Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy

Abiraterone blocks androgen synthesis and prolongs survival in castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis1,2. Abiraterone is metabolized in patients to D4A, which has even greater anti-tumor activity and structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone3. Here, we show that D4A is converted to at least 3 5α-reduced and 3 5β-reduced metabolites. The initial 5α-reduced metabolite, 3-keto-5α-abi, is more abundant than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abi and downstream metabolites are depleted, while D4A concentrations rise, effectively blocking production of a tumor-promoting metabolite and permitting D4A accumulation. Furthermore, dutasteride does not deplete three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacologic 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy

Aberrant brain entropy in posttraumatic stress disorder comorbid with major depressive disorder during the coronavirus disease 2019 pandemic

AimPreviously, neuroimaging studies on comorbid Posttraumatic-Major depression disorder (PTSD-MDD) comorbidity found abnormalities in multiple brain regions among patients. Recent neuroimaging studies have revealed dynamic nature on human brain activity during resting state, and entropy as an indicator of dynamic regularity may provide a new perspective for studying abnormalities of brain function among PTSD-MDD patients. During the COVID-19 pandemic, there has been a significant increase in the number of patients with PTSD-MDD. We have decided to conduct research on resting-state brain functional activity of patients who developed PTSD-MDD during this period using entropy.MethodsThirty three patients with PTSD-MDD and 36 matched TCs were recruited. PTSD and depression symptoms were assessed using multiple clinical scales. All subjects underwent functional magnetic resonance imaging (fMRI) scans. And the brain entropy (BEN) maps were calculated using the BEN mapping toolbox. A two-sample t-test was used to compare the differences in the brain entropy between the PTSD-MDD comorbidity group and TC group. Furthermore, correlation analysis was conducted between the BEN changes in patients with PTSD-MDD and clinical scales.ResultsCompared to the TCs, PTSD-MDD patients had a reduced BEN in the right middle frontal orbital gyrus (R_MFOG), left putamen, and right inferior frontal gyrus, opercular part (R_IFOG). Furthermore, a higher BEN in the R_MFOG was related to higher CAPS and HAMD-24 scores in the patients with PTSD-MDD.ConclusionThe results showed that the R_MFOG is a potential marker for showing the symptom severity of PTSD-MDD comorbidity. Consequently, PTSD-MDD may have reduced BEN in frontal and basal ganglia regions which are related to emotional dysregulation and cognitive deficits

Cross-talk between cAMP and MAPK pathways in HSD11B2 induction by hCG in placental trophoblasts.

Overexposure of the fetus to glucocorticoids in gestation is detrimental to fetal development. The passage of maternal glucocorticoids into the fetal circulation is governed by 11beta-Hydroxysteroid Dehydrogenase Type 2 (HSD11B2) in the placental syncytiotrophoblasts. Human chorionic gonadotropin (hCG) plays an important role in maintaining placental HSD11B2 expression via activation of the cAMP pathway. In this study, we investigated the relationship between the activation of the cAMP pathway by hCG and subsequent phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) or p38 mitogen-activated protein kinase (MAPK) pathways in the regulation of placental HSD11B2 expression in human placental syncytiotrophoblasts. We found that treatment of the placental syncytiotrophoblasts with either hCG or dibutyl cAMP (dbcAMP) could promote the phosphorylation of p38 and ERK1/2. Inhibition of p38 MAPK with SB203580 not only reduced the basal HSD11B2 mRNA and protein levels but also attenuated HSD11B2 levels induced by either hCG or dbcAMP. By contrast, inhibition of ERK1/2 with PD98059 increased the basal mRNA and protein levels of HSD11B2 and had no effect on HSD11B2 mRNA and protein levels induced by either hCG or dbcAMP. These data suggest that p38 MAPK is involved in both basal and hCG/cAMP-induced expression of HSD11B2, and ERK1/2 may play a role opposite to p38 MAPK at least in the basal expression of HSD11B2 in human placental syncytiotrophoblasts and that there is complicated cross-talk between hCG/cAMP and MAPK cascades in the regulation of placental HSD11B2 expression

Identification of genes involved in regulating the development of feathered feet in chicken embryo

ABSTRACT: The genetic and developmental factors driving the diverse distribution and morphogenesis of feathers and scales on bird feet are yet unclear. Within a single species, Guangxi domestic chickens exhibit dramatic variety in feathered feet, making them an accessible model for research into the molecular basis of variations in skin appendages. In this study, we used H&E staining to observe the morphogenesis of feathered feet, scaled feet and wings skin at different embryonic stages in Longsheng-Feng chickens and Guangxi Partridge chickens. We selected 4 periods (E6, E7, E8, and E12) that play an important role in feather development and performed transcriptome sequencing to screen for candidate genes associated with feathered feet. Through comparison and analysis of transcriptome data, we identified a set of differently expressed genes (DGEs), which were enriched in appendage organ development, hindlimb morphogenesis, activation of transcription factor binding, and binding of sequence-specific DNA in the cis-regulatory region. In addition, we identified some feathered feet-related genes by analyzing the classical signaling pathways that regulate feather development. Finally, we identified candidate genes that regulate feathered feet formation, which include TBX5, PITX1, ZIC1, FGF20, WNT11, WNT7A, WNT16, and SHH. Interestingly, we found that TBX5 was significantly overexpressed in the skin of the feathered feet and had the highest expression at E7 (P < 0.01), whereas PITX1 expression was significantly reduced at E7(P < 0.01). It is hypothesized that TBX5 and PITX1 regulate the development of hair follicles through the Wnt/β-catenin signaling pathway at E7. Our results provide a theoretical basis for investigating the molecular regulatory mechanisms underlying the formation of chicken feathered feet

Steroidogenic metabolism of galeterone reveals a diversity of biochemical activities

Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Delta(5),3beta-hydroxyl) structure of galeterone is identical to that of cholesterol, which makes endogenous steroids with the same structure (e.g., dehydroepiandrosterone and pregnenolone) substrates for the enzyme 3beta-hydroxysteroid dehydrogenase (3betaHSD). We found that galeterone is metabolized by 3betaHSD to Delta(4)-galeterone (D4G), which is further converted by steroid-5alpha-reductase (SRD5A) to 3-keto-5alpha-galeterone (5alphaG), 3alpha-OH-5alpha-galeterone, and 3beta-OH-5alpha-galeterone; in vivo it is also converted to the three corresponding 5beta-reduced metabolites. D4G inhibits steroidogenesis and suppresses AR protein stability, AR target gene expression, and xenograft growth comparably with galeterone, and further conversion by SRD5A leads to loss of several activities that inhibit the androgen axis that may compromise clinical efficacy. Together, these findings define a critical metabolic class effect of steroidal drugs with a Delta(5),3beta-hydroxyl structure

Effect of heat treatment on microstructure and properties of CrMnFeCoNiMo high entropy alloy coating

In this paper, CrMnFeCoNiMo high entropy alloy coating was prepared on 304 stainless steel by plasma cladding technology. The effects of different heat treatment processes on the microstructure, hardness, wear resistance and corrosion resistance of high entropy alloy coatings were studied. The XRD and SEM images of the coating show that the phase structure is mainly Ni–Cr–Co–Mo phase. The impurity phase-[CrFe] solid solution and Ni3Fe phase will be formed between 950 °C and 1050 °C. The homogenization effect of the coating composition is more excellent under the heat treatment conditions of 950 °C and more than 1 h holding time. The hardness of the coating is relatively high at 850 °C heat treatment temperature and holding for 1 h, which is 670 HV0.2. When the temperature rises to 950 °C and 1050 °C, the hardness of the coating decreases. The coating has relatively high wear resistance at 950 °C heat treatment temperature and holding for 1 h, and the friction coefficient is about 0.27. Moreover, under this heat treatment condition, the surface composition of the coating is uniform and the corrosion resistance is good. The self-corrosion current is 1.325 × 10−7 A and the self-corrosion potential is −0.202 V

Efficient and accurate strategies for differentially-private sliding window queries

Regularly releasing the aggregate statistics about data streams in a privacy-preserving way not only serves valuable commercial and social purposes, but also protects the privacy of individuals. This problem has already been studied under differential privacy, but only for the case of a single continuous query that covers the entire time span, e.g., counting the number of tuples seen so far in the stream. However, most real-world applications are window-based, that is, they are interested in the statistical information about streaming data within a window, instead of the whole unbound stream. Furthermore, a Data Stream Management System (DSMS) may need to answer numerous correlated aggregated queries simultaneously, rather than a single one. To cope with these requirements, we study how to release differentially private answers for a set of sliding window aggregate queries. We propose two solutions, each consisting of query sampling and composition. We first selectively sample a subset of representative sliding window queries from the set of all the submitted ones. The representative queries are answered by adding Laplace noises in a way satisfying differential privacy. For each non-representative query, we compose its answer from the query results of those representatives. The experimental evaluation shows that our solutions are efficient and effective

Phosphorylation of p38 MAPK (P-p38) and ERK1/2 induced by dbcAMP (100 µM) and hCG (10 IU/ml) in human placental syncytiotrophoblasts.

<p>Upper panels of each bar graph are the representative blots. The bar graphs are the average data of three experiments. *P<0.05, **P<0.01,***P<0.001 versus 0 min.</p