Background Dietary potassium (K+) has emerged as a modifiable factor for cardiovascular and kidney health in the general population, but its role in people with chronic kidney disease (CKD) is... Show moreBackground Dietary potassium (K+) has emerged as a modifiable factor for cardiovascular and kidney health in the general population, but its role in people with chronic kidney disease (CKD) is unclear. Here, we hypothesize that CKD increases the susceptibility to the negative effects of low and high K+ diets.Methods We compared the effects of low, normal and high KChloride (KCl) diets and a high KCitrate diet for 4 weeks in male rats with normal kidney function and in male rats with CKD using the 5/6th nephrectomy model (5/6Nx).Results Compared with rats with normal kidney function, 5/6Nx rats on the low KCl diet developed more severe extracellular and intracellular K+ depletion and more severe kidney injury, characterized by nephromegaly, infiltration of T cells and macrophages, decreased estimated glomerular filtration rate and increased albuminuria. The high KCl diet caused hyperkalemia, hyperaldosteronism, hyperchloremic metabolic acidosis and severe hypertension in 5/6Nx but not in sham rats. The high KCitrate diet caused hypochloremic metabolic alkalosis but attenuated hypertension despite higher abundance of the phosphorylated sodium chloride cotransporter (pNCC) and similar levels of plasma aldosterone and epithelial sodium channel abundance. All 5/6Nx groups had more collagen deposition than the sham groups and this effect was most pronounced in the high KCitrate group. Plasma aldosterone correlated strongly with kidney collagen deposition.Conclusions CKD increases the susceptibility to negative effects of low and high K+ diets in male rats, although the injury patterns are different. The low K+ diet caused inflammation, nephromegaly and kidney function decline, whereas the high K+ diet caused hypertension, hyperaldosteronism and kidney fibrosis. High KCitrate attenuated the hypertensive but not the pro-fibrotic effect of high KCl, which may be attributable to K+-induced aldosterone secretion. Our data suggest that especially in people with CKD it is important to identify the optimal threshold of dietary K+ intake.Graphical Abstract Show less
Chiu, Y.H.; Spierings, J.; Laar, J.M. van; Vries-Bouwstra, J.K. de; Dijk, M. van; Goldschmeding, R. 2023
OBJECTIVES:Fibrosis is the dominant hallmark of systemic sclerosis (SSc). Several mechanisms have been proposed to drive the disease process, but how these relate to skin fibrosis is poorly... Show moreOBJECTIVES:Fibrosis is the dominant hallmark of systemic sclerosis (SSc). Several mechanisms have been proposed to drive the disease process, but how these relate to skin fibrosis is poorly understood.METHODS:We performed a cross-sectional study on archival skin biopsies from 18 SSc patients and four controls. Dermal fibrosis and inflammatory cell infiltration were scored in HE and Masson’s Trichrome-stained sections. The presence of senescence was defined by P21 and/or P16 positivity in Ki-67 negative cells. Endothelial to mesenchymal transition (EndMT) was identified by co-localisation of CD31 and α-SMA in immunofluorescent double-stained sections, and by an enclosure of ERG positive endothelial cell nuclei by α-SMA stained cytoplasm in immunohistochemical double staining.RESULTS:The histological dermal fibrosis score of SSc skin biopsies was correlated with the modified Rodnan skin score (rho 0.55, p=0.042). Staining for markers of cellular senescence on fibroblasts was correlated with fibrosis score, inflammatory score, and CCN2 staining on fibroblasts. Moreover, EndMT was more abundant in skin from patients with SSc (p<0.01) but did not differ between groups with different fibrosis severity. The frequency of these EndMT features increased with the abundance of senescence markers and CCN2 on fibroblasts and dermal inflammation.CONCLUSIONS:EndMT and fibroblast senescence were more abundant in skin biopsies from SSc patients. This finding indicates that both senescence and EndMT are involved in the pathway leading to skin fibrosis and might be valuable biomarkers and/or possible targets for novel therapeutic interventions. Show less
Sramko, M.; Fi, S.A.K.; Wijnmaalen, A.P.; Tao, Q.; Geest, R.J.V.; Lamb, H.J.; Zeppenfeld, K. 2023
BACKGROUND Electroanatomical voltage mapping (EAVM) has been compared with late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR), which cannot delineate diffuse fibrosis. T1... Show moreBACKGROUND Electroanatomical voltage mapping (EAVM) has been compared with late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR), which cannot delineate diffuse fibrosis. T1-mapping CMR overcomes the limitations of LGE-CMR, but it has not been directly compared against EAVM. OBJECTIVES This study aims to assess the relationship between left ventricular (LV) endocardial voltage obtained by EAVM and extracellular volume (ECV) obtained by T1 mapping. METHODS The study investigated patients who underwent endocardial EAVM for ventricular arrhythmias (CARTO 3, Biosense Webster) together with preprocedural contrast-enhanced T1 mapping (Ingenia 3T, Philips Healthcare). After image integration, EAVM datapoints were projected onto LGE-CMR and ECV-encoded images. Average values of unipolar voltage (UV), bipolar voltage (BV), LGE transmurality, and ECV were merged from corresponding cardiac segments (6 per slice) and pooled for analysis. RESULTS The analysis included data from 628 segments from 18 patients (57 +/- 13 years of age, 17% females, LV ejection fraction 48% +/- 14%, nonischemic/ischemic cardiomyopathy/controls: 8/6/4 patients). Based on the 95th and 5th percentile values obtained from the controls, ECV >33%, BV <2.9 mV, and UV <6.7 mV were considered abnormal. There was a significant inverse association between voltage and ECV, but only in segments with abnormal ECV. Increased ECV could predict abnormal BV and UV with acceptable accuracy (area under the curve of 0.78 [95% CI: 0.74-0.83] and 0.84 [95% CI: 0.79-0.88]). CONCLUSIONS This study found a significant inverse relationship between LV endocardial voltage and ECV. Real-time integration of T1 mapping may guide catheter mapping and may allow identification of areas of diffuse fibrosis potentially related to ventricular arrhythmias. (J Am Coll Cardiol EP 2023;9:740-748) (c) 2023 Published by Elsevier on behalf of the American College of Cardiology Foundation. Show less
Patients with metabolic syndrome are often prescribed statins to prevent the development of cardiovascular disease. Conversely, data on their effects on non-alcoholic steatohepatitis (NASH) are... Show morePatients with metabolic syndrome are often prescribed statins to prevent the development of cardiovascular disease. Conversely, data on their effects on non-alcoholic steatohepatitis (NASH) are lacking. We evaluated these effects by feeding APOE*3-Leiden mice a Western-type diet (WTD) with or without atorvastatin to induce NASH and hepatic fibrosis. Besides the well-known plasma cholesterol lowering (−30%) and anti-atherogenic effects (severe lesion size −48%), atorvastatin significantly reduced hepatic steatosis (−22%), the number of aggregated inflammatory cells in the liver (−80%) and hepatic fibrosis (−92%) compared to WTD-fed mice. Furthermore, atorvastatin-treated mice showed less immunohistochemically stained areas of inflammation markers. Atorvastatin prevented accumulation of free cholesterol in the form of cholesterol crystals (−78%). Cholesterol crystals are potent inducers of the NLRP3 inflammasome pathway and atorvastatin prevented its activation, which resulted in reduced expression of the pro-inflammatory cytokines interleukin (IL)-1β (−61%) and IL-18 (−26%). Transcriptome analysis confirmed strong reducing effects of atorvastatin on inflammatory mediators, including NLRP3, NFκB and TLR4. The present study demonstrates that atorvastatin reduces hepatic steatosis, inflammation and fibrosis and prevents cholesterol crystal formation, thereby precluding NLRP3 inflammasome activation. This may render atorvastatin treatment as an attractive approach to reduce NAFLD and prevent progression into NASH in dyslipidemic patients. Show less
Romano, F.; Cozzi, M.; Monteduro, D.; Oldani, M.; Boon, C.J.F.; Staurenghi, G.; Salvetti, A.P. 2023
Purpose:To describe the imaging characteristics and topographic expansion of retinal pigment epithelium (RPE) and outer retinal atrophy in extensive macular atrophy with pseudodrusen-like... Show morePurpose:To describe the imaging characteristics and topographic expansion of retinal pigment epithelium (RPE) and outer retinal atrophy in extensive macular atrophy with pseudodrusen-like appearance.Methods:Three-year, prospective, observational study. Nine patients with extensive macular atrophy with pseudodrusen-like appearance (17 eyes; 6 women) with no other ocular conditions were annually examined; one eye was excluded because of macular neovascularization. Best-corrected visual acuity measurement, fundus photographs, blue-light autofluorescence, and optical coherence tomography were performed at each visit. Formation of atrophy was analyzed on optical coherence tomography at foveal and extrafoveal areas following the Classification of Atrophy Meeting recommendations. Spatial enlargement throughout four sectors was assessed on blue-light autofluorescence after placing an Early Treatment for Diabetic Retinopathy Study grid centered on the foveola.Results:Mean age was 53.0 +/- 2.1 years at baseline with a follow-up of 36.6 +/- 0.7 months. Thinning of the outer nuclear layer and disruption of the ellipsoid zone initially appeared above areas of RPE-Bruch membrane separation and preceded RPE atrophy. Subfoveal fibrosis was seen in 65% of the eyes. Superior sector involvement was found in all patients at baseline and was significantly larger than the other sectors at any time point (P < 0.001). Best-corrected visual acuity declined from 68.0 +/- 15.7 letters to 44.8 +/- 14.9 letters during the follow-up and was significantly associated with subfoveal atrophy (P < 0.001) and fibrosis (P = 0.02).Conclusion:Our findings suggest that primary alterations in patients with extensive macular atrophy with pseudodrusen-like appearance are present at the outer segment-RPE interface, with the superior Early Treatment for Diabetic Retinopathy Study sector being the most vulnerable, which progresses to extensive atrophy of the RPE and outer retinal layers. Accordingly, we propose a three-stage disease classification. Show less
Objective: No treatments are approved for Becker muscular dystrophy (BMD). This study investigated the efficacy and safety of givinostat, a histone deacetylase pan-inhibitor, in adults with BMD.... Show moreObjective: No treatments are approved for Becker muscular dystrophy (BMD). This study investigated the efficacy and safety of givinostat, a histone deacetylase pan-inhibitor, in adults with BMD. Methods: Males aged 18-65 years with a diagnosis of BMD confirmed by genetic testing were randomized 2:1 to 12 months treatment with givinostat or placebo. The primary objective was to demonstrate statistical superiority of givinostat over placebo for mean change from baseline in total fibrosis after 12 months. Secondary efficacy endpoints included other histological parameters, magnetic resonance imaging and spectroscopy (MRI and MRS) measures, and functional evaluations. Results: Of 51 patients enrolled, 44 completed treatment. At baseline, there was greater disease involvement in the placebo group than givinostat, based on total fibrosis (mean 30.8 vs. 22.8%) and functional endpoints. Mean total fibrosis did not change from baseline in either group, and the two groups did not differ at Month 12 (least squares mean [LSM] difference 1.04%; p = 0.8282). Secondary histology parameters, MRS, and functional evaluations were consistent with the primary. MRI fat fraction in whole thigh and quadriceps did not change from baseline in the givinostat group, but values increased with placebo, with LSM givinostat-placebo differences at Month 12 of -1.35% (p = 0.0149) and -1.96% (p = 0.0022), respectively. Adverse events, most mild or moderate, were reported by 88.2% and 52.9% patients receiving givinostat and placebo. Conclusion: The study failed to achieve the primary endpoint. However, there was a potential signal from the MRI assessments suggesting givinostat could prevent (or slow down) BMD disease progression. Show less
Karkampouna, S.; Helm, D. van der; Scarpa, M.; Hoek, B. van; Verspaget, H.W.; Goumans, M.J.; ... ; Julio, M.K.D. 2021
Oncofetal protein, CRIPTO, is silenced during homeostatic postnatal life and often re-expressed in different neoplastic processes, such as hepatocellular carcinoma. Given the reactivation of CRIPTO... Show moreOncofetal protein, CRIPTO, is silenced during homeostatic postnatal life and often re-expressed in different neoplastic processes, such as hepatocellular carcinoma. Given the reactivation of CRIPTO in pathological conditions reported in various adult tissues, the aim of this study was to explore whether CRIPTO is expressed during liver fibrogenesis and whether this is related to the disease severity and pathogenesis of fibrogenesis. Furthermore, we aimed to identify the impact of CRIPTO expression on fibrogenesis in organs with high versus low regenerative capacity, represented by murine liver fibrogenesis and adult murine heart fibrogenesis. Circulating CRIPTO levels were measured in plasma samples of patients with cirrhosis registered at the waitlist for liver transplantation (LT) and 1 year after LT. The expression of CRIPTO and fibrotic markers (alpha SMA, collagen type I) was determined in human liver tissues of patients with cirrhosis (on a basis of viral hepatitis or alcoholic disease), in cardiac tissue samples of patients with end-stage heart failure, and in mice with experimental liver and heart fibrosis using immuno-histochemical stainings and qPCR. Mouse models with experimental chronic liver fibrosis, induced with multiple shots of carbon tetrachloride (CCl4) and acute liver fibrosis (one shot of CCl4), were evaluated for CRIPTO expression and fibrotic markers. CRIPTO was overexpressed in vivo (Adenoviral delivery) or functionally sequestered by ALK4Fc ligand trap in the acute liver fibrosis mouse model. Murine heart tissues were evaluated for CRIPTO and fibrotic markers in three models of heart injury following myocardial infarction, pressure overload, and ex vivo induced fibrosis. Patients with end-stage liver cirrhosis showed elevated CRIPTO levels in plasma, which decreased 1 year after LT. Cripto expression was observed in fibrotic tissues of patients with end-stage liver cirrhosis and in patients with heart failure. The expression of CRIPTO in the liver was found specifically in the hepatocytes and was positively correlated with the Model for End-stage Liver Disease (MELD) score for end-stage liver disease. CRIPTO expression in the samples of cardiac fibrosis was limited and mostly observed in the interstitial cells. In the chronic and acute mouse models of liver fibrosis, CRIPTO-positive cells were observed in damaged liver areas around the central vein, which preceded the expression of alpha SMA-positive stellate cells, i.e., mediators of fibrosis. In the chronic mouse models, the fibrosis and CRIPTO expression were still present after 11 weeks, whereas in the acute model the liver regenerated and the fibrosis and CRIPTO expression resolved. In vivo overexpression of CRIPTO in this model led to an increase in fibrotic markers, while blockage of CRIPTO secreted function inhibited the extent of fibrotic areas and marker expression (alpha SMA, Collagen type I and III) and induced higher proliferation of residual healthy hepatocytes. CRIPTO expression was also upregulated in several mouse models of cardiac fibrosis. During myocardial infarction CRIPTO is upregulated initially in cardiac interstitial cells, followed by expression in alpha SMA-positive myofibroblasts throughout the infarct area. After the scar formation, CRIPTO expression decreased concomitantly with the alpha SMA expression. Temporal expression of CRIPTO in alpha SMA-positive myofibroblasts was also observed surrounding the coronary arteries in the pressure overload model of cardiac fibrosis.Furthermore, CRIPTO expression was upregulated in interstitial myofibroblasts in hearts cultured in an ex vivo model for cardiac fibrosis. Our results are indicative for a functional role of CRIPTO in the induction of fibrogenesis as well as a potential target in the antifibrotic treatments and stimulation of tissue regeneration. Show less
most frequent valvular heart diseases. The most common etiology of primary MR is the myxomatous degeneration of the mitral valve, encompassing fibroelastic deficiency and Barlow's disease. In... Show moremost frequent valvular heart diseases. The most common etiology of primary MR is the myxomatous degeneration of the mitral valve, encompassing fibroelastic deficiency and Barlow's disease. In severe chronic primary MR, the presence of symptoms, reduced left ventricular ejection fraction (LVEF) #60%, and increased left ventricular (LV) end-systolic diameter are indications for mitral valve repair (1,2). In asymptomatic patients, surgery should be considered if there is a high likelihood of durable mitral valve repair; low operative risk; and atrial fibrillation, pulmonary hypertension, flail leaflet, or dilated left atrium at sinus rhythm (1,2). The evidence showing the benefits of early surgery is accumulating. Data from a large cohort of 1,512 patients undergoing mitral valve surgery for isolated primary MR revealed that patients who were operated based only on high likelihood of successful mitral valve repair had the best outcome (3). The rationale for an early intervention is that the longstanding volume overload caused by severe MR may lead to irreversible LV dysfunction. LVEF is considered the parameter of reference to define LV function and to Show less
Background Right ventricular (RV) function and failure are key determinants of morbidity and mortality in various cardiovascular diseases. Myocardial fibrosis is regarded as a contributing factor... Show moreBackground Right ventricular (RV) function and failure are key determinants of morbidity and mortality in various cardiovascular diseases. Myocardial fibrosis is regarded as a contributing factor to heart failure, but its importance in RV failure has been challenged. This study aims to assess whether myocardial fibrosis drives the transition from compensated to decompensated volume load-induced RV dysfunction.MethodsWistar rats were subjected to aorto-caval shunt (ACS, n = 23) or sham (control, n = 15) surgery, and sacrificed after 1 month, 3 months, or 6 months. Echocardiography, RV pressure-volume analysis, assessment of gene expression and cardiac histology were performed.ResultsAt 6 months, 6/8 ACS-rats (75%) showed clinical signs of RV failure (pleural effusion, ascites and/or liver edema), whereas at 1 month and 3 months, no signs of RV failure had developed yet. Cardiac output has increased two- to threefold and biventricular dilatation occurred, while LV ejection fraction gradually decreased. At 1 month and 3 months, RV end-systolic elastance (Ees) remained unaltered, but at 6 months, RV Ees had decreased substantially. In the RV, no oxidative stress, inflammation, pro-fibrotic signaling (TGF beta 1 and pSMAD2/3), or fibrosis were present at any time point.ConclusionsIn the ACS rat model, long-term volume load was initially well tolerated at 1 month and 3 months, but induced overt clinical signs of end-stage RV failure at 6 months. However, no myocardial fibrosis or increased pro-fibrotic signaling had developed. These findings indicate that myocardial fibrosis is not involved in the transition from compensated to decompensated RV dysfunction in this model. Show less
Yepes-Calderon, M.; Sotomayor, C.G.; Rasmussen, D.G.K.; Hijmans, R.S.; Velde-Keyzer, C.A.T.; Londen, M. van; ... ; Born, J. van den 2020
The PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal... Show moreThe PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal associations between plasma and urine PRO-C6 and proven histological changes after kidney transplantation. The current study is a post-hoc analysis of 94 participants of the MECANO trial, a 24-month prospective, multicenter, open-label, randomized, controlled trial aimed at comparing everolimus-based vs. cyclosporine-based immunosuppression. PRO-C6 was measured in plasma and urine samples collected 6 and 24 months post-transplantation. Fibrosis was evaluated in biopsies collected at the same time points by Banff interstitial fibrosis/tubular atrophy (IF/TA) scoring and collagen staining (Picro Sirius Red; PSR); inflammation was evaluated by the tubulo-interstitial inflammation score (ti-score). Linear regression analyses were performed. Six-month plasma PRO-C6 was cross-sectionally associated with IF/TA score (Std. beta = 0.34), and prospectively with 24-month IF/TA score and ti-score (Std. beta = 0.24 and 0.23, respectively) (p < 0.05 for all). No significant associations were found between urine PRO-C6 and any of the biopsy findings. Fibrotic changes and urine PRO-C6 behaved differentially over time according to immunosuppressive therapy. These results are a first step towards non-invasive fibrosis detection after kidney transplantation by means of collagen VI synthesis measurement, and further research is required. Show less
Ma, J.; Sanchez Duffhues, G.; Goumans, M.J.; Dijke, P. ten 2020
Endothelial to mesenchymal transition (EndMT) is a complex biological process that gives rise to cells with multipotent potential. EndMT is essential for the formation of the cardiovascular system... Show moreEndothelial to mesenchymal transition (EndMT) is a complex biological process that gives rise to cells with multipotent potential. EndMT is essential for the formation of the cardiovascular system during embryonic development. Emerging results link EndMT to the postnatal onset and progression of fibrotic diseases and cancer. Moreover, recent reports have emphasized the potential for EndMT in tissue engineering and regenerative applications by regulating the differentiation status of cells. Transforming growth factor beta (TGF-beta) engages in many important physiological processes and is a potent inducer of EndMT. In this review, we first summarize the mechanisms of the TGF-beta signaling pathway as it relates to EndMT. Thereafter, we discuss the pivotal role of TGF-beta-induced EndMT in the development of cardiovascular diseases, fibrosis, and cancer, as well as the potential application of TGF-beta-induced EndMT in tissue engineering. Show less
Sramko, M.; Abdel-Kafi, S.; Geest, R.J. van der; Riva, M. de; Glashan, C.A.; Lamb, H.J.; Zeppenfeld, K. 2019
OBJECTIVES This study sought to determine new reference cutoffs for normal unipolar voltage (UV) and bipolar voltage (BV) that would be adjusted for the LV remodeling.BACKGROUND The definition of ... Show moreOBJECTIVES This study sought to determine new reference cutoffs for normal unipolar voltage (UV) and bipolar voltage (BV) that would be adjusted for the LV remodeling.BACKGROUND The definition of "normal" left ventricular (LV) endocardial voltage in patients with post-infarct scar is still lacking. The reference voltage of the noninfarcted myocardium (NIM) may differ between patients depending on LV structural remodeling and the ensuing interstitial fibrosis.METHODS Electroanatomic voltage mapping was integrated with isotropic late gadolinium-enhanced cardiac magnetic resonance in 15 patients with nonremodeted LV and 12 patients with remodeled LV (end-systolic volume index >50 ml/m(2) with ejection fraction <47% assessed by cardiac magnetic resonance). Reference voltages (fifth percentile values) were determined from pooled NIM segments without late gadolinium enhancement.RESULTS The cutoffs for normal BV and UV were >= 3.0 and >= 6.7 mV for nonremodeled LV and >= 2.1 and >= 6.4 mV for remodeled LV. Endocardial low-voltage area (LVA) defined by the adjusted cutoffs corresponded better to late gadolinium enhancement-detected scar than did LVA defined by uniform cutoffs. In 15 patients who underwent successful ablation of ventricular tachycardia, the LVA contained >97% of targeted evoked delayed potentials. Insights from whole-heart T1 mapping revealed more fibrotic NIM in patients with remodeled LV compared with nonremodeled LV.CONCLUSIONS This study found substantial differences in endocardial voltage of NIM in post-infarct patients with remodeled versus nonremodeled LV. The new adjusted cutoffs for "normal" BV and UV enable a patient-tailored approach to etectroanatomic voltage mapping of LV. (C) 2019 by the American College of Cardiology Foundation. Show less
Helm, D. van der; Barnhoorn, M.C.; Jonge-Muller, E.S.M. de; Molendijk, I.; Hawinkels, L.J.A.C.; Coenraad, M.J.; ... ; Verspaget, H.W. 2019
Autosomal Dominant Polycystic Kidney Disease is characterised by the development of fluid-filled cysts in the kidneys which lead to end-stage renal disease (ESRD). In the majority of cases, the... Show moreAutosomal Dominant Polycystic Kidney Disease is characterised by the development of fluid-filled cysts in the kidneys which lead to end-stage renal disease (ESRD). In the majority of cases, the disease is caused by a mutation in the Pkd1 gene. In a previous study, we demonstrated that renal injury can accelerate cyst formation in Pkd1 knock-out (KO) mice. In that study, we found that after injury four-jointed (Fjx1), an upstream regulator of planar cell polarity and the Hippo pathway, was aberrantly expressed in Pkd1 KO mice compared to WT. Therefore, we hypothesised a role for Fjx1 in injury/repair and cyst formation. We generated single and double deletion mice for Pkd1 and Fjx1, and we induced toxic renal injury using the nephrotoxic compound 1,2-dichlorovinyl-cysteine. We confirmed that nephrotoxic injury can accelerate cyst formation in Pkd1 mutant mice. This caused Pkd1 KO mice to reach ESRD significantly faster; unexpectedly, double KO mice survived significantly longer. Cyst formation was comparable in both models, but we found significantly less fibrosis and macrophage infiltration in double KO mice. Taken together, these data suggest that Fjx1 disruption protects the cystic kidneys against kidney failure by reducing inflammation and fibrosis. Moreover, we describe, for the first time, an interesting (yet unidentified) mechanism that partially discriminates cyst growth from fibrogenesis. (c) 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. Show less
Putten, M. van; Putker, K.; Overzier, M.; Adamzek, W.A.; Pasteuning-Vuhman, S.; Plomp, J.J.; Aartsma-Rus, A. 2019
