS 3-5) were targeted by 2-core biopsy followed by a 10-core systematic biopsy. Otherwise, 12-core systematic biopsy was performed. In AIUSP group, a 6-core targeted biopsy was performed. The primary endpoint was PCa detection rate. RESULTS: AIUSP detected the highest rate of PCa (66/133, 49.6%) compared to TRUS-SB (46/133, 34.6%, p = 0.036) and mpMRI (48/134, 35.8%, p = 0.052). Compared to TRUS-SB (35/133, 26.3%) and mpMRI (31/134, 23.1%) groups, clinically significant PCa (csPCa) detection rate was 32.3% (43/133) in AIUSP group. Overall biopsy core positive rate in the TRUS-SB group (11.0%, 176/1598) and in the mpMRI group (12.7%, 204/1608) was significantly lower than that in the AIUSP group (22.7%, 181/798, p < 0.001). CONCLUSIONS: AIUSP detected the highest rate of overall and significant PCa compared to TRUS-SB and mpMRI, and could be used as an alternative to systematic biopsy in the future. REGISTRATION: This trial was registered in ISRCTN (ISRCTN18033113).

Asp-containing actinomycin and tetracyclic chromophoric analogues from the Streptomyces sp. strain S22.

Three novel actinomycins, actimomycin S (1), neo-actinomycins C and D (2 and 3), and one new benzo[d]oxazole alkaloid (4) were isolated from the Streptomyces sp. strain S22, along with three known congeners F9 (5), X2 (6) and X0ß (7) and 2-acetylamino-3-hydroxyl-4-methyl-benzoic acid methyl ester (8). The structures of the new products were elucidated by spectroscopic methods, and the absolute configuration of amino acid residues was determined by Marfey's analysis. Actinomycin S contains an aspartic acid (Asp) residue in the ß-peptidolactone ring. This is the first report of an Asp residue within an actinomycin-type natural product. Notably, neo-actinomycins C and D feature a rare tetracyclic 5H-oxazolo[4,5-b]phenoxazine chromophore. Among these, neo-actinomycin D, with an unprecedented molecular formula, represents the highest molecular weight member in the actinomycin family. Actinomycins 1-3 exhibited antimicrobial activity against multiple resistant "ESKAPE" pathogens with MIC values ranging from 1.25 to 80.0 µg mL-1. In addition, 1-3 showed potent cytotoxic activities against the HepG2 liver carcinoma cell line with IC50 values of 0.10, 0.32, and 0.024 µM, respectively. Furthermore, 1 inhibited cell proliferation by inducing G0-G1 phase arrest in the cell cycle.