Current uptake and barriers to wider use of the International Ovarian Tumor Analysis (IOTA) models in Dutch gynaecological practice.

OBJECTIVE: Correct referral of women with an ovarian tumor to an oncology department remains challenging. The International Ovarian Tumor Analysis (IOTA) consortium has developed models with higher diagnostic accuracy than the alternative Risk of Malignancy Index (RMI). This study explores the uptake of the IOTA models in Dutch hospitals and factors that impede or promote implementation. Optimal implementation is crucial to improve pre-operative classification of ovarian tumors, which may lead to better patient referral to the appropriate level of care. STUDY DESIGN: In February 2021, an electronic questionnaire consisting of 37 questions was sent to all 72 hospitals in the Netherlands. One pre-selected gynaecologist per hospital was asked to respond on behalf of the department. RESULTS: The study had a response rate of 93% (67/72 hospitals). All respondents (100%) were familiar with the IOTA models with 94% using them in practice. The logistic regression 2 (LR2)-model, Simple ultrasound-based rules (SR) and Assessment of Different NEoplasias in the adneXa (ADNEX) model were used in respectively 40%, 67% and 73% of these hospitals. Respondents rated the models overall with an 8.2 (SD 1.8), 8.3 (SD 1.6) and 8.9 (SD 1.3) respectively for LR2, SR and ADNEX on a scale from 1 to 10. Moreover, 89% indicated to have confidence in the results of the IOTA models. The most important factors to improve further implementation are more training (43%), research on sensitivity, specificity and cost-effectiveness in the Dutch health care system (27%), easier usability (24%) and more consultation time (19%). CONCLUSION: The IOTA ultrasound models are adopted in the majority of Dutch hospitals with the ADNEX model being used the most. While Dutch gynecologists have a strong familiarity and confidence in the models, the uptake varies in reality. Areas that warrant improvement in the Dutch context are more uniformity, education and more research. These findings can be helpful for other countries considering adopting the IOTA models.

S100A8/A9 promotes parenchymal damage and renal fibrosis in obstructive nephropathy.

Despite advances in our understanding of the mechanisms underlying the progression of chronic kidney disease and the development of fibrosis, only limited efficacious therapies exist. The calcium binding protein S100A8/A9 is a damage-associated molecular pattern which can activate Toll-like receptor (TLR)-4 or receptor for advanced glycation end-products (RAGE). Activation of these receptors is involved in the progression of renal fibrosis; however, the role of S100A8/A9 herein remains unknown. Therefore, we analysed S100A8/A9 expression in patients and mice with obstructive nephropathy and subjected wild-type and S100A9 knock-out mice lacking the heterodimer S100A8/A9 to unilateral ureteral obstruction (UUO). We found profound S100A8/A9 expression in granulocytes that infiltrated human and murine kidney, together with enhanced renal expression over time, following UUO. S100A9 KO mice were protected from UUO-induced renal fibrosis, independently of leucocyte infiltration and inflammation. Loss of S100A8/A9 protected tubular epithelial cells from UUO-induced apoptosis and critical epithelial-mesenchymal transition steps. In-vitro studies revealed S100A8/A9 as a novel mediator of epithelial cell injury through loss of cell polarity, cell cycle arrest and subsequent cell death. In conclusion, we demonstrate that S100A8/A9 mediates renal damage and fibrosis, presumably through loss of tubular epithelial cell contacts and irreversible damage. Suppression of S100A8/A9 could be a therapeutic strategy to halt renal fibrosis in patients with chronic kidney disease.

Renal endothelial protein C receptor expression and shedding during diabetic nephropathy.

UNLABELLED: Essentials Endothelial protein C receptor (EPCR) promotes diabetic nephropathy (DN) outcome improvement. Renal expression and shedding of EPCR were measured in diabetic patients with or without DN. Inhibition of metalloproteinase-driven EPCR shedding restored glomerular endothelium phenotype. EPCR shedding through metalloproteinase ADAM17 contributes to the worsening of DN. SUMMARY: Background Diabetic nephropathy (DN) represents the leading cause of end-stage renal disease. The endothelial protein C receptor (EPCR) and its ligand (activated protein C) have been shown to ameliorate the phenotype of DN in mice. EPCR activity can be regulated by proteolytic cleavage involving ADAMs, yielding a soluble form of EPCR (sEPCR). Objective To characterize the renal expression and shedding of EPCR during DN. Methods EPCR levels were measured in plasma, urine and biopsy samples of diabetic patients with (n = 73) or without (n = 63) DN. ADAM-induced cleavage of EPCR was investigated in vitro with a human glomerular endothelium cell line. Results DN patients showed higher plasma and urinary levels of sEPCR than diabetic controls (112.2 versus 135.2 ng mL(-1) and 94.35 versus 140.6 ng mL(-1) , respectively). Accordingly, glomerular endothelial EPCR expression was markedly reduced in patients with DN, and this was associated with increased glomerular expression of ADAM-17 and ADAM-10. In vitro, EPCR shedding was induced by incubation of glomerular endothelium in high-glucose medium, and this shedding was suppressed by ADAM-17 inhibition or silencing, which led to improved vascular endothelial cadherin (VE-cadherin) expression and reduced mRNA expression of transforming growth factor (TGF)-ß. In addition, EPCR silencing led to minor effects on VE-cadherin but to a significant increase in TGF-ß mRNA expression. Conclusion Inhibition of ADAM-driven glomerular EPCR shedding restored the endothelial phenotype of glomerular endothelium, whereas EPCR silencing led to enhanced expression of TGF-ß, a marker of endothelial-mesenchymal transition. These findings demonstrate that EPCR shedding driven by ADAMs contributes to the worsening of DN.

Mice lacking the multidrug resistance protein 1 have a transiently impaired immune response during tuberculosis.

A T helper (Th) 1 immune response is important for host defense against tuberculosis. The multidrug resistance protein (Mrp) 1 is constitutively present at low levels on Th2 lymphocytes, and is expressed on Th1 lymphocytes upon activation. To determine the role of Mrp1 in the pathogenesis of tuberculosis, Mrp1 deficient (-/-) and normal wild type mice were intranasally infected with Mycobacterium tuberculosis. At 2 weeks after infection, Mrp1(-/-) mice had reduced levels of the Th1 cytokine interferon-gamma and an impaired granuloma formation in their lungs. At 5 weeks postinfection, M. tuberculosis outgrowth was enhanced in lungs and livers of Mrp1(-/-) mice. A more prolonged observation of these mice, up to 4 months, revealed no differences in survival or mycobacterial outgrowth. These data suggest that Mrp1 plays an early but dispensable role in the protective immune response to pulmonary tuberculosis.

Depletion of alveolar macrophages exerts protective effects in pulmonary tuberculosis in mice.

Mycobacterium tuberculosis bacilli are intracellular organisms that reside in phagosomes of alveolar macrophages (AMs). To determine the in vivo role of AM depletion in host defense against M. tuberculosis infection, mice with pulmonary tuberculosis induced by intranasal administration of virulent M. tuberculosis were treated intranasally with either liposome-encapsulated dichloromethylene diphosphonate (AM(-) mice), liposomes, or saline (AM(+) mice). AM(-) mice were completely protected against lethality, which was associated with a reduced outgrowth of mycobacteria in lungs and liver, and a polarized production of type 1 cytokines in lung tissue, and by splenocytes stimulated ex vivo. AM(-) mice displayed deficient granuloma formation, but were more capable of attraction and activation of T cells into the lung and had increased numbers of pulmonary polymorphonuclear cells. These data demonstrate that depletion of AMs is protective during pulmonary tuberculosis.

T cell apoptosis in human heart allografts: association with lack of co-stimulation?

It is unclear whether the intracardial immune reactivity after heart transplantation influences the peripheral immunological status (activation or nonresponsiveness) of the patient. Co-stimulation and activation-induced cell death (AICD) or apoptosis play an important role in determining the balance between lymphocyte reactivity and nonreactivity. Therefore, we studied the expression of co-stimulatory molecules and the process of apoptosis in biopsies of human heart allografts, using immunohistochemistry. Although a normal expression of co-stimulatory molecules on antigen-presenting cells was observed, the expression of their counter-structures on T cells was absent. This may be due to chronic T cell activation, which can lead to the induction of apoptosis via the Fas/Fas ligand pathway. In the infiltrates, a considerable percentage of the lymphocytes, but not the macrophages, were apoptotic. Apoptosis was confirmed by DNA fragmentation analysis. Increased numbers of Bax-expressing versus decreased numbers of Bcl2-expressing lymphocytes in comparison with normal lymphoid tissue confirmed a imbalance in favor of apoptosis. Apoptosis was biased towards CD4+ T cells (65.7% versus 26.6% in CD8+ T cells). Fas was expressed on most of the infiltrating cells. Fas ligand expression was also observed, not only on most of the T cells but also on all macrophages. Because macrophages were often detected in close contact with T cells, they may play a role in T cell regulation via the Fas/Fas ligand pathway. This study indicates that, during rejection, not only is tissue damage induced by infiltrating T cells, but also the infiltrating lymphocytes themselves are actively down-regulated (eg, AICD) by one another and by macrophages in the infiltrate. This regulatory process may affect the immunological status of the patient after heart transplantation.