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Yawara Kawano, Oksana Zavidij, Jihye Park, Michele Moschetta, Katsutoshi Kokubun, Tarek H Mouhieddine, Salomon Manier, Yuji Mishima, Naoka Murakami, Mark Bustoros, Romanos Sklavenitis Pistofidis, Mairead Reidy, Yu J Shen, Mahshid Rahmat, Pavlo Lukyanchykov, Esilida Sula Karreci, Shokichi Tsukamoto, Jiantao Shi, Satoshi Takagi, Daisy Huynh, Antonio Sacco, Yu-Tzu Tai, Marta Chesi, P Leif Bergsagel, Aldo M Roccaro, Jamil Azzi, Irene M Ghobrial
Despite significant advances in the treatment of multiple myeloma (MM), most patients succumb to disease progression. One of the major immunosuppressive mechanisms that is believed to play a role in myeloma progression, is the expansion of regulatory T-cells (Tregs). In this study, we demonstrate that myeloma cells drive Treg expansion and activation by secreting type-1 interferon (IFN). Blocking IFNAR1 (interferon alpha and beta receptor 1) on Tregs significantly decreases both, myeloma-associated Treg immunosuppressive function and myeloma progression...
March 20, 2018: Journal of Clinical Investigation
Andreas Weber, Mareike Barth, Jessica Isabel Selig, Silja Raschke, Konstantinos Dakaras, Alexander Hof, Julia Hesse, Jürgen Schrader, Artur Lichtenberg, Payam Akhyari
Calcific aortic valve disease is an active disease process with lipoprotein deposition, chronic inflammation, and progressive leaflet degeneration. Expression of ectonucleotidases, a group of membrane-bound enzymes that regulate the metabolism of ATP and its metabolites, may coregulate the degeneration process of valvular interstitial cells (VICs). The aim of this study was to investigate the role of the enzymes of the purinergic system in the degeneration process of VICs. Ovine VICs were cultivated in vitro under different prodegenerative conditions and treated with inhibitors of ectonucleoside triphosphate diphosphohydrolase 1 (CD39)/ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and 5'-nucleotidase (CD73), as well as with adenosine and adenosine receptor agonists...
March 20, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Jin-Xuan Fan, Zi-Hao Li, Xin-Hua Liu, Diwei Zheng, Ying Chen, Xian-Zheng Zhang
Oral drug administration is widely adopted for diverse drugs, and enjoys the convenience of use and capbility to reach different parts of the body via the bloodstream. However, it is generally not feasible for biomacromolecular anti-tumor drugs such as protein and nucleic acids due to the the limited absorption through gastrointestinal tract (GIT) and the poor tumor targeting. Here, we report a non-invasive thermally-sensitive programmable therapetic system using bacteria E. coli MG1655 as an vehicle for tumor treatments via oral administration...
March 20, 2018: Nano Letters
Honglin Jin, Chao Wan, Zhenwei Zou, Guifang Zhao, Lingling Zhang, Yuanyuan Geng, Tong Chen, Ai Huang, Fagang Jiang, Jue-Ping Feng, Jonathan F Lovell, Jing Chen, Gang Wu, Kunyu Yang
Immunosuppressive tumor microenvironments (TMEs) create tremendous obstacles for an effective cancer therapy. Herein, we developed a melittin-RADA32 hybrid peptide hydrogel loaded with doxorubicin (DOX) for a potent chemoimmunotherapy against melanoma through the active regulation of TMEs. The formed melittin-RADA32-DOX (MRD) hydrogel has an interweaving nanofiber structure and exhibits excellent biocompatibility, controlled drug release properties both in vitro and in vivo, and an enhanced killing effect to melanoma cells...
March 20, 2018: ACS Nano
Delia De Lisi, Ugo De Giorgi, Cristian Lolli, Giuseppe Schepisi, Vincenza Conteduca, Cecilia Menna, Giuseppe Tonini, Daniele Santini, Alberto Farolfi
To date, results of combination therapy studies have shown no meaningful clinical benefit over monotherapy and an unacceptably high degree of toxicity in the treatment of metastatic renal cell carcinoma (RCC), with the exception of a combination of immune-checkpoint inhibitors and the association of lenvatinib with everolimus. Lenvatinib is a potent multi-targeted tyrosine kinase inhibitor that targets VEGFR pathways. Everolimus inhibits primarily mTORC1 complex, a downstream effecter of the intracellular PI3K/AKT/mTOR pathway...
March 20, 2018: Expert Opinion on Drug Metabolism & Toxicology
Jacqueline M Zaengle-Barone, Abigail C Jackson, David M Besse, Bradford Becken, Mehreen Arshad, Patrick C Seed, Katherine J Franz
The unabated rise in bacterial resistance to conventional antibiotics, coupled with collateral damage to normal flora incurred by overuse of broad-spectrum antibiotics, necessitates the development of new antimicrobials targeted against pathogenic organisms. Here, we explore the antibacterial outcomes and mode of action of a prochelator that exploits the production of β-lactamase enzymes by drug-resistant bacteria to convert a non-toxic compound into a metal-binding antimicrobial agent directly within the microenvironment of pathogenic organisms...
March 20, 2018: ACS Infectious Diseases
Udesh Dhawan, Ming-Wen Sue, Kuan Chun Lan, Waradee Buddhakosai, Pao Hui Huang, Yi Cheng Chen, Po-Chun Chen, Wen-Liang Chen
Epithelial to Mesenchymal transition (EMT) is a highly orchestrated process motivated by the nature of physical, chemical composition of Tumor Microenvironment (TME). The role of physical framework of the tumor microenvironment in guiding cells towards EMT is poorly understood. To investigate this, breast cancer MDA-MB-231 and MCF-7 cells were cultured on nanochips comprising of Tantalum oxide nanodots ranging in diameter from 10 to 200nm, fabricated through electrochemical approach and collectively referred to as artificial microenvironments...
March 20, 2018: ACS Applied Materials & Interfaces
Forouzan Mohamadi, Somayeh Ebrahimi-Barough, Mohammad Reza Nourani, Akbar Ahmadi, Jafar Ai
Regeneration of peripheral nerve defects remained a remarkable clinical challenge. Engineered nerve conduits represent a promising strategy to improve functional recovery in peripheral nerve injury repair. However, nerve conduits require additional factors such as neurotrophic factors to create a more conducive microenvironment for nerve regeneration. Neurotrophic factors have well-demonstrated abilities to improve neurite outgrowth, making them great candidates for repairing of defected nerves. To this end, we examined the beneficial effects of repairing the transected rat sciatic nerve by loading of nerve growth factor (NGF) in nerve conduits...
March 20, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Pilar Carranza-Rosales, Nancy Elena Guzmán-Delgado, Irma Edith Carranza-Torres, Ezequiel Viveros-Valdez, Javier Morán-Martínez
Breast cancer is the most common cancer type diagnosed in women, it represents a critical public health problem worldwide, with 1,671,149 estimated new cases and nearly 571,000 related deaths. Research on breast cancer has mainly been conducted using two-dimensional (2D) cell cultures and animal models. The usefulness of these models is reflected in the vast knowledge accumulated over the past decades. However, considering that animal models are three-dimensional (3D) in nature, the validity of the studies using 2D cell cultures has recently been questioned...
March 20, 2018: Current Topics in Microbiology and Immunology
Lu Gan, Yanan Yang, Qian Li, Yi Feng, Tianshu Liu, Weijian Guo
Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and a catalytic component of PRC2, catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery. EZH2 also functions both as a transcriptional suppressor and a transcriptional co-activator, depending on H3K27me3 or not and on the different cellular contexts. Unsurprisingly, numerous studies have highlighted the role of EZH2 in cancer development and progression. Through modulating critical gene expression, EZH2 promotes cell survival, proliferation, epithelial to mesenchymal, invasion, and drug resistance of cancer cells...
2018: Biomarker Research
Hongyoon Choi, Kwon Joong Na
Although metabolic modulation in the tumor microenvironment (TME) is one of the key mechanisms of cancer immune escape, there is a lack of understanding of the comprehensive immune landscape of the TME and its association with tumor metabolism based on clinical evidence. We aimed to investigate the relationship between the immune landscape in the TME and tumor glucose metabolism in lung adenocarcinoma. Methods: Using RNA sequencing and image data, we developed a transcriptome-based tumor metabolism estimation model...
2018: Theranostics
Yunlei Zhang, Wei Ji, Lian He, Yiyan Chen, Xuezhi Ding, Yunjun Sun, Shengbiao Hu, Huijun Yang, Weitao Huang, Youming Zhang, Fei Liu, Liqiu Xia
Purpose: Systemic administration of free chemotherapeutic drugs leads to severe toxic effects, and physiological characteristics of solid tumors restrain the drugs from reaching the hypoxic regions. E. coli Nissle 1917 (EcN) has been known to penetrate the barrier and proliferate in the interface between the viable and necrotic regions of tumors. This study aimed to fabricate a nanoscale minicell via genetic engineering of EcN for targeted delivery of chemotherapeutic drugs to the hypoxic regions of tumors for cancer therapy...
2018: Theranostics
DanRong Hu, LiJuan Chen, Ying Qu, JinRong Peng, BingYang Chu, Kun Shi, Ying Hao, Lin Zhong, MengYao Wang, ZhiYong Qian
The combination of chemotherapy with photodynamic therapy (PDT) has attracted broad attention as it can overcome limitations of conventional chemo-treatment by using different modes of action. However, the efficacy of PDT to treat solid tumors is severely affected by hypoxia in tumors. Methods : In this study, we developed oxygen-generating theranostic nanoparticles (CDM NPs) by hierarchically assembling doxorubicin (DOX), chlorin e6 (Ce6) and colloidal manganese dioxide (MnO2 ) with poly (ε-caprolactone-co-lactide)-b-poly (ethylene glycol)-b-poly (ε-caprolactone-co-lactide) for treating breast cancer...
2018: Theranostics
Kai Huang, Chuan Fang, Kaikai Yi, Xing Liu, Hongzhao Qi, Yanli Tan, Junhu Zhou, Ying Li, Mingyang Liu, Yuqing Zhang, Jingxuan Yang, Jianning Zhang, Min Li, Chunsheng Kang
Exosomes play critical roles in intercellular communication in both nearby and distant cells in individuals and organs. Polymerase I and transcript release factor (PTRF), also known as Cavin1, has previously been described as a critical factor in caveola formation, and aberrant PTRF expression has been reported in various malignancies. However, the function of PTRF in tumor progression remains controversial, and its role in glioma is poorly understood. In this study, we report that PTRF is associated with malignancy grade and poor prognosis in glioma patients...
2018: Theranostics
Xiaoyu Wang, Libing Wang, Yan Xu, Guohua Zhang, Yunlin Wu, Ping Chen
Protein inhibitor of activated signal transducer and activator of transcription-1 (PIAS1) is an important regulator of the inflammatory signaling network, the expression of which was decreased in gastric cancer and implicated in the development of cancer. However, its mechanism has not been elucidated. The aim of the present study was to investigate the effect of PIAS1 on epithelial-mesenchymal transition (EMT) of gastric cancer cells within the inflammatory microenvironment. Recombinant adenovirus Ad5/F35-PIASl and Ad5/F35-null plasmids were constructed to transfect SGC7901 cells...
March 2018: Oncology Letters
Yifan Wang, Weiye Deng, Nan Li, Shinya Neri, Amrish Sharma, Wen Jiang, Steven H Lin
Since the approval of anti-CTLA4 therapy (ipilimumab) for late-stage melanoma in 2011, the development of anticancer immunotherapy agents has thrived. The success of many immune-checkpoint inhibitors has drastically changed the landscape of cancer treatment. For some types of cancer, monotherapy for targeting immune checkpoint pathways has proven more effective than traditional therapies, and combining immunotherapy with current treatment strategies may yield even better outcomes. Numerous preclinical studies have suggested that combining immunotherapy with radiotherapy could be a promising strategy for synergistic enhancement of treatment efficacy...
2018: Frontiers in Pharmacology
Yusheng Cheng, Hui Li, Yinan Deng, Yan Tai, Kaining Zeng, Yingcai Zhang, Wei Liu, Qi Zhang, Yang Yang
Emerging evidence indicate that cancer-associated fibroblasts (CAFs) affect tumor progression by reshaping the tumor microenvironment. Neutrophils are prominent components of solid tumors and important in cancer progression. Whether the phenotype and function of neutrophils in hepatocellular carcinoma (HCC) are influenced by CAFs is not well understood. Herein, we investigated the effect of HCC-derived CAFs (HCC-CAFs) on the neutrophils and explored the biological role of this effect. We found that HCC-CAFs induced chemotaxis of neutrophils and protected them from spontaneous apoptosis...
March 19, 2018: Cell Death & Disease
Mariusz Z Ratajczak, Mateusz Adamiak, Monika Plonka, Ahmed Abdel-Latif, Janina Ratajczak
Hematopoietic stem/progenitor cells (HSPCs) circulate in peripheral blood (PB) under normal conditions and their number increases in response to stress, inflammation, tissue/organ injury, and may increase up to 100-fold after administration of mobilization-inducing drugs. Mounting evidence suggests that mobilizing agent-induced mobilization of HSPCs from bone marrow into PB is a result of innate immunity-mediated sterile inflammation in the bone marrow (BM) microenvironment. A critical initiating role in this process is played by tissue/organ injury-mediated or pharmacologically induced release from bone marrow-residing granulocytes and monocytes of (i) danger-associated molecular patterns (DAMPs), (ii) reactive oxygen species (ROS), and (iii) proteolytic and lipolytic enzymes...
March 5, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Tom Verbiest, Rosemary Finnon, Natalie Brown, Lourdes Cruz-Garcia, Paul Finnon, Grainne O'Brien, Eleanor Ross, Simon Bouffler, Cheryl L Scudamore, Christophe Badie
Epidemiological studies have demonstrated an increased leukemia incidence following ionizing radiation exposure, but to date, the target cells and underlying mechanisms of radiation leukemogenesis remain largely unidentified. We engineered a mouse model carrying a different fluorescent marker on each chromosome 2, located inside the minimum deleted region occurring after radiation exposure and recognized as the first leukemogenic event. Using this tailored model, we report that following radiation exposure, more than half of asymptomatic CBA Sfpi1 GFP/mCh mice presented with expanding clones of preleukemic hematopoietic cells harboring a hemizygous interstitial deletion of chromosome 2...
March 3, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
T Einfalt, D Witzigmann, C Edlinger, S Sieber, R Goers, A Najer, M Spulber, O Onaca-Fischer, J Huwyler, C G Palivan
Despite tremendous efforts to develop stimuli-responsive enzyme delivery systems, their efficacy has been mostly limited to in vitro applications. Here we introduce, by using an approach of combining biomolecules with artificial compartments, a biomimetic strategy to create artificial organelles (AOs) as cellular implants, with endogenous stimuli-triggered enzymatic activity. AOs are produced by inserting protein gates in the membrane of polymersomes containing horseradish peroxidase enzymes selected as a model for natures own enzymes involved in the redox homoeostasis...
March 19, 2018: Nature Communications
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