Th-MYCN Mice with Caspase-8 Deficiency Develop Advanced Neuroblastoma with Bone Marrow Metastasis

Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow (BM). Advances in therapy and understanding of the metastatic process have been limited due in part, to the lack of animal models harboring BM disease. The widely employed transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the BM. This model recapitulates two frequent alterations in metastatic neuroblasoma, over-expression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. While over-expression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced BM metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix (ECM) structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation and down-regulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine transforming growth factor beta (TGF-β) pathway in various tumor models. Cytokine TGF-β can preferentially promote single cell motility and blood borne metastasis and therefore activation of this pathway may explain the enhanced BM metastasis observed in this animal model.Fil: Teitz, Tal. St. Jude Children’s Research Hospital. Department of Tumor Cell Biology; Estados UnidosFil: Inoue, Madoka. St. Jude Children’s Research Hospital. Department of Tumor Cell Biology; Estados UnidosFil: Valentine, Marcus B.. St. Jude Children’s Research Hospital. Department of Tumor Cell Biology; Estados UnidosFil: Zhu, Kejin. St. Jude Children’s Research Hospital. Department of Tumor Cell Biology; Estados UnidosFil: Rehg, Jerold E.. St. Jude Children’s Research Hospital. Department of Pathology; Estados UnidosFil: Zhao, Wei. St. Jude Children’s Research Hospital. Department of Biostatistics; Estados UnidosFil: Finkelstein, David. St. Jude Children’s Research Hospital. Department of Computational Biology; Estados UnidosFil: Wang, Yong-Dong. St. Jude Children’s Research Hospital. Hartwell Center for Bioinformatics and Biotechnology; Estados UnidosFil: Johnson, Melissa D.. St. Jude Children’s Research Hospital. Animal Imaging Center; Estados UnidosFil: Calabrese, Christopher. St. Jude Children’s Research Hospital. Animal Imaging Center; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Hakem, Razqallah. University of Toronto. Ontario Cancer Institute. Department of Medical Biophysics; CanadáFil: Weiss, William A.. University of California. Departments of Neurology, Pediatrics and Neurological Surgery; Estados UnidosFil: Lahti, Jill M.. St. Jude Children’s Research Hospital. Department of Tumor Cell Biology; Estados Unido

Precise let-7 expression levels balance organ regeneration against tumor suppression

The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics. DOI: http://dx.doi.org/10.7554/eLife.09431.00

Effect of pore water pressure on mechanical performance of recycled aggregate concrete under triaxial compression

The pore water pressure in concrete can significantly increase due to volume compression. Recycled aggregate concrete (RAC) possesses a more complex microstructure compared to natural aggregate concrete (NAC). Understanding the porosity and micromechanical properties of RAC is crucial for analysing its failure mechanism under the influence of coupled confining pressure and pore water pressure. This study compares the constituent proportions and micromechanical properties of interfacial transition zones (ITZs) and the adjacent paste matrix in NAC and RAC. Compressive stress-strain curves were obtained for concrete under coupled confining pressure and pore water pressure. The results indicate that the newly formed ITZ, which bonds to old mortar, outperformed the one bonded to natural aggregate when considering the same water-cement ratio. Compressive strength, ductility, and maximum volumetric strain gradually increased with increasing confining pressure. However, when pore water pressure was removed, compressive strength decreased while elastic modulus improved. Due to the inferior microstructures of RAC compared to NAC, the supportive effect of pore water becomes more pronounced. This is evident in the gradual increase in peak strain with increased pore water pressure for the stress-strain curves of RAC (100 % replacement ratio). Finally, a failure criterion and stress-strain theoretical model considering pore water pressure are proposed, and satisfactory fitting results are obtained.This article is published as Li, Yunan, Hanbing Zhao, Yong Hu, Fulin Qu, Dunming Zhu, Kejin Wang, and Wengui Li. "Effect of pore water pressure on mechanical performance of recycled aggregate concrete under triaxial compression." Cement and Concrete Composites (2023): 105402. doi: https://doi.org/10.1016/j.cemconcomp.2023.105402. © 2023 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Detector-device-independent quantum secret sharing with source flaws

Abstract Measurement-device-independent entanglement witness (MDI-EW) plays an important role for detecting entanglement with untrusted measurement device. We present a double blinding-attack on a quantum secret sharing (QSS) protocol based on GHZ state. Using the MDI-EW method, we propose a QSS protocol against all detector side-channels. We allow source flaws in practical QSS system, so that Charlie can securely distribute a key between the two agents Alice and Bob over long distances. Our protocol provides condition on the extracted key rate for the secret against both external eavesdropper and arbitrary dishonest participants. A tight bound for collective attacks can provide good bounds on the practical QSS with source flaws. Then we show through numerical simulations that using single-photon source a secure QSS over 136 km can be achieved

Silicon-based decoder for polarization-encoding quantum key distribution

Silicon-based polarization-encoding quantum key distribution (QKD) has been extensively studied due to its advantageous characteristics of its low cost and robustness. However, given the difficulty of fabricating polarized independent components on the chip, previous studies have only adopted off-chip devices to demodulate the quantum states or perform polarization compensation. In the current work, a fully chip-based decoder for polarization-encoding QKD was proposed. The chip realized a polarization state analyzer and compensated for the BB84 protocol without the requirement of additional hardware, which was based on a polarization-to-path conversion method utilizing a polarization splitter-rotator. The chip was fabricated adopting a standard silicon photonics foundry, which was of a compact design and suitable for mass production. In the experimental stability test, an average quantum bit error rate of 0.59% was achieved through continuous operation for 10 h without any polarization feedback. Furthermore, the chip enabled the automatic compensation of the fiber polarization drift when utilizing the developed feedback algorithm, which was emulated by a random fiber polarization scrambler. Moreover, a finite-key secret rate of 240 bps over a fiber spool of 100 km was achieved in the case of the QKD demonstration. This study marks an important step toward the integrated, practical, and large-scale deployment of QKD systems

Experimental Study of Bio-Security of Functionalized Single-Walled and Multi-Walled Carbon Nanotubes

In this study, the biological effects of functionalized carbon nanotubes (CNTs) were investigated on cell morphology, proliferation, apoptosis, tissue pathology and blood test in vivo & in vitro. The functionalized CNTs had good biocompatibility at lower concentrations, and the functionalized single-walled carbon nanotubes(SWCNTs) perform in the early period in the animal body and multi-walled carbon nanotubes(MWCNTs) mainly in the late. The results show successful functional groups and no change in toxicity in functional samples compared with the primary sample, and there is a safety dosage on the normal cells and tissue. In subsequent studies, antitumoral investigations of modified samples will be evaluated

Guizhi Fuling Capsule Exhibits Antidysmenorrhea Activity by Inhibition of Cyclooxygenase Activity

Guizhi Fuling capsule (GZFLc) is a modern preparation from traditional Chinese Medicine. Guizhi Fuling was first prescribed by Zhang Zhongjing almost two thousand years ago for the treatment of primary dysmenorrhea. It has also been used to treat uterine fibroids, dysfunctional uterine bleeding, and endometriosis. Although effective against dysmenorrhea clinically, there are limited information on the mechanism of its action. The major components responsible for the activity are not well defined. The aim of this study has been to elucidate a mechanism that may facilitate the development of a bioactivity-based assay for quality control during drug formulation and manufacturing. Using an oxytocin-induced mouse dysmenorrhea model, we showed that oral administration of GZFLc at 150 and 300 mg/kg, dosages relevant to clinic usages, significantly suppressed oxytocin-induced writhing response. The antidysmenorrhea effect was also demonstrated by a rotarod assay. We showed that GZFLc treatment significantly prolonged the hanging time of mice on the rotating rod. Histological studies showed that GZFLc treatment reduced lamina propria edema, while no effect on COX2 expression was detected. GZFLc instead exhibited direct inhibitory effect against COX2, a critical enzyme that catalyzes arachidonic acid conversion to prostaglandins. By HPLC profiling, we showed that paeoniflorin, paeonol, and cinnamaldehyde are the major components from the corresponding plants. At 5 and 10 mg/kg, both paeoniflorin and paeonol were active against induced dysmenorrhea. The study not only links GZFLc antidysmenorrhea activity to COX2 inhibition but also uncovers a mechanism of action by which an assay can be developed for bioefficacy evaluation of GZFLc

Competitive Degradation of Steroid Estrogens by Potassium Permanganate Combined with Ultrasound

The occurrence of natural estrogens including estrone (E1), 17β-estradiol (E2), and synthetic 17α-ethinylestradiol (EE2), which can be excreted by both humans and animals, and can enter the aqueous environment along with the discharge of domestic sewage, is a major concern since this may represent a serious health risk to humans even at extremely trace levels (ng·L−1). Simultaneous degradation of three coexisting steroid estrogens (SEs) in aqueous solutions by coupled ultrasound and KMnO4 systems (KMnO4/ultrasound) were investigated to find out whether there is a competitive degradation of multiple contaminants or not. Results indicate that the degradation ratios of target SEs were all more than 50% after 120 min reaction contact, greatly enhanced when compared with the single KMnO4 (2 mg·L−1) oxidation of E2 (37.0%), EE2 (34.4%), and E1 (34.0%), and the single sonochemical oxidation of E2 (37.1%), EE2 (31.1%), and E1 (29.7%). In the adopted processes, the degradations of SEs fit the first-order kinetic reaction, with different reaction rates. Kinetic parameters revealed there was little difference between coexisting SEs, which means there was almost no competitive degradation. The removal efficiency and degradation rate of SEs in natural water was higher than those in pure water, which suggested that the coupled KMnO4/ultrasound technology had prospective applications in the removal of complex contaminants in actual drinking water treatment

Oxygen-carbon nanotubes as a chemotherapy sensitizer for paclitaxel in breast cancer treatment.

To study the in vivo and in vitro effects of adding oxygen carbon nanotubes (CNTs) to chemotherapy for breast cancer.MCF-7 and SK-BR-3 breast cancer cells were co-cultured with paclitaxel and then exposed to oxygen-CNTs under hypoxic conditions. Cell proliferation, viability, and apoptosis rate were analyzed. Hypoxia-inducible factor-1 alpha (HIF-1α) expression was measured using reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Nude mice were used as a human breast cancer model to explore the impact of oxygen-CNTs on the in vivo chemotherapeutic effect of paclitaxel.Oxygen-CNTs had no significant effects on the growth of breast cancer cells under normoxia and hypoxia. However, in the hypoxic environment, oxygen-CNTs significantly enhanced the inhibitory effect of paclitaxel on cell proliferation, as well as the apoptosis rate. Under hypoxia, downregulation of HIF-1α and upregulation of caspase-3, caspase-8, caspase-9, LC3 and Beclin-1 were observed when paclitaxel was combined with oxygen-CNT. Furthermore, addition of oxygen-CNTs to chemotherapy was found to significantly reduce tumor weight in the tumor-bearing mice model.Oxygen-CNTs can significantly increase the chemotherapeutic effect of paclitaxel on breast cancer cells. Oxygen-CNTs may be a potential chemosensitizer in breast cancer therapy