Search

Simple Summary: With both prevalence and mortality increasing, endometrial cancer (EC) is the most common gynecological cancer in high-income countries. Despite significant advances in EC research and management, there are still unmet needs. Patients suffering from advanced-stage and recurrent EC lack treatment options and have poor prognosis. Robust preclinical models are crucial in the development of novel therapies, and xenograft models have recently gained increasing interest in drug discovery and precision medicine. A clear overview of all developed EC mouse xenograft models is currently lacking. The aim of this review is to summarize these studies, reporting on their methodology and main findings. The different models are grouped based on the source material used to generate the xenografts, i.e., cell lines, patient-derived tumors, or patient-derived tumor organoids, and on the location of tumor formation, i.e., heterotopic or orthotopic. Finally, the advantages and disadvantages of the different tumor source material and xenograft locations, as well as some considerations on the translational potential, limitations, and future directions of EC xenograft models, are discussed. Murine xenograft models are valuable and increasingly used preclinical tools in cancer research to understand disease pathogenesis and guide treatment options. The aim of this narrative review is to summarize the studies that employed mouse xenograft models, using cell lines, patient-derived tumors, or organoids, in endometrial cancer (EC) research, detailing their methodology and main findings. We identified 27 articles reporting on heterotopic EC xenografts, including subcutaneous, subrenal capsule, intraperitoneal, and retro-orbital models, and 18 articles using orthotopic xenografts. Subcutaneous xenografts generated using either cell lines or patient tumors have been widely used; however, their low engraftment rates and the inability to recapitulate main clinical features such as metastases limit their translational value. Subrenal capsule models showed improved engraftment rates compared to subcutaneous models, but tumors exhibited slower and constrained tumor growth. Orthotopic models are technically more challenging to generate and monitor, but tumor growth occurs in a relevant microenvironment and EC ortho-xenografts exhibit high engraftment rates and metastases to clinically relevant sites. Cell line-based xenograft (CDX) models are attractive tools because they are convenient, easy to use, and amenable to genetic modifications, making them suitable for proof-of-concept approaches and large-scale studies. EC xenografts developed from patient tumors (PDTXs) are more labor/cost-intensive for their establishment but can capture the genetic and molecular heterogeneity within and across histologic subtypes and can inform personalized patient treatment. EC organoid-based xenograft (PDOX) models combine the advantages of both CDXs and PDTXs since they are more time- and cost-effective, faithfully maintain tumor characteristics and therapeutic responses, and can be genetically modified. Despite substantial progress in EC management, there are still several unmet needs. Efficient targeted treatments are currently indicated only for a small subgroup of patients, while women with recurrent or advanced-stage EC have very few therapeutic options and their prognosis remains unfavorable. Novel (targeted) drugs, combinational regimens and tools to predict the real drug response in patients are urgently needed. Xenograft models are expected to inform about disease mechanisms and to help identify novel therapeutic options and suitable target patients. [ABSTRACT FROM AUTHOR]

Purpose: To build a machine learning model to predict histology (type I and type II), stage, and grade preoperatively for endometrial carcinoma to quickly give a diagnosis and assist in improving the accuracy of the diagnosis, which can help patients receive timely, appropriate, and effective treatment. Materials and Methods: This study used a retrospective database of preoperative examinations (tumor markers, imaging, diagnostic curettage, etc.) in patients with endometrial carcinoma. Three algorithms (random forest, logistic regression, and deep neural network) were used to build models. The AUC and accuracy were calculated. Furthermore, the performance of machine learning models, doctors' prediction, and doctors with the assistance of models were compared. Results: A total of 329 patients were included in this study with 16 features (age, BMI, stage, grade, histology, etc.). A random forest algorithm had the highest AUC and Accuracy. For histology prediction, AUC and accuracy was 0.69 (95% CI=0.67-0.70) and 0.81 (95%CI=0.79-0.82). For stage they were 0.66 (95% CI=0.64-0.69) and 0.63 (95% CI=0.61-0.65) and for differentiation grade 0.64 (95% CI=0.63-0.65) and 0.43 (95% CI=0.41-0.44). The average accuracy of doctors for histology, stage, and grade was 0.86 (with AI) and 0.79 (without AI), 0.64 and 0.53, 0.5 and 0.45, respectively. The accuracy of doctors' prediction with AI was higher than that of Random Forest alone and doctors' prediction without AI. Conclusion: A random forest model can predict histology, stage, and grade of endometrial cancer preoperatively and can help doctors in obtaining a better diagnosis and predictive results. [ABSTRACT FROM AUTHOR]

Study Question: Are the primary cell cultures and cell lines used in endometriosis research of sufficient quality?Summary Answer: Primary cells used in endometriosis research lack purity and phenotypic characterisation, and cell lines are not genotypically authenticated.What Is Known Already: The poor reproducibility of in vitro research and the lack of authenticity of the cell lines used represent reasons of concern in the field of reproductive biology and endometriosis research.Study Design, Size, Duration: In the present study, past in vitro research in the field of endometriosis was systematically reviewed to determine whether the appropriate quality controls were considered. In addition, we explored the performance of Paired Box 2 (Pax2) as an endometrium specific marker in endometrial and endometriotic primary cell cultures; we also characterised the most diffused endometriosis cell lines with respect to important markers including the short tandem repeat (STR) profile.Participants/materials, Setting, Methods: Literature review part: almost 300 published protocols describing the isolation and creation of primary cell cultures from endometriosis were reviewed. Wet-lab part: primary cells isolated from 13 endometriosis patients were analysed by immunohistochemistry, immunofluorescence and FACS for the expression of Pax2. Cell lines Z11 and Z12, the most diffused endometriosis cell lines, were characterised with respect to the expression of Pax2, steroid hormone receptors and STR profile.Main Results and the Role Of Chance: From the literature review work, we underscored the lack of sufficient cell purity and phenotypic characterisation of primary cell cultures, which present high risk of contaminations from surrounding non-endometriotic tissues. Past work based on the use of cell lines was reviewed as well, and it emerged that cell line authentication was never performed.In an effort to address these weaknesses for future research, we present data on the performance of Pax2, a suitable marker to exclude ovarian (and other non-endometrial) cell contaminations from primary cell cultures; STR profiles of cell lines Z11 and Z12 were analysed and indicated that the cells were authentic. These profiles are now available for authentication purposes to researchers wishing to perform experiments with these cells.A quality control pipeline to assure sufficient quality of in vitro research in the field of reproductive biology and endometriosis is proposed. We encourage scientists, research institutes, journal reviewers, editors and funding bodies to raise awareness of the problem and adopt appropriate policies to solve it in the future.Large-scale Data: STR profiles of cell lines Z11 and Z12 are deposited at the Cellosaurus database-web.expasy.org.Limitations, Reasons For Caution: There may be additional markers suitable to assess cell quality.Wider Implications Of the Findings: Future in vitro research in endometriosis and the reliability of outcomes can be improved by using the recommendations presented in this study.Study Funding/competing Interest(s): The study was partly financed by the 'Stichting Fertility Foundation' (The Netherlands). The authors declare no existing conflict of interest.Trial Registration Number: Non-applicable. [ABSTRACT FROM AUTHOR]

Our understanding of the intracrine (or local) regulation of estrogen and other steroid synthesis and degradation expanded in the last decades, also thanks to recent technological advances in chromatography mass-spectrometry. Estrogen responsive tissues and organs are not passive receivers of the pool of steroids present in the blood but they can actively modify the intra-tissue steroid concentrations. This allows fine-tuning the exposure of responsive tissues and organs to estrogens and other steroids in order to best respond to the physiological needs of each specific organ. Deviations in such intracrine control can lead to unbalanced steroid hormone exposure and disturbances. Through a systematic bibliographic search on the expression of the intracrine enzymes in various tissues, this review gives an up-to-date view of the intracrine estrogen metabolisms, and to a lesser extent that of progestogens and androgens, in the lower female genital tract, including the physiological control of endometrial functions, receptivity, menopausal status and related pathological conditions. An overview of the intracrine regulation in extra gynecological tissues such as the lungs, gastrointestinal tract, brain, colon and bone is given. Current therapeutic approaches aimed at interfering with these metabolisms and future perspectives are discussed. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) technology has expanded in the last decades with significant improvements in the reliability, sequencing chemistry, pipeline analyses, data interpretation and costs. Such advances make the use of NGS feasible in clinical practice today. This review describes the recent technological developments in NGS applied to the field of oncology. A number of clinical applications are reviewed, i.e., mutation detection in inherited cancer syndromes based on DNA-sequencing, detection of spliceogenic variants based on RNA-sequencing, DNA-sequencing to identify risk modifiers and application for pre-implantation genetic diagnosis, cancer somatic mutation analysis, pharmacogenetics and liquid biopsy. Conclusive remarks, clinical limitations, implications and ethical considerations that relate to the different applications are provided. [ABSTRACT FROM AUTHOR]

Macrophages play a crucial role in all stages of cutaneous wound healing responses and dysregulation of macrophage function can result in derailed wound repair. The phenotype of macrophages is influenced by the wound microenvironment and evolves during healing from a more pro-inflammatory (M1) profile in early stages, to a less inflammatory pro-healing (M2) phenotype in later stages of repair. The aim of the current study was to investigate the potential of exogenous administration of M2 macrophages to promote wound healing in an experimental mouse model of cutaneous injury. Bone marrow derived macrophages were stimulated in-vitro with IL-4 or IL-10 to obtain two different subsets of M2-polarized cells, M2a or M2c respectively. Polarized macrophages were injected into full-thickness excisional skin wounds of either C57BL/6 or diabetic db/db mice. Control groups were injected with non-polarized (M0) macrophages or saline. Our data indicate that despite M2 macrophages exhibit an anti-inflammatory phenotype in-vitro, they do not improve wound closure in wild type mice while they delay healing in diabetic mice. Examination of wounds on day 15 post-injury indicated delayed re-epithelialization and persistence of neutrophils in M2 macrophage treated diabetic wounds. Therefore, topical application of ex-vivo generated M2 macrophages is not beneficial and contraindicated for cell therapy of skin wounds. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation and oxidative stress play fundamental roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). Previously, we reported that myeloperoxidase (MPO), an aggressive oxidant-generating neutrophil enzyme, is associated with NASH severity in man. We now investigated the hypothesis that MPO contributes to the development and progression of NASH. Methodology: Low-density lipoprotein receptor-deficient mice with an MPO-deficient hematopoietic system (LDLR-/-/MPO-/-tp mice) were generated and compared with LDLR-/-/MPO+/+tp mice after induction of NASH by high-fat feeding. Results: High-fat feeding caused a ,4-fold induction of liver MPO in LDLR-/-/MPO+/+ mice which was associated with hepatic sequestration of MPO-positive neutrophils and high levels of nitrotyrosine, a marker of MPO activity. Importantly, LDLR-/-/MPO-/-tp mice displayed markedly reduced hepatic neutrophil and T-lymphocyte infiltration (p<0.05), and strong down regulation of pro-inflammatory genes such as TNF-α and IL-6 (p<0.05, p<0.01) in comparison with LDLR-/-/MPO+/+tp mice. Next to the generalized reduction of inflammation, liver cholesterol accumulation was significantly diminished in LDLR-/-/MPO-/-tp mice (p = 0.01). Moreover, MPO deficiency appeared to attenuate the development of hepatic fibrosis as evident from reduced hydroxyproline levels (p<0.01). Interestingly, visceral adipose tissue inflammation was markedly reduced in LDLR-/-/MPO-/-tp mice, with a complete lack of macrophage crown-like structures. In conclusion, MPO deficiency attenuates the development of NASH and diminishes adipose tissue inflammation in response to a high fat diet, supporting an important role for neutrophils in the pathogenesis of metabolic disease. [ABSTRACT FROM AUTHOR]

Endometriosis is defined as the presence of endometrial tissue outside the uterus. It affects 10-15% of women during reproductive age and has a big personal and social impact due to chronic pelvic pain, subfertility, loss of work-hours and medical costs. Such conditions are exacerbated by the fact that the correct diagnosis is made as late as 8-11 years after symptom presentation. This is due to the lack of a reliable non-invasive diagnostic test and the fact that the reference diagnostic standard is laparoscopy (invasive, expensive and not without risks). High-molecular weight gadofosvesettrisodium is used as contrast agent in Magnetic Resonance Imaging (MRI). Since it extravasates from hyperpermeable vessels more easily than from mature blood vessels, this contrast agent detects angiogenesis efficiently. Endometriosis has high angiogenic activity. Therefore, we have tested the possibility to detect endometriosis non-invasively using Dynamic Contrast-Enhanced MRI (DCE-MRI) and gadofosveset-trisodium as a contrast agent in a mouse model. Endometriotic lesions were surgically induced in nine mice by autologous transplantation. Three weeks after lesion induction, mice were scanned by DCE-MRI. Dynamic image analysis showed that the rates of uptake (inwash), persistence and outwash of the contrast agent were different between endometriosis and control tissues (large blood vessels and back muscle). Due to the extensive angiogenesis in induced lesions, the contrast agent persisted longer in endometriotic than control tissues, thus enhancing the MRI signal intensity. DCE-MRI was repeated five weeks after lesion induction, and contrast enhancement was similar to that observed three weeks after endometriosis induction. The endothelial-cell marker CD31 and the pericyte marker asmooth- muscle-actin (mature vessels) were detected with immunohistochemistry and confirmed that endometriotic lesions had significantly higher prevalence of new vessels (CD31 only positive) than the uterus and control tissues. The diagnostic value of gadofosveset-trisodium to detect endometriosis should be tested in human settings. [ABSTRACT FROM AUTHOR]

Activation of the transcription factor NF-&kgr;B appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-&kgr;B inhibitor I&kgr;Bα in atherosclerosis. Myeloid-specific deletion of I&kgr;Bα results in larger and more advanced lesions in LDL-R-deficient mice without affecting the compositional phenotype of the plaques or systemic inflammatory markers in the plasma. We show that IkBa-deleted macrophages display enhanced adhesion to an in vitro endothelial cell layer, coinciding with an increased expression of the chemokine CCL5. Also, in vivo we found that IkBαdel mice had more leukocytes adhering to the luminal side of the endothelial cell layers that cover the atherosclerotic plaques. Moreover, we introduce ER-MP58 in this paper as a new immunohistochemical tool for quantifying newly recruited myeloid cells in the atherosclerotic lesion. This staining confirms that in IkBαdel mice more leukocytes are attracted to the plaques. In conclusion, we show that I&kgr;Bα deletion in myeloid cells promotes atherogenesis, probably through an induced leukocyte recruitment to plaques. [ABSTRACT FROM AUTHOR]

Background: The p38&agr; Mitogen-Activated Protein Kinase (MAPK) regulates stress- and inflammation-induced cellular responses. Factors implicated in the development of atherosclerosis including modified low-density lipoprotein (LDL), cytokines and even shear stress induce p38 activation in endothelial cells and macrophages, which may be important for plaque formation. This study investigates the effects of endothelial- and macrophage-specific deficiency of p38&agr; in atherosclerosis development, in Apolipoprotein E deficient (ApoE-/-) mice. Methodology/Principal Findings: ApoE-/- mice with macrophage or endothelial cell-specific p38&agr; deficiency were fed a high cholesterol diet (HCD) for 10 weeks and atherosclerosis development was assessed by histological and molecular methods. Surprisingly, although p38&agr;-deficiency strongly attenuated oxidized LDL-induced expression of molecules responsible for monocyte recruitment in endothelial cell cultures in vitro, endothelial-specific p38&agr; ablation in vivo did not affect atherosclerosis development. Similarly, macrophage specific deletion of p38&agr; did not affect atherosclerotic plaque development in ApoE-/- mice. Conclusions: Although previous studies implicated p38&agr; signaling in atherosclerosis, our in vivo experiments suggest that p38&agr; function in endothelial cells and macrophages does not play an important role in atherosclerotic plaque formation in ApoE deficient mice. [ABSTRACT FROM AUTHOR]

Background: The aim of the current study was to investigate the role of p55 TNF Receptor (p55 TNFR), the main signaling receptor for the pro-inflammatory cytokine tumor necrosis factor (TNF), in the development of two vascular disorders: atherosclerosis and angiotensin (Ang) II-induced abdominal aortic aneurysms (AAA). Methodology/Principal Findings: p55 TNFR deficient mice were crossed to an LDL receptor deficient background and were induced for the development of either atherosclerosis or AngII-induced AAA, and compared to littermate controls, wild-type for p55 TNFR expression. p55 TNFR deficient mice developed 43% smaller atherosclerotic lesions in the aortic sinuses compared to controls. Moreover, expression of CD68, a macrophage specific marker, exhibited a 50% reduction in the aortic arches. Decreased atherosclerosis correlated with a strong down-regulation in the expression of adhesion molecules, such as VCAM-1 and ICAM-1, by p55 TNFR deficient endothelium. In addition, expression levels of the pro-inflammatory cytokines and chemokines TNF, IL-6, MCP-1 and RANTES were significantly reduced in aortas of p55 TNFR deficient mice. In contrast, in the AngII-induced model of AAA, p55 TNFR deficiency correlated with a slight trend towards increased aneurismal lethality, but the incidence of aortic rupture due to a dissecting aneurysm, and the expansion of the suprarenal aorta were not significantly different compared to controls. Conclusion/Significance: We found that p55 TNFR expression promotes atherosclerosis, among other mechanisms, by enhancing expression of endothelial adhesion molecules, while it seems to have no major role in the development of AngIIinduced AAA. [ABSTRACT FROM AUTHOR]

Using targeted mutagenesis in mice, we have blocked shedding of endogenous murine TNF by deleting its cleavage site. Mutant mice produce physiologically regulated levels of transmembrane TNF (tmTNF), which suffice to support thymocyte proliferation but cannot substitute for the hepatotoxic activities of wild-type TNF following LPS/-galactosamine challenge in vivo and are not sufficient to support secondary lymphoid organ structure and function. Notably, however, tmTNF is capable of exerting anti-Listerial host defenses while remaining inadequate to mediate arthritogenic functions, as tested in the tristetraprolin-deficient model of TNF-dependent arthritis. Most interestingly, in the EAE model of autoimmune demyelination, tmTNF suppresses disease onset and progression and retains the autoimmune suppressive properties of wild-type TNF. Together, these results indicate that tmTNF preserves a subset of the beneficial activities of TNF while lacking detrimental effects. These data support the hypothesis that selective targeting of soluble TNF may offer several advantages over complete blockade of TNF in the treatment of chronic inflammation and autoimmunity. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is the most common gynaecological malignancy in Western society and the majority of cases are estrogen dependent. While endocrine drugs proved to be of insufficient therapeutic value in the past, recent clinical research shows promising results by using combinational regimens and pre-clinical studies and identified potential novel endocrine targets. Relevant pre-clinical models can accelerate research in this area. In the present study we describe an orthotopic and estrogen dependent xenograft mouse model of EC. Tumours were induced in one uterine horn of female athymic nude mice using the well-differentiated human endometrial adenocarcinoma Ishikawa cell line—modified to express the luciferase gene for bioluminescence imaging (BLI). BLI and contrast-enhanced computed-tomograph (CE-CT) were used to measure non-invasive tumour growth. Controlled estrogen exposure was achieved by the use of MedRod implants releasing 1.5 μg/d of 17β-estradiol (E2) in ovariectomized mice. Stable E2 serum concentration was demonstrated by LC-MS/MS. Induced tumours were E2 responsive as increased tumour growth was observed in the presence of E2 but not placebo, assessed by BLI, CE-CT, and tumour weight at sacrifice. Metastatic spread was assessed macroscopically by BLI and histology and was seen in the peritoneal cavity, in the lymphovascular space, and in the thoracic cavity. In conclusion, we developed an orthotopic xenograft mouse model of EC that exhibits the most relevant features of human disease, regarding metastatic spread and estrogen dependency. This model offers an easy to manipulate estrogen dosage (by simply adjusting the MedRod implant length), image-guided monitoring of tumour growth, and objectively measurable endpoints (including tumour weight). This is an excellent in vivo tool to further explore endocrine drug regimens and novel endocrine drug targets for EC. [ABSTRACT FROM AUTHOR]

Vitamin K2 (menaquinone) concentrations were measured in a wide range of cheeses and the effects of fat content, ripening and origin of the cheeses were investigated. Moreover, the menaquinone content of cheese was compared with that of other foods known to contain vitamin K2. It was found that cheese and curd are the most important sources of long-chain menaquinones in the Western diet and, in general, hard cheeses are richer in menaquinones than soft cheeses. However, the actual menaquinone content varies substantially and is dependent on the type of cheese, the time of ripening, the fat content and the geographic area where the cheeses are produced. Given the fact that poor vitamin K status has been mentioned as a risk factor for cardiovascular disease and mortality, while there is no clear evidence for adverse cardiovascular effects of dairy fats, cheese should be considered as a recommendable component in a heart-healthy diet. [ABSTRACT FROM AUTHOR]

Background: The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer., Methods: A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis., Results: A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype., Conclusion: A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.

Purpose of Review: Atherosclerosis is a chronic inflammatory disease of the medium and large-sized arteries. Nuclear factor kappaB transcription factors are major regulators of inflammatory responses, and aberrant nuclear factor kappaB regulation is linked to a large number of diseases. Focusing on macrophages, this review will discuss recent literature on the role of nuclear factor kappaB and the signaling pathways regulating its activity in atherosclerosis., Recent Findings: After the initial identification of activated nuclear factor kappaB in human atherosclerotic lesions, the involvement of this family of transcription factors in atherogenesis has gained growing attention. It is now clear that signaling pathways activating nuclear factor kappaB, and nuclear factor kappaB action, constitute major players at all stages of the atherosclerotic process. Long considered a pro-atherogenic factor, recent studies indicate that the actual role of nuclear factor kappaB might prove to be far more complex. Apart from activating many pro-inflammatory genes linked to atherogenesis, nuclear factor kappaB regulates cellular processes such as cell survival and proliferation. In addition, its important role in inflammatory resolution and anti-inflammatory gene transcription suggests that its activation at different cell types or different stages of the atherosclerotic process might have distinct and opposing results., Summary: The numerous diseases in which aberrant nuclear factor kappaB action is found to play a crucial role makes it an intensively studied target for drug interventions. However, given its pleiotropic functions in inflammation and immunity, a more targeted modulation of its activity, at a cell type-specific or disease stage-specific level, could provide safer therapeutic solutions.

Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor-dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.