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.

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.

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.

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.

[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.

Genomic analyses of diverse wild and cultivated accessions provide insights into the evolutionary history of jujube.

The Chinese jujube (Ziziphus jujuba Mill.), a member of the Rhamnaceae family, is an important perennial fruit tree crop of substantial economic, ecological and nutritional value, and is also used as a traditional herbal medicine. Here, we report the resequencing of 493 jujube accessions, including 202 wild and 291 cultivated accessions at >16× depth. Our population genomic analyses revealed that the Shanxi-Shaanxi area of China was jujube's primary domestication centre and that jujube was then disseminated into East China before finally extending into South China. Divergence events analysis indicated that Ziziphus acidojujuba and Ziziphus jujuba diverged around 2.7 Mya, suggesting the interesting possibility that a long pre-domestication period may have occurred prior to human intervention. Using the large genetic polymorphism data set, we identified a 15-bp tandem insertion in the promoter of the jujube ortholog of the POLLEN DEFECTIVE IN GUIDANCE 1 (POD1) gene, which was strongly associated with seed-setting rate. Integrating genome-wide association study (GWAS), transcriptome data, expression analysis and transgenic validation in tomato, we identified a DA3/UBIQUITIN-SPECIFIC PROTEASE 14 (UBP14) ortholog, which negatively regulate fruit weight in jujube. We also identified candidate genes, which have likely influenced the selection of fruit sweetness and crispness texture traits among fresh and dry jujubes. Our study not only illuminates the genetic basis of jujube evolution and domestication and provides a deep and rich genomic resource to facilitate both crop improvement and hypothesis-driven basic research, but also identifies multiple agriculturally important genes for this unique perennial tree fruit species.

First Report of Ergot (Claviceps purpurea) on Drunken Horse Grass (Achnatherum inebrians) in China.

Drunken horse grass (Achnatherum inebrians) belongs to the family Poaceae: it is mainly distributed in the natural grasslands of northern and northwestern in China. Ergot is a disease that can not only affect the growth of the grass, but also cause livestock poisoning (Coufal-Majewski et al. 2016). In September 2018, ergot was observed in a large area (about 15 ha) in Xinghai county, Qinghai province, China (35° 47' N, 99° 53' E, Altitude 3559 m). Around 65% of the plants of Achnatherum inebrians were affected. Symptoms initially showed drop-like honeydew on the ears of drunken horse grass, and later brown to dark brown sclerotia were observed. These were straight to slightly curved, measured 6.7 to 13.5 × 1.5 to 2.1 mm, which was approximately 1 to 4 times the size of healthy seeds. Sixteen spikes with typical symptoms were collected from eight different fields. Sclerotia were disinfested by immersion in 75% ethanol for 30 s and 1% NaClO for 90 s, rinsed three times in sterilized water, plated on potato dextrose agar (PDA) medium, incubated at 24°C in the dark and isolates purified by culturing from single spores. Finally, 16 single-spore cultures with similar phenotypes were obtained from these sclerotia. Colonies produced on PDA for 15 days at 24 ℃ were grayish white with fluffy aerial mycelium, about 60 mm in diameter. Conidia were hyaline, ovoid to cylindrical, 5.42 to 7.69 × 2.85 to 3.75 µm (avg. 5.67 × 3.2; n = 50). These morphological characteristics were consistent with the descriptions of Claviceps species in general (PíchovÁ et al. 2018). To further identify the Claviceps spp., isolate NSZJ (=MHLZU-AI20201012) was selected as a representative for molecular characterization. Two nuclear protein-coding genes TUB2 and MCM7 were amplified by T2/T12 (O'Donnell and Cigelnik 1997) and CARCA-F/M456-5R (Rehner and Buckley 2005), respectively, and sequenced. Sequences were deposited in GenBank (accession nos. MW115640 for TUB2 and MW115641 for MCM7). A BLAST analysis of these two segments showed >99% identity with those sequences of isolate W3 of C. purpurea (Pazoutová et al. 2014). To confirm the pathogenicity on drunken horse grass, 20 healthy plants (2-year-old) grown in an experimental field at the College of Pasture Agriculture Science and Technology, Yuzhong Campus of Lanzhou University in China (104° 39' E, 35° 89' N, altitude1653m) were spray-inoculated with conidial suspension (1 × 106 conidia/ml) during the flowering period. Another 20 plants in the field were sprayed with sterilized distilled water as controls. All plants were individually covered with transparent polyethylene bags for 24 h to maintain high relative humidity. After 7 to 10 days, small yellowish-white drops of honeydew were observed in some florets. At 22 days post inoculation, all the inoculated panicles developed three to six sclerotia per head, ranging in size from 6.7 to 13.5 mm, while control plants remained healthy. The same pathogen was consistently re-isolated from inoculated spikes and confirmed by morphological and molecular characterization as described above. Claviceps purpurea was reported to be associated with ergot in A. lemmonii in Idaho and A. robustum in Montana (Alderman et al. 2004). To our knowledge, this is the first report of C. purpurea causing ergot in A. inebrians in China.

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.

[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.

[Discussion on high quality development and authentication system construction of Dao-di herbs based on blockchain].

Dao-di herbs are an important part of clinical medicine in traditional Chinese medicine. They are also precious wealth left to human beings from history, which contain deep traditional Chinese cultural connotations and play an important role in supporting and serving the Chinese medicine business. The relevant policy documents introduced by various national ministries and commissions have many contents and requirements related to the promotion of Dao-di herbs protection and industrial development. Due to the Dao-di herbs industry has a series of characteristics, such as a long chain, many involved links, long cycles, multiple production entities, multiple locations, and various types, the high-quality development of the industry has put forward higher requirements on the linkage between upstream and downstream, production entities, traceability of the whole process and information sharing. This article takes Dao-di herbs certification work as an application scenario and entry point, and discusses it from the perspective of block chain and information technology. It proposes the following work ideas: establish multi-party consensus from the macro-organizational management, business, and operational technical levels, and unblock channels for data and information, to achieve institutionalization of certification; establish certification-related standards and specifications to achieve certification standardization; build a certification hardware system to achieve certification networking; build a certification software system to develop functions for specific information content such as identity, origin, production, production process, quality, product and brand of authentic medicinal material production interactively, and realize certification programmatic; data security and sharing of related production activities to achieve socialization of certification. Make full use of modern technologies such as blockchain, the internet of things, big data and information technology, and through the joint participation of management, production, use and the public, the whole process information of Daodi herbs is integrated to form an interconnected information sharing application mode, thus, to serve and promote the high-quality development of Dao-di herbs industry.

[Cultivation strategy on cluster brand of ecological agriculture of Dao-di herbs].

The cluster brand is the embodiment of the core competitiveness of an industry. Developing and cultivating cluster brand of ecological agriculture of Dao-di herbs not only helps to optimize the value chain of the Chinese medicinal materials(CMMs) industry cluster, realize the value-added of the CMMs industry cluster, but also enhance the visibility and influence of the industrial cluster, enhance the core competitiveness of the industrial cluster. This has important practical significance for promoting the "orderly" "safe" and "effective" development of the Dao-di herbs. Based on the industry development status of CMMs, this article introduces several concepts related to cluster brands and their relationships, and focuses on the cultivation models and strategies of cluster brand in the CMMs industry. Based on the current status of the development of the CMMs industry, this article introduces several concepts related to cluster brands and their interrelationships. It discusses the cultivation models and strategies of cluster brands in the CMMs industry, industry associations, Chinese medicine companies and individual growers as the support, insists on the ecological cultivation of authentic medicinal materials and the cultivation of cluster brands. Finally, it points out the direction for the high-quality development of the ecological agriculture of CMMs.

[Preparation and evaluation of gastric adhesive-floating pellets for Bolo leaf phenols].

Gastric adhesive-floating pellets for Bolo leaf phenols (BLP) were prepared by extrusion-spheronization method, with chitosan as skeleton bioadhesive material, and stearyl alcohol as help-bleaching agent to evaluate its in vitro adhesivity, floatability and in vivo retention situation, and investigate its in vitro release characteristics. The in vitro adhesivity and floatability were evaluated respectively by in vitro tissue retention method and visual observation method. The retention of pellets in rats was investigated by in vivo tissue retention method and in vivo imaging of small animals. In addition, the in vitro release of p-coumaric acid and caffeic acid as the index components in pellets were evaluated. Results showed that the in vitro adhesivity of the prepared gastric adhesive-floating pellets reached (73.2±3.4)%, and the pellets could float immediately in simulated gastric fluid for more than 12 h; the retention rate of adhesive-floating pellets in rats reached more than 40% after 6 h, while the retention rate of common reference pellets was decreased by 15% as compared with the gastric adhesive-floating pellets, with significant difference (P<0.01); the drug in vitro release time can reach more than 6 h, and the drug release behaviors were lined with Higuchi equation. In vivo and in vitro studies showed that, the gastrointestinal bioadhesive and floating pellets prepared in this study have good bioadhesivity, floatability and good sustained release characteristics.

[Bioavailability in vivo and in vitro transepithelial transport across Caco-2 cell monolayer of pueraria flavonoids bio-adhesive and floating pellets].

To study the bioavailability of pueraria flavonoids bio-adhesive and floating pellets, the absorption of puerarin was studied using Caco-2 cell monolayer by liquid chromatography (HPLC) method, comparing the P(app) of pueraria flavonoids bio-adhesive and floating pellets with different bio-adhesive materials. Drugs were administered at a dose of 100 mg·kg(-1) via ig. The plasma concentration of puerarin was determined by HPLC, the pharmacokinetics were calculated with the WinNonlin 6.0 software. The results showed that the P(app) of bio-adhesive and floating pellets with hydroxypropyl methylcellulose (HPMC)-cabomer was largest, which had a significant difference (P < 0.05). The AUC(0-t) of pueraria flavonoids bio-adhesive and floating pellets was 1.79 times of pueraria flavonoids, the C(max) of pueraria flavonoids bio-adhesive and floating pellets and pueraria flavonoids had a significant difference (P < 0.05). What's more the MRT had prolonged. In conclusion, pueraria flavonoids bio-adhesive and floating pellets with HPMC-cabomer could significantly facilitate the transport of puerarin on Caco-2 cellular monolayers. The bioavailability of pueraria flavonoids bio-adhesive and floating pellets with HPMC-cabomer was increased more than pueraria flavonoids with a sustained release effect.

[Discussion on present situation of study on pesticide residues in Chinese herbal medicines].

Pesticide residues in traditional Chinese medicine has attracted widespread attention at home and abroad. This paper analyzed the pollution present situation and existing problems of pesticide residue for Chinese herbal medicines, explicited the analytical methods of pesticide residues in Chinese herbal medicines. Meanwhile, the commonly used pesticide residue degradation and application in Chinese herbal medicines were discussed. Moreover, on the basis of analysis of pesticide residue standards, this paper proposed the necessity and urgency of the limit standard of pesticide residues in Chinese herbal medicines, and provided a scientific references for deepening research and developing safe, green medicines.

The Biosynthetic Pathways of Tanshinones and Phenolic Acids in Salvia miltiorrhiza.

Secondary metabolites from plants play key roles in human medicine and chemical industries. Due to limited accumulation of secondary metabolites in plants and their important roles, characterization of key enzymes involved in biosynthetic pathway will enable metabolic engineering or synthetic biology to improve or produce the compounds in plants or microorganisms, which provides an alternative for production of these valuable compounds. Salvia miltiorrhiza, containing tanshinones and phenolic acids as its active compounds, has been widely used for the treatment of cardiovascular and cerebrovascular diseases. The biosynthetic analysis of secondary metabolites in S. miltiorrhiza has made great progress due to the successful genetic transformation system, simplified hairy roots system, and high-throughput sequencing. The cloned genes in S. miltiorrhiza had provided references for functional characterization of the post-modification steps involved in biosynthesis of tanshinones and phenolic acids, and further utilization of these steps in metabolic engineering. The strategies used in these studies could provide solid foundation for elucidation of biosynthetic pathways of diterpenoids and phenolic acids in other species. The present review systematically summarizes recent advances in biosynthetic pathway analysis of tanshinones and phenolic acids as well as synthetic biology and metabolic engineering applications of the rate-limiting genes involved in the secondary metabolism in S. miltiorrhiza.

[Good agricultural practice (GAP) of Chinese materia medica (CMM) for ten years: achievements, problems and proposals].

This paper aims to summarize the achievements during the implementation process of good agricultural practice (GAP) in Chinese Materia Medica (CMM), and on basis of analyzing the existing problems of GAP, to propose further implementation of GAP in TCM growing. Since the launch of GAP in CMM growing ten years ago, it has acquired great achievements, including: (1) The promulgation of a series of measures for the administration of the GAP approval in the CMM growing; (2) The expanded planting area of CMM; (3) The increased awareness of standardized CMM growing among farmers and enterprises; (4) The establishment of GAP implementation bases for CMM growing; (5) The improvement of theory and methodology for CMM growing; (6) The development of a large group of experts and scholars in GAP approval for CMM production. The problems existing in the production include: (1) A deep understanding of GAP and its certification is still needed; (2) The distribution of the certification base is not reasonable; (3) The geo-economics effect and the backward farming practices are thought to be the bottlenecks in the standardization of CMM growing and the scale production of CMM; (4) Low comparative effectiveness limits the development of the GAP; (5) The base of breeding improved variety is blank; (6) The immature of the cultivation technique lead to the risk of production process; (7) The degradation of soil microbial and the continuous cropping obstacle restrict the sustainable development of the GAP base. To further promote the health and orderly GAP in the CMM growing, the authors propose: (1) To change the mode of production; (2) To establish a sound standard system so as to ensure quality products for fair prices; (3) To fully consider the geo-economic culture and vigorously promote the definite cultivating of traditional Chinese medicinal materials; (4) To strengthen the transformation and generalization of basic researches and achievements, in order to provide technical support for the CMM production; (5) To deepen the understanding of GAP, to vigorously promote ecological planting and precision agriculture, in order to overcome the continuous cropping obstacle. The authors think that despite the fact that we are still facing with a huge array of management and technological problems, the GAP in the CMM growing has already enjoyed widespread support and showed great potential. In the future, with people's deeper understanding of GAP and the great progress of the science and technology, the GAP will constantly be fused with the theory, methodology and technology in the modern agriculture like precision agriculture, eco-agriculture and etc.

Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen.

We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35- to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications.

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.

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).