Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype.

Triple-negative breast cancer (TNBC) is an aggressive subtype with no targeted therapeutics. The luminal androgen receptor (LAR) subtype constitutes 15% of TNBC and is enriched for androgen receptor (AR) and AR target genes. Here, we show that a cohort of TNBC not only expresses AR at a much higher rate (∼80%) but also expresses AR splice variants (AR-SVs) (∼20%), further subclassifying LAR-TNBC. Higher AR and AR-SV expression and corresponding aggressive phenotypes are observed predominantly in specimens obtained from African American women. LAR TNBC specimens are enriched for interferon, Janus kinase (JAK)-signal activator and transducer (STAT), and androgen signaling pathways, which are exclusive to AR-expressing epithelial cancer cells. AR- and AR-SV-expressing TNBC cell proliferation and xenograft and patient-tumor explant growth are inhibited by AR N-terminal domain-binding selective AR degrader or by a JAK inhibitor. Biochemical analysis suggests that STAT1 is an AR coactivator. Collectively, our work identifies pharmacologically targetable TNBC subtypes and identifies growth-promoting interaction between AR and JAK-STAT signaling.

Next-generation bromodomain inhibitors of the SWI/SNF complex enhance DNA damage and cell death in glioblastoma.

Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis. While surgical resection is the primary treatment, adjuvant temozolomide (TMZ) chemotherapy and radiotherapy only provide slight improvement in disease course and outcome. Unfortunately, most treated patients experience recurrence of highly aggressive, therapy-resistant tumours and eventually succumb to the disease. To increase chemosensitivity and overcome therapy resistance, we have modified the chemical structure of the PFI-3 bromodomain inhibitor of the BRG1 and BRM catalytic subunits of the SWI/SNF chromatin remodelling complex. Our modifications resulted in compounds that sensitized GBM to the DNA alkylating agent TMZ and the radiomimetic bleomycin. We screened these chemical analogues using a cell death ELISA with GBM cell lines and a cellular thermal shift assay using epitope tagged BRG1 or BRM bromodomains expressed in GBM cells. An active analogue, IV-129, was then identified and further modified, resulting in new generation of bromodomain inhibitors with distinct properties. IV-255 and IV-275 had higher bioactivity than IV-129, with IV-255 selectively binding to the bromodomain of BRG1 and not BRM, while IV-275 bound well to both BRG1 and BRM bromodomains. In contrast, IV-191 did not bind to either bromodomain or alter GBM chemosensitivity. Importantly, both IV-255 and IV-275 markedly increased the extent of DNA damage induced by TMZ and bleomycin as determined by nuclear γH2AX staining. Our results demonstrate that these next-generation inhibitors selectively bind to the bromodomains of catalytic subunits of the SWI/SNF complex and sensitize GBM to the anticancer effects of TMZ and bleomycin. This approach holds promise for improving the treatment of GBM.

Differences in prevalence and management of chronic kidney disease among T2DM inpatients at the grassroots in Beijing and Taiyuan: a retrospective study.

PURPOSE: Chronic kidney disease (CKD) has been one of the most common complications in type 2 diabetes mellitus (T2DM) patients. This retrospective study aimed to investigate the regional differences in the prevalence and management of CKD in T2DM inpatients from two grassroots hospitals in Beijing and Taiyuan. METHODS: The sociodemographic status, health history, lifestyle information, biochemical parameters and drug choices of the patients were collected from the Diabetes Care Information System using a retrospective cross-sectional analysis. The presence of CKD was defined as albuminuria (urine albumin-to-creatinine ratio of ≥ 30 mg/g) and/or as a reduced estimated glomerular filtration rate (< 60 ml/min/1.73 m2). RESULTS: 858 patients with T2DM in Beijing and 1,085 patients with T2DM in Taiyuan were included, with a median age of 61.0 and 61.9 years, respectively. The duration of diabetes was 10.5 and 10.3 years, respectively. The prevalence of CKD in Beijing (39.2%) was significantly higher than in Taiyuan (22.4%). The overall ABC control (A = haemoglobin A1c; B = blood pressure; C = cholesterol) in both the Beijing and Taiyuan groups were not ideal. Patients with CKD tended to use insulin, renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and dyslipidaemia therapy in Taiyuan than in Beijing. The actual proportion of carbohydrate, fat and protein in calories was 49.6%:35.4%:14.4% in Beijing and 61.5%:27.8%:10.8% in Taiyuan. CONCLUSIONS: The higher prescription rates of RAAS inhibitors, SGLT-2i and dyslipidaemia therapy may underlie the fluctuations in the prevalence of CKD in Beijing or Taiyuan. Intensive insulin therapy and personal nutritional guidance, along with the extensive use of RAAS inhibitors, SGLT-2i and dyslipidaemia therapy during follow-up, can all play a positive role in the management of CKD in patients with T2DM in both Beijing and Taiyuan.

Metabolism-Guided Selective Androgen Receptor Antagonists: Design, Synthesis, and Biological Evaluation for Activity against Enzalutamide-Resistant Prostate Cancer.

A major challenge for new drug discovery in the area of androgen receptor (AR) antagonists lies in predicting the druggable properties that will enable small molecules to retain their potency and stability during further studies in vitro and in vivo. Indole (compound 8) is a first-in-class AR antagonist with very high potency (IC50 = 0.085 µM) but is metabolically unstable. During the metabolic studies described herein, we synthesized new small molecules that exhibit significantly improved stability while retaining potent antagonistic activity for an AR. This structure-activity relationship (SAR) study of more than 50 compounds classified with three classes (Class I, II, and III) and discovered two compounds (32c and 35i) that are potent AR antagonists (e.g., IC50 = 0.021 µM, T1/2 = 120 min for compound 35i). The new antagonists exhibited improved in vivo pharmacokinetics (PK) with high efficacy antiandrogen activity in Hershberger and antiandrogen Enz-Res tumor xenograft models that overexpress AR (LNCaP-AR).

Inhibiting androgen receptor splice variants with cysteine-selective irreversible covalent inhibitors to treat prostate cancer.

Androgen receptor (AR) and its splice variants (AR-SVs) promote prostate cancer (PCa) growth by orchestrating transcriptional reprogramming. Mechanisms by which the low complexity and intrinsically disordered primary transactivation domain (AF-1) of AR and AR-SVs regulate transcriptional programming in PCa remains poorly defined. Using omics, live and fixed fluorescent microscopy of cells, and purified AF-1 and AR-V7 recombinant proteins we show here that AF-1 and the AR-V7 splice variant form molecular condensates by liquid-liquid phase separation (LLPS) that exhibit disorder characteristics such as rapid intracellular mobility, coactivator interaction, and euchromatin induction. The LLPS and other disorder characteristics were reversed by a class of small-molecule-selective AR-irreversible covalent antagonists (SARICA) represented herein by UT-143 that covalently and selectively bind to C406 and C327 in the AF-1 region. Interfering with LLPS formation with UT-143 or mutagenesis resulted in chromatin condensation and dissociation of AR-V7 interactome, all culminating in a transcriptionally incompetent complex. Biochemical studies suggest that C327 and C406 in the AF-1 region are critical for condensate formation, AR-V7 function, and UT-143's irreversible AR inhibition. Therapeutically, UT-143 possesses drug-like pharmacokinetics and metabolism properties and inhibits PCa cell proliferation and tumor growth. Our work provides critical information suggesting that clinically important AR-V7 forms transcriptionally competent molecular condensates and covalently engaging C327 and C406 in AF-1, dissolves the condensates, and inhibits its function. The work also identifies a library of AF-1-binding AR and AR-SV-selective covalent inhibitors for the treatment of PCa.

Temperature-affected nano-deformation behavior of nanometals in ultrahigh-strain-rate formation processes.

As metal forming processes move toward high speed, high throughput, high precision and small scale with temperature dependence, clarifying the fundamental nano-deformation behavior of metals is critical for the optimization of manufacturing processes, and the control of nano-optical, electrical, mechanical or surface properties. Unfortunately, limited by the time scale and sample size, the effect of temperature on the deformation behavior of nano-metals during the ultrahigh-strain-rate forming process remains largely unexplored. This study demonstrates the nonlinear effect of temperature on the formability of nano-metals for the first time. Temperatures below 673 K facilitated the formability of nano-metals benefiting from the temperature-promoted dislocation proliferation process, whereas temperatures above 673 K weakened the plasticity of the nano-metal due to the activation of phase transformation. Frequent phase transition activation and accelerated dislocation annihilation at high temperatures reduced interstitial transport channels and delayed atomic transfer. Based on the temperature response of nano-metals in deformation mechanisms, defect evolution behavior and formability, the constitutive model and nano-deformation mechanism map of nano-metals in ultrahigh-strain-rate forming processes are proposed. The objective of this work is to provide basic support for the reasonable matching of nano-forming technology and processing temperature, and the determination of the optimal process window through fundamental nano-deformation behavior exploration.

Relationship between the UPLC Fingerprints of Citrus reticulata "Chachi" Leaves and Their Antioxidant Activities.

Citrus reticulata "Chachi" (CRC) leaves contain abundant flavonoids, indicating that they possess good nutritional/pharmacological research and development potential. This study aims to explore chemical antioxidant quality markers based on the spectrum-effect relationship and quality control strategy of CRC leaves. The ultrahigh performance liquid chromatography (UPLC) system was used to establish chromatographic fingerprints of Citrus reticulata "Chachi" leaves. Simultaneously, they were evaluated by using similarity analysis (SA), hierarchical cluster analysis (HCA), and principal component analysis (PCA). Afterwards, the DPPH assay was adopted to study the antioxidant effects. The spectrum-effect relationship between UPLC fingerprints and DPPH radical-scavenging activities was studied with grey relational analysis (GRA). Analysis results indicated that there were twenty-one common peaks of fourteen batches of CRC leaves which were from different regions of Guangdong province, and their similarities ranged from 0.648 to 0.997. HCA results showed that fourteen batches of samples of CRC leaves could be divided into six classes at Euclidean distance of 5. The results from GRA showed that tangeretin and hesperidin were the main flavonoids responsible for the antioxidant activity in CRC leaves. In conclusion, this research established a chromatographic analysis method suitable for CRC leaves and demonstrated that chromatographic fingerprints analysis combined with the antioxidant activity could be used to evaluate the material basis of CRC leaves and may provide a reference to establish a quality standard.

Metal-free visible-light-driven cascade cyclization reaction to synthesize 2-oxindoles via benzoyl and phenylsulfinyl radicals with acrylamide derivatives.

A metal-free visible-light-driven cascade cyclization reaction to synthesize 3-methyl-3-acetophenone-2-oxindoles and 3-methyl-3-(methylsulfonyl)benzene-2-oxindoles in yields up to 96% and 99%, via benzoyl and phenylsulfinyl radicals with acrylamide derivatives is reported, respectively. Extensive studies, including gram-scale, radical capture and isotope experiments, were performed to indicate that the reaction may involve a radical process.

Selection of fertilization strategies for different sperm parameters in vitro fertilization.

Background: Fertilization is a prerequisite for successful human reproduction. The choice of clinical fertilization strategy is crucial and directly affects clinical outcomes. This study analyzes the most appropriate assisted reproductive technology (ART) strategy based on sperm parameters. Methods: Semen samples were divided into six groups based on semen progressive motility (PR) and semen density (SD): HMLD (high motility-low density) (PR ≥32% and sperm density <15×106/mL, n=60), HMID (high motility-intermediate density) (PR ≥32% and 15×106/mL ≤ SD <30×106/mL, n=106), HMHD (high motility-high density) (PR ≥32% and SD ≥30×106/mL, n=1,009), LMLD (low motility-low density) (PR <32% and SD <15×106/mL, n=99), LMID (low motility-intermediate density) (PR <32% and 15×106/mL ≤ SD <30×106/mL, n=77), and LMHD (low motility-high density) (PR <32% and SD ≥30×106/mL, n=164). We analyzed hyaluronic acid binding (HAB) assay and acrosin activity, along with fertilization, embryonic development, and pregnancy outcomes, to demonstrate the correlation of sperm parameters with fertilization function. Results: In the PR <32% groups, the rate of intracytoplasmic sperm injection (ICSI) treatment decreased with increasing sperm concentration. Specifically, approximately 10% of in vitro fertilization (IVF) treatment cycles required a rescue ICSI when sperm PR was <32% accompanied by SD ≥15×106/mL and PR ≥32% accompanied by SD <30×106/mL, which was significantly higher than HMHD group, P<0.001. Sperm acrosin activity and HAB ability were significantly higher in the groups with good sperm parameters, P<0.05. Conclusions: The findings of this study suggest, fertilization ability of sperm is closely related to sperm motility and density. In clinical practice, IVF strategies should be refined based on male sperm parameters.

[Current status and development strategy of ISO/TC 249 standards for Chinese materia medica].

The internationalization of traditional Chinese medicine(TCM) is one of the strategic development objectives in China, which has been incorporated into the national strategy as an important part of the Belt and Road Initiative development strategy. As the basis and prerequisite of TCM development, Chinese materia medica(CMM) has a direct impact on the internationalization of TCM. The International Organization for Standardization(ISO) is a global organization composed of national standardization bodies, and the ISO standards impact the world's economy, trade, communication and cooperation. Based on a brief introduction to ISO/Traditional Chinese Medicine Technical Committee(ISO/TC 249), this study elaborates the necessity of establishing ISO standards for CMM and analyzes the current status and challenges faced by the formulation of international standards for CMM. Finally, this study puts forward the development strategy of international standards for CMM. Specifically, efforts should be made to develop top-level design with international market demands as the guidance and improve the quality of standards to accelerate the transformation of domestic high-quality standards into international standards. Moreover, measures should be taken to give full play to the positive role of enterprises in the formulation of standards, vigorously cultivate compound talents for international standardization of TCM, and constantly strengthen international cooperation. The experience and thinking are of guiding significance for the scientific, efficient and reasonable formulation of high-quality ISO standards for CMM in the future.

The Prevalence, Progress and Risk Factor Control of Chronic Kidney Disease in Chinese Adults With Type 2 Diabetes Mellitus in Primary Care.

Objective: This study aimed to evaluate the prevalence of chronic kidney disease (CKD) in Chinese adults with T2DM in primary care, and the association of HbA1c, blood pressure (BP) and triglycerides (TG), i.e. ABC control at follow up (FU) with the progress and regression of CKD. Methods: A total of 5123 patients with ≥3 measurements of estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), HbA1c, BP, LDL-C and TG, and FU ≥ 12 months were included into final analysis. The presence of CKD was defined as the presence of albuminuria (UACR ≥ 30 mg/g), impaired eGFR (eGFR < 60 ml/min/1.73 m2) or both, and was categorised as low, moderate and high/very high risk. The change of CKD risk for outcome was categorised as stable (no change), progress (risk increase) and regress (risk decrease) from baseline to the last visits (LV). Results: The prevalence of CKD, impaired eGFR and albuminuria was 29.6%, 5.8% and 27.1% at baseline, with 70.4%, 20.3%, 7.0% and 2.3% of patients distributed in low, moderate, high and very high risk group. There were 3457 (67.5%), 1120 (21.8%) and 546 (10.7%) patients had CKD outcome risk stable, progressed and regressed respectively. The proportion of patients reaching targets of BP ≤ 130/80 mmHg, HbA1c<7.5%, LDL-C<2.60 mmol/L increased from baseline to FU and LV, together with increased usage of insulin, RAS inhibitors and lipid lowering medications. After multivariable adjustment, the HbA1c<7.5% (OR: 0.66, 95%CI 0.56-0.78), TG< 1.7 mmol/L (OR: 0.81, 95%CI 0.68-0.96) at FU and BP ≤ 130/80 mmHg at LV (OR: 0.82, 95%CI 0.70-0.95) was negatively associated with CKD outcome risk progress. Conclusion: The prevalence of CKD was high with 21.8% of patients progressing to higher CKD outcome risk at FU, attention should be paid on long term and better ABC control.

ß-Cell function and body mass index are predictors of exercise response in elderly patients with prediabetes.

AIMS/INTRODUCTION: To explore the predicting factors of exercise response (whether the participants converted to diabetes) in elderly patients with prediabetes. MATERIALS AND METHODS: This is a retrospective subgroup analysis of the registered clinical trial with previous publication of the same cohort. A total of 248 participants with prediabetes were randomized to the aerobic training (n = 83) group, resistance training (n = 82) group and control group (n = 83). The patients who finished the 2-year exercise intervention were included in this analysis to explore the factors impacting exercise response. RESULTS: A total of 113 patients with prediabetes completed 2 years of exercise, with 56 participants in the aerobic exercise group and 57 in the resistance exercise group. Patients who reversed to normal glucose tolerance, remained in prediabetes and developed diabetes were 18 (15.90%), 70 (62.00%) and 25 (22.10%), respectively. Logistic regression showed that baseline, homeostatic model 2 assessment of ß-cell function (ß = -0.143, P = 0.039), hemoglobin A1c (ß = 3.301, P = 0.007) and body mass index (ß = 0.402, P = 0.012) were related to exercise response, whereas the waist-to-hip ratio (ß = -3.277, P = 0.693) and types of exercise (ß = 1.192, P = 0.093) were not significantly related to exercise response. CONCLUSIONS: Baseline homeostatic model 2 assessment of ß-cell function, hemoglobin A1c and body mass index were the predictors for the response to exercise in elderly patients with prediabetes.

Novel structural-related analogs of PFI-3 (SRAPs) that target the BRG1 catalytic subunit of the SWI/SNF complex increase the activity of temozolomide in glioblastoma cells.

Glioblastoma (GBM) is the most aggressive and treatment-refractory malignant adult brain cancer. After standard of care therapy, the overall median survival for GBM is only ∼6 months with a 5-year survival <10%. Although some patients initially respond to the DNA alkylating agent temozolomide (TMZ), unfortunately most patients become resistant to therapy and brain tumors eventually recur. We previously found that knockout of BRG1 or treatment with PFI-3, a small molecule inhibitor of the BRG1 bromodomain, enhances sensitivity of GBM cells to temozolomide in vitro and in vivo GBM animal models. Those results demonstrated that the BRG1 catalytic subunit of the SWI/SNF chromatin remodeling complex appears to play a critical role in regulating TMZ-sensitivity. In the present study we designed and synthesized Structurally Related Analogs of PFI-3 (SRAPs) and tested their bioactivity in vitro. Among of the SRAPs, 9f and 11d show better efficacy than PFI-3 in sensitizing GBM cells to the antiproliferative and cell death inducing effects of temozolomide in vitro, as well as enhancing the inhibitor effect of temozolomide on the growth of subcutaneous GBM tumors.

Mussel-Inspired Fabrication of PDA@PAN Electrospun Nanofibrous Membrane for Oil-in-Water Emulsion Separation.

Emulsified oily wastewater threatens human health seriously, and traditional technologies are unable to separate emulsion containing small sized oil droplets. Currently, oil-water emulsions are usually separated by special wettability membranes, and researchers are devoted to developing membranes with excellent antifouling performance and high permeability. Herein, a novel, simple and low-cost method has been proposed for the separation of emulsion containing surfactants. Polyacrylonitrile (PAN) nanofibers were prepared via electrospinning and then coated by polydopamine (PDA) by using self-polymerization reactions in aqueous solutions. The morphology, structure and oil-in-water emulsion separation properties of the as-prepared PDA@PAN nanofibrous membrane were tested. The results show that PDA@PAN nanofibrous membrane has superhydrophilicity and almost no adhesion to crude oil in water, which exhibits excellent oil-water separation ability. The permeability and separation efficiency of n-hexane/water emulsion are up to 1570 Lm-2 h-1 bar-1 and 96.1%, respectively. Furthermore, after 10 cycles of separation, the permeability and separation efficiency values do not decrease significantly, indicating its good recycling performance. This research develops a new method for preparing oil-water separation membrane, which can be used for efficient oil-in-water emulsion separation.

Targeting the Bromodomain of BRG-1/BRM Subunit of the SWI/SNF Complex Increases the Anticancer Activity of Temozolomide in Glioblastoma.

Glioblastoma (GBM) is a deadly and incurable brain cancer with limited therapeutic options. PFI-3 is a small-molecule bromodomain (BRD) inhibitor of the BRM/BRG1 subunits of the SWI/SNF chromatin remodeling complex. The objective of this study is to determine the efficacy of PFI-3 as a potential GBM therapy. We report that PFI-3 binds to these BRDs when expressed in GBM cells. PFI-3 markedly enhanced the antiproliferative and cell death-inducing effects of temozolomide (TMZ) in TMZ-sensitive GBM cells as well as overcame the chemoresistance of highly TMZ-resistant GBM cells. PFI-3 also altered gene expression in GBM and enhanced the basal and interferon-induced expression of a subset of interferon-responsive genes. Besides the effects of PFI-3 on GBM cells in vitro, we found that PFI-3 markedly potentiated the anticancer effect of TMZ in an intracranial GBM animal model, resulting in a marked increase in survival of animals bearing GBM tumors. Taken together, we identified the BRG1 and BRM subunits of SWI/SNF as novel targets in GBM and revealed the therapeutic potential of applying small molecule inhibitors of SWI/SNF to improve the clinical outcome in GBM using standard-of-care chemotherapy.

Extraction vs. Nonextraction on Soft-Tissue Profile Change in Patients with Malocclusion: A Systematic Review and Meta-Analysis.

OBJECTIVES: We aimed to summarize the current evidence regarding the impact of extraction vs. nonextraction in orthodontic treatment on patients' soft-tissue profile with malocclusion. METHODS: Between April 30th and November 30th, 2020, we searched PubMed and SCOPUS for published papers from inception to November 2020 using "orthodontic," "extraction," "nonextraction," and "Malocclusion." Included studies were summarized, and relevant data were extracted and analyzed using Review Manager 5.4. RESULTS: Pooled data from four controlled trials demonstrated a nonsignificant difference between extraction and nonextraction in terms of SNA (MD = 0.50, 95% CI: -0.37, 1.38; p = 0.26), SNB (MD = 0.11, 95% CI: -1.23, 1.44; p = 0.88), FMA (MD = 1.82, 95% CI: -2.39, 6.02; p = 0.40), IMPA (MD = 0.06, 95% CI: -8.83, -8.94; p = 0.99), overjet (MD = -1.47, 95% CI: -6.21, 3.26; p = 0.54), and overbite (MD = 0.50, 95% CI: -1.40, 2.40; p = 0.60). On the other hand, the extraction method significantly increased the ANB compared with the nonextraction group (MD = 0.78, 95% CI: 0.25, 1.31; p = 0.004). CONCLUSION: The current evidence demonstrated that nonextraction protocols for orthodontic treatment are a safe and effective alternative to extraction protocols; individually tailored treatment strategies should be applied. More randomized controlled trials are critically needed to safely make an evidence-based treatment conclusion.

Exploration and Biological Evaluation of Basic Heteromonocyclic Propanamide Derivatives as SARDs for the Treatment of Enzalutamide-Resistant Prostate Cancer.

A series of propanamide derivatives were designed, synthesized, and pharmacologically characterized as selective androgen receptor degraders (SARDs) and pan-antagonists that exert a broad-scope androgen receptor (AR) antagonism. Incorporating different basic heteromonocyclic B-ring structural elements in the common A-ring-linkage-B-ring nonsteroidal antiandrogen general pharmacophore contributed to a novel scaffold of small molecules with SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-69 (11), UT-155 (12), and UT-34 (13). Compound 26f exhibited inhibitory and degradation effects in vitro in a wide array of wtAR, point mutant, and truncation mutant-driven prostate cancers (PCs). Further, 26f inhibited tumor cell growth in a xenograft model composed of enzalutamide-resistant (EnzR) LNCaP cells. These results demonstrate an advancement toward the development of novel SARDs and pan-antagonists with efficacy against EnzR prostate cancers.

Agar-stabilized sulfidated microscale zero-valent iron: Its stability and performance in chromate reduction.

Sulfidated microscale zero-valent iron (SmZVI) attracts much attention recently in remediation of contaminated groundwater, but whether polymer coating on SmZVI would impact on its reactivity and capacity is yet to be understood. In this work, SmZVI was prepared by milling mZVI with elemental sulfur, and its stability in agar solution was evaluated. The impact of polymer coating on SmZVI grains' capacity and reactivity for chromate reduction was then examined. Experimental results indicated that SmZVI having the best overall performance was attained by grinding mZVI with elemental sulfur at 0.05 S/Fe molar ratio for 10 h. SmZVI's stability can be substantially improved if dispersed in 2.0 g/L agar solution. Existence of agar films on the SmZVI grain (A-SmZVI) lowered the material's capacity for chromate reduction by 56%, and the associated reaction kinetics by 70.4%, as estimated by pseudo first-order reaction model using the early-stage experimental data. Analysis of XPS spectra of A-SmZVI post reaction with chromate indicated that multiple reductive species including Fe0, Fe(II), FeS, and S(-II) may have jointly participated in the redox reaction taking place on the A-SmZVI-water interface. Fitting of XPS data supported that S(-II) was oxidized to SO42-, S2O32-, and S0, in order of decreasing surface concentration.

[Analysis of economic benefits of Chinese medicine eco-agriculture based on multiple stakeholders].

As the most advanced environment-friendly production model in the international society, ecological agriculture of Chinese materia medica(CMM) is the only way for the development of modern agriculture. With the proposal of the declaration on ecolo-gical agriculture of CMM, "Don't grab land from farmland, don't be enemies of grass and insects, don't be afraid of barren slopes and forests, and live up to the green and green mountains", the ecological planting of CMM has blossomed all over the country, and formed a scientific theory, technology and model. Based on the theory and method of economics, this paper expounds the comprehensive benefits and development advantages of ecological agriculture of CMM from the perspectives of farmers(producers), patients(consumers) and the country. From the perspective of medicinal farmers, the input and output income of conventional agriculture and ecological agriculture of CMM such as Panax ginseng, Astragalus propinquus, Atractylodes lancea, and Bupleurum chinense were compared, and it was found that ecological agriculture of CMM had obvious advantages in net income, average annual income and input-output ratio, which could better promote farmers' income. From the perspective of patients, according to the same dose, the content of active ingredients in ecologically planted CMMs is significantly higher than that in conventionally-planted herbs, and the amount of effective substances taken by patients is also higher, so as to achieve better therapeutic effect. At the national level, ecological planting of CMM is the key to ensuring the high-quality development of CMM industry, increasing farmers' income, ensuring the safety of people's drug use and promoting the sustainable development of agriculture. It is also an important part of realizing the harmonious development of economy, society and environment and promoting ecological civilization. In general, the declaration on ecological agriculture of CMM embo-dies the core characteristics and goals of ecological agriculture, and also points of the path and vision of ecological agriculture of CMM in the future. The declaration will guide production practice, promote the benefit of farmers, and lay the foundation for the sustainable development of CMM industry.

An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer.

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.