Polyketides with α-glucosidase inhibitory and neuroprotective activities from Aspergillus versicolor associated with Pedicularis sylvatica.

Aspergillus versicolor, an endophytic fungus associated with the herbal medicine Pedicularis sylvatica, produced four new polyketides, aspeversins A-D (1-2 and 5-6) and four known compounds, O-methylaverufin (2), aversin (3), varilactone A (7) and spirosorbicillinol A (8). Their structures were elucidated by extensive spectroscopic data analysis, and their absolute configurations were determined by calculated electronic circular dichroism (ECD) and Mo2(AcO)4-induced CD data. Compound 5 was found to exhibit α-glucosidase inhibitory activity with an IC50 value of 25.57 µM. An enzyme kinetic study indicated that 5 was a typical uncompetitive inhibitor toward α-glucosidase, which was supported by a molecular docking study. Moreover, compounds 1-3 and 5 also improved the cell viability of PC12 cells on a 1-methyl-4-phenylpyridinium (MPP+)-induced Parkinson's disease model, indicating their neuroprotective potential as antiparkinsonian agents.

Exosome from adipose-derived mesenchymal stem cells attenuates scar formation through microRNA-181a/SIRT1 axis.

Pathological scarring is the greatest challenge after injury. Exosome from adipose-derived mesenchymal stem cells has been reported effective to improve hypertrophic scar. This study focused on the possible mechanisms during this process. Exosomes from adipose-derived mesenchymal stem cells were extracted first. Hypertrophic scar tissue and paired normal skin tissue were collected from patients. Mice skin incision model and fibroblasts model were established. TGF-ß1 was used to stimulate fibroblasts to myofibroblasts transdifferentiation. It was found that exosomes injection could decrease collagen sediment after wound healing. During which, the expression of microRNA-181a decreased. Further, we found that expression of microRNA-181a in scar tissue was higher than in normal skin. Then hypertrophic scar-derived fibroblasts were used for in vitro study. It was found that similar to the use of exosomes, microRNA-181a inhibitor decreased the expression of collagen and α-SMA. While microRNA-181a mimics suppressed the effects of exosomes. During fibroblast to myofibroblast trans-differentiation, level of microRNA-181a well as levels of scar-related molecules also decreased with the use of exosomes and vice versa. SIRT1 was confirmed one of the downstream targets of microRNA-181a. Suppression of SIRT1 led to diminished effects of exosomes in hypertrophic scar derived fibroblasts. In mice skin incision model, injection of SIRT1 inhibitor led to increased collagen synthesis. In conclusion, exosomes from Adipose-derived mesenchymal stem cells are promising to antagonize scarring through the regulation of microRNA-181a/SIRT1 axis.

Dynamic Distribution Characteristics of Oil and Water during Water Flooding in a Fishbone Well with Different Branch Angles.

Lab experiments, field pilots, and numerical modeling focusing on fluid flow aspects have indicated that multi-branch wells are technically effective and promising. Several researchers have conducted some experiments for a fishbone well strategy with mixed results. Our objective in this work is to study the impact of the different fishbone well patterns, such as branch angle, on the distribution of remaining oil after water flooding. In this paper, the interference effect between branches on oil recovery is studied in three steps. First, the interferences between fishbone wells with different branch angles were measured by hydro-electric simulation experiments. Second, two-dimensional visualization water flooding experiments were carried out to clarify the remaining oil distribution at different branch angles. Third, the distribution of oil and water in fishbone wells was verified by establishing a numerical model. The modeling results agree well with the experimental phenomena. At the same time, the variation trend of water and oil production in each branch is analyzed by numerical simulation results. The results indicate that the production is strongly dependent on the branch angles, and the highest recovery was 60.2% at a 45° branch angle.

Paeoniflorin Suppresses TBHP-Induced Oxidative Stress and Apoptosis in Human Umbilical Vein Endothelial Cells via the Nrf2/HO-1 Signaling Pathway and Improves Skin Flap Survival.

Random-pattern skin flap is a vital technique frequently applied in reconstruction surgeries for its convenience and effectiveness in solving skin defects. However, ischemic necrosis, especially in the distal areas of the flap, still needs extra attention after surgery. Earlier evidence has suggested that paeoniflorin (PF) could stimulate angiogenesis and suppress ischemic cardiovascular disease. However, few studies have focused on the role of PF in flap survival. In this study, we have demonstrated that the human umbilical vein endothelial cells (HUVECs) treated with PF can alleviate tert-butyl hydroperoxide (TBHP)-stimulated cellular dysfunction and apoptosis. To better evaluate, HUVECs' physiology, cell tube formation, migration, and adhesion were assessed. Mechanistically, PF protects HUVECs against apoptosis via stimulating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. PF also downregulates mitochondrial ROS production to reduce excessive intracellular ROS production induced by TBHP and restore TBHP-induced mitochondrial depolarization. As a result, silencing Nrf2 partially abolishes the protective effect of PF exposure on HUVECs. In in vivo experiments, the oral administration of PF was shown to have enhanced the vascularization of regenerated tissues and promote flap survival. However, the PF-mediated protection was partially lost after co-treatment with ML385, a selective Nrf2 inhibitor, suggesting that PF is a crucial modulator regulating the Nrf2/HO-1 signaling pathway. In summary, our data have provided a new insight into PF as a potential therapy for enhancing random-pattern flap viability.

Classification of Prostate Transitional Zone Cancer and Hyperplasia Using Deep Transfer Learning From Disease-Related Images.

Purpose The diagnosis of prostate transition zone cancer (PTZC) remains a clinical challenge due to their similarity to benign prostatic hyperplasia (BPH) on MRI. The Deep Convolutional Neural Networks (DCNNs) showed high efficacy in diagnosing PTZC on medical imaging but was limited by the small data size. A transfer learning (TL) method was combined with deep learning to overcome this challenge. Materials and methods A retrospective investigation was conducted on 217 patients enrolled from our hospital database (208 patients) and The Cancer Imaging Archive (nine patients). Using T2-weighted images (T2WIs) and apparent diffusion coefficient (ADC) maps, DCNN models were trained and compared between different TL databases (ImageNet vs. disease-related images) and protocols (from scratch, fine-tuning, or transductive transferring). Results PTZC and BPH can be classified through traditional DCNN. The efficacy of TL from natural images was limited but improved by transferring knowledge from the disease-related images. Furthermore, transductive TL from disease-related images had comparable efficacy to the fine-tuning method. Limitations include retrospective design and a relatively small sample size. Conclusion Deep TL from disease-related images is a powerful tool for an automated PTZC diagnostic system. In developing regions where only conventional MR scans are available, the accurate diagnosis of PTZC can be achieved via transductive deep TL from disease-related images.

The emergence of various genetic alterations mediated the Osimertinib resistance of a patient harboring heterozygous germline EGFR T790M: a case report.

Epidermal growth factor receptor (EGFR) T790M is the major mechanism mediating resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Despite the high frequency of EGFR activating mutations among East Asian lung cancer patients, germline T790M has been the subject of very little research. Questions remain as to whether germline T790M develops resistance to Osimertinib and if so, through which mechanisms. This study examined a patient harboring germline EGFR T790M who acquired resistance to Osimertinib therapy. After the failure of first-line icotinib therapy, which was administered for only 3 months, targeted next-generation sequencing of plasma samples collected at icotinib progression and the re-analysis of the baseline tissue biopsy sample revealed EGFR T790M with allelic frequencies approximating 50%. Lymphocyte genomic deoxyribonucleic acid (DNA) sequencing confirmed the germline heterozygous status of the T790M mutation. In addition to the EGFR T790M, a concurrent EGFR L858R was detected from the baseline tissue sample. Osimertinib therapy was initiated resulting in a partial response within 1 month of the commencement of the therapy. After 15.2 months of Osimertinib therapy, disease progression was evaluated due to the presence of pleural effusion. The targeted sequencing of plasma and pleural effusion samples revealed the emergence of EGFR G719A, tumor protein p53 (TP53) Q136X, and the co-amplification of Cyclin D1, fibroblast growth factor (FGF) 19, FGF3, and FGF4. This case highlights the importance of conducting next-generation sequencing-based molecular testing during both diagnostic and disease progression assessments to reveal sensitizing mutations and mutations that could mediate primary and acquired resistance to targeted therapeutics.

Effects of D-α-tocopherol polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles on the absorption, pharmacokinetics, and pharmacodynamics of salinomycin sodium.

Although salinomycin sodium (SS) has shown in-vitro potential to inhibit cancer stem cell growth and development, its low water solubility makes it a poor candidate as an oral chemotherapeutic agent. To improve the bioavailability of SS, SS was encapsulated here using D-α-tocopherol polyethylene glycol succinate (TPGS)-emulsified poly(lactic-co-glycolic acid) (PLGA) nanoparticles and compared with its parent SS in terms of absorption, pharmacokinetics, and efficacy in suppressing nasopharyngeal carcinomas stem cells. The pharmacokinetics of SS and salinomycin sodium-loaded D-α-tocopherol polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles (SLN) prepared by nanoprecipitation were analyzed in-vivo by timed-interval blood sampling and oral administration of SS and SLN to rats. Sensitive liquid chromatography-mass spectrometry (LC-MS) was developed to quantify plasma drug concentrations. SS and SLN transport in Caco-2 cells was also investigated. The therapeutic efficacy of SS and SLN against cancer stem cells was determined by orally administering the drugs to mice bearing CNE1 and CNE2 nasopharyngeal carcinoma xenografts and then evaluating CD133 cell proportions and tumorsphere formation. The in-vivo trial with rats showed that the Cmax, AUC(0-t), and Tmax for orally administered SLN were all significantly higher than those for SS (P<0.05). These findings were corroborated by a Caco-2 cell Transwell assay showing that relative SLN absorption was greater than that of SS on the basis of their apparent permeability coefficients (Papp). Significantly, therapeutic SLN efficacy against nasopharyngeal carcinoma stem cells was superior to that of SS. TPGS-emulsified PLGA nanoparticles effectively increase SS solubility and bioavailability. SLN is, therefore, promising as an oral chemotherapeutic agent against cancer stem cells.

miR­144­3p regulates the resistance of lung cancer to cisplatin by targeting Nrf2.

Chemotherapeutic drug resistance is correlated with treatment failure and poor prognosis among lung cancer patients. Numerous studies indicate the relevance of miRNAs in inducing certain drug resistance. In the course of the study, we unexpectedly found that miR­144­3p could regulate the cisplatin resistance of lung cancer cells via Nrf2. However, Nrf2 also could reverse activate the expression of miR­144­3p by binding to the ARE box in the miR­144­3p promoter. This may be a self­protection mechanism of the body. In addition, we also found that in other cancer cell lines, such as HepG2, miR­144­3p also had the function of regulating cisplatin resistance. These findings may provide some theoretical reference for the clinical inhibition of cisplatin resistance.

Acoustic radiation force impulse imaging of human prostates: initial in vivo demonstration.

Reliably detecting prostate cancer (PCa) has been a challenge for current imaging modalities. Acoustic radiation force impulse (ARFI) imaging is an elasticity imaging method that uses remotely generated, focused acoustic beams to probe tissue stiffness. A previous study on excised human prostates demonstrated ARFI images portray various prostatic structures and has the potential to guide prostate needle biopsy with improved sampling accuracy. The goal of this study is to demonstrate the feasibility of ARFI imaging to portray internal structures and PCa in the human prostate in vivo. Custom ARFI imaging sequences were designed and implemented using a modified Siemens Antares™ scanner with a three-dimensional (3-D) wobbler, end-firing, trans-cavity transducer, EV9F4. Nineteen patients were consented and imaged immediately preceding surgical prostatectomy. Pathologies and anatomic structures were identified in histologic slides by a pathologist blinded to ARFI data and were then registered with structures found in ARFI images. The results demonstrated that when PCa is visible, it generally appears as bilaterally asymmetric stiff structures; benign prostatic hyperplasia (BPH) appears heterogeneous with a nodular texture; the verumontanum and ejaculatory ducts appears softer compared with surrounding tissue, which form a unique 'V' shape; and the boundary of the transitional zone (TZ) forms a stiff rim separating the TZ from the peripheral zone (PZ). These characteristic appearances of prostatic structures are consistent with those found in our previous study of prostate ARFI imaging on excised human prostates. Compared with the matched B-mode images, ARFI images, in general, portray prostate structures with higher contrast. With the end-firing transducer used for this study, ARFI depth penetration was limited to 22 mm. Image contrast and resolution were decreased as compared with the previous ex vivo study due to the small transducer aperture. Even with these limitations, this study suggests ARFI imaging holds promise for guidance of targeted prostate needle biopsy and focal therapy, as well as aiding assessment of changes during watchful waiting/active surveillance.

Acoustic radiation force impulse imaging of human prostates ex vivo.

It has been challenging for clinicians using current imaging modalities to visualize internal structures and detect lesions inside human prostates. Lack of contrast among prostatic tissues and high false positive or negative detection rates of prostate lesions have limited the use of current imaging modalities in the diagnosis of prostate cancer. In this study, acoustic radiation force impulse (ARFI) imaging is introduced to visualize the anatomical and abnormal structures in freshly excised human prostates. A modified Siemens Antares ultrasound scanner (Siemens Medical Solutions USA Inc., Malvern, PA) and a Siemens VF10-5 linear array were used to acquire ARFI images. The transducer was attached to a three-dimensional (3-D) translation stage, which was programmed to automate volumetric data acquisition. A depth dependent gain (DDG) method was developed and applied to 3-D ARFI datasets to compensate for the displacement gradients associated with spatially varying radiation force magnitudes as a function of depth. Nine human prostate specimens were collected and imaged immediately after surgical excision. Prostate anatomical structures such as seminal vesicles, ejaculatory ducts, peripheral zone, central zone, transition zone and verumontanum were visualized with high spatial resolution and in good agreement with McNeal's zonal anatomy. The characteristic appearance of prostate pathologies, such as prostate cancerous lesions, benign prostatic hyperplasia, calcified tissues and atrophy were identified in ARFI images based upon correlation with the corresponding histologic slides. This study demonstrates that ARFI imaging can be used to visualize internal structures and detecting suspicious lesions in the prostate and appears promising for image guidance of prostate biopsy.

Characterizing stiffness of human prostates using acoustic radiation force.

Acoustic Radiation Force Impulse (ARFI) imaging has been previously reported to portray normal anatomic structures and pathologies in ex vivo human prostates with good contrast and resolution. These findings were based on comparison with histological slides and McNeal's zonal anatomy. In ARFI images, the central zone (CZ) appears darker (smaller displacement) than other anatomic zones and prostate cancer (PCa) is darker than normal tissue in the peripheral zone (PZ). Since displacement amplitudes in ARFI images are determined by both the underlying tissue stiffness and the amplitude of acoustic radiation force that varies with acoustic attenuation, one question that arises is how the relative displacements in prostate ARFI images are related to the underlying prostatic tissue stiffness. In linear, isotropic elastic materials and in tissues that are relatively uniform in acoustic attenuation (e.g., liver), relative displacement in ARFI images has been shown to be correlated with underlying tissue stiffness. However, the prostate is known to be heterogeneous. Variations in acoustic attenuation of prostatic structures could confound the interpretation of ARFI images due to the associated variations in the applied acoustic radiation force. Therefore, in this study, co-registered three-dimensional (3D) ARFI datasets and quantitative shear wave elasticity imaging (SWEI) datasets were acquired in freshly-excised human prostates to investigate the relationship between displacement amplitudes in ARFI prostate images and the matched reconstructed shear moduli. The lateral time-to-peak (LTTP) algorithm was applied to the SWEI data to compute the shear-wave speed and reconstruct the shear moduli. Five types of prostatic tissue (PZ, CZ, transition zone (TZ) and benign prostatic hyperplasia (BPH), PCa and atrophy) were identified, whose shear moduli were quantified to be 4.1 +/- 0.8 kPa, 9.9 +/- 0.9 kPa, 4.8 +/- 0.6 kPa, 10.0 +/- 1.0 kPa and 8.0 kPa, respectively. Linear regression was performed to compare ARFI displacement amplitudes and the inverse of the corresponding reconstructed shear moduli at multiple depths. The results indicate an inverse relation between ARFI displacement amplitude and reconstructed shear modulus at all depths. These findings support the conclusion that ARFI prostate images portray underlying tissue stiffness variations.

An integrated indenter-ARFI imaging system for tissue stiffness quantification.

The goal of this work is to develop and characterize an integrated indenter-ARFI (acoustic radiation force impulse) imaging system. This system is capable of acquiring matched datasets of ARFI images and stiffness profiles from ex vivo tissue samples, which will facilitate correlation of ARFI images of tissue samples with independently-characterized material properties. For large and homogeneous samples, the indenter can be used to measure the Young's moduli by using Boussinesq's solution for a load on the surface ofa semi-infinite isotropic elastic medium. Experiments and finite element method (FEM) models were designed to determine the maximum indentation depth and minimum sample size for accurate modulus reconstruction using this solution. Applying these findings, indentation measurements were performed on three calibrated commercial tissue-mimicking phantoms and the results were in good agreement with the calibrated stiffness. For heterogeneous tissue samples, indentation can be used independently to characterize relative stiffness variation across the sample surface, which can then be used to validate the stiffness variation in registered ARFI images. Tests were performed on heterogeneous phantoms and freshly-excised colon cancer specimens to detect the relative stiffness and lesion sizes using the combined system. Normalized displacement curves across the lesion surface were calculated and compared. Good agreement ofthe lesion profiles was observed between indentation and ARFI imaging.

Acoustic radiation force impulse (ARFI) imaging of the gastrointestinal tract.

The evaluation of lesions in the gastrointestinal (GI) tract using ultrasound can suffer from poor contrast between healthy and diseased tissue. Acoustic Radiation Force Impulse (ARFI) imaging provides information about the mechanical properties of tissue using brief, high-intensity, focused ultrasound to generate radiation force and ultrasonic correlation-based methods to track the resulting tissue displacement. Using conventional linear arrays, ARFI imaging has shown improved contrast over B-mode images when applied to solid masses in the breast and liver. The purpose of this work is to (1) investigate the potential for ARFI imaging to provide improvements over conventional B-mode imaging of GI lesions and (2) demonstrate that ARFI imaging can be performed with an endocavity probe. ARFI images of an adenocarcinoma of the gastroesophageal (GE) junction, status-post chemotherapy and radiation treatment, demonstrate better contrast between healthy and fibrotic/malignant tissue than standard B-mode images. ARFI images of healthy gastric, esophageal, and colonic tissue specimens differentiate normal anatomic tissue layers (i.e., mucosal, muscularis and adventitial layers), as confirmed by histologic evaluation. ARFI imaging of ex vivo colon and small bowel tumors portray interesting contrast and structure that are not as well defined in B-mode images. An endocavity probe created ARFI images to a depth of over 2 cm in tissue-mimicking phantoms, with maximum displacements of 4 microm. These findings support the clinical feasibility of endocavity ARFI imaging to guide diagnosis and staging of disease processes in the GI tract.

[Development and application of ultrasound technology for hyperthermia].

It has been a long time since ultrasound hyperthermia began to be used in the clinical management of cancers and benign diseases. Numerous biological and clinical investigations have demonstrated that: hyperthermia in the range of 41-45 degrees C can significantly enhance clinical response to radiation therapy and chemotherapy, and high-temperature hyperthermia (greater than 65 degrees C) alone is now being used as an alternative to conventional invasive surgery for selective tissue destruction, causing tumor coagulation and necrosis. As a promising noninvasive and effective local therapy, HIFU has attracted great attention. China is advanced in the clinical applications of HIFU. This article gives an introduction of the development and applications of ultrasound hyperthermia technology, and also provides a general review of a selection of ultrasound hyperthermia systems both in clinical use and under development.