Iron Metabolism and Inflammatory Mediators in Patients with Renal Dysfunction.

Chronic kidney disease (CKD) affects around 850 million people worldwide, posing significant challenges in healthcare due to complications like renal anemia, end-stage kidney disease, and cardiovascular diseases. This review focuses on the intricate interplay between iron metabolism, inflammation, and renal dysfunction in CKD. Renal anemia, prevalent in CKD, arises primarily from diminished erythropoietin (EPO) production and iron dysregulation, which worsens with disease progression. Functional and absolute iron deficiencies due to impaired absorption and chronic inflammation are key factors exacerbating erythropoiesis. A notable aspect of CKD is the accumulation of uremic toxins, such as indoxyl sulfate (IS), which hinder iron metabolism and worsen anemia. These toxins directly affect renal EPO synthesis and contribute to renal hypoxia, thus playing a critical role in the pathophysiology of renal anemia. Inflammatory cytokines, especially TNF-α and IL-6, further exacerbate CKD progression and disrupt iron homeostasis, thereby influencing anemia severity. Treatment approaches have evolved to address both iron and EPO deficiencies, with emerging therapies targeting hepcidin and employing hypoxia-inducible factor (HIF) stabilizers showing potential. This review underscores the importance of integrated treatment strategies in CKD, focusing on the complex relationship between iron metabolism, inflammation, and renal dysfunction to improve patient outcomes.

Spontaneous regression of multiple solitary plasmacytoma harboring Epstein-Barr virus: a case report and literature review.

We report a rare case of spontaneous regression (SR) in an elderly untreated patient with multiple solitary plasmacytoma (MSP). Diagnosis of MSP was confirmed through surgical resection of the left nasal cavity mass and subsequent biopsy of the right humerus. The patient was considered ineligible for chemotherapy due to poor performance status. At 3-month post-diagnosis, the patient's condition worsened with deteriorating bone lesions and emergence of a new serum monoclonal protein. However, these clinical findings completely disappeared at 6 months, and positron emission tomography-computed tomography at 1 year confirmed complete metabolic remission. Notably, peripheral blood lymphocyte counts were inversely correlated with tumor progression and remission. Pathological re-evaluation of the initial biopsy specimens revealed programmed cell death protein 1 (PD-1) expression in tumor-infiltrating CD8+ T cells. In addition, tumor cells were infected with Epstein-Barr virus (EBV) but were negative for programmed cell death ligand 1 (PD-L1) expression, which is the most potent immune escape mechanism in tumor cells. While the mechanism underlying SR remains unclear, our findings suggest that host immune response as well as EBV infection may contribute to SR. Further studies are needed to elucidate the clinicopathologic mechanisms of tumor regression in plasma cell neoplasms.

Another cause of treatable dementia: rapid cognitive improvement after carotid endarterectomy. Illustrative case.

BACKGROUND: Revascularization techniques in cervical internal carotid artery (ICA) stenosis are indicated to prevent the onset or recurrence of ischemic events in the setting of atherosclerotic carotid artery disease. Recent reports, case series, and comparative studies have suggested that revascularization techniques may also improve cognitive outcome in both symptomatic and asymptomatic patients, thus raising the question of whether another surgically treatable dementia has presented itself. OBSERVATIONS: A 70-year-old right-handed female with a history of hypertension, diabetes, and bilateral silent cerebral infarcts was evaluated for progressive cognitive impairment over a 1-year period, which was associated with a severe left cervical ICA stenosis. Carotid endarterectomy (CEA) was indicated as a revascularization technique, and the patient showed significant neurocognitive improvement as early as one month postoperatively, consistent with blood flow restoration to the left hemisphere on control imaging. LESSONS: This case serves as a reminder that CEA may improve the cognitive outcome of patients previously impaired by uncomplicated severe cervical ICA atherosclerotic disease, which can be another cause of treatable dementia. Further prospective studies may help to assess this potential benefit.

Seasonal Effects on Relapse of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Retrospective Multicenter Cohort Study in Japan (J-CANVAS).

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a type of systemic vasculitis characterized by autoantibody development against the neutrophil proteins leukocyte proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA. We previously reported that newly developed AAV in Japan was influenced by seasonal variations and that AAV was less frequently observed in autumn.1.

An optimized protocol for isolation of murine pancreatic single cells with high yield and purity.

Here, we present a protocol for rapidly isolating single cells from the mouse pancreas, minimizing damage caused by digestive enzymes in exocrine cells. We guide you through steps to optimize the dissection sequence, enzyme composition, and operational procedures, resulting in high yields of viable pancreatic single cells. This protocol can be applied across a wide range of research areas, including single-cell sequencing, gene expression profiling, primary cell culture, and even the development of spheroids or organoids. For complete details on the use and execution of this protocol, please refer to Jiang et al. (2023).1.

Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which CRC patients take either placebo or EcN for two weeks prior to resection of neoplastic and adjacent normal colorectal tissue (ACTRN12619000210178). We detect enrichment of EcN in tumor samples over normal tissue from probiotic-treated patients (primary outcome of the trial). Next, we develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate. Oral delivery of this strain results in increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. To assess therapeutic potential, we engineer EcN to locally release a cytokine, GM-CSF, and blocking nanobodies against PD-L1 and CTLA-4 at the neoplastic site, and demonstrate that oral delivery of this strain reduces adenoma burden by ~50%. Together, these results support the use of EcN as an orally-deliverable platform to detect disease and treat CRC through the production of screening and therapeutic molecules.

Sutimlimab suppresses SARS-CoV-2 mRNA vaccine-induced hemolytic crisis in a patient with cold agglutinin disease.

Cold agglutinin disease (CAD) is a rare form of acquired autoimmune hemolytic anemia driven mainly by antibodies that activate the classical complement pathway. Several patients with CAD experience its development or exacerbation of hemolysis after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or after receiving the SARS-CoV-2 mRNA vaccine. Therefore, these patients cannot receive an additional SARS-CoV-2 mRNA vaccination and have a higher risk of severe SARS-CoV-2 infection. Sutimlimab is a monoclonal antibody that inhibits the classical complement pathway of the C1s protein and shows rapid and sustained inhibition of hemolysis in patients with CAD. However, whether sutimlimab could also inhibit hemolysis caused by SARS-CoV-2 mRNA vaccination is uncertain. Here, we present the case of a 70-year-old man with CAD who repeatedly experienced a hemolytic crisis after receiving SARS-CoV-2 mRNA vaccines. The patient eventually underwent SARS-CoV-2 mRNA vaccination safely, without hemolytic attack, under classical pathway inhibition therapy with sutimlimab. This report suggests that appropriate sutimlimab administration can suppress SARS-CoV-2 mRNA vaccination-induced CAD exacerbation, and that it could be a preventive strategy to minimize hemolytic attacks in susceptible populations.

Loss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis.

Osteoarthritis (OA) is characterised by an irreversible degeneration of articular cartilage. Here we show that the BMP-antagonist Gremlin 1 (Grem1) marks a bipotent chondrogenic and osteogenic progenitor cell population within the articular surface. Notably, these progenitors are depleted by injury-induced OA and increasing age. OA is also caused by ablation of Grem1 cells in mice. Transcriptomic and functional analysis in mice found that articular surface Grem1-lineage cells are dependent on Foxo1 and ablation of Foxo1 in Grem1-lineage cells caused OA. FGFR3 signalling was confirmed as a promising therapeutic pathway by administration of pathway activator, FGF18, resulting in Grem1-lineage chondrocyte progenitor cell proliferation, increased cartilage thickness and reduced OA. These findings suggest that OA, in part, is caused by mechanical, developmental or age-related attrition of Grem1 expressing articular cartilage progenitor cells. These cells, and the FGFR3 signalling pathway that sustains them, may be effective future targets for biological management of OA.

Slightly Hydrogen-Ordered State of Ice IV Evidenced by In Situ Neutron Diffraction.

Ice IV is a metastable high-pressure phase of ice in which the water molecules exhibit orientational disorder. Although orientational ordering is commonly observed for other ice phases, it has not been reported for ice IV. We conducted in situ powder neutron diffraction experiments for DCl-doped D2O ice IV to investigate its hydrogen ordering. We found abrupt changes in the temperature derivative of unit-cell volume, dV/dT, at ∼120 K, and revealed a slightly ordered structure at low temperatures based on the Rietveld method. The occupancy of the D1 site deviates from 0.5 in particular; it increased when samples were cooled at higher pressures and reached 0.174(14) at 2.38 GPa, 58 K. Our results evidence the presence of a low-symmetry hydrogen-ordered state corresponding to ice IV. It seems, however, difficult to experimentally access the completely ordered phase corresponding to ice IV by slow cooling at high pressure.

A Case of Cystic Retroperitoneal Dedifferentiated Liposarcoma Diagnosed by Percutaneous Image-Guided Biopsy.

Introduction: Dedifferentiated liposarcoma (DDLP) was initially defined as a tumor containing differentiated liposarcoma and distinct regions of nonlipogenic spindle cell or pleomorphic sarcoma. Retroperitoneal liposarcomas feature a characteristic appearance with a predominantly fatty component, and cystic liposarcomas are rare. We describe a case of retroperitoneal DDLP predominantly consisting of multilocular cysts. Case Presentation: A 77-year-old man previously visited a doctor because an echo scan unexpectedly revealed an abdominal tumor. Contrast computed tomography (CT) disclosed a large multilocular cystic tumor spanning from the left upper abdomen to the retroperitoneum, and poorly marginated soft tissue structures were present around the abdominal aorta, inferior vena cava, pancreas, mesentery, and left kidney. CT also revealed a right lung mass. The soft tissue structures in the retroperitoneal cystic tumor and right lung mass were strongly enhanced on 2-deoxy-2-[fluorine-18] fluoro-d-glucose positron emission tomography, suggesting a malignant retroperitoneal tumor and lung metastasis. CT-guided percutaneous biopsy targeting the left perirenal soft tissue structure was performed, and the tumor was diagnosed as DDLP. Lung metastasis was present, and the retroperitoneal tumor surrounded multiple organs. Therefore, the tumor was not suitable for surgical resection but it was indicated for chemotherapy based on multidisciplinary discussion. Conclusion: We experienced a case of retroperitoneal cystic DDLP diagnosed by percutaneous image-guided biopsy and treated appropriately based on the pathological diagnosis.

Sudden-onset hypertension leading to the diagnosis of unilateral hydronephrosis due to ureteropelvic junction obstruction.

We present a case of a 41-year-old female who developed hypertension over a three-month period and was subsequently diagnosed with ureteropelvic junction obstruction (UPJO). The patient came to our department with elevated blood pressure. Blood examinations revealed normal renal function, hypokalemia and increased renin-angiotensin system (RAS) activity, as indicated by elevated level of plasma renin activity and plasma aldosterone level. A computed tomography imaging further revealed dilation of the left renal pelvis, atrophy of the left kidney, and indications of obstruction at the junction between the renal pelvis and ureter. Surgical intervention in the form of a left pyeloplasty successfully resolved the unilateral hydronephrosis, corrected the elevated RAS activity, normalized the blood pressure, and ameliorated the hypokalemia. This case emphasizes that elevated blood pressure might be the sole clinical indication of hydronephrosis. It's crucial to consider hydronephrosis due to UPJO as a potential cause, especially when diagnosing hypertension associated with RAS hyperactivity in young adults. It also highlights the effectiveness of surgical intervention in treating hypertension in such scenarios.

Early Phase Persistent Changes in the White Blood Cell Fraction in Patients With Advanced Urothelial Carcinoma Treated With Pembrolizumab: A Multicenter Retrospective Study.

BACKGROUND/AIM: The association of clinical outcomes with posttreatment persistent changes in eosinophils and other white blood cell (WBC) subtypes in patients with advanced urothelial cancer (UC) treated with pembrolizumab after the failure of platinum-based chemotherapy is unclear. PATIENTS AND METHODS: We retrospectively analyzed 87 patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy. The changes in WBC subtypes from pretreatment were evaluated three and six weeks after pembrolizumab administration. The association between the changes in the WBC subtypes and clinical outcomes was then evaluated using the Kaplan-Meier method and a Cox regression model. RESULTS: Among WBC subtypes, significant changes in the absolute (AEC) and relative eosinophil count (REC) and the neutrophil-to-eosinophil ratio (NER) were observed at three and six weeks compared with pretreatment (p<0.001). Multivariable Cox regression analyses revealed that a persistent decrease in AEC and REC and a persistent increase in NER were associated with poor overall survival. CONCLUSION: Persistent increase in AEC and REC and decrease in NER in the early phase after pembrolizumab may be significant early predictive markers of improved clinical outcomes in patients with advanced UC receiving pembrolizumab.

Influence of the irrigation flow pattern and catheter tip design on the lesion formation: an ex vivo experimental model.

BACKGROUND: Lesion formation during catheter ablation is influenced by the power, contact force (CF), time, and catheter stability. However, the influence of the irrigation effects on lesion formation remains unknown. METHODS: An ex vivo experiment using conductive gel was performed. Using three different catheter designs (TactiFlex ™ SE [TF], IntellaNav MiFi ™ OI [MiFi], QDOT MICRO™ [QDOT]), a cross-sectional analysis of the lesion size and surface lesion type of 10g/40W lesions with a combination of various ablation times was performed in protocol 1. A longitudinal analysis (combination of various powers [30, 40, and 50W] and various ablation times with a 10g setting) was performed to investigate the influence of the auto-regulated irrigation system (QDOT) on lesion formation in protocol 2. RESULTS: The lesion formation with the QDOT catheter tended to create larger ablation lesions, while that with the TF catheter created smaller lesions than the other catheters. The lesion surface characteristics were divided into two patterns: ring (MiFi catheter and QDOT) and crescent (TF) patterns. The auto-regulated irrigation system did not influence the lesion formation, and the relationship between the lesion formation and RF energy exhibited similar changes regardless of the ablation power setting. CONCLUSION: The lesion formation and lesion surface characteristics differed among the different irrigation tip designs. An auto-regulated irrigation system did not affect the lesion creation or surface lesion characteristics. Care should be given to the inter-product differences in the lesion characteristics during RF catheter ablation, partly due to the irrigation flow control and tip design.

Simultaneous Visualization of the Thoracic Duct and Blood Vessels Using MRI: A Comparison Between Balanced Turbo-field-echo and Spin-echo.

OBJECTIVE: Magnetic resonance thoracic ductography (MRTD), concomitant with blood vessel imaging, provides useful anatomical information. The purpose of this study was to assess the visibility of the thoracic duct and blood vessels simultaneously by MRTD using balanced turbo-field-echo (bTFE) and turbo spin-echo (TSE). METHODS: MRTDs concomitant with blood vessel imaging on bTFE and TSE were obtained for 10 healthy volunteers with a 1.5T-magnetic resonance unit. Visibility of the thoracic duct, blood vessels in the thoracic region; motion artifacts; and overall image quality were scored by two radiologists using three-to-five-point scales; those were compared between bTFE and TSE. RESULTS: The thoracic duct was generally well-visualized on MRTD sequences. The upper part of the thoracic duct was better visualized on TSE than on bTFE (p < 0.05). The blood vessels were well visualized on bTFE and TSE; the bilateral subclavian arteries and the right subclavian veins were better visualized on TSE than on bTFE (all p < 0.05). Motion artifacts and overall image quality were better on TSE than on bTFE (p = 0.0039 and 0.0020, respectively). CONCLUSION: MRTD concomitant with blood vessel imaging on TSE has better visibility of the thoracic duct and blood vessels than bTFE.

Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis.

While adult pancreatic stem cells are thought not to exist, it is now appreciated that the acinar compartment harbors progenitors, including tissue-repairing facultative progenitors (FPs). Here, we study a pancreatic acinar population marked by trefoil factor 2 (Tff2) expression. Long-term lineage tracing and single-cell RNA sequencing (scRNA-seq) analysis of Tff2-DTR-CreERT2-targeted cells defines a transit-amplifying progenitor (TAP) population that contributes to normal homeostasis. Following acute and chronic injury, Tff2+ cells, distinct from FPs, undergo depopulation but are eventually replenished. At baseline, oncogenic KrasG12D-targeted Tff2+ cells are resistant to PDAC initiation. However, KrasG12D activation in Tff2+ cells leads to survival and clonal expansion following pancreatitis and a cancer stem/progenitor cell-like state. Selective ablation of Tff2+ cells prior to KrasG12D activation in Mist1+ acinar or Dclk1+ FP cells results in enhanced tumorigenesis, which can be partially rescued by adenoviral Tff2 treatment. Together, Tff2 defines a pancreatic TAP population that protects against Kras-driven carcinogenesis.

Distribution and clinical impact of molecular subtypes with dark zone signature of DLBCL in a Japanese real-world study.

The distribution and clinical impact of cell-of-origin (COO) subtypes of diffuse large B-cell lymphoma (DLBCL) outside Western countries remain unknown. Recent literature also suggests that there is an additional COO subtype associated with the germinal center dark zone (DZ) that warrants wider validation to generalize clinical relevance. Here, we assembled a cohort of Japanese patients with untreated DLBCL and determined the refined COO subtypes, which include the DZ signature (DZsig), using the NanoString DLBCL90 assay. To compare the distribution and clinical characteristics of the molecular subtypes, we used a data set from the cohort of British Columbia Cancer (BCC) (n = 804). Through the 1050 patient samples on which DLBCL90 assay was successfully performed in our cohort, 35%, 45%, and 6% of patients were identified to have germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and DZsig-positive (DZsigpos) DLBCL, respectively, with the highest prevalence of ABC-DLBCL, differing significantly from the BCC result (P < .001). GCB-DLBCL, ABC-DLBCL, and DZsigpos-DLBCL were associated with 2-year overall survival rates of 88%, 75%, and 66%, respectively (P < .0001), with patients with DZsigpos-DLBCL having the poorest prognosis. In contrast, GCB-DLBCL without DZsig showed excellent outcomes after rituximab-containing immunochemotherapy. DZsigpos-DLBCL was associated with the significant enrichment of tumors with CD10 expression, concurrent MYC/BCL2 expression, and depletion of microenvironmental components (all, P < .05). These results provide evidence of the distinct distribution of clinically relevant molecular subtypes in Japanese DLBCL and that refined COO, as measured by the DLBCL90 assay, is a robust prognostic biomarker that is consistent across geographical areas.

Kinetics of Glucoregulatory Peptide Hormones during Hemodialysis with Cellulose Triacetate and Polysulfone Dialyzers in Patients with Diabetes and End-Stage Kidney Disease.

The mechanisms behind reported decreases in plasma insulin and glucagon during hemodialysis (HD) are not clear. Here, we investigated these mechanisms during HD treatment and the characteristics of insulin and glucagon removal when using two super high-flux membranes. In an experimental study, clearance, adsorption rates, and reduction rates of insulin and glucagon were investigated when using cellulose triacetate (CTA) and polysulfone (PS) membranes in a closed circuit using bovine blood. In a clinical study, 20 diabetes patients with end-stage kidney disease who were stable on HD were randomly selected for two HD sessions with two different membranes. At 1 h after the initiation of HD, insulin and glucagon clearance were measured, and the reduction rates were also investigated. In the experimental study, the PS membrane showed significantly higher clearance, adsorption rates, and reduction rates of insulin and glucagon compared with the CTA membrane. Although glucagon was detected in the ultrafiltration fluids in both membranes, insulin was absent in the PS membrane. In the clinical study, both membranes showed significant reductions in plasma insulin and glucagon at each time point. The PS membrane showed significantly higher insulin clearance and reduction rates compared with the CTA membrane. The two membranes showed no significant difference in glucagon clearance, but the glucagon reduction rate was significantly higher with the PS membrane. Our findings show that HD with the two super high-flux membranes used removes significant amounts of glucoregulatory peptide hormones from plasma in patients with diabetes and end-stage kidney disease, potentially affecting their glucose metabolism.

Neuroblastoma suppressor of tumorigenicity 1 is associated with the severity of interstitial fibrosis and kidney function decline in IgA nephropathy.

INTRODUCTION: Recently, circulating neuroblastoma suppressor of tumorigenicity 1 (NBL1) was shown to be strongly associated with kidney disease progression and histological lesions in patients with diabetic kidney disease. This study aimed to examine whether serum NBL1 level was also associated with kidney function and renal histological findings in patients with IgA nephropathy. METHODS: We evaluated the levels of NBL1 in 109 patients with newly diagnosed biopsy-proven primary IgAN, between 2009 and 2018, at the Nihon University School of Medicine Itabashi Hospital, Tokyo, Japan, using serum obtained immediately before the renal biopsy, and examined the relationship between serum NBL1, renal function and renal histological findings assessed using the Oxford Classification (MEST score). Furthermore, we analyzed the association of serum NBL1 with kidney function decline over time in patients with IgA nephropathy who had follow-up data on the estimated glomerular filtration rate (n = 76). RESULTS: Serum NBL1 levels in patients with newly diagnosed IgA nephropathy were elevated, as compared to those in healthy individuals (n = 93). Logistic regression analysis demonstrated that the serum NBL1 level was independently and significantly associated with tubular atrophy/interstitial fibrosis. Immunohistochemical staining revealed that NBL1 was highly expressed in the tubulointerstitium. Furthermore, Spearman's rank correlation identified a significant correlation between serum NBL1 level and estimated glomerular filtration rate slope. CONCLUSIONS: The serum NBL1 level was significantly associated with the severity of renal interstitial fibrosis and kidney disease progression in patients with newly diagnosed IgA nephropathy. Thus, circulating NBL1 may serve as a good biomarker for evaluating renal interstitial fibrosis and the risk of kidney disease progression.