DHODH inhibition represents a therapeutic strategy and improves abiraterone treatment in castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is an aggressive disease with poor prognosis, and there is an urgent need for more effective therapeutic targets to address this challenge. Here, we showed that dihydroorotate dehydrogenase (DHODH), an enzyme crucial in the pyrimidine biosynthesis pathway, is a promising therapeutic target for CRPC. The transcript levels of DHODH were significantly elevated in prostate tumors and were negatively correlated with the prognosis of patients with prostate cancer. DHODH inhibition effectively suppressed CRPC progression by blocking cell cycle progression and inducing apoptosis. Notably, treatment with DHODH inhibitor BAY2402234 activated androgen biosynthesis signaling in CRPC cells. However, the combination treatment with BAY2402234 and abiraterone decreased intratumoral testosterone levels and induced apoptosis, which inhibited the growth of CWR22Rv1 xenograft tumors and patient-derived xenograft organoids. Taken together, these results establish DHODH as a key player in CRPC and as a potential therapeutic target for advanced prostate cancer.

TRIM29 facilitates gemcitabine resistance via MEK/ERK pathway and is modulated by circRPS29/miR-770-5p axis in PDAC.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Chemotherapy based on gemcitabine (GEM) remains the first-line drug for patients with advanced PDAC. However, GEM resistance impairs its therapeutic effectiveness. Therefore, identifying effective therapeutic targets are urgently needed to overcome GEM resistance. METHODS: The clinical significance of Tripartite Motif Containing 29 (TRIM29) was identified by exploring GEO datasets and TCGA database and its potential biological functions were predicted by GSEA analysis. The regulatory axis was established by bioinformatics analysis and validated by mechanical experiments. Then, in vitro and in vivo assays were performed to validate the roles of TRIM29 in PDAC GEM resistance. RESULTS: High TRIM29 expression was associated with poor prognosis of PDAC and functional experiments demonstrated that TRIM29 promoted GEM resistance in PDAC GEM-resistant (GR) cells. Furthermore, we revealed that circRPS29 promoted TRIM29 expression via competitive interaction with miR-770-5p and then activated MEK/ERK signaling pathway. Additionally, both in vitro and in vivo functional experiments demonstrated that circRPS29/miR-770-5p/TRIM29 axis promoted PDAC GEM resistance via activating MEK/ERK signaling pathway. CONCLUSION: Our results identify the significance of the signaling axis, circRPS29/miR-770-5p/TRIM29-MEK/ERK, in PDAC GEM resistance, which will provide novel therapeutic targets for PDAC treatment.

Nondestructive qualitative and quantitative analysis of Yaobitong capsule using near-infrared spectroscopy in tandem with chemometrics.

The purpose of the study is to present a nondestructive qualitative and quantitative approach of hard-shell capsule using near-infrared (NIR) spectroscopy combined with chemometrics. The Yaobitong capsule (YBTC) was used for demonstration of the proposed approach and the NIR spectra were collected using a handheld fiber probe (FP) without the damage of capsule shell. By comparing the differences and similarities of the NIR spectra of capsule shells, contents and intact capsules, a preliminary conclusion can be drawn that the NIR spectra contained the information of the contents. Characteristic variables were selected by competitive adaptive weighted resampling (CARS) method, and least squares support vector machine (LSSVM) method based on particle swarm optimization (PSO) algorithm was applied to the construction of quantitative models. The relative standard error of prediction (RSEP) values of five saponins including notoginsenoside R1, ginsenoside Rg1, Re, Rb1, and Rd were 3.240%, 5.468%, 5.303%, 5.043%, and 3.745%, respectively. In addition, for qualitative model, three different types of adulterated capsules were designed. The model established by data driven version of soft independent modeling of class analogy (DD-SIMCA) demonstrated a satisfactory result that all adulterated capsules were identified accurately after an appropriate number of principal components (PCs) were chosen. The results indicated that although the NIR spectra collection was affected by capsule shell, sufficient content information can be obtained for quantitative and qualitative analysis after combining with chemometrics. It further proved that acquired NIR spectra do contain the effective component information of the capsule. This study provided a reference for the rapid nondestructive quality analysis of traditional Chinese medicine (TCM) capsule without damaging capsule shell.

Rapid monitoring approaches for concentration process of lanqin oral solution by near-infrared spectroscopy and chemometric models.

Qualitative and quantitative detection methods based on near-infrared spectroscopy (NIRs) have been proposed in the process analysis of traditional Chinese medicine in recent years. In this study, rapid monitoring methods were developed for quality control of concentration process of lanqin oral solution (LOS). Partial least squares regression (PLSR) method was adopted to construct quantitative models for epigoitrin, geniposide, baicalin, berberine hydrochloride and density. Simultaneously, the genetic algorithm joint extreme learning machine (GA-ELM) was first applied in qualitative analysis of NIRs to distinguish end point of concentration process. Results of PLSR models were satisfactory with the relative standard error of calibration valued at 3.80%, 3.75%, 3.79%, 11.5% and 1.22% for epigoitrin, geniposide, baicalin, berberine hydrochloride and density respectively, and the residual predictive deviation values were higher than 3. For qualitative analysis, the GA-ELM model obtained 100% prediction accuracy. The PLSR quantitative models and the end point discrimination model constructed by GA-ELM correspond with the requirements of practical applications. The results indicate that NIRs in combination with chemometrics has great potential in improving the efficiency in production.

A Spray-on, Nanocomposite-Based Sensor Network for in-Situ Active Structural Health Monitoring.

A new breed of nanocomposite-based spray-on sensor is developed for in-situ active structural health monitoring (SHM). The novel nanocomposite sensor is rigorously designed with graphene as the nanofiller and polyvinylpyrrolidone (PVP) as the matrix, fabricated using a simple spray deposition process. Electrical analysis, as well as morphological characterization of the spray-on sensor, was conducted to investigate percolation characteristic, in which the optimal threshold (~0.91%) of the graphene/PVP sensor was determined. Owing to the uniform and stable conductive network formed by well-dispersed graphene nanosheets in the PVP matrix, the tailor-made spray-on sensor exhibited excellent piezoresistive performance. By virtue of the tunneling effect of the conductive network, the sensor was proven to be capable of perceiving signals of guided ultrasonic waves (GUWs) with ultrahigh frequency up to 500 kHz. Lightweight and flexible, the spray-on nanocomposite sensor demonstrated superior sensitivity, high fidelity, and high signal-to-noise ratio under dynamic strain with ultralow magnitude (of the order of micro-strain) that is comparable with commercial lead zirconate titanate (PZT) wafers. The sensors were further networked to perform damage characterization, and the results indicate significant application potential of the spray-on nanocomposite-based sensor for in-situ active GUW-based SHM.

Variation in the dielectric properties of freshly excised colorectal cancerous tissues at different tumor stages.

The study was designed to identify differences in the dielectric properties of ex vivo colorectal cancerous tissues at different tumor stages. To date, 130 freshly excised colorectal cancerous specimens underwent measurement of both relative permittivity and conductivity on the serosal and mucosal surfaces of the carcinoma nidus, and the mucosa of the surgical resection margin ranging from 50 to 500 MHz at the Larmor frequencies. Tumor node metastasis staging was determined according to pathological reports for each patient. There were statistically significant differences in the relative permittivity of both colorectal cancerous serosa and mucosa among stages ≤I, II, III, and IV and between stages ≤II and ≥III (P < 0.05) at most frequencies under 300 MHz; statistically significant differences in conductivity were also observed for most of the measured frequencies (P < 0.05). The significant differences in dielectric characteristics among tumor stages, especially between early and advanced stages, have value for selecting appropriate surgical strategies. The presented ex vivo data provide important information for magnetic resonance electrical properties tomography in vivo system because the frequencies of 64 MHz (1.5T) and 128 MHz (3T) are usually used in clinical settings. Bioelectromagnetics. 38:522-532, 2017. © 2017 Wiley Periodicals, Inc.

Anti-Warburg effect of rosmarinic acid via miR-155 in gastric cancer cells.

BACKGROUND: The Warburg effect refers to glycolytic production of adenosine triphosphate under aerobic conditions, and is a universal property of most cancer cells. Chronic inflammation is a key factor promoting the Warburg effect. This study aimed to determine whether rosmarinic acid (RA) has an anti-Warburg effect in gastric carcinoma in vitro and in vivo. The mechanism for the anti-Warburg effect was also investigated. METHODS: An MTT assay was used to examine MKN45 cell growth in vitro. An enzyme-linked immunosorbent assay was used to detect proinflammatory cytokines. Real-time polymerase chain reaction was used to evaluate levels of microRNA expression in cells. Protein expression was determined by Western blotting assay. Mouse xenograft models were established using MKN45 cells to assess the anti-Warburg effect in gastric carcinoma in vivo. RESULTS: RA suppressed glucose uptake and lactate production. It also inhibited expression of transcription factor hypoxia-inducible factor-1α, which affects the glycolytic pathway. Inflammation promoted the Warburg effect in cancer cells. As expected, RA inhibited proinflammatory cytokines and microRNAs related to inflammation, suggesting that RA may suppress the Warburg effect via an inflammatory pathway, such as that involving interleukin (IL)-6/signal transducer and activator of transcription-3 (STAT3). miR-155 was found to be an important mediator in the relationship between inflammation and tumorigenesis. We further showed that miR-155 was the target gene regulating the Warburg effect via inactivation of the IL-6/STAT3 pathway. Moreover, we found that RA suppressed the Warburg effect in vivo. CONCLUSION: RA might potentially be a therapeutic agent for suppressing the Warburg effect in gastric carcinoma.