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Gain of function of cardiac voltage-gated sodium channel (Nav1.5) leads to Long QT Syndrome Type 3 (LQT3). LQT3 phenotype can be exacerbated by expanding the perinexus, which is an intercellular nanodomain with high density of Nav1.5 in the intercalated disc. Following this finding, we found that elevating extracellular sodium and widening the perinexus synergistically exacerbated LQT3 phenotype, Importantly, we also found that perinexal expansion increases the susceptibility to cardiac arrest in aged LQT3, which demonstrated that perinexal expansion is an arrhythmogenic risk especially in aged LQT3 patients. Furthermore, we observed that the perinexus narrows with aging and conceals LQT3 phenotype, which suggests that perinexal narrowing may have a cardio-protective role during aging in LQT3. Surprisingly, following the finding of the synergistic effect of extracellular sodium elevation and perinexal widening on LQT3 phenotype in drug-induced LQT3 guinea pig hearts, we found that this synergistic effect was not observed in genetically-modified LQT3 mouse hearts, which is due to high sodium also increasing transient outward potassium current (Ito). In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts which functionally express Ito channels. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose. / Doctor of Philosophy / Long QT Syndrome Type 3 (LQT3) is an inherited heart disease with the phenotype of long QT interval in ECG. It has been found that LQT3 phenotype gets worse when a very tiny space in the heart, termed as the perinexus, is wide due to cardiac edema. Following this finding, we also found that increasing sodium concentration together with wide perinexus can further exacerbate LQT3 phenotype in guinea pig hearts. Furthermore, we found that widening the perinexus in aged LQT3 hearts causes cardiac death but not in adult, which suggests that perinexal widening worsens LQT3 phenotype and even leads to cardiac death in aged hearts. Besides, we found that the perinexus narrows with aging and there is no difference in LQT3 phenotype between adult and aged hearts, which suggests that the narrow perinexus during aging may protect the hearts from cardiac death in LQT3. Surprisingly, we discovered that increasing sodium and widening the perinexus together fails to exacerbate LQT3 phenotype when compared with widening the perinexus alone in LQT3 mouse hearts, which is due to high sodium increasing transient outward potassium current (Ito). Notably, Ito channels are not functionally expressed in guinea pig hearts. In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose.

Modern manufacturing needs to optimize the entire product lifecycle to satisfy the customer needs. The advancement of sensing technologies has brought a data rich environment for manufacturing and provide a great opportunity for real-time, proactive quality assurance. However, due to the lack of methods for analyzing heterogeneous types of data, the transformation of data to information and knowledge for effective decision making in manufacturing is still a challenging problem. In particular, functional variables can represent the in situ process conditions and rich product performance information, and are widely encountered in various manufacturing processes. In this dissertation, I will focus on modeling of manufacturing processes with in situ process (functional) variables, and integrating these functional variables and other measured variables for the manufacturing modeling. The modeling is explored by extracting informative features through the integration of multiple functional variables, functional variables and offline setting variables, and quantitative and qualitative quality variables. After an introduction in Chapter 1, three research tasks are investigated. First, a functional variable selection problem is studied in Chapter 2 to identify the significant functional variables as well as their features in a logistic regression model. A hierarchical non-negative garrote constrained estimation method is proposed. Second, the quality-process relationships for scalar offline setting variables, functional in situ process variables, and manufacturing quality responses are studied in Chapter 3. A functional graphical model that can integrate functional variables in a graphical model is proposed and investigated. Third, the quantitative and qualitative quality responses are jointly modeled with scalar offline setting variables and functional in situ process variables in Chapter 4. A functional quantitative and qualitative model is proposed and investigated. Finally, I summarize the research contribution and discuss future research directions in Chapter 5. The proposed methodologies have broad applications in manufacturing processes with functional variables, and are demonstrated in a crystal growth process with multiple functional variables (Chapter 2), a plasma spray process with multiple scalar and functional variables (Chapter 3), and an additive manufacturing process called fused deposition modeling with quantitative and qualitative quality responses (Chapter 4). / Ph. D.

La sensibilité et la sévérité d'explosion des différents mélanges gaz/vapeur-poussière ont été étudiées grâce à des dispositifs standards (sphère de 20 L, tube de Hartmann). Les spécificités des explosions de mélanges hybrides gaz/poussière ont été mises en évidence. En fait, même pour des concentrations de gaz inférieures à la limite inférieure d'explosivité (LIE), la probabilité d'inflammation et la gravité d'explosion peuvent être considérablement augmentées, ce qui permettra notamment de conduire à de grands changements dans la détermination des zones ATEX. Il a été, par exemple, démontré que ces mélanges peuvent être explosifs même lorsque la concentration en poudre et la concentration en vapeur sont respectivement en dessous de la concentration minimale explosive et de la LIE. En outre, des effets de synergie ont été observés et la vitesse de montée en pression de mélanges hybrides peut être supérieure à celles des gaz purs. Les origines de ces spécificités ne doivent pas être recherchées dans la modification d'un paramètre unique, mais peuvent probablement être attribuées aux effets combinés sur l'hydrodynamique (propagation de la flamme), le transfert thermique et la cinétique de combustion. Des expériences ont été menées afin de souligner l'importance de chaque contribution. Basé sur des schémas cinétiques classiques à coeur rétrécissant prenant en compte des diverses contraintes lors d'une réaction non-catalytique de gaz/solide et sur des modèles de combustion homogène pour les gaz, un modèle a été développé pour représenter l'évolution temporelle de la pression d'explosion pour ces mélanges / The explosion sensitivity and severity of various gas/vapor-dust mixtures have been studied thanks to specifically modified apparatuses based on a 20 L sphere and a Hartmann tube. The specificities of gas/dust hybrid mixtures explosions have been highlighted. In fact, even for gas concentrations lower than the lower explosivity limit (LEL), the ignition probability and the explosion severity can be greatly increased, which will notably lead to great changes in the Ex zones determination. For instance, it has been shown that such mixtures can be explosive when both the dust and gas concentrations are below their respective minimum explosive concentration and LEL. Moreover, synergistic effects have been observed and the rate of pressure rise of hybrid mixtures can be greater than those of the pure gases themselves. The origins of these specificities should not be sought in the modification of a single parameter, but could probably be attributed to combined impacts on hydrodynamics (flame propagation), thermal transfer and combustion kinetics. Experiments have been carried out in order to underline the significance of each contribution. Based on classical shrinking core models taking into account the various limitations during a non-catalytic gas/solid reaction and on homogeneous combustion for gases, a model has been developed to represent the time evolution of the explosion pressure for such mixtures

Tout composant envoyé dans l'espace est soumis à de nombreuses contraintes (radiations, température) qui peuvent conduire à une défaillance de l'ensemble du système. Dans un avenir proche, ces contraintes deviendront de plus en plus critiques à mesure que les agences spatiales développeront des missions visant d'autres planètes, telles que Jupiter, pour lesquelles la contrainte radiative est extrême. Dans ce travail, deux types d'effets dus aux radiations sont étudiés : les effets cumulatifs et les effets transitoires. L'un correspond à la dégradation induite par les radiations au cours du temps, tandis que l'autre correspond à un événement ponctuel qui peut se produire à tout moment lorsque le système est dans l'espace. Pour garantir le bon fonctionnement en vol, des normes de qualification des composants électroniques ont été élaborées par différentes agences spatiales. Toutes ces normes précisent que les effets cumulatifs et transitoires doivent être vérifiés à l'aide de composants intacts pour chaque essai. Par conséquent, les effets cumulatifs sont traités séparément des effets transitoires, alors qu'il y a une forte probabilité qu'ils apparaissent simultanément pendant une mission spatiale. L'étude des effets de synergie est alors le thème principal de cette thèse.Sur un amplificateur opérationnel bipolaire, la réponse de sortie du composant due à un événement transitoire est directement liée aux paramètres internes du composant, qui varient sous l’effet des radiations. A l’aide d’une comparaison entre trois amplificateurs opérationnels différents partageant la même référence, l'impact du design sur la dégradation due aux radiation est étudié.Récemment, des défaillances imprévues ont été reportées pour lesquelles le mode de défaillance semblait indiquer qu'une structure de protection contre les décharges électrostatiques (ESD) était en cause. Par conséquent, pour comprendre si ces protections peuvent causer des défaillances inattendues, la dégradation des « Gate Grounded n-MOSFET » (GGnMOS) est également étudiée. / Any system sent to space is submitted to many constraints (radiations, temperature) which may lead to a failure of the whole system. In a close future, these constraints will become more and more critical as the space agencies are developing missions aiming at others planets such as Jupiter for which the radiative constraint is extremely harsh. In this work, two types of radiation effects are studied: the cumulative effects and the transient effects. One corresponds to the radiation-induced degradation over time, while the other corresponds to a punctual event that can happen at any time when the system is in space. To ensure a proper functioning of a system sent to space, qualifications standards for electronic components have been developed by different space agencies. All of these standards specify that the components must be tested for cumulative and transient effects, using pristine components for each test. Therefore, cumulative effects are treated separately from transient effects, while there is a significant probability that they will appear simultaneously during a space mission. The study of the synergistic effects is then the main frame of this thesis.On a bipolar operational amplifier, the output response of the component due to a transient event is directly related to the internal parameters of the component, which vary over time once in space. Through a comparison between three different operational amplifier sharing the same reference, the impact of the design over the degradation is explained.Lately, some unexpected failures were reported for which the failure mode seemed to indicate that an Electrostatic Discharge (ESD) protection structure was involved. Therefore, to understand if those protections may cause some unexpected failures, the degradation of gate grounded n-MOSFET (GGnMOS) will be investigated next.

Esse trabalho teve como objetivo o estudo da toxicidade aguda e crônica da ação isolada e de misturas binárias de três medicamentos veterinários (Monensina, Sulfametazina e Enrofloxacina) para o organismo teste Daphnia magna. A toxicidade aguda da enrofloxacina determinada foi de CE50 - 54.36 mgL-1, da monensina CE50 - 15.11mgL-1 e da sulfametazina CE50 - 183.80 mgL-1. Para os ensaios de toxicidade crônica foram determinados 3 \"endpoints\" (sobrevivência, reprodução e tamanho do adulto) e foi determinado o CEO para a enrofloxacina de 0,33 mgL-1, da monensina 0,09 mgL-1 e da sulfametazina de 6,8 mgL-1. Para fazer uma comparação entre os testes das substâncias isoladas e das misturas binárias foi utilizado o conceito de unidade tóxica (UT), essa comparação foi feita através da soma das UT dos ensaios individuais e comparando com os resultados dos ensaios de misturas para determinar se houve ação sinérgica, aditiva ou antagônica. O ensaio agudo de mistura monensina/enrofloxacina apresentou ação sinérgica já os ensaios monensina/sulfametazina e sulfametazina/enrofloxacina apresentaram ação antagônica. Os ensaios crônicos de mistura monensina/enrofloxacina e monensina/sulfametazina apresentaram ação sinérgica, porém não foram dosedependente e o ensaio sulfametazina/enrofloxacina apresentou ação antagônica. Com base nesse estudo é possível concluir que a mistura desses medicamentos interfere na sua toxicidade, podendo causar efeitos sinérgicos ou antagônicos / This work aims to study the acute and chronic toxicity of the isolated and binary mixtures action of three veterinary drugs (Monensin, Sulfamethazine and Enrofloxacin) for the test organism Daphnia magna. The determined acute toxicity of enrofloxacin was EC50 - 54.36 mgL-1, monensin EC50 - 15.11 mgL-1 and sulfamethazine EC50 - 183.80 mgL-1. In the chronic toxicity tests were determined 3 endpoints (survival, reproduction and adult size) and the LOEC determined for enrofloxacina was 0.33 mgL-1, monensin 0.09 mgL-1 and sulfamethazine 6.8 mgL-1. To make a comparison between the tests of isolated substances and binary mixtures it was used the concept of toxic unit (TU), this comparison was made by adding the UT of individual studies and comparing the test results of mixtures to determine whether there was a synergistic action, additive or antagonistic. The acute mixture assay monensin/enrofloxacin showed synergistic action yet the assays monensin/sulfamethazine and sulfamethazine/enrofloxacin showed antagonistic action. The chronic mixing assays monensin / enrofloxacin and monensin / sulfamethazine showed synergistic action, but were not dose-dependent and testing sulfamethazine / enrofloxacin present antagonistic action. Based on this study it can be concluded that the mixing of these drugs interferes with its toxicity, and may cause synergistic or antagonistic effect

The character of woven textiles is dependent on both the materials and the loom technology used. While digitally-controlled jacquard looms are a major development in weaving technology, they have mostly been used in developing representational and pictorial weaving. Such three-dimensional weaving as exists, utilises materials in predictably similar ways. Here, through systematic experimentation, three shrinking and two resisting yarns have been combined in multi-layer weaves in order to explore their potential for form-generating behaviour. Three-dimensional form occurs when the shrinking yarn/s place the resisting yarn/s under tension. To relieve this tension, the resisting yarn moves within the weave, creating waves or folds. The resulting form is highly sensitive to variation, demonstrating emergent behaviour, and identifying the woven textile as a complex system. Demonstrating the variety of form possible from a limited number of materials, the results represent a small body of work aiming to re-form weaving. The exploration of synergistic material combinations is therefore shown to be an exercise of value to fields from art textiles through to industry. It demonstrates that there is great development potential in woven textiles. Understanding the behaviour of materials is fundamental to furthering form-based weaving.

Introdução: o sarcoma de Ewing é um dos tipo mais agressivos de câncer pediátrico. Esse tipo de câncer é um tumor primitivo neuroectodérmico, grupo que inclui ainda outros tumores pediátricos como o meduloblastoma e o neuroblastoma. Apesar de avanços significativos desde o surgimento da quimioterapia, ainda há necessidade de aumento dos índices de cura, redução da toxicidade da quimioterapia e redução da resistência ao tratamento em pacientes com essa doença. Inibidores da acetilação de histonas (HDACIs ou HDIs) e bifosfonatos têm um futuro promissor no tratamento de câncer, especialmente quando utilizados conjuntamente ou em associação com outros agentes citotóxicos, como antineoplásicos clássicos. No entanto, os efeitos destes tratamentos combinados ainda não haviam sido devidamente estudados em Sarcoma de Ewing. Objetivos: este estudo se propôs a avaliar, in vitro, os efeitos do inibidor da acetilação de histonas, butirato sódico (NaB), do bifosfonato, zoledronato (ZA), da associação destes dois agentes e de combinações dos mesmos com antineoplásicos clássicos sobre a proliferação, viabilidade e sobrevivência celular em sarcoma de Ewing. Métodos: as linhagens celulares de sarcoma de Ewing, SK-ES-1 e RD-ES, foram tratadas com NaB, ZA, doxorrubicina, etoposídeo ou vincristina e com diferentes combinações destes agentes. O crescimento tumoral in vitro, incluindo parâmetros de proliferação e viabilidade celular, foi analisado pelos métodos de contagem celular por exclusão com azul de tripan e MTT. Os efeitos tardios (sobrevivência) também foram estudados através da determinação da formação de colônias (ensaio colonogênico). Resultados: a combinação de NaB e ZA teve um efeito citotóxico sinérgico 72h após o tratamento, persistindo durante 10-14 dias após o tratamento, em ambas as linhagens celulares testadas. Todas as combinações entre NaB ou ZA e os antineoplásicos clássicos testados apresentaram efeitos citotóxicos sinérgicos 72h após os tratamentos em ambas linhagens celulares, com a exceção das seguintes associações: NaB + VCR e ZA + Doxo, que apresentaram apenas efeito aditivo nas células RD-ES, quando comparados com cada um dos agentes em monoterapia. Estes efeitos “agudos” observados em ambas as linhagens celulares de sarcoma de Ewing foram confirmados pelo ensaio clonogênico. Conclusão: os dados obtidos sugerem que o uso combinado de bifosfonatos e HDIs e a associação destes agentes com quimioterápicos clássicos representam promissoras alternativas no tratamento de sarcoma de Ewing e proporcionam a base para novos estudos. / Background: Ewing sarcoma, often referred to as Ewing’s sarcoma family tumors, is a peripheral primitive neuroectodermal tumor. Ewing sarcoma is the second most common solid bone and soft tissue malignancy of children and young adults. Despite significant advances in cancer chemotherapy, there is still need for increased rates of cure, reduction of toxicity of chemotherapy and reduced resistance to treatment in patients with this disease. Histone deacetylase inhibitors (HDACIs or HDIs) and bisphosphonates have a promising future in the treatment of cancer as targeted anticancer drugs, especially when used together or in combination with other cytotoxic agents. However, the effects of these combined treatments have not yet been properly evaluated in Ewing sarcoma. Objective: In the present study, we evaluated the in vitro cytotoxic effects (on cellular proliferation, viability, and survival) elicited by the co-treatment of sodium butyrate (NaB) and zoledronic acid (ZA) alone or in combination with three anti-cancer drugs strongly recommended to treat Ewing sarcoma (doxorubicin, etoposide and vincristine) in two human cell lines. Methods: two Ewing sarcoma cell lines, SK-ES-1 and RD-ES, were treated with NaB, ZA, doxorubicin, etoposide, vincristine and with different combinations of these drugs. The proliferation and cell viability were analyzed by counting cell in a hemocytometer, by exclusion of trypan blue and by MTT assay. The survival and proliferation of cells were also studied by clonogenic assay. Results: our results demonstrate that the combination of NaB and ZA has a synergistic cytotoxic effect at 72h after treatment, persisting for 10-14 days post-treatment, in both cell lines tested. All combinations between NaB or ZA and classical antineoplastic drugs demonstrated a synergistic cytotoxic effect at 72h post-treatment in SK-ES-1 and RD-ES cells, with the exception of NaB plus VCR, and ZA plus Doxo, which showed only an additive effect in RD-ES cells when compared to each agent alone. These acute effects observed in both Ewing sarcoma cells were confirmed by the clonogenic assay. Conclusion: These data suggest that HDIs and bisphosphonate co-treatment in combination with classical chemotherapeutic drugs is a promising therapeutic venue the treatment of Ewing sarcoma, and provide a basis for further study in this field.

abstract: Relapse after tumor dormancy is one of the leading causes of cancer recurrence that ultimately leads to patient mortality. Upon relapse, cancer manifests as metastases that are linked to almost 90% cancer related deaths. Capture of the dormant and relapsed tumor phenotypes in high-throughput will allow for rapid targeted drug discovery, development and validation. Ablation of dormant cancer will not only completely remove the cancer disease, but also will prevent any future recurrence. A novel hydrogel, Amikagel, was developed by crosslinking of aminoglycoside amikacin with a polyethylene glycol crosslinker. Aminoglycosides contain abundant amount of easily conjugable groups such as amino and hydroxyl moieties that were crosslinked to generate the hydrogel. Cancer cells formed 3D spheroidal structures that underwent near complete dormancy on Amikagel high-throughput drug discovery platform. Due to their dormant status, conventional anticancer drugs such as mitoxantrone and docetaxel that target the actively dividing tumor phenotype were found to be ineffective. Hypothesis driven rational drug discovery approaches were used to identify novel pathways that could sensitize dormant cancer cells to death. Strategies were used to further accelerate the dormant cancer cell death to save time required for the therapeutic outcome. Amikagel’s properties were chemo-mechanically tunable and directly impacted the outcome of tumor dormancy or relapse. Exposure of dormant spheroids to weakly stiff and adhesive formulation of Amikagel resulted in significant relapse, mimicking the response to changes in extracellular matrix around dormant tumors. Relapsed cells showed significant differences in their metastatic potential compared to the cells that remained dormant after the induction of relapse. Further, the dissertation discusses the use of Amikagels as novel pDNA binding resins in microbead and monolithic formats for potential use in chromatographic purifications. High abundance of amino groups allowed their utilization as novel anion-exchange pDNA binding resins. This dissertation discusses Amikagel formulations for pDNA binding, metastatic cancer cell separation and novel drug discovery against tumor dormancy and relapse. / Dissertation/Thesis / Doctoral Dissertation Bioengineering 2016

Introdução: o sarcoma de Ewing é um dos tipo mais agressivos de câncer pediátrico. Esse tipo de câncer é um tumor primitivo neuroectodérmico, grupo que inclui ainda outros tumores pediátricos como o meduloblastoma e o neuroblastoma. Apesar de avanços significativos desde o surgimento da quimioterapia, ainda há necessidade de aumento dos índices de cura, redução da toxicidade da quimioterapia e redução da resistência ao tratamento em pacientes com essa doença. Inibidores da acetilação de histonas (HDACIs ou HDIs) e bifosfonatos têm um futuro promissor no tratamento de câncer, especialmente quando utilizados conjuntamente ou em associação com outros agentes citotóxicos, como antineoplásicos clássicos. No entanto, os efeitos destes tratamentos combinados ainda não haviam sido devidamente estudados em Sarcoma de Ewing. Objetivos: este estudo se propôs a avaliar, in vitro, os efeitos do inibidor da acetilação de histonas, butirato sódico (NaB), do bifosfonato, zoledronato (ZA), da associação destes dois agentes e de combinações dos mesmos com antineoplásicos clássicos sobre a proliferação, viabilidade e sobrevivência celular em sarcoma de Ewing. Métodos: as linhagens celulares de sarcoma de Ewing, SK-ES-1 e RD-ES, foram tratadas com NaB, ZA, doxorrubicina, etoposídeo ou vincristina e com diferentes combinações destes agentes. O crescimento tumoral in vitro, incluindo parâmetros de proliferação e viabilidade celular, foi analisado pelos métodos de contagem celular por exclusão com azul de tripan e MTT. Os efeitos tardios (sobrevivência) também foram estudados através da determinação da formação de colônias (ensaio colonogênico). Resultados: a combinação de NaB e ZA teve um efeito citotóxico sinérgico 72h após o tratamento, persistindo durante 10-14 dias após o tratamento, em ambas as linhagens celulares testadas. Todas as combinações entre NaB ou ZA e os antineoplásicos clássicos testados apresentaram efeitos citotóxicos sinérgicos 72h após os tratamentos em ambas linhagens celulares, com a exceção das seguintes associações: NaB + VCR e ZA + Doxo, que apresentaram apenas efeito aditivo nas células RD-ES, quando comparados com cada um dos agentes em monoterapia. Estes efeitos “agudos” observados em ambas as linhagens celulares de sarcoma de Ewing foram confirmados pelo ensaio clonogênico. Conclusão: os dados obtidos sugerem que o uso combinado de bifosfonatos e HDIs e a associação destes agentes com quimioterápicos clássicos representam promissoras alternativas no tratamento de sarcoma de Ewing e proporcionam a base para novos estudos. / Background: Ewing sarcoma, often referred to as Ewing’s sarcoma family tumors, is a peripheral primitive neuroectodermal tumor. Ewing sarcoma is the second most common solid bone and soft tissue malignancy of children and young adults. Despite significant advances in cancer chemotherapy, there is still need for increased rates of cure, reduction of toxicity of chemotherapy and reduced resistance to treatment in patients with this disease. Histone deacetylase inhibitors (HDACIs or HDIs) and bisphosphonates have a promising future in the treatment of cancer as targeted anticancer drugs, especially when used together or in combination with other cytotoxic agents. However, the effects of these combined treatments have not yet been properly evaluated in Ewing sarcoma. Objective: In the present study, we evaluated the in vitro cytotoxic effects (on cellular proliferation, viability, and survival) elicited by the co-treatment of sodium butyrate (NaB) and zoledronic acid (ZA) alone or in combination with three anti-cancer drugs strongly recommended to treat Ewing sarcoma (doxorubicin, etoposide and vincristine) in two human cell lines. Methods: two Ewing sarcoma cell lines, SK-ES-1 and RD-ES, were treated with NaB, ZA, doxorubicin, etoposide, vincristine and with different combinations of these drugs. The proliferation and cell viability were analyzed by counting cell in a hemocytometer, by exclusion of trypan blue and by MTT assay. The survival and proliferation of cells were also studied by clonogenic assay. Results: our results demonstrate that the combination of NaB and ZA has a synergistic cytotoxic effect at 72h after treatment, persisting for 10-14 days post-treatment, in both cell lines tested. All combinations between NaB or ZA and classical antineoplastic drugs demonstrated a synergistic cytotoxic effect at 72h post-treatment in SK-ES-1 and RD-ES cells, with the exception of NaB plus VCR, and ZA plus Doxo, which showed only an additive effect in RD-ES cells when compared to each agent alone. These acute effects observed in both Ewing sarcoma cells were confirmed by the clonogenic assay. Conclusion: These data suggest that HDIs and bisphosphonate co-treatment in combination with classical chemotherapeutic drugs is a promising therapeutic venue the treatment of Ewing sarcoma, and provide a basis for further study in this field.