Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients' bed.

BACKGROUND: Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H\u2009+-rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma. METHOD: MG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin. RESULTS: Preclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients. CONCLUSION: This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Advanced Hybrid Solid Fuels

Enabling hybrid rocket propulsion to compete with solid and liquid propulsion is the target of the renewed international interest in hybrid rockets. From the performances standpoint, conventional hybrids may compete with conventional liquids such as LOX Kerosene and could be much better than solids but they have 2 major drawbacks; A low burning rate of current solid fuels represents the main one to overcome for successful operations of hybrid propulsion on large scale. Combustion problems with a low combustion efficiency, instabilities and a high level of residuals (difficult mastering of the combustion with a multiport motor) Moreover, to be really attractive, new formulations have to bring a decisive advantage with a much higher specific impulse. nevertheless these new formulations have to keep the 3 major ones of hybrids; a safe operating mode due to a very high level of mechanical properties, a cheap manufacturing process due to a pure fuel solid grain and the capability to be stopped on demand. Some formulations appears really attractive with a high burning rate and a good combustion with or without a large increase of the specific impulse The present paper describes the efforts, by a joint team of investigators, to reach this objective by promoting the use of novel energetic ingredients in hybrid solid fuels and will give an example of application. A variety of new formulations was tested keeping in mind that both combustion behavior and mechanical properties of solid fuel grains are important for applications. Thus, a systematic experimental investigation was planned to determine the relevant properties of several candidate formulations. For this purpose, a micro-sized hybrid rocket motor test bench was implemented for quasi-steady solid grain regression rate measurements, CO 2 laser for radiative primer charge ignition, and exhaust gases dump system. The solid grain is shaped as a traditional fuel cylinder with one central perforation. Air or mixtures of oxygen and nitrogen, injected at the head-end of the motor, were used as gaseous oxidizer. This apparatus allows, on a relative scale, a quick classification of fuel regression rates and their sensitivity to operating conditions. Three main directions were explored for developing advanced solid fuel compositions. The first one resorts to nano-sized energetic particles cast in HTPB solid fuel grains. The second direction resorts to fuels characterized by the presence of a liquid surface, resulting in droplets entrainment. Paraffin-based fuels were investigated revealing, for the investigated compositions, severe structural problems due to poor mechanical properties. The third investigated direction specifically addresses to metal hydrides compositions. In particular magnesium and aluminum hydrides formulations were analyzed, showing increases in the solid fuel regression rates depending on the hydride mass fraction. The incorporation of metal hydride in HTPB-based fuel induces also an energetic increase. For aluminum hydride, the expected specific impulse (vacuum, ε= 40) augmentation is 32 s

New high energetic composite propellants for space applications: refrigerated solid propellant

Cryogenic solid propellants (CSP) are a new kind of chemical propellants that use frozen products to ensure the mechanical resistance of the grain. The objective is to combine the high performances of liquid propulsion and the simplicity of solid propulsion. The CSP concept has few disadvantages. Storability is limited by the need of permanent cooling between motor loading and firing. It needs insulations that increase the dry mass. It is possible to limit significantly these drawbacks by using a cooling temperature near the ambient one. It will permit not to change the motor materials and to minimize the supplementary dry mass due to insulator. The designation “Refrigerated Solid Propellant” (RPS) is in that case more appropriate as “Cryogenic Solid Propellant.” SNPE Matériaux Energétiques is developing new concept of composition e e with cooling temperature as near the ambient temperature as possible. They are homogeneous and the main ingredients are hydrogen peroxide, polymer and metal or metal hydride, they are called “HydroxalaneTM.” This concept allows reaching a high energy level. The expected specific impulse is between 355 and 375 s against 315 s for hydroxyl-terminated polybutadiene (HTPB) / ammonium perchlorate (AP) / Al composition. However, the density is lower than for current propellants, between 1377 and 1462 kg/m3 compared to around 1800 kg/m3 . This is an handicap only for volume-limited application. Works have been carried out at laboratory scale to define the quality of the raw materials and the manufacturing process to realize sample and small grain in a safer manner. To assess the process, a small grain with an internal bore had been realized with a composition based on aluminum and water. This grain had shown very good quality, without any defect, and good bonding properties on the insulator