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1.
Soc Hist Med ; 36(2): 284-315, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37533510

RESUMO

During the Second World War, the Hadfield Spears ambulance took care of around 22,000 wounded and/or sick patients across three continents. This article analyses how military attacks and instances of violence impacted on the psychological, emotional and physical health of those attending the wounded within this mobile unit. While historiography of allied medicine develops apace, analysis of the Free French health service remains rare. Yet the history of the Hadfield Spears ambulance provides a fascinating window into the neglected issue of attacks on healthcare in wartime, as well as a fresh scope for combining macro and micro perspectives. The deployment of both approaches suggests potent ways to connect intimate responses to attacks to broader histories of allied frictions and cooperation. Crucially, it offers rich insights into the development of a transnational 'ethos of stoicism', which helped to sustain the hospital's community, in a fraught allied diplomatic context.

2.
PLoS One ; 13(10): e0205491, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30321203

RESUMO

Robust preclinical testing is essential to predict clinical safety and efficacy and provide data to determine safe dose for first-in-man studies. There are a growing number of examples where the preclinical development of drugs failed to adequately predict clinical adverse events in part due to their assessment with inappropriate preclinical models. Preclinical investigations of T cell receptor (TCR)-based immunotherapies prove particularly challenging as these biologics are human-specific and thus the conventional testing in animal models is inadequate. As these molecules harness the full force of the immune system, and demonstrate tremendous potency, we set out to design a preclinical package that would ensure adequate evaluation of these therapeutics. Immune Mobilising Monoclonal TCR Against Cancer (ImmTAC) molecules are bi-specific biologics formed of an affinity-enhanced TCR fused to an anti-CD3 effector function. ImmTAC molecules are designed to activate human T lymphocytes and target peptides within the context of a human leukocyte antigen (HLA), thus require an intact human immune system and peptidome for suitable preclinical screening. Here we draw upon the preclinical testing of four ImmTAC molecules, including IMCgp100, the first ImmTAC molecule to reach the clinic, to present our comprehensive, informative and robust approach to in vitro preclinical efficacy and safety screening. This package comprises a broad range of cellular and molecular assays using human tissues and cultured cells to test efficacy, safety and specificity, and hence predict human responses in clinical trials. We propose that this entirely in vitro package offers a potential model to be applied to screening other TCR-based biologics.


Assuntos
Anticorpos Biespecíficos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Proteínas/farmacologia , Anticorpos de Cadeia Única/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Técnicas In Vitro , Fluxo de Trabalho
3.
BMC Cancer ; 15: 200, 2015 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-25885043

RESUMO

BACKGROUND: Cutaneous melanoma is the most lethal skin cancer and its incidence in developed countries has dramatically increased over the past decades. Localized tumors are easily treated by surgery, but advanced melanomas lack efficient treatment and are associated with very poor outcomes. Thus, understanding the processes underlying melanoma development and progression is critical. The Transforming Growth Factor beta (TGFß) acts as a potent tumor suppressor in human melanoma, by inhibiting cell growth and preventing cellular migration and invasion. METHODS: In this study, we aimed at elucidating the molecular mechanisms underlying TGFß-mediated tumor suppression. Human cutaneous melanoma cell lines, derived from different patients, were used to assess for cell cycle analysis, apoptosis/caspase activity and cell migration. Techniques involved immunoblotting, immunohistochemistry, real time PCR and luciferase reporter assays. RESULTS: We found the leukemia inhibitory factor (LIF) to be strongly up-regulated by TGFß in melanoma cells, defining LIF as a novel TGFß downstream target gene in cutaneous melanoma. Interestingly, we also showed that TGFß-mediated LIF expression is required for TGFß-induced cell cycle arrest and caspase-mediated apoptosis, as well as for TGFß-mediated inhibition of cell migration. Moreover, we found that TGFß-mediated LIF expression leads to activation of transcription of the cell cycle inhibitor p21 in a STAT3-dependent manner, and further showed that p21 is required for TGFß/LIF-mediated cell cycle arrest and TGFß-induced gene activation of several pro-apoptotic genes. CONCLUSIONS: Together, our results define the LIF/p21 signaling cascade as a novel tumor suppressive-like pathway in melanoma, acting downstream of TGFß to regulate cell cycle arrest and cell death, further highlight new potential therapeutic strategies for the treatment of cutaneous melanoma.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fator Inibidor de Leucemia/biossíntese , Melanoma/genética , Neoplasias Cutâneas/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fator Inibidor de Leucemia/genética , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Cultura Primária de Células , Ligação Proteica , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fator de Crescimento Transformador beta1/metabolismo , Melanoma Maligno Cutâneo
4.
Anal Biochem ; 441(2): 182-4, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23872007

RESUMO

Western blot is an extensively used method for protein detection in cell biology. To optimize this procedure, here we examined a panel of buffers for their ability to efficiently transfer proteins from SDS-polyacrylamide gels onto nitrocellulose membranes in a short 12-min period, designated here as fast semidry transfer. Our results show for the first time that HEPES- and HEPPS/EPPS-based buffers represent the most efficient buffers for fast semidry transfer.


Assuntos
Colódio/química , Eletroforese em Gel de Poliacrilamida/métodos , Membranas Artificiais , Proteínas/isolamento & purificação , Soluções Tampão , Eletroforese em Gel de Poliacrilamida/economia , HEPES/química , Fatores de Tempo
5.
Cell Signal ; 25(2): 490-500, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23085456

RESUMO

Over the past decades, the incidence of cutaneous melanoma in developed countries has increased faster than any other cancer. Although most patients have localized disease at the time of diagnosis and are cured by surgical excision of the primary tumor, melanoma can be highly malignant and the survival dramatically decreases for advanced stage melanomas. It is thus necessary to understand the progression of this disease. Cell migration and invasion promote tumor metastasis, the major cause of melanoma cancer morbidity and death. In this study, we investigated the role of the TGFß/Smad signaling pathway in melanoma tumor progression and found TGFß to potently inhibit both cell migration and invasion in human melanoma cell lines, established from different patients. Furthermore, we elucidated the molecular mechanisms by which TGFß exerts its effects and found the plasminogen activation system (PAS) to play a central role in the regulation of these effects. We found TGFß to strongly up-regulate the Plasminogen Activator Inhibitor-1 (PAI-1) in melanoma cells, leading to reduced plasmin generation and activity and, in turn to inhibition of cell migration and invasion. Together, our results define TGFß as a potent suppressor of tumor progression in cutaneous melanoma, inhibiting both cell migration and invasion.


Assuntos
Movimento Celular/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ativadores de Plasminogênio/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Adulto , Idoso , Sobrevivência Celular/efeitos dos fármacos , Feminino , Fibrinolisina/metabolismo , Humanos , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/química , Inibidor 1 de Ativador de Plasminogênio/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteínas Smad/antagonistas & inibidores , Proteínas Smad/genética , Proteínas Smad/metabolismo , Células Tumorais Cultivadas , Regulação para Cima
6.
Biomaterials ; 33(7): 2345-50, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22177619

RESUMO

A femtosecond laser based transfection method using off-resonance plasmonic gold nanoparticles is described. For human cancer melanoma cells, the treatment leads to a very high perforation rate of 70%, transfection efficiency three times higher than for conventional lipofection, and very low toxicity (<1%). Off-resonance laser excitation inhibited the fracture of the nanoparticles into possibly toxic DNA intercalating particles. This efficient and low toxicity method is a promising alternative to viral transfection for skin cancer treatment.


Assuntos
Terapia Genética/métodos , Lasers , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Transfecção/métodos , Linhagem Celular Tumoral , Sobrevivência Celular , Técnicas de Transferência de Genes , Ouro/química , Humanos , Melanoma/genética , Melanoma/terapia , Nanopartículas/química
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