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1.
Cell Tissue Bank ; 2023 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-37624485

RESUMEN

With the present paper, the Working Group on Cells, Tissues and Organs and other experts of the Superior Health Council of Belgium aimed to provide stakeholders in material of human origin with advice on critical aspects of serological and nucleic acid test (NAT) testing, to improve virological safety of cell- and tissue and organ donation. The current paper focusses on a number of preanalytical variables which can be critical for any medical biology examination: (1) sampling related variables (type of samples, collection of the samples, volume of the sample, choice of specific tubes, identification of tubes), (2) variables related to transport, storage and processing of blood samples (transport, centrifugation and haemolysis, storage before and after centrifugation, use of serum versus plasma), (3) variables related to dilution (haemodilution, pooling of samples), and (4) test dependent variables (available tests and validation). Depending on the type of donor (deceased donor (heart-beating or non-heart beating) versus living donor (allogeneic, related, autologous), and the type of donated human material (cells, tissue or organs) additional factors can play a role: pre- and post-mortem sampling, conditions of sampling (e.g. morgue), haemodilution, possibility of retesting.

2.
Neuro Oncol ; 23(2): 240-250, 2021 02 25.
Artículo en Inglés | MEDLINE | ID: mdl-33130898

RESUMEN

BACKGROUND: Histologically classified glioblastomas (GBM) can have different clinical behavior and response to therapy, for which molecular subclassifications have been proposed. We evaluated the relationship of epigenetic GBM subgroups with immune cell infiltrations, systemic immune changes during radiochemotherapy, and clinical outcome. METHODS: 450K genome-wide DNA methylation was assessed on tumor tissue from 93 patients with newly diagnosed GBM, treated with standard radiochemotherapy and experimental immunotherapy. Tumor infiltration of T cells, myeloid cells, and Programmed cell death protein 1 (PD-1) expression were evaluated. Circulating immune cell populations and selected cytokines were assessed on blood samples taken before and after radiochemotherapy. RESULTS: Forty-two tumors had a mesenchymal, 27 a receptor tyrosine kinase (RTK) II, 17 RTK I, and 7 an isocitrate dehydrogenase (IDH) DNA methylation pattern. Mesenchymal tumors had the highest amount of tumor-infiltrating CD3+ and CD8+ T cells and IDH tumors the lowest. There were no significant differences for CD68+ cells, FoxP3+ cells, and PD-1 expression between groups. Systemically, there was a relative increase of CD8+ T cells and CD8+ PD-1 expression and a relative decrease of CD4+ T cells after radiochemotherapy in all subgroups except IDH tumors. Overall survival was the longest in the IDH group (median 36 mo), intermediate in RTK II tumors (27 mo), and significantly lower in mesenchymal and RTK I groups (15.5 and 16 mo, respectively). CONCLUSIONS: Methylation based stratification of GBM is related to T-cell infiltration and survival, with IDH and mesenchymal tumors representing both ends of a spectrum. DNA methylation profiles could be useful in stratifying patients for immunotherapy trials.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Metilación de ADN , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Isocitrato Deshidrogenasa/genética , Regiones Promotoras Genéticas
3.
Cell Metab ; 31(4): 862-877.e14, 2020 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-32268117

RESUMEN

Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cell-cycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets.


Asunto(s)
Células Endoteliales/metabolismo , Neoplasias Pulmonares/metabolismo , Degeneración Macular/metabolismo , Neovascularización Patológica/metabolismo , Transcriptoma , Animales , Células Endoteliales/citología , Células Endoteliales/patología , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia de ARN , Análisis de la Célula Individual
4.
Front Med (Lausanne) ; 6: 230, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31681784

RESUMEN

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition affecting mainly the gastro-intestinal tract with two main entities: Crohn's disease (CD) and ulcerative colitis (UC). Although the exact mechanisms underlying the initial development of IBD are not fully understood, it is believed that an abnormal immune response is elicited against the intestinal microbiota in genetically predisposed individuals. Crucial elements of the etiopathogenesis have been elucidated by research using human biological materials. The estimated prevalence of IBD is 0.5% in the Western world. Although incidence rates are increasing, both conditions are not "common" in general terms mandating a multicentric approach. Biological material from numerous Belgian patients have been collected over time in a number of university hospitals in Belgium (UH Ghent: 800 CD patients, 350 UC patients, 600 normal controls; UH Leuven: 2,600 CD patients, 1,380 UC patients, 98 IC/IBDU patients, 6,260 normal controls). Within the setting of the Flemish Center Medical Innovation (CMI) initiative and later on the Flemish biobank network a prospective study was set-up across three Belgian IBD centers (University Hospitals Brussels, Ghent, and Leuven). Human biological materials and data have been collected prospectively from newly diagnosed CD and UC patients. The analyses hereof have generated new insights which have been published in the most renowned journals. The approach of well-thought off, multi-centric, structured, and systematic biobanking has proven to be a success-story and thus a textbook case for multi-centric banking of human biological materials. This story is being told in this article.

5.
Front Med (Lausanne) ; 6: 141, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31294024

RESUMEN

From as early as 2005, different guidelines and quality standards covering biobank activities and sample handling methods have been developed to improve and guarantee the reproducibility of biomarker research. Ten years on, the BBMRI.be Quality working group wanted to gauge the current situation of these aspects in the biobanks of the BBMRI.be network. To this end, two online surveys were launched (fall 2017 and fall 2018) to the biobank quality managers in the BBMRI.be network to determine the status and setup of their current quality management system (QMS) and how their QMS and related practices have evolved over a 14 month time period. All biobanks addressed by the two surveys provided a complete response (12 and 13, respectively). A QMS was implemented in 85% of biobanks, with 4 standards emerging as primary basis. Supplementary guidelines were used, with a strong preference for the ISBER best practices for biobanks. The Standard Preanalytical Code-an indicator of the preanalytical lifecycle of a biospecimen impacting the downstream analysis results-was already implemented in 50% of the biobanks while the other half intends future implementation. To assess and maintain the quality of their QMS, 62% of biobanks used self-assessment tools and 71% participated in proficiency testing schemes. The majority of biobanks had implemented procedures for general and biobank specific activities. However, policies regarding the business and sustainability aspect of biobank were only implemented in a limited number of biobanks. A clear desire for a peer-review audit was expressed by 69% of biobanks, with over half of them intending to implement the recently published biobank standard ISO20387. Overall, the biobanks of the BBMRI.be network have actively implemented a solid quality approach in their practices. The implementation of ISO 20387 may bring further professionalization of activities. Based on the needs expressed in this survey, the Quality working group will be setting up an audit program for the BBMRI.be biobanks, to enhance, harmonize and streamline their activities. On the whole, the biobanks in the BBMRI.be network are able to substantially contribute to translational research, as a primary facilitator guaranteeing high quality standards and reproducibility.

6.
Front Med (Lausanne) ; 6: 309, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31998730

RESUMEN

The low reproducibility of biomarker research is a major holdback for the translation of research results to the bedside. Sample integrity has been identified as a key factor that contributes to improved reproducibility. The key mission of biobanks is to ensure that all activities and materials are managed according to standardized procedures and best practices to ensure and preserve sample integrity. When handling large numbers of biospecimens automation of sample handling and storage is often the method of choice to maintain and improve sample integrity. In December 2013, the centralized Biobank of the University Hospitals and the Catholic University of Leuven (UZ KU Leuven) decided to implement automated systems for sample storage and retrieval, one for storage at -20°C and one for storage at -80°C. Here we describe the extensive process of installation, acceptance, validation, and implementation of these two systems. Overall it took about 4 years to effectively take the systems into production. Multiple issues resulted in the delayed implementation, with labware change, quality of the initial installation, and misunderstanding of biobank concerns being the most impacting. Significant effort in terms of time and resources from both the automated store supplier as well as the biobank itself was needed to achieve a successful implementation. Within 15 months of actual integration in the biobank workflow, over 63 k samples were placed into the systems. Actual hands-on sample handling and retrieval times were substantially reduced, although this implied the shift of dedicated personnel time from the researchers' laboratories to the biobank. With the successful implementation of automated frozen sample storage systems, the centralized UZ KU Leuven Biobank is now also able to efficiently support large-scale translational research.

8.
Cell Tissue Bank ; 19(4): 681-695, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30159824

RESUMEN

This paper on the biological tests carried out on serum/plasma samples from donors of human body material (HBM) is the result of a project of the working Group of Superior Health Council of Belgium formed with experts in the field of HBM and infectious serology. Indeed, uncertainty about the interpretation of biological test results currently leads to the sometimes unjustified cancelling of planned donations or the rejection of harvested HBM, whilst more sophisticated diagnostic algorithms would still allow the use of organs or HBM that would otherwise have been rejected. NAT tests will not be discussed in this publication. In the first part some general aspects as the need for a formal agreement between the Tissue Establishment l and the laboratory responsible for the biological testing, but also some specifications regarding testing material, the choice of additional biological tests, and some general aspects concerning interpretation and reporting are discussed. In a second part, detailed information and recommendations concerning the interpretation are presented for each of the mandatory tests (human immunodeficiency virus, hepatitis B virus, hepatitis C virus and syphilis) is presented. A number of not mandatory, but regularly used optional serological tests (e.g. for the detection of antibodies to Toxoplasma gondii, Epstein-Barr virus, human T cell leukemia virus and cytomegalovirus) are also extensively discussed. Although the project was meant to provide clarification and recommendations concerning the Belgian legislation, the majority of recommendations are also applicable to testing of donors of tissues and cells in other (European) countries.


Asunto(s)
Bioensayo/métodos , Cuerpo Humano , Suero/metabolismo , Donantes de Tejidos , Trasplante , Anticuerpos Antivirales/inmunología , Bélgica , Humanos , ARN Viral/análisis , Sífilis/sangre , Sífilis/diagnóstico , Virosis/sangre , Virosis/diagnóstico
9.
Acta Chir Belg ; 117(3): 149-156, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27931166

RESUMEN

INTRODUCTION: Decompressive craniectomy can be a life-saving procedure. Later reconstruction of the skull using the stored bone flap ("cranioplasty") is often associated with complications. These complications require new procedures and often result in the reconstruction of the skull using an expensive patient-specific cranial implant. PATIENTS & METHODS: All adult patients who underwent cranioplasty after decompressive craniectomy in the last 10 years in our center were included (74 patients). Bone flap size, duration of the procedure, age, and other clinical parameters were included in our analysis. RESULTS: 29.7% of our patients who received in the first place an autologous cranioplasty developed a complication which necessitated removal of the bone flap and the implantation of a custom-made implant. Descriptive statistics demonstrate a significantly higher amount of complications in younger patients (20-40 years, p = 0.027). We also saw a trend toward lower complications when bone flaps were stored according to a biobank protocol (p = 0.075). CONCLUSIONS: Cranioplasty using the stored bone flap after decompressive craniectomy is associated with a high percentage of complications. Selecting patients at risk could possibly indicate cases where an immediate custom-made implant technique would be required.


Asunto(s)
Craniectomía Descompresiva/efectos adversos , Procedimientos de Cirugía Plástica/efectos adversos , Complicaciones Posoperatorias/epidemiología , Cráneo/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Prótesis e Implantes , Estudios Retrospectivos , Factores de Riesgo , Colgajos Quirúrgicos , Resultado del Tratamiento , Adulto Joven
10.
BMC Med Ethics ; 17: 15, 2016 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-26926004

RESUMEN

BACKGROUND: Balancing the rights and obligations of custodians and applicants in relation to access to biobanks is of utmost importance to guarantee trust and confidence. This study aimed to reveal which issues divide different stakeholders in an attempt to determine the rights and/or obligations held on human biological materials (HBM) and data. METHODS: Twenty-eight informants in the Benelux and Scandinavia were interviewed in order to capture the perspectives of experts and stakeholders in relation to the rights and obligations held by custodians and applicants with respect to access to HBM and data. RESULTS: There was no consensus among the informants on whether the custodian of a biobank should decide upon the scientific merits and the utility of an access request. Nearly all informants agreed that a new request or an amendment to the initial request has to be submitted when an applicant wants to use leftover HBM in a new or follow-up project. Several informants felt that it might be justified to charge higher access fees to external or industrial applicants that did not contribute (directly or indirectly) to the collection of HBM and data. Most informants agreed that a custodian of a biobank could request the sharing and return of research results. It was furthermore argued that some of the benefits of research projects should be fed back into biobanks. CONCLUSIONS: The interviews revealed a rather complex web of rights and obligations allocated to the custodian and the applicant in relation to access to HBM and data stored in biobanks. Some rights and obligations are negotiated on a case-by-case basis, while others are stipulated in access arrangements. We did find a consensus on the attribution of certain general rights to the custodians and the applicant.


Asunto(s)
Acceso a la Información/ética , Bancos de Muestras Biológicas/ética , Investigación Biomédica/ética , Responsabilidad Social , Humanos , Consentimiento Informado , Investigación Cualitativa , Países Escandinavos y Nórdicos , Confianza
11.
Biopreserv Biobank ; 12(6): 415-22, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25496154

RESUMEN

PURPOSE: The current study investigates whether access arrangements relevant for biobanking contain clear information on key access conditions. It furthermore assesses the extent to which these access conditions are harmonized across biobank initiatives. METHODS: A comparative analysis was conducted of access arrangements developed by 26 organizations, 36 biobank networks, and 20 biobanks worldwide. RESULTS: The study demonstrates a lack of clear information on 21 key access conditions relevant for biobanking. Furthermore, it confirms that the harmonization across biobank initiatives is limited. CONCLUSION: Many biobank initiatives need to be more transparent on how they apply the studied access conditions.


Asunto(s)
Bancos de Muestras Biológicas
12.
Cell Tissue Bank ; 14(4): 525-60, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24052113

RESUMEN

The transplantation of conventional human cell and tissue grafts, such as heart valve replacements and skin for severely burnt patients, has saved many lives over the last decades. The late eighties saw the emergence of tissue engineering with the focus on the development of biological substitutes that restore or improve tissue function. In the nineties, at the height of the tissue engineering hype, industry incited policymakers to create a European regulatory environment, which would facilitate the emergence of a strong single market for tissue engineered products and their starting materials (human cells and tissues). In this paper we analyze the elaboration process of this new European Union (EU) human cell and tissue product regulatory regime-i.e. the EU Cell and Tissue Directives (EUCTDs) and the Advanced Therapy Medicinal Product (ATMP) Regulation and evaluate its impact on Member States' health care systems. We demonstrate that the successful lobbying on key areas of regulatory and policy processes by industry, in congruence with Europe's risk aversion and urge to promote growth and jobs, led to excessively business oriented legislation. Expensive industry oriented requirements were introduced and contentious social and ethical issues were excluded. We found indications that this new EU safety and health legislation will adversely impact Member States' health care systems; since 30 December 2012 (the end of the ATMP transitional period) there is a clear threat to the sustainability of some lifesaving and established ATMPs that were provided by public health institutions and small and medium-sized enterprises under the frame of the EUCTDs. In the light of the current economic crisis it is not clear how social security systems will cope with the inflation of costs associated with this new regulatory regime and how priorities will be set with regard to reimbursement decisions. We argue that the ATMP Regulation should urgently be revised to focus on delivering affordable therapies to all who are in need of them and this without necessarily going to the market. The most rapid and elegant way to achieve this would be for the European Commission to publish an interpretative document on "placing on the market of ATMPs," which keeps tailor-made and niche ATMPs outside of the scope of the medicinal product regulation.


Asunto(s)
Trasplante de Células/economía , Trasplante de Células/legislación & jurisprudencia , Comercio , Atención a la Salud/legislación & jurisprudencia , Unión Europea , Legislación como Asunto , Trasplantes/economía , Trasplante de Células/ética , Atención a la Salud/economía , Atención a la Salud/ética , Industria Farmacéutica/legislación & jurisprudencia , Humanos , Legislación como Asunto/ética , Políticas
13.
J Biol Chem ; 288(38): 27200-27207, 2013 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-23940028

RESUMEN

Streptozotocin (STZ) is widely used as diabetogenic agent in animal models for diabetic nephropathy (DN). However, it is also directly cytotoxic to kidneys, making it difficult to distinguish between DN-related and STZ-induced nephropathy. Therefore, an improved protocol to generate mice for DN studies, with a quick and robust achievement of the diabetic state, without direct kidney toxicity is required. To investigate the mechanism leading to STZ-induced nephropathy, kidney damage was induced with a high dose of STZ. This resulted in delayed gastric emptying, at least partially caused by impaired desacyl ghrelin clearance. STZ uptake in the kidneys is to a large extent mediated by the sodium/glucose cotransporters (Sglts) because the Sglt inhibitor phlorizin could reduce STZ uptake in the kidneys. Consequently, the direct toxic effects in the kidney and the gastric dilatation were resolved without interfering with the ß-cell toxicity. Furthermore, pancreatic STZ uptake was increased, hereby decreasing the threshold for ß-cell toxicity, allowing for single low non-nephrotoxic STZ doses (70 mg/kg). In conclusion, this study provides novel insights into the mechanism of STZ toxicity in kidneys and suggests a more efficient regime to induce DN with little or no toxic side effects.


Asunto(s)
Nefropatías Diabéticas/prevención & control , Células Secretoras de Insulina/metabolismo , Riñón/metabolismo , Florizina/farmacología , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Animales , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/inducido químicamente , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Relación Dosis-Respuesta a Droga , Células Secretoras de Insulina/patología , Riñón/lesiones , Riñón/patología , Masculino , Ratones , Transportador 1 de Sodio-Glucosa/metabolismo , Estreptozocina/efectos adversos , Estreptozocina/farmacocinética , Estreptozocina/farmacología
14.
Cell Tissue Bank ; 13(3): 487-98, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22718427

RESUMEN

With this analysis we would like to raise some issues that emerge as a result of recent evolutions in the burgeoning field of human cells, tissues, and cellular and tissue-based product (HCT/P) transplantation, and this in the light of the current EU regulatory framework. This paper is intended as an open letter addressed to the EU policy makers, who will be charged with the review and revision of the current legislation. We propose some urgent corrections or additions to cope with the rapid advances in biomedical science, an extensive commercialization of HCT/Ps, and the growing expectation of the general public regarding the ethical use of altruistically donated cells and tissues. Without a sound wake-up call, the diverging interests of this newly established 'healthcare' industry and the wellbeing of humanity will likely lead to totally unacceptable situations, like some of which we are reporting here.


Asunto(s)
Preparaciones Farmacéuticas/economía , Bancos de Tejidos/economía , Trasplante Homólogo/economía , Unión Europea , Humanos , Internacionalidad , Transferencia de Tecnología
15.
Cell Tissue Bank ; 13(1): 1-7, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21360142

RESUMEN

Human donor skin allografts are suitable and much used temporary biological (burn) wound dressings. They prepare the excised wound bed for final autografting and form an excellent substrate for revascularisation and for the formation of granulation tissue. Two preservation methods, glycerol preservation and cryopreservation, are commonly used by tissue banks for the long-term storage of skin grafts. The burn surgeons of the Queen Astrid Military Hospital preferentially use partly viable cryopreserved skin allografts. After mandatory 14-day bacterial and mycological culture, however, approximately 15% of the cryopreserved skin allografts cannot be released from quarantine because of positive culture. To maximize the use of our scarce and precious donor skin, we developed a glycerolisation-based recovery method for these culture positive cryopreserved allografts. The inactivation and preservation method, described in this paper, allowed for an efficient inactivation of the colonising bacteria and fungi, with the exception of spore-formers, and did not influence the structural and functional aspects of the skin allografts.


Asunto(s)
Bacterias/efectos de los fármacos , Criopreservación/métodos , Hongos/efectos de los fármacos , Glicerol/farmacología , Trasplante de Piel , Piel/efectos de los fármacos , Piel/microbiología , Humanos , Donantes de Tejidos , Trasplante Homólogo
16.
Cell Transplant ; 20(8): 1285-97, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21294959

RESUMEN

Pleomorphic adenoma gene-like 1 (PLAGL1) has been linked to transient neonatal diabetes mellitus. Here, we investigated the role of the related pleomorphic adenoma gene 1 (PLAG1) in glucose homeostasis. PLAG1 transgenic mice in which expression of the PLAG1 transgene can be targeted to different organs by Cre-mediated modulation were crossed with Pdx1-Cre or Ngn3-Cre mice, resulting in double transgenic P1-Pdx1Cre or P1-Ngn3Cre mice, respectively. P1-Pdx1Cre and P1-Ngn3Cre mice developed hyperplasia of pancreatic islets due to increased ß- and δ- but not α-cell proliferation. In young P1-Pdx1Cre mice (less than 15 weeks) there was a balanced increase in the pancreatic content of insulin and somatostatin, which was associated with normoglycemia. In older P1-Pdx1Cre mice the pancreatic somatostatin content far exceeded that of insulin, leading to the progressive development of severe hypoglycemia beyond 30 weeks. In contrast, in older P1-Ngn3Cre mice the relative increase of the pancreatic insulin content exceeded that of somatostatin and these mice remained normoglycemic. In conclusion, forced expression of PLAG1 under the control of the Pdx1 or Ngn3 promoter in murine pancreas induces different degrees of endocrine hormone imbalances within the pancreas, which is associated with hypoglycemia in P1-Pdx1Cre mice but not P1-Ngn3Cre mice. These results suggest that once stem cell-derived islet transplantations become possible, the appropriate balance between different hormone-producing cells will need to be preserved to prevent deregulated glucose metabolism.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas de Unión al ADN/metabolismo , Glucosa/metabolismo , Proteínas de Homeodominio/metabolismo , Integrasas/metabolismo , Islotes Pancreáticos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Hormonas Pancreáticas/metabolismo , Transactivadores/metabolismo , Animales , Proliferación Celular , Glucagón , Prueba de Tolerancia a la Glucosa , Homeostasis , Hiperplasia , Hipoglucemia/patología , Insulina , Islotes Pancreáticos/patología , Islotes Pancreáticos/ultraestructura , Trasplante de Islotes Pancreáticos , Ratones , Ratones Transgénicos , Tamaño de los Órganos , Somatostatina , Factores de Tiempo
17.
Ann Surg Oncol ; 18(3): 684-90, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20842458

RESUMEN

BACKGROUND: Neoadjuvant chemoradiotherapy is the standard of care for patients with locally advanced mid and distal rectal cancer. Tumor regression is variable, and this study was designed to evaluate the pathological response and impact on long-term disease control in responders and nonresponders. METHODS: A total of 303 consecutive patients with cStage II and III mid and distal rectal adenocarcinoma were identified. The mean age was 64 years and 63% were men. Patients received neoadjuvant chemoradiotherapy (45 Gy) with a continuous infusion of 5-fluorouracil. Total mesorectal excision (TME) was performed after an interval of 6-8 weeks. Tumors were stratified as responders (ypT0 or ypT1) and nonresponders (≥ypT3). All ypT2 were separately categorized. RESULTS: Tumors of 84 patients were classified as responders (27.5%) versus nonresponders in 144 patients (47.5%). Pathological tumor stage was ypT2 in 75 patients (25%). After a median follow-up of 55 months, the 5-year cancer-specific survival rate was 98% and the disease-free survival rate was 91% in responders versus 82% (P < 0.0025) and 60% (P < 0.0001), respectively, for the nonresponders. CONCLUSIONS: After neoadjuvant chemoradiotherapy and TME surgery for locally advanced rectal cancer and complete or near-complete pathological tumor response oncological outcome is very good. These results set the standards for a rectum-sparing strategy.


Asunto(s)
Adenocarcinoma/terapia , Antimetabolitos Antineoplásicos/uso terapéutico , Fluorouracilo/uso terapéutico , Terapia Neoadyuvante , Neoplasias del Recto/terapia , Adenocarcinoma/secundario , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Terapia Combinada , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Cuidados Preoperatorios , Estudios Prospectivos , Radioterapia Adyuvante , Neoplasias del Recto/patología , Inducción de Remisión , Tasa de Supervivencia , Resultado del Tratamiento , Adulto Joven
20.
Diabetes ; 59(8): 1957-65, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20522588

RESUMEN

OBJECTIVE: It is believed that an organism remains normoglycemic despite an increase in the beta-cell mass because of decreased insulin production by beta-cells on a per-cell basis. However, some transgenic mouse models with beta-cell hyperplasia suggest that insulin production remains excessive and that normoglycemia is maintained by insulin resistance. METHODS: Here, we investigated the effect of an increased beta-cell mass on glycemia and insulin resistance by grafting excess normal islets in normoglycemic mice, as well as using targeted PLAG1 expression in beta-cells, which leads to beta-cell expansion. RESULTS: In both models, fasting plasma insulin levels were increased, even though animals were normoglycemic. After an intraperitoneal glucose tolerance test, plasma insulin levels increased, which was associated with improved glucose clearing. Under these conditions, normoglycemia is maintained by hepatic insulin resistance as demonstrated by hyperinsulinemic euglycemic clamp experiments. CONCLUSIONS: In conclusion, we demonstrate that when excess beta-cells are grafted, insulin production on a per beta-cell basis is not sufficiently decreased, leading to hyperinsulinemia and hepatic insulin resistance. This observation might be important for the design of stem cell-based islet replacement therapies.


Asunto(s)
Glucemia/metabolismo , Proteínas de Unión al ADN/genética , Hiperinsulinismo/genética , Resistencia a la Insulina/genética , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/trasplante , Trasplante de Islotes Pancreáticos/fisiología , Animales , División Celular , Regulación de la Expresión Génica , Glucagón/sangre , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Homeostasis , Insulina/sangre , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
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