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1.
Bioinformatics ; 40(5)2024 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-38741151

RESUMEN

MOTIVATION: Systems biology aims to better understand living systems through mathematical modelling of experimental and clinical data. A pervasive challenge in quantitative dynamical modelling is the integration of time series measurements, which often have high variability and low sampling resolution. Approaches are required to utilize such information while consistently handling uncertainties. RESULTS: We present BayModTS (Bayesian modelling of time series data), a new FAIR (findable, accessible, interoperable, and reusable) workflow for processing and analysing sparse and highly variable time series data. BayModTS consistently transfers uncertainties from data to model predictions, including process knowledge via parameterized models. Further, credible differences in the dynamics of different conditions can be identified by filtering noise. To demonstrate the power and versatility of BayModTS, we applied it to three hepatic datasets gathered from three different species and with different measurement techniques: (i) blood perfusion measurements by magnetic resonance imaging in rat livers after portal vein ligation, (ii) pharmacokinetic time series of different drugs in normal and steatotic mice, and (iii) CT-based volumetric assessment of human liver remnants after clinical liver resection. AVAILABILITY AND IMPLEMENTATION: The BayModTS codebase is available on GitHub at https://github.com/Systems-Theory-in-Systems-Biology/BayModTS. The repository contains a Python script for the executable BayModTS workflow and a widely applicable SBML (systems biology markup language) model for retarded transient functions. In addition, all examples from the paper are included in the repository. Data and code of the application examples are stored on DaRUS: https://doi.org/10.18419/darus-3876. The raw MRI ROI voxel data were uploaded to DaRUS: https://doi.org/10.18419/darus-3878. The steatosis metabolite data are published on FairdomHub: 10.15490/fairdomhub.1.study.1070.1.


Asunto(s)
Teorema de Bayes , Flujo de Trabajo , Animales , Ratas , Humanos , Ratones , Biología de Sistemas/métodos , Hígado/metabolismo , Programas Informáticos , Imagen por Resonancia Magnética/métodos
2.
Liver Int ; 43(1): 34-48, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35986903

RESUMEN

BACKGROUND AND AIMS: Chronic liver disease (CLD) patients and liver transplant (LT) recipients have an increased risk of morbidity and mortality from coronavirus disease 2019 (COVID-19). The immunogenicity of COVID-19 vaccines in CLD patients and LT recipients is poorly understood. The present study aimed to evaluate the immunogenicity of COVID-19 vaccines in CLD patients and LT recipients. METHODS: We searched electronic databases for eligible studies. Two reviewers independently conducted the literature search, extracted the data and assessed the risk of bias of included studies. The rates of detectable immune response were pooled from single-arm studies. For comparative studies, we compared the rates of detectable immune response between patients and healthy controls. The meta-analysis was conducted using the Stata software with a random-effects model. RESULTS: In total, 19 observational studies involving 4191 participants met the inclusion criteria. The pooled rates of detectable humoral immune response after two doses of COVID-19 vaccination in CLD patients and LT recipients were 95% (95% confidence interval [CI] = 88%-99%) and 66% (95% CI = 57%-74%) respectively. After two doses of vaccination, the humoral immune response rate was similar in CLD patients and healthy controls (risk ratio [RR] = 0.96; 95% CI = 0.90-1.02; p = .14). In contrast, LT recipients had a lower humoral immune response rate after two doses of vaccination than healthy controls (RR = 0.68; 95% CI = 0.59-0.77; p < .01). CONCLUSIONS: Our meta-analysis demonstrated that COVID-19 vaccination induced strong humoral immune responses in CLD patients but poor humoral immune responses in LT recipients.


Asunto(s)
COVID-19 , Hepatopatías , Trasplante de Hígado , Humanos , Vacunas contra la COVID-19 , COVID-19/prevención & control , Bases de Datos Factuales , Receptores de Trasplantes , Anticuerpos Antivirales
3.
4.
Mol Syst Biol ; 16(2): e8985, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32090478

RESUMEN

The mechanisms of organ size control remain poorly understood. A key question is how cells collectively sense the overall status of a tissue. We addressed this problem focusing on mouse liver regeneration. Using digital tissue reconstruction and quantitative image analysis, we found that the apical surface of hepatocytes forming the bile canalicular network expands concomitant with an increase in F-actin and phospho-myosin, to compensate an overload of bile acids. These changes are sensed by the Hippo transcriptional co-activator YAP, which localizes to apical F-actin-rich regions and translocates to the nucleus in dependence of the integrity of the actin cytoskeleton. This mechanism tolerates moderate bile acid fluctuations under tissue homeostasis, but activates YAP in response to sustained bile acid overload. Using an integrated biophysical-biochemical model of bile pressure and Hippo signaling, we explained this behavior by the existence of a mechano-sensory mechanism that activates YAP in a switch-like manner. We propose that the apical surface of hepatocytes acts as a self-regulatory mechano-sensory system that responds to critical levels of bile acids as readout of tissue status.


Asunto(s)
Citoesqueleto de Actina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Ácidos y Sales Biliares/metabolismo , Canalículos Biliares/metabolismo , Proteínas de Ciclo Celular/metabolismo , Hepatocitos/citología , Actinas/metabolismo , Animales , Núcleo Celular/metabolismo , Células Cultivadas , Hepatocitos/metabolismo , Regeneración Hepática , Masculino , Mecanotransducción Celular , Ratones , Miosinas/metabolismo , Tamaño de los Órganos , Transporte de Proteínas , Biología de Sistemas , Proteínas Señalizadoras YAP
5.
FASEB J ; 33(2): 3063-3073, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30383439

RESUMEN

Aging is often associated with a decreased autophagic activity that contributes to the high sensitivity of aged livers to ischemia reperfusion injury (IRI). Blood from young animals can positively affect aged animals. This study was designed to evaluate the effect of young plasma in a model of liver IRI in aged rats. Aged rats were treated with pooled plasma collected from young rats before ischemia. Administration of young plasma restored aging-induced suppression in hepatic autophagic activity and reduced liver IRI. Inhibition of the young-plasma-restored autophagic activity abrogated the beneficial effect of young plasma against liver IRI. Similarly, young serum restored autophagic activity and reduced cellular injury after hypoxia/reoxygenation (H/R) in primary old rat hepatocytes. Mechanistic studies showed thatadministration of young plasma increased AMPK phosphorylation and led to unc-51-like autophagy activating kinase (ULK)1 activation. Furthermore, AMPK-inhibition abrogated the young serum-induced ULK1 activation and autophagic activity and diminished the protective action of young serum against H/R injury in primary old rat hepatocytes, whereas AMPK-activation potentiated the effects of young serum. Young plasma could restore age-impaired autophagy, at least in part, via AMPK/ULK1 signaling. Restoration of age-impaired autophagic activity may be a critical contributing mechanism to young-plasma-afforded protection against liver IRI in aged rats.-Liu, A., Yang, J., Hu, Q., Dirsch, O., Dahmen, U., Zhang, C., Gewirtz, D. A., Fang, H., Sun, J. Young plasma attenuates age-dependent liver ischemia reperfusion injury.


Asunto(s)
Envejecimiento , Autofagia , Hepatopatías/prevención & control , Plasma/química , Daño por Reperfusión/prevención & control , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , Plasma/metabolismo , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal
6.
Sensors (Basel) ; 20(24)2020 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-33321713

RESUMEN

Decellularized tissue is an important source for biological tissue engineering. Evaluation of the quality of decellularized tissue is performed using scanned images of hematoxylin-eosin stained (H&E) tissue sections and is usually dependent on the observer. The first step in creating a tool for the assessment of the quality of the liver scaffold without observer bias is the automatic segmentation of the whole slide image into three classes: the background, intralobular area, and extralobular area. Such segmentation enables to perform the texture analysis in the intralobular area of the liver scaffold, which is crucial part in the recellularization procedure. Existing semi-automatic methods for general segmentation (i.e., thresholding, watershed, etc.) do not meet the quality requirements. Moreover, there are no methods available to solve this task automatically. Given the low amount of training data, we proposed a two-stage method. The first stage is based on classification of simple hand-crafted descriptors of the pixels and their neighborhoods. This method is trained on partially annotated data. Its outputs are used for training of the second-stage approach, which is based on a convolutional neural network (CNN). Our architecture inspired by U-Net reaches very promising results, despite a very low amount of the training data. We provide qualitative and quantitative data for both stages. With the best training setup, we reach 90.70% recognition accuracy.


Asunto(s)
Procesamiento de Imagen Asistido por Computador , Hígado , Semántica , Hígado/diagnóstico por imagen , Redes Neurales de la Computación
7.
Int J Mol Sci ; 21(10)2020 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-32443776

RESUMEN

Age is one of the key risk factors to develop malignant diseases leading to a high incidence of hepatic tumors in the elderly population. The only curative treatment for hepatic tumors is surgical removal, which initiates liver regeneration. However, liver regeneration is impaired with aging, leading to an increased surgical risk for the elderly patient. Due to the increased risk, those patients are potentially excluded from curative surgery. Aging impairs autophagy via lipofuscin accumulation and inhibition of autophagosome formation. Autophagy is a recycling mechanism for eukaryotic cells to maintain homeostasis. Its principal function is to degrade endogenous bio-macromolecules for recycling cellular substances. A number of recent studies have shown that the reduced regenerative capacity of the aged remnant liver can be restored by promoting autophagy. Autophagy can be activated via multiple mTOR-dependent and mTOR-independent pathways. However, inducing autophagy through the mTOR-dependent pathway alone severely impairs liver regeneration. In contrast, recent observations suggest that inducing autophagy via mTOR-independent pathways might be promising in promoting liver regeneration. Conclusion: Activation of autophagy via an mTOR-independent autophagy inducer is a potential therapy for promoting liver regeneration, especially in the elderly patients at risk.


Asunto(s)
Envejecimiento/patología , Autofagia , Regeneración Hepática , Hígado/metabolismo , Envejecimiento/metabolismo , Animales , Humanos , Hígado/crecimiento & desarrollo , Hígado/fisiología
8.
FASEB J ; 32(9): 5186-5198, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29913561

RESUMEN

Growth differentiation factor 11 (GDF11) has been implicated in a variety of aging conditions and the regulation of organ regeneration after injury; however, the role of GDF11 in liver ischemia reperfusion injury (IRI) is unknown. The aim of the current study was to investigate the possible role of GDF11 in liver IRI. We investigated the effects of GDF11 in liver IRI in both young (3 mo) and old (22 mo) mice in vivo, and in primary young and old mouse hepatocytes in vitro. Both serum and hepatic GDF11 protein expression levels increased with age and after IRI. Treatment with recombinant GDF11 significantly increased IRI-induced elevations of serum aminotransferase levels, worsened the histologic status of livers, and impaired liver regeneration. In contrast, inhibition of GDF11 activity with neutralizing Abs significantly decreased liver injury and improved liver regeneration after IRI. In vitro, treatment with recombinant GDF11 significantly delayed cell proliferation in cultured hepatocytes that were subjected to hypoxia/reoxygenation insult. Moreover, suppression of cell-cycle progression may be a key mechanism by which GDF11 inhibited hepatocyte regeneration. Collectively, rather than acting as a rejuvenating agent, GDF11 worsens hepatocellular injury and impairs liver regeneration after IRI.-Liu, A., Dong, W., Peng, J., Dirsch, O., Dahmen, U., Fang, H., Zhang, C., Sun, J. Growth differentiation factor 11 worsens hepatocellular injury and liver regeneration after liver ischemia reperfusion injury.


Asunto(s)
Proteínas Morfogenéticas Óseas/metabolismo , Factores de Diferenciación de Crecimiento/metabolismo , Hepatocitos/metabolismo , Regeneración Hepática/fisiología , Hígado/metabolismo , Daño por Reperfusión/metabolismo , Animales , Ciclo Celular/fisiología , Proliferación Celular/fisiología , Células Cultivadas , Hepatocitos/patología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión/patología
9.
BMC Med Educ ; 19(1): 146, 2019 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-31092236

RESUMEN

BACKGROUND: Medical schools globally now use objective structured clinical examinations (OSCEs) for assessing a student's clinical performance. In Germany, almost all of the 36 medical schools have incorporated at least one summative OSCE into their clinical curriculum. This nationwide study aimed to examine whether the introduction of OSCEs shifted studying time. The authors explored what resources were important for studying in preparation for OSCEs, how much time students spent studying, and how they performed; each compared to traditionally used multiple choice question (MCQ) tests. METHODS: The authors constructed a questionnaire comprising two identical sections, one for each assessment method. Either section contained a list of 12 study resources requesting preferences on a 5-point scale, and two open-ended questions about average studying time and average grades achieved. During springtime of 2015, medical schools in Germany were asked to administer the web-based questionnaire to their students in years 3-6. Statistical analysis compared the responses on the open-ended questions between the OSCE and MCQs using a paired t-test. RESULTS: The sample included 1131 students from 32 German medical schools. Physical examination courses were most important in preparation for OSCEs, followed by class notes/logs and the skills lab. Other activities in clinical settings (e.g. medical clerkships) and collaborative strategies ranked next. Conversely, resources for gathering knowledge (e.g. lectures or textbooks) were of minor importance when studying for OSCEs. Reported studying time was lower for OSCEs compared to MCQ tests. The reported average grade, however, was better on OSCEs. CONCLUSIONS: The study findings suggest that the introduction of OSCEs shifted studying time. When preparing for OSCEs students focus on the acquisition of clinical skills and need less studying time to achieve the expected level of competence/performance, as compared to the MCQ tests.


Asunto(s)
Competencia Clínica/normas , Evaluación Educacional , Facultades de Medicina , Estudiantes de Medicina , Adulto , Análisis de Varianza , Curriculum , Educación de Pregrado en Medicina , Evaluación Educacional/normas , Femenino , Humanos , Masculino , Proyectos Piloto , Encuestas y Cuestionarios , Análisis y Desempeño de Tareas
10.
Zentralbl Chir ; 144(6): 606-613, 2019 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-31826295

RESUMEN

BACKGROUND: Video-based analysis concepts are being is increasingly applied in medical education. These tools are mainly used to obtain information about the individual performance of a candidate and to provide feedback. The present study explores whether video-based analysis of practical skills can also be used for the development of surgical training. METHODS: First, the performance of students in semester 10 (n = 38) in a surgical suture exercise (duration: 3 min) was video-documented. The video material was then analysed using 10 specific criteria. The analysis then served as a basis for the development of error prevention exercises. In the following, the effects of the additional teaching units on the performance in the suture exercise were examined in a pilot study using a two-group comparison. RESULTS: The video sequences were reviewed independently by 2 experts. Typical errors could be observed in the handling of the surgical instruments, the handling of the suture material as well as in the motion sequence. Then, additional teaching units dealing with the identified error areas (handling of the instruments and the suture material) were developed. The results of the two-group comparison (before and after implementation of the new exercises) showed that completing the additional teaching units had a medium effect on the result quality of the suture exercise (Cohen's d = 0.73). CONCLUSION: Video analysis of practical skills seems to be a suitable basis for the development of surgical training. Typical errors can be identified in terms of type and frequency, and preventive exercises can be developed, which have a positive effect on the quality of the results of a practical task.


Asunto(s)
Competencia Clínica , Educación Médica , Humanos , Proyectos Piloto
11.
Zentralbl Chir ; 144(6): 532-535, 2019 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-31067573

RESUMEN

The "Masterplan Medizinstudium 2020" from the German Federal Government should not be underestimated as only one among many announcement. Thus, the Surgical Working Group on Medical Education (CAL) of the German Association of Surgeons (DGCH) comments on the intended measures of the "Masterplan Medizinstudium 2020" and discusses the challenges, consequences and duties arising from the "Masterplan Medizinstudium 2020" for the representatives of the surgical societies and those engaged in surgical undergraduate training.


Asunto(s)
Educación Médica , Alemania , Sociedades Médicas
12.
Zentralbl Chir ; 144(6): 573-579, 2019 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-31842239

RESUMEN

Competency-based medical education is needed in order to meet the requirements of medical care currently and in the future. The basis of this are activity-based learning objectives that are merged in competency-based catalogues. A basis for a core curriculum of undergraduate medical training is the National Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM). Already in 2013, for surgery, the competencies which medical students should have achieved after completing the practical year (PJ) in relation to surgical diseases were defined in the special part of the National Catalogue of Learning Objectives in Surgery (NKLC). In the now amended general part of the NKLC, interdisciplinary competencies were defined and consented from all surgical disciplines, that are relevant for all surgical disciplines and that all representatives from the different surgical disciplines should incorporate in their surgical training. The complete NKLC is now available for faculties, teachers and students for trial (available online: https://www.dgch.de/index.php?id=190&L=528). The guiding principle for the entire development process was to make sure that students gain all competencies they need when starting to work as a medical doctor and therefor to increase patient safety.


Asunto(s)
Educación de Pregrado en Medicina , Facultades de Medicina , Competencia Clínica , Curriculum , Alemania , Humanos , Aprendizaje
13.
BMC Med Educ ; 18(1): 103, 2018 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-29743057

RESUMEN

BACKGROUND: Given the expected increase in those entering retirement, the number of practising physicians is predicted to decrease. Conversely, the number of physicians needed is set to increase, due to higher demands resulting from the increasing average age of the German population. This may cause a deficit in the availability and accessibility of medical care for the population in Germany, as well as in other countries. As such, there needs to be a specific focus on the next generation of physicians. Will they fill the gap in those medical specialties where it is most needed? This study aims to investigate (a) preferences for medical specialties over time and (b) the reasoning behind these preferences among students. METHODS: Over three subsequent years, all medical students from the Jena Faculty of Medicine were repeatedly invited to participate in an online survey. The questionnaire consisted of three parts to explore the students' (1) preferred postgraduate specialty, (2) the reasons for their decision and (3) socio-demographic data. Data analysis was performed using Fisher's exact tests and logistic regression analysis. RESULTS: The number of students completing the questionnaire in a given year ranged from 180 to 320, resulting in a total number of 720 completed questionnaires. Between 40 and 50% of the students preferred internal medicine as postgraduate specialty. About 25% of the students were interested in a surgical specialty. Diagnostics and psychiatric medical fields were preferred by about 10% of all students for each field in each year of the survey. A large percentage (about 18%) of the students remained undecided. The factors influencing the students' specialty preferences were most frequently reconciliation of work and family life, career goals as well as predicted workload. The factors depended on the preferred medical specialty. CONCLUSION: The influencing factors should be taken into account for recruiting prospective residents. Doing so could increase the chance to attract the number of physicians needed to ensure adequate medical care in the field of interest, according to the growing health needs of the population.


Asunto(s)
Selección de Profesión , Especialización/estadística & datos numéricos , Estudiantes de Medicina/psicología , Adulto , Estudios Transversales , Toma de Decisiones , Femenino , Alemania , Humanos , Masculino , Estudios Prospectivos , Encuestas y Cuestionarios , Adulto Joven
14.
Int J Mol Sci ; 19(4)2018 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-29621129

RESUMEN

Multimodal treatment concepts including liver transplantation for hepatocellular carcinoma (HCC), extended resection methods and neoadjuvant chemotherapy for colorectal liver metastasis significantly improve patients’ outcome. However, surgery-induced hepatic ischemia-reperfusion injury (IRI) and chemotherapy-associated hepatotoxicity result in hepatocellular damage and compromised liver function. Activation of common key pathways in ischemic liver and hepatotoxic injury results in oxidative stress, inflammatory responses and apoptosis causing organ damage. Controlling liver damage before and during surgery is essential for the postoperative outcome. Nigella sativa has a long tradition as a natural remedy. In the essential oil, Thymoquinone (TQ) was identified as the main component and responsible for most of the therapeutic effects. Therefore, this systematic review aimed to summarize the hepatoprotective effects of TQ and its potential suitability to improve surgical outcome by reducing surgical ischemic injury and hepatotoxicity of neoadjuvant chemotherapy. The key findings can be summarized as TQ having strong antioxidant, anti-inflammatory, antifibrotic, anti-/proapoptotic and anticarcinogenic effects. Almost no side effects were reported irrespective of a large dose range, suggesting a wide therapeutic window. These results give rise to the expectation that TQ could evolve to a novel powerful drug to reduce hepatic injury.


Asunto(s)
Benzoquinonas/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Animales , Benzoquinonas/química , Humanos , Nigella sativa/química , Estrés Oxidativo/efectos de los fármacos
15.
Liver Transpl ; 23(4): 510-526, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28133883

RESUMEN

Carbon monoxide (CO) exerts protective effects on hepatic ischemia/reperfusion injury (IRI), but the underlying molecular mechanisms are not fully understood. High-mobility group box 1 (HMGB1) is an important mediator of injury and inflammation in hepatic IRI. Here, we investigated whether CO could attenuate hepatic IRI via inhibition of HMGB1 release, particularly through sirtuin 1 (SIRT1). CO was released by treatment with carbon monoxide-releasing molecule (CORM)-2. CORM-2-delivered CO ameliorated hepatic IRI, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory responses, and less severe ischemia/reperfusion-associated histopathologic changes. Treatment with CORM-2 significantly inhibited IRI-induced HMGB1 translocation and release. SIRT1 expression was increased by CORM-2 pretreatment. When CORM-2-induced SIRT1 expression was inhibited using EX527, HMGB1 translocation and release were increased and hepatic IRI was worsened, whereas SIRT1 activation by resveratrol reversed this trend. In vitro, CORM-2 reduced hypoxia/reoxygenation-induced HMGB1 translocation and release, these inhibitions were blocked by SIRT1 inhibition using EX527 or SIRT1 small interfering RNA both in alpha mouse liver 12 cells and RAW264.7 macrophages. Moreover, SIRT1 directly interacted with and deacetylated HMGB1. IRI increased HMGB1 acetylation, which was abolished by CORM-2 treatment via SIRT1. In conclusion, these results suggest that CO may increase SIRT1 expression, which may decrease HMGB1 acetylation and subsequently reduce its translocation and release, thereby protecting against hepatic IRI. Liver Transplantation 23 510-526 2017 AASLD.


Asunto(s)
Monóxido de Carbono/farmacología , Proteína HMGB1/metabolismo , Inflamación/prevención & control , Trasplante de Hígado/efectos adversos , Sustancias Protectoras/farmacología , Daño por Reperfusión/prevención & control , Sirtuina 1/metabolismo , Acetilación , Animales , Carbazoles/farmacología , Inflamación/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Compuestos Organometálicos/uso terapéutico , Células RAW 264.7 , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Resveratrol , Estilbenos/farmacología
16.
Hepatology ; 63(3): 951-64, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26610202

RESUMEN

UNLABELLED: Cholestasis is a common complication in liver diseases that triggers a proliferative response of the biliary tree. Bile duct ligation (BDL) is a frequently used model of cholestasis in rodents. To determine which changes occur in the three-dimensional (3D) architecture of the interlobular bile duct during cholestasis, we used 3D confocal imaging, surface reconstructions, and automated image quantification covering a period up to 28 days after BDL. We show a highly reproducible sequence of interlobular duct remodeling, where cholangiocyte proliferation initially causes corrugation of the luminal duct surface, leading to an approximately five-fold increase in surface area. This is analogous to the function of villi in the intestine or sulci in the brain, where an expansion of area is achieved within a restricted volume. The increase in surface area is further enhanced by duct branching, branch elongation, and loop formation through self-joining, whereby an initially relatively sparse mesh surrounding the portal vein becomes five-fold denser through elongation, corrugation, and ramification. The number of connections between the bile duct and the lobular bile canalicular network by the canals of Hering decreases proportionally to the increase in bile duct length, suggesting that no novel connections are established. The diameter of the interlobular bile duct remains constant after BDL, a response that is qualitatively distinct from that of large bile ducts, which tend to enlarge their diameters. Therefore, volume enhancement is only due to net elongation of the ducts. Because curvature and tortuosity of the bile duct are unaltered, this enlargement of the biliary tree is caused by branching and not by convolution. CONCLUSION: BDL causes adaptive remodeling that aims at optimizing the intraluminal surface area by way of corrugation and branching.


Asunto(s)
Conductos Biliares/fisiopatología , Colestasis/fisiopatología , Animales , Conductos Biliares/patología , Colestasis/patología , Modelos Animales de Enfermedad , Ligadura , Ratones Endogámicos C57BL
17.
BMC Cancer ; 17(1): 896, 2017 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-29282035

RESUMEN

BACKGROUND: Hepatocellular (HCC) and cholangiocellular carcinomas (CCC) display an exceptionally poor prognosis. Especially for advanced disease no efficient standard therapy is currently available. Recently, somatostatin analogs have been evaluated for the treatment of HCC, however, with contradictory results. Besides, for both malignancies the chemokine receptor CXCR4 has been discussed as a possible new target structure. METHODS: Expression of somatostatin receptor (SSTR) subtypes 1, 2A, 3, 4, and 5, and of CXCR4 was evaluated in a total of 71 HCCs and 27 CCCs by immunohistochemistry using well-characterized novel monoclonal antibodies. RESULTS: In HCC tumor cells, frequency and intensity of expression of SSTRs and CXCR4 were only low. CXCR4 was present in about 40% of the HCCs, although at a low intensity. SSTR5, SSTR2, and SSTR3 were detected in about 15%, 8%, and 5% of the HCC tumors, respectively. SSTR and CXCR4 expression was much higher in CCC than in HCC. CXCR4 and SSTR1 were present in 60% and 67% of the CCC samples, respectively, followed by SSTR2 and SSTR5, which were detected in 30% and 11% of the tumors, respectively. Most notably, CXCR4 was intensely expressed on the tumor capillaries in about 50% of the HCCs and CCCs. CXCR4 expression on tumor vessels was associated with poor patient outcomes. CONCLUSIONS: CCC, but not HCC, may be suitable for SSTR-based treatments. Because of the predominant expression of SSTR1, pan-somatostatin analogs should be preferred. In both HCC and CCC, indirect targeting of tumors via the CXCR4-positive tumor capillaries may represent a promising additional therapeutic strategy.


Asunto(s)
Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor/metabolismo , Capilares/patología , Carcinoma Hepatocelular/patología , Colangiocarcinoma/patología , Receptores CXCR4/metabolismo , Receptores de Somatostatina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/irrigación sanguínea , Neoplasias de los Conductos Biliares/metabolismo , Capilares/metabolismo , Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/metabolismo , Colangiocarcinoma/irrigación sanguínea , Colangiocarcinoma/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia
18.
J Surg Res ; 216: 207-218, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28807209

RESUMEN

BACKGROUND: Steatotic livers are particularly vulnerable to ischemia/reperfusion injury (IRI). One of the reasons is an underlying impairment of autophagy. Autophagy is regulated by glycogen synthase kinase 3b (GSK3b) and extracellular signal-regulated kinases (ERK1/2) pathways. Both of them are target proteins of a cell-protective drug, lithium chloride. Lithium chloride treatment reduces IRI in many organs including liver. Therefore, we aimed to investigate the effect of lithium chloride treatment on autophagy induction in steatotic rat livers. We also wanted to evaluate the related cell-protective effects on the enhanced hepatic IRI. MATERIALS AND METHODS: After inducing hepatic steatosis, rats were injected with lithium chloride or normal saline for 3 d before being subjected to 70% selective warm ischemia for 60 min. After reperfusion, rats were observed for 30 min, 6, 24, and 48 h. RESULTS: Lithium chloride appeared to protect hepatocytes from IRI via its ability to induce autophagy by modulation of both GSK3b and ERK1/2 pathways. Hepatic damage was significantly decreased in the treatment group as indicated by a reduced inflammatory response, less apoptosis, less necrosis, and lower liver enzyme levels. CONCLUSIONS: Simultaneous modulation of GSK3b and ERK1/2 pathways might be an interesting strategy to reduce IRI in steatotic livers with an impairment of autophagy.


Asunto(s)
Autofagia/efectos de los fármacos , Hígado Graso/complicaciones , Cloruro de Litio/uso terapéutico , Hígado/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Daño por Reperfusión/prevención & control , Animales , Autofagia/fisiología , Biomarcadores/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Cloruro de Litio/farmacología , Hígado/irrigación sanguínea , Hígado/metabolismo , Hígado/patología , Masculino , Sustancias Protectoras/farmacología , Ratas , Ratas Endogámicas Lew , Daño por Reperfusión/complicaciones , Daño por Reperfusión/metabolismo
19.
Eur Surg Res ; 58(5-6): 246-262, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28746936

RESUMEN

BACKGROUND: Expectations towards surgeons in modern surgical practice are extremely high with minimal complication rates and maximal patient safety as paramount objectives. Both of these aims are highly dependent on individual technical skills that require sustained, focused, and efficient training outside the clinical environment. At the same time, there is an increasing moral and ethical pressure to reduce the use of animals in research and training, which has fundamentally changed the practice of microsurgical training and research. Various animal models were introduced and widely used during the mid-20th century, the pioneering era of experimental microsurgery. Since then, high numbers of ex vivo training concepts and quality control measures have been proposed, all aiming to reduce the number of animals without compromising quality and outcome of training. SUMMARY: Numerous microsurgical training courses are available worldwide, but there is no general agreement concerning the standardization of microsurgical training. The major aim of this literature review and recommendation is to give an overview of various aspects of microsurgical training. We introduce here the findings of a previous survey-based analysis of microsurgical courses within our network. Basic principles behind microsurgical training (3Rs, good laboratory practice, 3Cs), considerations around various microsurgical training models, as well as several skill assessment tools are discussed. Recommendations are formulated following intense discussions within the European Society for Surgical Research (ESSR) and the International Society for Experimental Microsurgery (ISEM), based on scientific literature as well as on several decades of experience in the field of experimental (micro)surgery and preclinical research, represented by the contributing authors. Key Messages: Although ex vivo models are crucial for the replacement and reduction of live animal use, living animals are still indispensable at every level of training which aims at more than just a basic introduction to microsurgical techniques. Modern, competency-based microsurgical training is multi-level, implementing different objective assessment tools as outcome measures. A clear consensus on fundamental principles of microsurgical training and more active international collaboration for the sake of standardization are urgently needed.


Asunto(s)
Microcirugia/educación , Alternativas al Uso de Animales , Animales , Competencia Clínica , Microcirugia/normas , Modelos Animales
20.
Int J Mol Sci ; 18(1)2017 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-28275217

RESUMEN

Ischemia/reperfusion injury (IRI) occurs inevitably in liver transplantations and frequently during major resections, and can lead to liver dysfunction as well as systemic disorders. High-mobility group box 1 (HMGB1) plays a pathogenic role in hepatic IRI. In the normal liver, HMGB1 is located in the nucleus of hepatocytes; after ischemia reperfusion, it translocates to the cytoplasm and it is further released to the extracellular space. Unlike the well-explored functions of nuclear and extracellular HMGB1, the role of cytoplasmic HMGB1 in hepatic IRI remains elusive. We hypothesized that cytoplasmic HMGB1 interacts with binding proteins involved in the hepatocellular response to IRI. In this study, binding proteins of cytoplasmic HMGB1 during hepatic IRI were identified. Liver tissues from rats with warm ischemia reperfusion (WI/R) injury and from normal rats were subjected to cytoplasmic protein extraction. Co-immunoprecipitation using these protein extracts was performed to enrich HMGB1-protein complexes. To separate and identify the immunoprecipitated proteins in eluates, 2-dimensional electrophoresis and subsequent mass spectrometry detection were performed. Two of the identified proteins were verified using Western blotting: betaine-homocysteine S-methyltransferase 1 (BHMT) and cystathionine γ-lyase (CTH). Therefore, our results revealed the binding of HMGB1 to BHMT and CTH in cytoplasm during hepatic WI/R. This finding may help to better understand the cellular response to IRI in the liver and to identify novel molecular targets for reducing ischemic injury.


Asunto(s)
Citoplasma/metabolismo , Proteína HMGB1/metabolismo , Hepatocitos/metabolismo , Daño por Reperfusión/metabolismo , Animales , Western Blotting , Electroforesis en Gel Bidimensional , Hígado/metabolismo , Masculino , Espectrometría de Masas , Unión Proteica , Ratas Endogámicas Lew , Isquemia Tibia
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