RESUMEN
Since Ghana's independence in 1957, the country has seen an ebb and flow of reforms intended to expand and fund state healthcare, informed by diverse notions of affordability and adequate provision. Cycles of attempted health reforms have emerged from disparate political and economic ideologies, themselves a product of broader global histories and specific national experiences. Based on group interviews with people across most administrative regions of Ghana, this paper examines how the formative historical experiences of different generations gives rise to a multiplicity of understandings of what constitutes a 'fair' distribution of national health resources. It discusses the forms and contents of arguments that people of different ages raised in both rural and urban settings in the course of the study - with particular reference to the operation of Ghana's current National Health Insurance Scheme, and in light of their perceptions of the justice or injustice of present day healthcare in relation to earlier periods.
Asunto(s)
Atención a la Salud , Pacientes , Humanos , Ghana , Instituciones de Salud , Programas Nacionales de SaludRESUMEN
As a contribution to the existing literature on deliberate or unintended neglect, concealment and ignorance regarding significant and enduring public health problems-produced by economic marginality, lack of political power and institutional failures affecting specific places and groups-this article discusses the history of epidemic sleeping sickness and endemic onchocerciasis in colonial northern Ghana from 1909 to 1957. Despite accumulating evidence of their serious impacts on the health of northern communities, and calls to action on the part of some health officials, both diseases were only officially recognised as significant risks when it was no longer politically possible to deny them. The particular histories of each disease, in the same region over the same decades, reveal two comparable and interrelated trajectories of neglect.
RESUMEN
Antibody-drug conjugates (ADC) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSC), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation. ADCs targeting 5T4 were constructed by site-specifically conjugating the antibody with payloads that possess different mechanisms of action, either a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer or a microtubule-destabilizing tubulysin, so that each ADC had a drug:antibody ratio of 2. The resulting ADCs demonstrated significant target-dependent activity in vitro and in vivo; however, the ADC conjugated with a PBD payload (5T4-PBD) elicited more durable antitumor responses in vivo than the tubulysin conjugate in xenograft models. Likewise, the 5T4-PBD more potently inhibited the growth of 5T4-positive CSCs in vivo, which likely contributed to its superior antitumor activity. Given that the 5T4-PBD possessed both potent antitumor activity as well as anti-CSC activity, and thus could potentially target bulk tumor cells and CSCs in target-positive indications, it was further evaluated in non-GLP rat toxicology studies that demonstrated excellent in vivo stability with an acceptable safety profile. Taken together, these preclinical data support further development of 5T4-PBD, also known as MEDI0641, against 5T4+ cancer indications. Mol Cancer Ther; 16(8); 1576-87. ©2017 AACR.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Benzodiazepinas/uso terapéutico , Inmunoconjugados/uso terapéutico , Pirroles/uso terapéutico , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Benzodiazepinas/efectos adversos , Benzodiazepinas/farmacología , Línea Celular Tumoral , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacología , Masculino , Ratones , Ratones Desnudos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Pirroles/efectos adversos , Pirroles/farmacología , Ratas Sprague-Dawley , Moduladores de Tubulina/efectos adversos , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Major histocompatibility complex (MHC) class I chain-related protein A (MICA) and MHC class I chain-related protein B (MICB) are polymorphic proteins that are induced upon stress, damage or transformation of cells which act as a 'kill me' signal through the natural-killer group 2, member D receptor expressed on cytotoxic lymphocytes. MICA/B are not thought to be constitutively expressed by healthy normal cells but expression has been reported for most tumour types. However, it is not clear how much of this protein is expressed on the cell surface. METHODS: Using a novel, well-characterised antibody and both standard and confocal microscopy, we systematically profiled MICA/B expression in multiple human tumour and normal tissue. RESULTS: High expression of MICA/B was detected in the majority of tumour tissues from multiple indications. Importantly, MICA/B proteins were predominantly localised intracellularly with only occasional evidence of cell membrane localisation. MICA/B expression was also demonstrated in most normal tissue epithelia and predominantly localised intracellularly. Crucially, we did not observe qualitative differences in cell surface expression between tumour and MICA/B expressing normal epithelia. CONCLUSIONS: This demonstrates for the first time that MICA/B is more broadly expressed in normal tissue and that expression is mainly intracellular with only a small fraction appearing on the cell surface of some epithelia and tumour cells.
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Antígenos de Histocompatibilidad Clase I/biosíntesis , Neoplasias/genética , Línea Celular Tumoral , Membrana Celular/genética , Citoplasma/genética , Regulación Neoplásica de la Expresión Génica , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Células Asesinas Naturales/inmunología , Neoplasias/clasificación , Neoplasias/patología , Linfocitos T Citotóxicos/metabolismoRESUMEN
Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR.
Asunto(s)
Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/administración & dosificación , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-1/metabolismo , Antígeno B7-H1/metabolismo , Unión Competitiva , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Femenino , Humanos , Activación de Linfocitos/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Melanoma/inmunología , Melanoma/patología , Melanoma/prevención & control , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/prevención & control , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Fabs are an important class of antibody fragment as both research reagents and therapeutic agents. There are a plethora of methods described for their recombinant expression and purification. However, these do not address the issue of excessive light chain production that forms light chain dimers nor do they describe a universal purification strategy. Light chain dimer impurities and the absence of a universal Fab purification strategy present persistent challenges for biotechnology applications using Fabs, particularly around the need for bespoke purification strategies. This study describes methods to address light chain dimer formation during Fab expression and identifies a novel CH 1 affinity resin as a simple and efficient one-step purification for correctly assembled Fab.
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Expresión Génica , Fragmentos Fab de Inmunoglobulinas/biosíntesis , Fragmentos Fab de Inmunoglobulinas/aislamiento & purificación , Cadenas Ligeras de Inmunoglobulina/biosíntesis , Cadenas Ligeras de Inmunoglobulina/aislamiento & purificación , Dimerización , Fragmentos Fab de Inmunoglobulinas/genética , Cadenas Ligeras de Inmunoglobulina/genética , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genéticaRESUMEN
We describe a method for high-throughput, parallel purification of secreted proteins to analyse large numbers of protein samples in cell-based assays for the discovery of protein therapeutics. The procedure is generic and capable of 96 parallel purifications and compatible, in both yield and purity, with a wide assay range. By optimising expression and purification steps as well as using novel hardware, in particular a chromatography press capable to purify target proteins from viscous media, we exemplify the process for the generation of single-chain Fv antibody fragments (scFv) and the purification of full-length IgG. The described process can operate robustly with a throughput of over 2,000 samples per month.