Prostate cancer (PC) bone metastases (BM) is a debilitating disease morbidity that primarily affects the axial skeleton. PCBM are associated to a variety of bone alterations from increased bone density (osteosclerotic), to reduced bone density (osteolytic). Structurally, PCBM present with irregular bone distribution, loss of collagen alignment and increased porosity that mimic features of woven bone that forms during development, but is not replaced by normal trabecular bone. The irregular woven bone structure persists and adversely affects bone strength and predisposing to fractures. We hypothesize that PCBMs induce dysregulated repair-like bone remodeling activity leading to distinct protein signatures that correlate with the extent of osteosclerotic and osteolytic characteristics in different PCBM subtypes. We performed tandem mass spectrometry to measure the protein composition of lumbar vertebrae specimens from 3 age-matched controls and 32 cadaveric PCBM specimens: 17 defined as osteosclerotic and 15 as osteolytic based on microcomputed tomography bone volume vs total volume measurements. We employed unsupervised hierarchical clustering and dimension reduction techniques to cluster specimens with distinct protein composition profiles. Differential expression analysis was correlated with PC histopathological in the respective vertebrae. A 20-protein signature was assessed for the ability to segregate PCBM specimens based on expression of the respective transcripts in publicly available RNA sequencing databases of primary and metastatic prostate cancer specimens. Osteosclerotic PCBM specimens are enriched in bone sialoprotein 2, osteopontin, osteonectin, and the proteoglycans osteomodulin, lumican, biglycan and decorin. While osteolytic specimens exhibit elevated levels of cathepsin G, myeloblastin, and neutrophil elastase compared to the osteosclerotic specimens. Unsupervised clustering segregated the 3 control samples and 17 osteosclerotic samples into distinct groups. The 15 osteolytic samples separated into three subgroups: one clustering with controls (n=3), one exhibiting features that overlap with osteosclerotic lesions (n=6), and one unique osteolytic group (n=6). The differences in protein distribution are also associated to the histological characterisation of the specimens and surprisingly, with lesion transcript profiles from PCBMs in 3 annotated datasets. Proteomic profiling revealed differences between predominantly osteosclerotic and osteolytic PCBM that highlight altered mineralization processes, and suggesting potential biomarkers PCBM. The osteosclerotic samples are characterized by proteins that promote bone production and mineralization. The osteolytic lesions displayed signatures of immune cell activity. The proteomic segregation of three PCBM molecular subtypes demonstrates the sensitivity of MS-based analysis, highlighting its promise for further characterizing PCBM subtypes. Dennis Xie, Felipe Eltit, Bita Mojtahedzadeh, Raphaele Charest-Morin, Colm Morriessey, Eva Corey, Lawrence D. True, Michael C. Haffner, Michael E. Cox. Proteomics Classification of Prostate Cancer Bone Metastases [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A076.

Giant cell tumors of bone (GCTB) are rare but aggressive, locally destructive tumors. They typically affect young people, significantly reducing their quality of life and increasing mortality rates. Giant cell tumors of bone are composed of osteoclast-like giant cells that respond to increased secretion of RANKL by stromal cells, triggering osteolysis. For over a decade, denosumab, a monoclonal antibody targeting this receptor activator, has been approved as a neo-adjuvant to facilitate surgical resection or in the setting of inoperable tumors. Denosumab treatment has shown rapid pain improvement and tumor size reduction in the spine. Although variable degrees of tumor mineralization have been observed in clinical applications of this drug, the nature of this newly formed mineralized tissue has yet to be determined. To characterize both mineralization and collagen organization in the newly formed bone, we conducted extensive analyses on 4 posttreatment giant cell tumor vertebral samples, involving quantitative backscattered imaging, electron probe microanalysis, and a novel method for determining the alignment of collagen fibrils using second harmonic generation. Additionally, biological mechanisms involved in bone mineralization and matrix formation were analyzed using histological staining and mass spectroscopy. Our results concluded that denosumab treatment after giant cell tumor of bone in the spine was associated with the formation of woven bone and increased mineral density in a matrix of disorganized collagen fibers characterized by increased collagen III content, with the response appearing to depend on patient age and extension of treatment. To our knowledge, this is the first comprehensive material-based study on the bone formed during denosumab treatment for GCTB, providing valuable information on how denosumab affects bone quality and how the reported methodology can be applied to similar studies.

Cobalt-chromium alloys are widely used in orthopedic implants due to their excellent toughness, wear resistance, and biocompatibility. However, cobalt ions released as consequence of corrosion or wear, trigger cytokine secretion and promote inflammation and pain in periprosthetic tissues. Transient receptor potential (TRP) channels are a family of voltage-dependent Ca2+ permeable channels involved in various physiological and pathological processes. Because of their permeability and modulation by divalent cations, we studied how TRP channels’ activity is influenced by cobalt ions. We used primary human synovial fibroblasts and through qPCR we found relevant expression of TRPC1, TRPC4, TRPV2, TRPV4, TRPM4 and TRPM7 mRNA in synovial fibroblasts. Next, we exposed synovial fibroblasts to cobalt ions and/or selective pharmacology of TRPV2 and TRPV4 channels. We observed that TRPV2 and TRPV4 are sensitized by cobalt exposure, increasing intracellular calcium in synovial fibroblasts. Furthermore, exposure to TRPV2 and TRPV4 antagonists inhibited the basal long-term intracellular calcium increase, and reduced the secretion of IL-6, IL-8, TNF-a, and VEGF-a triggered by cobalt exposure. However, the sole activation of TRPV2 and TRPV4 did not trigger secretion or expression of these cytokines. Our findings demonstrate for the first time that metal ions released from orthopedic implants, can modulate the function of TRP channels and may contribute to the pathogenesis of fibrosis and inflammation associated with biomedical implants. Notably, we propose a molecular mechanism in which TRPV2 and TRPV4 channels are potentially involved in mediating inflammatory and fibrotic responses in peri-implant tissues. However, further studies are necessary to elucidate the regulatory role of cytosolic calcium in the development of adverse local tissue reactions.

Prostate cancer frequently metastasizes to bone, leading to a spectrum of osteosclerotic and osteolytic lesions that cause debilitating symptoms. Accurate differentiation of bone tissue or lesion types can provide opportunity for local pathologic investigation, which is critical for understanding the bone metastasis and remains challenging. Current imaging methods lack the ability to directly differentiate tissues based on collagen organization and may induce invasive effect on bone tissues. We introduce Polarization-Sensitive Optical Coherence Tomography (PS-OCT) to investigate normal, osteosclerotic, and osteolytic bone tissues. High-resolution PS-OCT imaging reveals collagen fiber arrangement, enabling nuanced distinction of degree of collagen alignment among different bone tissue types or regions. We present a novel feature named degree of ordered organization (DOO), derived from the multiple contrasts of PS-OCT that can quantitatively evaluate bone samples from different pathologic groups, including control,osteoblastic and osteolytic tissues. The capacity of PS-OCT to differentiate trabecular/lamellar and irregular (woven bone) regions within the same specimen is tested and validated on ex-vivo samples extracted from 13 subjects. Our study is the first time that PS-OCT is applied to metastatic bone disease with the aim of enhancing the understanding of bone-related pathologies, and potentially impacting clinical practice. This work demonstrates that PS-OCT can provide useful insight into bone microstructures, and thus it has potential applications across diverse bone disorders.### Competing Interest StatementThe authors have declared no competing interest.

Currently available animal models for calcium oxalate kidney stones are limited in their translational potential. Particularly with increasing interest in gut microbiota involvement in kidney stone disease, there are limited animal models which can be used. As such, we have developed a novel diet-induced hyperoxaluria murine model which addresses some of the shortcomings of other currently available models. Mice C57BL/6 mice were fed a 1.5

Bone metastases are the most severe and prevalent consequences of prostate cancer (PC), affecting more than 80% of patients with advanced PC. PCBMs generate pain, pathological fractures, and paralysis. As modern therapies increase survival, more patients are suffering from these catastrophic consequences. Radiographically, PCBMs are predominantly osteosclerotic, but the mechanisms of abnormal bone formation and how this pathological increase in bone density is related to fractures are unclear. In this study, we conducted a comprehensive analysis on a cohort of 76 cadaveric PCBM specimens and 12 cancer-free specimens as controls. We used micro-computed tomography to determine 3D organization and quantify bone characteristics, quantitative backscattering electron microscopy to characterize mineral content and details in bone structure, nanoindentation to determine mechanical properties, and histological and immunohistochemical analysis of bone structure and composition. We define 4 PCBM phenotypes: osteolytic, mixed lytic-sclerotic, and 2 subgroups of osteosclerotic lesions-those with residual trabeculae, and others without residual trabeculae. The osteosclerotic lesions are characterized by the presence of abnormal bone accumulated on trabeculae surfaces and within intertrabecular spaces. This abnormal bone is characterized by higher lacunae density, abnormal lacunae morphology, and irregular lacunae orientation. However, mineral content, hardness, and elastic modulus at micron-scale were indistinguishable between this irregular bone and residual trabeculae. The collagen matrix of this abnormal bone presents with irregular organization and a prominent collagen III composition. These characteristics suggest that osteosclerotic PCBMs initiate new bone deposition as woven bone; however, the lack of subsequent bone remodeling, absence of lamellar bone deposition on its surface, and presence of collagen III distinguish this pathologic matrix from conventional woven bone. Although the mineralized matrix retains normal bone hardness and stiffness properties, the lack of fibril anisotropy presents a compromised trabecular structure, which may have clinical implications.

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology (PD12)1 May 2024PD12-06 THE IMPACT OF URINARY MICROBIOTA COMPOSITION ON IMMUNE AND INFLAMMATORY RESPONSES IN A HEALTHY MOUSE MODEL Dalia Othman, Igor Moskalev, Ana Luque-Badillo, Cesar Monjaras-Avila, Sarah Hanstock, Felipe Eltit, Sheryl Munshan, Breanna Nelson, Alberto Contreras-Sanz, Peter Black, and Dirk Lange Dalia OthmanDalia Othman , Igor MoskalevIgor Moskalev , Ana Luque-BadilloAna Luque-Badillo , Cesar Monjaras-AvilaCesar Monjaras-Avila , Sarah HanstockSarah Hanstock , Felipe EltitFelipe Eltit , Sheryl MunshanSheryl Munshan , Breanna NelsonBreanna Nelson , Alberto Contreras-SanzAlberto Contreras-Sanz , Peter BlackPeter Black , and Dirk LangeDirk Lange View All Author Informationhttps://doi.org/10.1097/01.JU.0001008772.30001.48.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recent discoveries identified the existence of the urinary microbiota in the bladder. Although previous work has investigated urinary microbiota composition across healthy and diseased states, no efforts have explored its actual role in the bladder. Given pre-existing evidence that commensal microbiota affects immune responses, we hypothesize the urinary microbiota of the bladder may affect the local immune response. In bladder cancer (BCa), intravesical Bacillus Calmette-Guérin (BCG) treatment acts as an immunostimulatory agent to prevent recurrence in non-muscle invasive bladder cancer (NMIBC). The objective of this study was to examine the role of urinary microbiota composition in determining bladder immune responses in a healthy environment, using BCG as an immunostimulatory agent. METHODS: To assess the role of the urinary microbiome on the BCG-induced inflammatory response, mice underwent ultrasound-guided instillation of BCG into the bladder lumen. The mice had either a healthy or a disrupted urinary microbiota. Disruption was achieved through antibiotic (gentamicin or clindamycin) instillation prior to BCG treatment. Whole bladder, spleen, and bladder-draining lymph node tissue was collected to assess changes in immune cell populations through fluorescence-activated cell sorting (FACS) and histology. RESULTS: FACS analysis observed significant shifts across immune cell populations. Gentamicin instillation induced a pro-inflammatory environment through elevated M1 and reduced M2 macrophages, compared to control. Subsequent BCG treatment shifted the environment towards an anti-inflammatory response by increasing M2 and reducing M1 macrophages, which was also observed in mice with a healthy microbiota. Immunohistochemistry of bladder tissue similarly reflected the FACs analysis findings. Hematoxylin and eosin staining of bladder sections demonstrated significant irritation of the urothelium lining, with urothelial cell shedding observed. CONCLUSIONS: Urinary microbiota composition may be an important mediator of immune responses in the healthy bladder. Current work is investigating its impact on mediating key immune responses in the treatment of NMIBC, as it may be a target to improve responsiveness to BCG treatment. Source of Funding: Lotte & John Hecht Memorial FoundationCanadian Urological Association Scholarship Foundation © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e258 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Dalia Othman More articles by this author Igor Moskalev More articles by this author Ana Luque-Badillo More articles by this author Cesar Monjaras-Avila More articles by this author Sarah Hanstock More articles by this author Felipe Eltit More articles by this author Sheryl Munshan More articles by this author Breanna Nelson More articles by this author Alberto Contreras-Sanz More articles by this author Peter Black More articles by this author Dirk Lange More articles by this author Expand All Advertisement PDF downloadLoading ...

To explore the pathways and mechanisms driving inflammation and fibrosis in stented ureters. In total, six healthy female pigs underwent cystoscopic unilateral ureteral stent insertion (6 Fr). After 14 days indwelling time, ureteral tissue was harvested in three pigs, while the remaining three pigs had their stents removed, and were recovered for 7 days. Three separate pigs served as controls. Tissue from stented and contralateral ureters was analysed histologically to evaluate tissue remodelling and classify the degree of inflammation and fibrosis, while genome, proteome and immunohistochemistry analysis was performed to assess changes at the transcriptional and translational levels. Finally, immunofluorescence was used to characterize the cell composition of the immune response and pathways involved in inflammation and fibrosis. Statistical analysis was performed using GraphPad Prism and RStudio for Welch ANOVA, Kruskal–Wallis and Dunnett’s T3 multiple comparison test. Stents cause significant inflammation and fibrosis of ureters. Gene set enrichment analysis confirmed fibrotic changes and tissue proliferation and suggests that epithelial–mesenchymal transition is a driver of fibrosis. Moreover, IL-6/JAK/STAT and TNFα via NF-κB signalling might contribute to chronic inflammation promoting a profibrotic environment. Immunostaining confirmed epithelial–mesenchymal transition in the urothelium and NF-κB expression in ureters stented for 14 days. Tissue alterations do not fully recover after 7 days. Histological evaluation showed that contralateral, unstented ureters are affected by mild inflammation. Our study showed that stenting has a significant impact on the ureter. Chronic inflammation and epithelial–mesenchymal transition are drivers of fibrosis, potentially impairing ureteral functionality in the long term. Furthermore, we observed mild inflammation in contralateral, unstented ureters.

Hemostasis preserves blood fluidity and prevents its loss after vessel injury. The maintenance of blood fluidity requires a delicate balance between pro-coagulant and fibrinolytic status. Endothelial cells (ECs) in the inner face of blood vessels maintain hemostasis through balancing anti-thrombotic and pro-fibrinolytic activities. Dyslipidemias are linked to hemostatic alterations. Thus, it is necessary a better understanding of the underlying mechanisms linking hemostasis with dyslipidemia. Statins are drugs that decrease cholesterol levels in the blood and are the gold standard for treating hyperlipidemias. Statins can be classified into natural and synthetic molecules, approved for the treatment of hypercholesterolemia. The classical mechanism of action of statins is by competitive inhibition of a key enzyme in the synthesis pathway of cholesterol, the HMG-CoA reductase. Statins are frequently administrated by oral ingestion and its interaction with other drugs and food supplements is associated with altered bioavailability. In this review we deeply discuss the actions of statins beyond the control of dyslipidemias, focusing on the actions in thrombotic modulation, vascular and cardiovascular-related diseases, metabolic diseases including metabolic syndrome, diabetes, hyperlipidemia, and hypertension, and chronic diseases such as cancer, chronic obstructive pulmonary disease, and chronic kidney disease. Furthermore, we were prompted to delved deeper in the molecular mechanisms by means statins regulate coagulation acting on liver, platelets, and endothelium. Clinical evidence show that statins are effective regulators of dyslipidemia with a high impact in hemostasis regulation and its deleterious consequences. However, studies are required to elucidate its underlying molecular mechanism and improving their therapeutical actions.

Prostate-specific membrane antigen (PSMA) is expressed in epithelial cells of the prostate gland and is strongly upregulated in prostatic adenocarcinoma, with elevated expression correlating with metastasis, progression, and androgen independence. Because of its specificity, PSMA is a major target of prostate cancer therapy; however, detectable levels of PSMA are also found in other tissues, especially in salivary glands and kidney, generating bystander damage of these tissues. Antibody target therapy has been used with relative success in reducing tumor growth and prostate specific antigen (PSA) levels. However, since antibodies are highly stable in plasma, they have prolonged time in circulation and accumulate in organs with an affinity for antibodies such as bone marrow. For that reason, a second generation of PSMA targeted therapeutic agents has been developed. Small molecules and minibodies have had promising clinical trial results, but concerns about their specificity had arisen with side effects due to accumulation in salivary glands and kidneys. Herein we study the specificity of small molecules and minibodies that are currently being clinically tested. We observed a high affinity of these molecules for PSMA in prostate, kidney and salivary gland, suggesting that their effect is not prostate specific. The search for specific prostate target agents must continue so as to optimally treat patients with prostate cancer, while minimizing deleterious effects in other PSMA expressing tissues.

Background: High-density lipoprotein (HDL) is recognized as a protective factor against several vascular diseases. Oxidative stress derived from severe systemic inflammation promotes conversion from HDL to oxidized HDL (oxHDL), which circulates in the bloodstream directly interacting with vascular endothelial cells (ECs). oxHDL not only loses its atheroprotective properties, but acquires procoagulant features, indicating a role for oxHDL in the modulation of coagulant status. Indeed, some studies have shown that oxHDL modulates both blood coagulation and fibrinolysis. Importantly, oxHDL plasma level have been linked with organ failure in UCI patients. However, whether oxHDL elicits a ECs-mediated procoagulant phenotype generating organ failure and death, and the underlying molecular mechanism is not known. Therefore, we sought to determine whether oxHDL-treated rats and high-oxHDL ICU patients exhibit a procoagulant phenotype and its association with kidney injury and mortality. Moreover, we investigated whether oxHDL induces a procoagulant protein expression reprograming in ECs to elucidate the underlying molecular mechanism for this condition.Methods: Human ECs, oxHDL-treated rats and ICU patients were subjected to several cellular and molecular studies, coagulation analyses, kidney injury assessment and mortality determination.Results: ECs exposed to oxHDL, but not to HDL, modifies the endothelial protein expression profile acquiring procoagulant features. Importantly, rats treated with oxHDL, but not HDL-treated, exhibited a procoagulant phenotype characterized by acute kidney injury and increased risk of death. Noteworthy, ICU patients showed increased levels of oxHDL associated with altered coagulation factors, acute kidney injury and increased risk of death.Conclusion: Increased circulating oxHDL generates an endothelial-dependent procoagulant phenotype that associates with acute kidney injury and increased risk of death.

Sepsis syndrome is a highly lethal uncontrolled response to an infection, which is characterized by sepsis-induced coagulopathy (SIC). High-density lipoprotein (HDL) exhibits antithrombotic activity, regulating coagulation in vascular endothelial cells. Sepsis induces the release of several proinflammatory molecules, including reactive oxygen species, which lead to an increase in oxidative stress in blood vessels. Thus, circulating lipoproteins, such as HDL, are oxidized to oxHDL, which promotes hemostatic dysfunction, acquiring prothrombotic properties linked to the severity of organ failure in septic-shock patients (SSP). However, a rigorous and comprehensive investigation demonstrating that oxHDL is associated with a coagulopathy-associated deleterious outcome of SSP, has not been reported. Thus, we investigated the participation of plasma oxHDL in coagulopathy-associated sepsis pathogenesis and elucidated the underlying molecular mechanism. A prospective study was conducted on 42 patients admitted to intensive care units, (26 SSP and 16 non-SSP) and 39 healthy volunteers. We found that an increased plasma oxHDL level in SSP was associated with a prothrombotic phenotype, increased mortality and elevated risk of death, which predicts mortality in SSP. The underlying mechanism indicates that oxHDL triggers an endothelial protein expression reprogramming of coagulation factors and procoagulant adhesion proteins, to produce a prothrombotic environment, mainly mediated by the endothelial LOX-1 receptor. Our study demonstrates that an increased plasma oxHDL level is associated with coagulopathy in SSP through a mechanism involving the endothelial LOX-1 receptor and endothelial protein expression regulation. Therefore, the plasma oxHDL level plays a role in the molecular mechanism associated with increased mortality in SSP.

The immune system is the first defense against potentially dangerous chemicals, infections, and damaged cells. Interactions between immune cells and inflammatory mediators increase the coordinated activation of cross-talking signaling pathways, resulting in an acute response necessary to restore homeostasis but potentially detrimental if uncontrolled and prolonged. Plastic production exceeds million tons per year, becoming a global concern due to the stability of its constituent polymers, low density, which allows them to spread easily, and small size, which prevents proper removal by wastewater treatment plants, promoting environmental accumulation and increasing health threats. The interaction between plastic particles and the immune system is still being investigated, owing to growing evidence of increased risk not only for dietary intake due to its presence in food packaging, drinking water, and even fruits and vegetables, but also to emerging evidence of new intake pathways such as respiratory and cutaneous. We discuss in depth the impact of small plastic particles on the immune response across the body, with a focus on the nervous system and peripheral organs and tissues such as the gastrointestinal, respiratory, lymphatic, cardiovascular, and reproductive systems, as well as the involvement in increased susceptibility to worsening concomitant diseases and future perspectives in the exploration of potential therapeutics.

Resumen Antecedentes Las reacciones tisulares adversas (RTAs) a implantes de cadera afectan a una alta proporción de pacientes. Si bien fueron inicialmente descritas en articulaciones de metal sobre metal, un creciente número de estudios señala su presencia en otros tipos de implante. El gran número de pacientes con prótesis de cadera en el mundo señala la urgencia de comprender cabalmente los mecanismos que dan origen a RTAs para el desarrollo de alternativas de monitoreo, diagnóstico y terapéuticas eficientes. Ámbito de revisión y público objetivo En la siguiente revisión bibliográfica, abarcamos desde la corrosión y el desgaste de los materiales utilizados en implantes de cadera hasta los mecanismos celulares e inmunológicos involucrados, con el fin de ofrecer una visión actualizada de antecedentes clínicos y científicos a estudiantes, cirujanos ortopédicos e investigadores.

Bone metastases (BM) occur in ~80% of advanced prostate cancer (PC) patients, and are a major cause of morbidity. PCBMs are predominantly osteoblastic with mixed, and lytic regions; all of which compromise bone strength. How PCs alter bone structure is unresolved. Prolonged use of modern androgen receptor (AR) targeting agents has increased development of AR pathway-independent PC phenotypes. We hypothesize that defining the structural changes, cellular composition, and PC classification of PCBM-affected bone will help reveal mechanisms of PCBM pathology, and identify potential therapeutic opportunities. We analyze the 3D structure of 14 cadaveric PCBM lumbar vertebrae using micro-computed tomography (microCT). We performed scanning electron microscopy quantitative backscattering electron (qBSE), and energy-dispersive X-ray spectroscopy (EDX) to determine mineral morphology and composition. We analyzed sequential decalcified sections for collagen structure, fibril orientation, and extracellular matrix composition using bright field and polarized light microscopy. We determined lesion structure and cell distribution from two PCBM vertebral specimens resected during decompression surgery using histology and immunohistochemistry, and characterized PCBM cell populations using single cell RNA sequencing (sc RNA Seq) on one vertebral specimen. MicroCT imaging revealed three distinct dysmorphic bone patterns: 1) osteolytic, defined by thinned broken trabecula of well-organized mineral and collagen structures; 2) osteoblastic, with disorganized matrix deposited on pre-existing trabecula; and 3) osteoblastic, with little, if any, residual trabecula, and dominated by accumulation of disorganized mineralized matrix. qBSE and EDX revealed heterogeneous mineral composition, with higher variability in mineral content. Disorganized matrix had a higher voids or “lacunae” density, poorly organized collagen fiber alignment, and higher decorin and pan-proteoglycan content. Sc RNA Seq revealed a PCBM tumor microenvironment composed of a variety of immune cells, hematopoietic progenitors, and bone resident cells. Importantly, we identified AR-high, AR-low, and double-negative PC cells in the same lesion, with minimum neuroendocrine component. Simultaneous presence of these PC phenotypes was confirmed by immunohistochemistry. Morphologically, AR-positive cells adopt two configurations in PCBM, i) clusters within bone cavities in which cells maintain secretory polarization and resemble prostate acini, and ii) diffuse cells in intimate contact with bone-resident cells that lack polarization. PCBM lesions have abnormal bone structures lacking collagen organization, and with mineral heterogeneity consistent with bone weakness. PC cells interact with bone cells, but how distinct PC phenotypes affect bone turnover and structure need further analysis. Citation Format: Felipe Eltit, Qiong Wang, Raphaële Charest-Morin, Colm Morrissey, Eva Corey, Rizhi Wang, Michael E. Cox. Prostate cancer metastasis induces irregular bone formation associated to specific androgen dependent phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 273.

BACKGROUND:Hydronephrosis and renal impairment may persist even after relieving an obstruction, particularly in cases of chronic obstruction. Obstruction can cause fibrotic changes of the ureter, potentially contributing to long-term kidney damage. OBJECTIVE:To characterise pathophysiological changes of obstructed ureters with focus on inflammatory responses triggering fibrosis and potential impairment of ureteral function. DESIGN, SETTING, AND PARTICIPANTS:Eighty-eight mice were randomly assigned to unilateral ureteral obstruction (UUO) for 2 d, UUO for 7 d, and UUO for 7 d followed by 8 d of recovery, or a control group (no prior surgical intervention). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Peristaltic rate was determined over 2 min by direct visualisation with a microscope, while hydronephrosis was assessed by ultrasound. Obstructed and contralateral ureters were harvested, and underwent histopathological evaluation. We quantified 44 cytokines/chemokines, and five matrix metalloproteases using Luminex technology. Cell composition was characterised via immunofluorescence. Statistical significance was assessed using Welch analysis of variance, Kruskal-Wallis test, and Dunnett's T3 multiple comparison test. RESULTS AND LIMITATIONS:Obstruction resulted in hydronephrosis and significantly impaired peristalsis. Marked fibrosis was observed in lamina propria, muscle layer, and adventitia. Connective tissue in obstructed ureters showed hyperaemia and leucocyte infiltration. Unsupervised hierarchical clustering demonstrated different cytokine/chemokine patterns between groups. Ureters obstructed for 7 d followed by recovery were notably different from other groups. Inflammatory cytokines, chemoattractants, and matrix metalloproteases increased significantly in obstructed ureters. Contralateral unobstructed ureters showed significantly increased levels of chemokines and matrix metalloproteases. Immunofluorescence confirmed activation of T cells, Th1 and Th2 cells, and M1 macrophages in obstructed and contralateral ureters, and a shift to M2 macrophages following prolonged obstruction. CONCLUSIONS:Ureteral obstruction triggers severe inflammation and fibrosis, which may irreversibly impair ureteral functionality. Function of the unobstructed contralateral ureter may be regulated by a systemic immune response as a result of the obstruction. PATIENT SUMMARY:Here, we studied in more detail the way the ureter responds to being blocked. We conclude that a strong immune response is activated by the blockage, leading to changes in the structure of the ureter possibly impacting function, which may not be reversible. This immune response also spreads to the opposite ureter, possibly allowing it to change its function to compensate for the reduced functionality of the blocked ureter.

CoCrMo alloys have been widely used in total hip implants because of their excellent mechanical properties and corrosion resistance. Unfortunately, in the past decade, adverse local tissue reactions (ALTRs) arising from fretting corrosion products of CoCrMo alloys used in hip implants affected a significant number of patients. Despite their importance to the corrosion process and ALTRs, the chemical nature and formation mechanisms of these fretting corrosion particles have not been clearly identified. In this study, we first analyzed the chromium rich corrosion particles retrieved from patients with failed CoCrMo hip implants. We further carried out in vitro fretting experiments to study their nature and formation process. The results showed that the fretting corrosion particles in vivo were mainly amorphous nanoparticles with varying chromium and phosphate contents. Similar particles could be generated in the laboratory fretting tests between CoCrMo and Ti alloy only in simulated body fluid containing P and Ca. Volume loss of CoCrMo during fretting tests also strongly depended on the type of the testing fluid. Volume loss of CoCrMo was almost ten time higher in 0.9% saline solution than phosphate buffered solution and the simulated body fluid. However, such a big difference was not observed in the absence of fretting based on corrosion current densities derived from polarization dynamics. This study clarified the formation process of the fretting particles from CoCrMo hip implants and established proper particle processing protocols for future mechanistic studies at both cellular and tissue levels.

You have accessJournal of UrologyCME1 May 2022MP05-17 INFLAMMATORY CYTOKINES PROMOTE FIBROSIS IN OBSTRUCTED URETERS Alina Reicherz, Felipe Eltit, Khaled Almutairi, Roman Herout, Michael Cox, Ben Chew, and Dirk Lange Alina ReicherzAlina Reicherz More articles by this author , Felipe EltitFelipe Eltit More articles by this author , Khaled AlmutairiKhaled Almutairi More articles by this author , Roman HeroutRoman Herout More articles by this author , Michael CoxMichael Cox More articles by this author , Ben ChewBen Chew More articles by this author , and Dirk LangeDirk Lange More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002522.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To better understand the impact of ureteral obstruction on ureteral tissue, triggered inflammatory response and fibrotic changes. METHODS: Twenty-four murine ureters were obstructed unilaterally for 7 days. 11 mice were euthanized after clamp removal; 13 mice were recovered after clamp removal for 8 days. Unobstructed ureters from 9 mice served as controls. Peristalsis was determined by magnified observation, and hydronephrosis was evaluated by ultrasound. Ureters were harvested, and ureteral tissue was evaluated histologically. 44 cytokines, chemokines and 5 matrix-metalloproteases were quantified using Multiplex panels (Eve Technologies). RESULTS: We observed grade 4 hydronephrosis in all obstructed mice. Similarly, peristalsis was reduced significantly and did not recover fully during the 8 days recovery after clamp removal. Histologically, obstructed ureters showed urothelial changes, fibrosis of lamina propria and adventitia, and thickened muscular layers. Collagen fibres infiltrate the muscular layer of all obstructed ureters but are not observed in non-obstructed ureters. Inflammatory changes in the connective tissue of obstructed ureters are characterized by hyperaemia and leukocytes. Through unsupervised hierarchical clustering, we demonstrate a different cytokine pattern between the groups in which all samples cluster. The highest similarities are observed between the control group and the group of contralateral ureters (ipsilateral side obstructed for 7 days). The group of ureters obstructed for 7 days, and their contralateral ureters are the most different. Consistently, matrix-metalloproteases (MMP-2, MMP-3 and MMP-8) increased significantly after obstruction. Cytokines from T-cell recruitment (IL-16, TARC, MDC) were increased in the obstructed ureter. In addition, the unobstructed, contralateral ureters showed significantly increased levels of cytokines of T-helper cells (Th1: IFN-γ, IL-2, IL-12p40, TNFα; Th2: IL-9, IL-10, IL-13). CONCLUSIONS: Ureteral obstruction triggered a pro-inflammatory response and subsequent fibrosis. These changes seem to impair long-term ureteral functionality. Strikingly, the increase of pro-inflammatory cytokines in the contralateral ureters indicates a systemic effect of unilateral ureteral obstruction. Source of Funding: Alina Reicherz (RE 4611/2-1) is funded by the German Research Foundation (DFG) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e74 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alina Reicherz More articles by this author Felipe Eltit More articles by this author Khaled Almutairi More articles by this author Roman Herout More articles by this author Michael Cox More articles by this author Ben Chew More articles by this author Dirk Lange More articles by this author Expand All Advertisement PDF DownloadLoading ...