Two-dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors

<p>Abstract</p> <p>Background</p> <p>This phase I, randomized, multicenter, open-label study investigated the pharmacokinetics, safety, and efficacy of the oral mammalian target of rapamycin inhibitor everolimus in Chinese patients with advanced solid tumors.</p> <p>Methods</p> <p>A total of 24 patients with advanced breast cancer (n = 6), gastric cancer (n = 6), non-small cell lung cancer (n = 6), or renal cell carcinoma (n = 6) who were refractory to/unsuitable for standard therapy were randomized 1:1 to oral everolimus 5 or 10 mg/day. Primary end points were pharmacokinetic parameters and safety and tolerability. Pharmacokinetic 24-h profiles were measured on day 15; trough level was measured on days 2, 8, 15, 16, and 22. Tolerability was assessed continuously. This final analysis was performed after all patients had received 6 months of study drug or had discontinued.</p> <p>Results</p> <p>Everolimus was absorbed rapidly; median T_maxwas 3 h (range, 1-4) and 2 h (range, 0.9-6) in the 5 and 10 mg/day groups, respectively. Pharmacokinetic parameters increased dose proportionally from the 5 and 10 mg/day doses. Steady-state levels were achieved by day 8 or earlier. The most common adverse events suspected to be related to everolimus therapy were increased blood glucose (16.7% and 41.7%) and fatigue (16.7% and 33.3%) in the everolimus 5 and 10 mg/day dose cohorts, respectively. Best tumor response was stable disease in 10 (83%) and 6 (50%) patients in the 5 and 10 mg/day groups, respectively.</p> <p>Conclusions</p> <p>Everolimus 5 or 10 mg/day was well tolerated in Chinese patients with advanced solid tumors. The observed safety and pharmacokinetic profile of everolimus from this study were consistent with previous studies.</p> <p>Trial registration</p> <p>Chinese Health Authorities 2008L09346</p

A deep learning model for drug screening and evaluation in bladder cancer organoids

Three-dimensional cell tissue culture, which produces biological structures termed organoids, has rapidly promoted the progress of biological research, including basic research, drug discovery, and regenerative medicine. However, due to the lack of algorithms and software, analysis of organoid growth is labor intensive and time-consuming. Currently it requires individual measurements using software such as ImageJ, leading to low screening efficiency when used for a high throughput screen. To solve this problem, we developed a bladder cancer organoid culture system, generated microscopic images, and developed a novel automatic image segmentation model, AU2Net (Attention and Cross U2Net). Using a dataset of two hundred images from growing organoids (day1 to day 7) and organoids with or without drug treatment, our model applies deep learning technology for image segmentation. To further improve the accuracy of model prediction, a variety of methods are integrated to improve the model’s specificity, including adding Grouping Cross Merge (GCM) modules at the model’s jump joints to strengthen the model’s feature information. After feature information acquisition, a residual attentional gate (RAG) is added to suppress unnecessary feature propagation and improve the precision of organoids segmentation by establishing rich context-dependent models for local features. Experimental results show that each optimization scheme can significantly improve model performance. The sensitivity, specificity, and F1-Score of the ACU2Net model reached 94.81%, 88.50%, and 91.54% respectively, which exceed those of U-Net, Attention U-Net, and other available network models. Together, this novel ACU2Net model can provide more accurate segmentation results from organoid images and can improve the efficiency of drug screening evaluation using organoids

Study on the Gamma Irradiation Characteristics of a Carbon Nanotube Sponge/Polydimethylsiloxane/Tungsten Oxide Flexible Force-Sensitive Structure

This paper proposes a new type of flexible force-sensitive structure that is resistant to gamma radiation and is made of tungsten oxide (WO3) powder, polydimethylsiloxane (PDMS), and carbon nanotube (CNT) sponge. The thickness of the sample was 2.2 mm, the middle interlayer was composed of a carbon nanotube (CNT) sponge and PDMS to form a conductive layer, and the upper and lower layers were made of tungsten oxide and PDMS, which formed a gamma-ray shielding layer. When the particle size of the tungsten oxide powder was 50 nm, 100 nm, and 1 µm, the composite force-sensitive structure exhibited better force-sensitive performance. The composite force-sensitive structure was irradiated with doses of 5, 20, 50, and 100 KGy through 60Co- rays with an energy of 1.25 MeV. The results showed that the force-sensitive characteristics changed little in significance after irradiation by different doses of gamma rays, indicating that the force-sensitive structure has good resistance to gamma radiation. This flexible stress sensor can be used in soft robots and health inspection, even in harsh environments without significant performance loss

Study on the Flavor Compounds of Fo Tiao Qiang under Different Thawing Methods Based on GC&ndash;IMS and Electronic Tongue Technology

&ldquo;Fo Tiao Qiang&rdquo; is a famous dish with Chinese characteristics. It is delicious, rich in materials, and high in nutritional value. Through physical and chemical analysis, electronic tongue, gas chromatography&ndash;ion mobility spectroscopy, and other technologies, the present study explored the quality characteristics and flavor differences of Fo Tiao Qiang by using different thawing methods (natural thawing, ultrasonic thawing, microwave thawing, and water bath thawing). The results show that the protein content was slightly higher in Fo Tiao Qiang with ultrasonic thawing than others. The fat content of the microwave-thawed Fo Tiao Qiang was significantly lower than the other three kinds of samples. After ultrasonic thawing, the number of free amino acids in the samples were the highest and the umami taste was the best. Compared with natural thawing, most of the flavor substances decreased in ultrasonic thawing, microwave thawing, and water bath thawing. However, several substances increased, such as alpha-terpineol, beta-phenylethyl alcohol, phenylacetaldehyde, cis-rose oxide, isobutyl acetate, and 2&ndash;3-pentanedione. This study revealed the changing laws of different thawing methods on the quality characteristics and flavor characteristics of Fo Tiao Qiang. It provides theoretical guidance for the industrial production and quality control of Fo Tiao Qiang

A Solid-State Wire-Shaped Supercapacitor Based on Nylon/Ag/Polypyrrole and Nylon/Ag/MnO₂ Electrodes

In this work, a novel wire-shaped supercapacitor based on nylon yarn with a high specific capacitance and energy density was developed by designing an asymmetric configuration and integrating pseudocapacitive materials for both electrodes. The nylon/Ag/MnO2 yarn was prepared as a positive electrode by electrochemically depositing MnO2 on a silver-paste-coated nylon yarn. Additionally, PPy was prepared on nylon/Ag yarn by chemical polymerization firstly to enlarge the surface roughness of nylon/Ag, and then the PPy could be easily coated on the chemically polymerized nylon/Ag/PPy by electrochemical polymerization to obtain a nylon/Ag/PPy yarn-shaped negative electrode. The wire-shaped asymmetric supercapacitor (WASC) was fabricated by assembling the nylon/Ag/MnO2 electrode, nylon/Ag/PPy electrode and PAANa/Na2SO4 gel electrolyte. This WASC showed a wide potential window of 1.6 V and a high energy density varying from 13.9 to 4.2 μWh cm−2 with the corresponding power density changing from 290 to 2902 μW cm−2. Meanwhile, because of the high flexibility of the nylon substrate and superior adhesion of active materials, the WASC showed a good electrochemical performance stability under different bending conditions, suggesting its good flexibility. The promising performance of this novel WASC is of great potential for wearable/portable devices in the future

Liposome Lipid-Based Formulation Has the Least Influence on rAAV Transduction Compared to Other Transfection Agents

Recombinant adeno-associated virus (rAAV) vectors are considered ideal vehicles for human gene therapy. Meanwhile, non-viral strategies, such as transfection agents (TAs), have also shown promise to deliver genetic materials, such as siRNA. Transduction with the rAAV vector is performed concurrently with transfection with plasmid DNA or RNA. In the present study, we report that various TAs inhibited rAAV-mediated transgene expression at diverse levels. Overall, cationic polymers and dendrimers dramatically blocked rAAV transduction, while lipid-based liposomes displayed the least effect. The inhibitory effect was dependent on the dose of TAs and the timing of infection, suggesting that the early stages of viral infection were involved. In addition, the present results indicate that the transgene expression of rAAV vectors was significantly increased by liposome-mediated transfection with adenoviral helper genes. At the same time, this was dramatically inhibited by liposome-mediated transfection with the trichosanthin gene encoding a type I ribosome-inactivating protein isolated from traditional Chinese medicine. Furthermore, liposomes also have little effect on rAAV-mediated transgene expression in vivo. Taken together, these findings suggest liposome as the best choice of TAs, which should be used in combination with rAAV-mediated gene therapy. Keywords: liposome lipid-based formulation, rAAV, transduction, transfection agents, trichosanthi

Determining Surface Shape of Translucent Objects with the Combination of Laser-Beam-Based Structured Light and Polarization Technique

In this study, we focus on the 3D surface measurement and reconstruction of translucent objects. The proposed approach of surface-shape determination of translucent objects is based on the combination of the projected laser-beam-based sinusoidal structured light and the polarization technique. The theoretical analyses are rigorously completed in this work, including the formation, propagation, and physical features of the generated sinusoidal signal by the designed optical system, the reflection and transmission of the projected monochromatic fringe pattern on the surface of the translucent object, and the formation and the separation of the direct-reflection and the global components of the surface radiance of the observed object. The results of experimental investigation designed in accordance with our theoretical analyses have confirmed that accurate reconstructions can be obtained using the one-shot measurement based on the proposed approach of this study and Fourier transform profilometry, while the monochromaticity and the linearly-polarized characteristic of the projected sinusoidal signal can be utilized by using a polarizer and an optical filter simultaneously for removing the global component, i.e., the noised signal contributed by multiply-scattered photons and the background illuminance in the frame of our approach. Moreover, this study has also revealed that the developed method is capable of getting accurate measurements and reconstructions of translucent objects when the background illumination exists, which has been considered as a challenging issue for 3D surface measurement and reconstruction of translucent objects

PD-1, PD-L1 (B7-H1) and Tumor-Site Immune Modulation Therapy: The Historical Perspective

Abstract The current success of targeted inhibition against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Death 1/Programmed Death Ligand 1 (PD-1/PD-L1, herein collectively referred to as PD) pathways is hailed as a cancer immunotherapy breakthrough. PD-L1, known also as B7 homolog 1 (B7-H1), was initially discovered by Dr. Lieping Chen in 1999. To recognize the seminal contributions by Chen to the development of PD-directed therapy against cancer, the Chinese American Hematologist and Oncologist Network (CAHON) decided to honor him with its inaugural Lifetime Achievement Award in Hematology and Oncology at the CAHON’s 2015 annual meeting. This essay chronicles the important discoveries made by Chen in the exciting field of immuno-oncology, which goes beyond his original fateful finding. It also argues that PD-directed therapy should be appropriately considered as Tumor-Site Immune Modulation Therapy to distinguish it from CTLA-4-based immune checkpoint blocking agents

Research on the High Sensitivity Detection Method of Carbon Nanotube/Polydimethylsiloxane Composites Structure

In this paper, a carbon nanotube (CNT)/polydimethylsiloxane (PDMS) composite force-sensitive structure with good flexibility is proposed and fabricated, and the measurement of scanning electron microscopy (SEM) and Raman are carried out. The equivalent circuit of force-sensitive test of structure is performed and analyzed under direct current (DC) and alternating current (AC) conditions. Under AC conditions, experimental results further show that the sensitivity and sensitivity factors of force-sensitive structures are 0.15 KPa−1 and 2.17 in the pressure range of 600–1000 KPa compressive stress and 20–50% tensile stress, respectively. These results are increased by 36.4% and 38.2% compared to the results of compressive stress (0.11 KPa−1) and tensile stress (1.57) under DC conditions, respectively. It shows that the carbon nanotube/PDMS composite has higher test accuracy under AC conditions

Auxiliary Sensor-Based Borehole Transient Electromagnetic System for the Nondestructive Inspection of Multipipe Strings

Transient electromagnetic (TEM) techniques are widely used in the field of geophysical prospecting. In borehole detection, the nondestructive inspection (NDI) of a metal pipe can be performed efficiently using the properties of eddy currents. However, with increasing concern for safety in oil and gas production, more than one string of pipe is used to protect wellbores, which complicates data interpretation. In this paper, an auxiliary sensor-based borehole TEM system for the NDI of multipipe strings is presented. On the basis of the characteristics of the borehole TEM model, we investigate the principle behind the NDI of multipipe strings using multiple time slices of induced electromotive force (EMF) in a single sensor. The results show that the detection performance of NDI is strongly influenced by eddy-current diffusion in the longitudinal direction. To solve this problem, we used time slices of the induced EMF in both the main and auxiliary sensors. The performance of the proposed system was verified by applying it to an oil well with a production casing and liner. Moreover, field experiments were conducted, and the results demonstrate the effectiveness of the proposed method