Interstitial Deposition Research Articles

Two distinct phenotypes of calcium oxalate stone formers could imply different long-term risks for renal function.

Endoscopic and biopsy findings have identified two distinct phenotypes among individuals with calcium oxalate (CaOx) kidney stones. The first type has normal renal papillae but shows interstitial mineral deposition, known as Randall's plaque. The other phenotype presents with collecting duct plugging and a higher incidence of loss of papilla tissue mass. With Randall's plaque, renal papilla injury involves the loss of small patches of calcified tissue (Randall's plaque detaching with the stone), which likely results in damage to only a few nephrons. In contrast, collecting duct mineral plugs are very large, causing obstruction to tubular flow. Since each terminal collecting duct drains thousands of nephrons, ductal plugs could lead to the degeneration of many nephrons and a significant loss of renal glomeruli. New visualization techniques for immune cells in papillary biopsies have revealed that the Randall's plaque phenotype is marked by the accumulation of macrophages around the plaque regions. In contrast, preliminary data on the plugging phenotype shows collecting duct damage with mineral plugsand increased T-lymphocytes throughout the papilla. These regions also show tubulitis, i.e., T-cell infiltration into nearby collecting duct epithelium. This suggests that while some CaOx stone formers may have some papillary inflammation but with minimal damage to nephrons, others suffer from obstruction to flow for many nephrons that may also include destructive inflammation in the renal tissue. We propose that CaOx stone formers with the plugging phenotype will have a higher long-term risk for loss of renal function.

Two distinct phenotypes of calcium oxalate stone formers could imply different long-term risks for renal function.

Endoscopic and biopsy findings have identified two distinct phenotypes among individuals with calcium oxalate (CaOx) kidney stones. One phenotype exhibits normal renal papillae but shows interstitial mineral deposition, known as Randall's plaque. The other phenotype presents with collecting duct plugging and a higher incidence of loss of papilla tissue mass. With Randall's plaque, renal papilla injury involves the loss of small patches of calcified tissue (Randall's plaque detaching with the stone), which likely results in damage to only a few nephrons. In contrast, collecting duct mineral plugs are very large, causing obstruction to tubular flow. Since each terminal collecting duct drains thousands of nephrons, ductal plugs could lead to the degeneration of many nephrons and a significant loss of renal glomeruli. New visualization techniques for immune cells in papillary biopsies have revealed that the Randall's plaque phenotype is marked by the accumulation of macrophages around the plaque regions. In contrast, preliminary data on the plugging phenotype shows collecting duct damage with mineral plugs, increased T-lymphocytes throughout the papilla, and tubulitis, characterized by T-cell infiltration into nearby collecting duct epithelium. This suggests that while some CaOx stone formers may have some papillary inflammation but with minimal damage to nephrons, others suffer from obstruction to flow for many nephrons that may also include destructive inflammation in the renal tissue. We propose that the long-term risks for loss of renal function will be greater for CaOx stone formers with the plugging phenotype.

Transcription factor Twist1 drives fibroblast activation to promote kidney fibrosis via signaling proteins Prrx1/TNC

The transcription factor Twist1 plays a vital role in normal development in many tissue systems and continues to be important throughout life. However, inappropriate Twist1 activity has been associated with kidney injury and fibrosis, though the underlying mechanisms involved remain incomplete. Here, we explored the role of Twist1 in regulating fibroblast behaviors and the development kidney fibrosis. Initially Twist1 protein and activity was found to be markedly increased within interstitial myofibroblasts in fibrotic kidneys in both humans and rodents. Treatment of rat kidney interstitial fibroblasts with transforming growth factor-β1 (a profibrotic factor) also induced Twist1 expression in vitro. Gain- and loss-of-function experiments supported that Twist1 signaling was responsible for transforming growth factor-β1-induced fibroblast activation and fetal bovine serum-induced fibroblast proliferation. Mechanistically, Twist1 protein promoted kidney fibroblast activation by driving the expression of downstream signaling proteins, Prrx1 and TNC. Twist1 directly enhanced binding to the promoter of Prrx1 but not TNC, whereas the promoter of TNC was directly bound by Prrx1. Finally, mice with fibroblast-specific deletion of Twist1 exhibited less Prrx1 and TNC protein abundance, interstitial extracellular matrix deposition and kidney inflammation in both the unilateral ureteral obstruction and ischemic-reperfusion injury-induced kidney fibrotic models. Inhibition of Twist1 signaling with Harmine, a β-carboline alkaloid, improved extracellular matrix deposition in both injury models. Thus, our results suggest that Twist1 signaling promotes the activation and proliferation of kidney fibroblasts, contributing to the development of interstitial fibrosis, offering a potential therapeutic target for chronic kidney disease.

Effect of compatibility of Corni Fructus before and after wine-processing with Astragali Radix on plasma metabolomics in diabetic nephropathy rats based on UHPLC-Q-TOF-MS/MS

Based on the processing and compatibility, this study explored the effects of components in Corni Fructus(CF) and Astragali Radix(AR) on plasma metabolomics in diabetic nephropathy rats. SD rats were randomly divided into four groups and diabetic nephropathy rat model was induced by high-fat diet combined with 30 mg·kg~(-1) streptozotocin(STZ). Histopathological observations of kidney tissue sections of rats in each group were conducted using HE, PAS, and Masson staining. Ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UHPLC-Q-TOF-MS/MS) metabolomics method was employed to investigate the effects of CF before and after wine-processing combined with AR-related components on plasma metabolites in diabetic nephropathy rats. After drug treatment, kidney tissue damage and interstitial collagen fiber deposition area in diabetic nephropathy rats were improved to varying degrees(P<0.001). The detection results of plasma metabolomics showed that 71 biomarkers related to the pathogenesis of diabetic nephropathy were identified in diseased rats, mainly involving linoleic acid metabolism, caffeine metabolism, glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, arachidonic acid metabolism, phenylalanine metabolism, retinol metabolism, and ether lipid metabolism. After drug intervention, 26 of them were significantly downregulated, with better efficacy observed in precision processed herb-pair group(P-CG_5). This study elucidated from the perspective of plasma metabolomics that P-CG_5 could improve metabolic disorders in diabetic nephropathy through pathways such as phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and caffeine metabolism, providing theoretical support and experimental basis for the clinical application of CF and AR compatibility in traditional Chinese medicine.

Co-delivery of fucoxanthin and Twist siRNA using hydroxyethyl starch-cholesterol self-assembled polymer nanoparticles for triple-negative breast cancer synergistic therapy

IntroductionTriple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer with an extremely dismal prognosis and few treatment options. As a desmoplastic tumor, TNBC tumor cells are girdled by stroma composed of cancer-associated fibroblasts (CAFs) and their secreted stromal components. The rapidly proliferating tumor cells, together with the tumor stroma, exert additional solid tissue pressure on tumor vasculature and surrounding tissues, severely obstructing therapeutic agent from deep intratumoral penetration, and resulting in tumor metastasis and treatment resistance. ObjectivesFucoxanthin (FX), a xanthophyll carotenoid abundant in marine algae, has attracted widespread attention as a promising alternative candidate for tumor prevention and treatment. Twist is a pivotal regulator of epithelial to mesenchymal transition, and its depletion has proven to sensitize antitumor drugs, inhibit metastasis, reduce CAFs activation and the following interstitial deposition, and increase tumor perfusion. The nanodrug delivery system co-encapsulating FX and nucleic acid drug Twist siRNA (siTwist) was expected to form a potent anti-TNBC therapeutic cyclical feedback loop. Methods and resultsHerein, our studies constituted a novel self-assembled polymer nanomedicine (siTwist/FX@HES-CH) based on the amino-modified hydroxyethyl starch (HES-NH2) grafted with hydrophobic segment cholesterol (CH). The MTT assay, flow cytometry apoptosis analysis, transwell assay, western blot, and 3D multicellular tumor spheroids growth inhibition assay all showed that siTwist/FX@HES-CH could kill tumor cells and inhibit their metastasis in a synergistic manner. The in vivo anti-TNBC efficacy was demonstrated that siTwist/FX@HES-CH remodeled tumor microenvironment, facilitated interstitial barrier crossing, killed tumor cells synergistically, drastically reduced TNBC orthotopic tumor burden and inhibited lung metastasis. ConclusionSystematic studies revealed that this dual-functional nanomedicine that targets both tumor cells and tumor microenvironment significantly alleviates TNBC orthotopic tumor burden and inhibits lung metastasis, establishing a new paradigm for TNBC therapy.

Benchmarking digital displays (monitors) for histological diagnoses: the nephropathology use case

AimThe digital transformation of the pathology laboratory is being continuously sustained by the introduction of innovative technologies promoting whole slide image (WSI)-based primary diagnosis. Here, we proposed a real-life benchmark...

Clinical, Endoscopic, and Histopathologic Observations in Gastrointestinal Amyloidosis.

Amyloidosis is a group of systemic disorders caused by extracellular deposition of misfolded serum proteins. Gastrointestinal (GI) involvement is associated with a higher risk of GI bleeding, especially if mucosal lesions are present. Our study aims to evaluate the frequency of GI manifestations in patients with amyloidosis, to clinically characterize these patients and to describe the endoscopic and histopathologic findings in GI amyloidosis. A retrospective, single-center study of all patients admitted with amyloidosis and GI manifestations was conducted at a German University Hospital between July 2003 and June 2023. Clinical, endoscopic, and histopathological data was retrieved from medical records. Between July 2003 and June 2023, 63 patients with different types of amyloidosis were included into the study. Twenty-three (36,5%) were diagnosed with GI involvement of amyloidosis (60.9% male, median age 62 ± 18.28 years). The distribution of the types of amyloidosis were amyloid light chain (AL) at 52.5%, transthyretin (ATTR) at 21.7%, amyloid A (AA) at 13.0%, and unknown at 18%. Initial GI symptoms were present in 78.3% of the patients and included mainly diarrhea (34.8%), and abdominal pain (30.4%) Affected GI organs were primarily the colon (60,8%) and the stomach (39.1%). Endoscopic findings were ulcerations (47.8%), mucosal inflammation (43.5%), polyps (26.1%), erosions (13.0%), vascular malformation, polypoid protrusion, submucosal hematoma, erythema, metaplasia, and diverticulum. Histopathological findings included vascular wall thickening, (peri-)vascular and interstitial amyloid deposition. Gastrointestinal bleeding occurred in 39.1% of the patients. The mortality rate 5 years after diagnosis was 47.8%. Gastrointestinal amyloidosis can present with multiple symptoms and endoscopic findings, rendering diagnosis a challenge. Of clinical relevance, GI bleeding was a frequent event in our patient cohort. Therefore, clinicians must be aware of GI bleeding as a manifestation of amyloidosis and definite diagnosis should be achieved based on biopsy results.

Bone Marrow Interstitial Light-Chain Amyloid and Its Microenvironment

Amyloid deposition and neighboring tissue responses remain poorly understood. Patient series have shown that with Congo red staining of marrow biopsies about 20% of AL patients have interstitial deposits, 40% have vascular and 40% have no amyloid seen and that marrow amyloid is rare in patients with myeloma. (Ann Hematol. 2011;90(1):101-6; Am J Clin Pathol. 2003;120(4):610-6) The constituents of the deposits have been summarized for 65 AL biopsies, a third with extensive interstitial deposits; apolipoproteins E, A-IV and J are prominently present in the examples offered as well as in an extensive summary of the amyloid proteome.(Amyloid. 2022;29(3):156-64; Crit Rev Biochem Mol Biol. 2021;56(5):526-42) With the goal of achieving a better understanding of the impact AL amyloid deposits might have on the marrow microenvironment we undertook a systematic assessment, within the limitations of specimen availability and quality, of the CD138-depleted marrow mononuclear cells (MNC) and marrow and blood plasma from AL patients with (+MA) and without (-MA) interstitial marrow amyloid. Data on the 49 consenting AL patients are archived in the Harvard Dataverse (https://doi.org/10.7910/DVN/TDFMAI). We compared +MA and -MA CD138-depleted MNC from AL patients by gene expression profiling (GEP) on the Illumina platform; reads were mapped to the UCSC hg19 human genome with Tophat 2/Bowtie 2. Normalization and differential expression analyses were performed with Cuffdiff.(Methods Mol Biol. 2016;1374:339-61) We also compared a different set of +MA and -MA CD138-depleted MNC by single-cell RNA-sequencing (scRNA seq) employing the 10X Genomics Chromium Single Cell 3′ method in our core facility and processing the samples for evaluation through CellRanger, Seurat v. 4.0.3 and the Azimuth marrow reference-based method at the 31 cell type resolution. In addition, we compared peripheral blood and marrow plasma from these patients by immunoprecipitation and immunoblot with respect to apolipoproteins and free light chains (FLC) in complex with the erythroid protein TMCC2 and by ELISA for marrow apolipoprotein E and J levels. GEP showed no differential expression of genes for proteolytic enzymes or apolipoproteins between the groups but +MA cases had significantly up-regulated erythroid genes involved in oxygen transport, including transmembrane and coiled-coil domain family 2 ( TMCC2). In +MA marrows at the single-cell level, CD14+ monocytes were increased by 22%, granulocyte-monocyte progenitors decreased by 66%, and erythroid-megakaryocyte progenitors and early and late erythroid progenitors increased up to five-fold. Gene enrichment studies showed that in +MA marrows pathways for TNFα signaling via NFκ-B were significantly active (Figure 1); immune activation and monocyte hypoxia were also significantly enriched. As shown in Figure 2, apolipoprotein J is strongly associated with FLC in blood and E is not, while in +MA marrow plasma apolipoproteins J and E are strongly present in association with FLC. By ELISA, there is also significantly more apolipoprotein E and J in +MA marrow plasma. Our data suggest that erythroid-related activity is enhanced in marrows with interstitial amyloid and that a red blood cell related protein, TMCC2, is associated with apolipoproteins and FLC, possibly providing a loose cargo of chaperones that may abet fibril formation by FLC with predisposed secondary structures whose fragmentation sites are made optimally accessible by the loose complex; sites in the FR4 and 5' constant region of AL FLC may be highly vulnerable if exposed in such fashion to perivisceral proteases associated with matrix remodeling. The marrow microenvironment is clearly impacted by the presence of interstitial amyloid. In HSC from +MA marrows there is increased signaling in pathways that affect lineage commitments such as TNF-α/NF-κB and PI3 kinase/AKT/mTOR. In monocytes from +MA specimens there is evidence of modulation of NF-kB. Both alterations are possibly due to apolipoprotein E, although there is no evidence that monocyte transcription of APO E in +MA CD138-depleted marrow MNC is increased. In conclusion, marrows with interstitial amyloid provide opportunities to study amyloid's impact on cellular behavior, regenerative activity and chaperone involvement in amyloid deposition.

Clinical significance of kidney immune complex deposition in children with acute interstitial nephritis disease

Background Acute interstitial nephritis (AIN) is a relatively rare cause of acute kidney injury (AKI) in children. Immune complex (IC) deposition was rare in renal pathology of AIN. Methods Based on the status and position of IC deposition, a total of 78 children with AIN were divided into two groups: the non-IC group and IC group. IC group was further divided into two subgroups: intraglomerular (IG)-IC group and extraglomerular (EG)-IC group. To compare the clinical and histological features, renal outcomes between groups. Results The IC deposition, IG-IC and EG-IC deposition were observed in 22 (28.21%), 12 (15.38%) and 10 (12.82%) children, respectively. The IC group demonstrated a higher frequency of AKI, higher level of Scr, urine N-acetyl-β-D-glucosidase (NAG) enzyme, retinol-binding protein (RBP), neutrophil gelatinase-associated lipocalin (NGAL), higher frequency of neutrophils, plasma cells and eosinophils infiltrate, higher scores of interstitial inflammation (i), total inflammation (ti) and interstitial edema, lower level of estimated glomerular filtration rate (eGFR) as compared to non-IC group (p < 0.05, p < 0.01). EG-IC deposition positively moderate correlated with levels of RBP, IG-IC deposition positively moderate correlated with plasma cell infiltrate, interstitial inflammation (i), total inflammation (ti) and interstitial edema. Interstitial inflammation, EG-IC deposition and interstitial edema were risk factors for AKD in AIN, and interstitial fibrosis/tubular atrophy (IF/TA) was a risk factor for CKD in children with AIN. Conclusion IG-IC and EG-IC deposition positively correlated with severe clinical manifestations, glomerular and tubular injuries, and EG-IC deposition was risk factor for the progression of AIN in children.

Unraveling Atrial Myopathy

Atrial fibrillation (AF) is the most common arrhythmia encountered, especially in the elderly. AF leads to fivefold risk of stroke. However, there is a no temporal association found when we compare the onset of AF and stroke suggesting that the presence of AF is not mandatory for stroke occurrence. This has led to concept of atrial myopathy suggesting that a diseased atrium can provoke stroke without AF. Atrial interstitial fibrosis, inflammation, and extracellular matrix deposition can initiate and perpetuate atrial myopathy leading to stasis of blood flowing through the atria and may lead to stroke without intervening AF. AF may be just a marker of atrial myopathy. The present paper reviews the emerging concept of atrial myopathy, its pathogenesis, precursors, and diagnosis.

Amyloid myopathy: expanding the clinical spectrum of transthyretin amyloidosis—case report and literature review

We identified two patients with transthyretin (ATTR) amyloid myopathy (one ATTR variant amyloidosis, ATTRv; one wild-type ATTR amyloidosis, ATTRwt). Myopathy was the initial manifestation in ATTRwt, whereas it followed neuropathy and cardiomyopathy in ATTRv. The ATTRwt patient showed muscular tracer uptake on 99mTc-DPD planar scintigraphy at the time of initial diagnosis, consistent with ATTR amyloid myopathy. The ATTRv patient underwent heart transplantation because of progressive heart failure. Within the next two years, progressive myopathic symptoms and extracardiac tracer uptake on 99mTc-DPD planar scintigraphy were documented, attributable to ATTR amyloid myopathy. Interstitial amyloid deposits were confirmed by muscle biopsy in both patients, with a particularly high amyloid burden in the adipose tissue. This case report highlights the frequent concomitant presence of cardiac ATTR amyloidosis and ATTR amyloid myopathy. ATTR amyloid myopathy may precede cardiac manifestation in ATTRwt or occur after heart transplantation in ATTRv. Due to the high diagnostic accuracy of 99mTc-DPD scintigraphy for detecting ATTR amyloid myopathy and the emergence of novel therapeutics, it is important to increase the awareness of its presence.

Clinical Correlation of Histopathological Classification, Scoring, and Grading in Amyloid Nephropathies: Single-Center Experience

Objective: Amyloidosis is disorder of various etiologies in which abnormally folded fibrillary protein deposits with more than thirty forms infiltrate into extracellular spaces of affected organs. Renal involvement is clinically characterized by decreased estimated glomerular filtration rate (eGFR) and proteinuria. The aim of present study was to classify and grade renal amyloidosis cases using renal amyloid prognostic score (RAPS) systems, correlate clinical data and chronic kidney disease (CKD) stages. Methods: We retrospectively analyzed kidney biopsies of 45 patients diagnosed with renal amyloidosis applied between 2017-2022 to our department and scored each of patients according to RAPS. Results: 8.9% of patients had RAPS score 1, 53.3% had 2 and 37.8% had 3. Urea, serum creatinine and proteinuria levels of RAPS3 patients were significantly higher and eGFR levels were lower compared to RAPS1 patients (p&amp;lt;0.01). According to CKD stages, no significant difference was observed in glomerular amyloid deposition class and score, vascular and interstitial amyloid deposition scores, and glomerular sclerosis (p&amp;gt;0.05). The interstitial fibrosis, inflammation values and RAPS scores were found to be significantly higher in advanced CKD stages (p&amp;lt;0.05). Majority of patients at CKD stage 1-2 had RAPS score 2 (73.68%), while 57.1% of at stage 3 and 66.7% at stage 4-5 had RAPS score of 3 (p=0.0015). Conclusion: As a result, the intestinal fibrosis, inflammation values, RAPS scores were significantly higher in advanced CKD stages. Distribution pattern of amyloid in the renal parenchyma compartment, grade of RAPS and eGFR were associated with urea/creatinine, proteinuria levels and thus with CKD stage.

Multi-omic spatial profiling in COVID-19 lung revels temporal evolution of the disease and novel collagen VI biomarker for outcome

Abstract Whilst the peripheral immune response to COVID-19 infection is well characterised, less is known about the tissue response in the lungs of affected patients. We conducted a multi-omic investigation in post-mortem lung tissue from fatal COVID-19 infection comprising bulk Quantseq RNA sequencing, spatial transcriptomic profiling on the Nanostring GeoMX, multiplex immunohistochemistry on the Lunaphore COMET and in-situ transcriptomcics with RNAscope. We found the SARS-CoV-2 virus was progressively cleared in more temporally advanced disease. Furthermore, collagen VI was found to be transcriptionally up-regulated by bulk sequencing and within the interstitium on spatial transcriptomics. These findings were supported by multiplex immunohistochemistry at a proteomic level which showed fibrillar deposition of collagen VI in the interstitum. To validate these findings clinically, we looked at blood markers for collagen VI synthesis and degradation by ELISA in a cohort of severe and mildly infected COVID-19 patients. Blood markers of collagen VI synthesis (PRO-C6) was significantly predictive for mortality in hospitalised (p = 0.0065) and intensive care (p = 0.028) COVID-19 patients. Overall, blood PRO-C6 levels, based on increase interstitial lung deposition, could help identify high-risk of patients enabling better treatment stratification. The study also demonstrates the power of post-mortem investigation and spatial profiling in elucidating clinically relevant insights into complex disease phenomena.

Activation of Kir2.1 improves myocardial fibrosis by inhibiting Ca 2+ overload and the TGF-β1/Smad signaling pathway.

The inwardly rectifying potassium channel Kir2.1 is closely associated with many cardiovascular diseases. However, the effect and mechanism of Kir2.1 in diabetic cardiomyopathy remain unclear. In vivo, we use STZ to establish the model, and ventricular structural changes, myocardial inflammatory infiltration, and myocardial fibrosis severity are detected by echocardiography, histological staining, immunohistochemistry, and western blot analysis, respectively. In vitro, a myocardial fibrosis model is established with high glucose. The Kir2.1 current amplitude, intracellular calcium concentration, fibrosis-related proteins, and TGF-β1/Smad pathway proteins are detected by whole-cell patch clamp, calcium probes, western blot analysis, and immunofluorescence, respectively. The in vivo results show that compared to diabetic cardiomyopathy, zacopride (a Kir2.1 selective agonist) significantly reduces the left ventricular systolic diameter and diastolic diameter, increases the left ventricular ejection fraction and left ventricular short-axis shortening, improves the degree of cell necrosis, and reduces the expression of myocardial interstitial fibrosis protein and collagen fibre deposition area. The in vitro results show that the current amplitude and protein expression of Kir2.1 are both decreased in the high glucose-induced myocardial fibrosis model. Additionally, zacopride significantly upregulates the expression of Kir2.1 and inhibits the expressions of the fibrosis-related proteins α-SMA, collagen I, and collagen III. Activation of Kir2.1 reduces the intracellular calcium concentration and inhibits the protein expressions of TGF-β1 and p-Smad 2/3. Activation of Kir2.1 can improve myocardial fibrosis induced by diabetic cardiomyopathy, and the possible mechanism may be related to inhibiting Ca 2+ overload and the TGF-β1/Smad signaling pathway.

Time to reconsider the perception and management of hypertensive heart disease.

Time to reconsider the perception and management of hypertensive heart disease.

Bioinformatics analysis reveals the potential role of matrix metalloproteinases in immunity and urolithiasis.

The pathogenesis of urolithiasis remains unclear, making the development of medications for treatment and prevention stagnant. Randall's plaques (RPs) begin as interstitial calcium phosphate crystal deposits, grow outward and breach the renal papillary surface, acting as attachment for CaOx stones. Since matrix metalloproteinases (MMPs) can degrade all components of extracellular matrix (ECM), they might participate in the breach of RPs. Besides, MMPs can modulate the immune response and inflammation, which were confirmed to be involved in urolithiasis. We aimed to investigate the role of MMPs in the development of RPs and stone formation. The public dataset GSE73680 was mined to identify differentially expressed MMPs (DEMMPs) between normal tissues and RPs. WGCNA and three machine learning algorithms were performed to screen the hub DEMMPs. In vitro experiments were conducted for validation. Afterwards, RPs samples were classified into clusters based on the hub DEMMPs expression. Differentially expressed genes (DEGs) between clusters were identified and functional enrichment analysis and GSEA were applied to explore the biological role of DEGs. Moreover, the immune infiltration levels between clusters were evaluated by CIBERSORT and ssGSEA. Five DEMMPs, including MMP1, MMP3, MMP9, MMP10, and MMP12, were identified between normal tissues and RPs, and all of them were elevated in RPs. Based on WGCNA and three machine learning algorithms, all of five DEMMPs were regarded as hub DEMMPs. In vitro validation found the expression of hub DEMMPs also increased in renal tubular epithelial cells under lithogenic environment. RPs samples were divided into two clusters and cluster A exhibited higher expression of hub DEMMPs compared to cluster B. Functional enrichment analysis and GSEA found DEGs were enriched in immune-related functions and pathways. Moreover, increased infiltration of M1 macrophages and enhanced levels of inflammation were observed in cluster A by immune infiltration analysis. We assumed that MMPs might participate in RPs and stone formation through ECM degradation and macrophages-mediated immune response and inflammation. Our findings offer a novel perspective on the role of MMPs in immunity and urolithiasis for the first time, and provide potential biomarkers to develop targets for treatment and prevention.

Apoptosis in lupus nephritis patients: a study of Bcl-2 to assess glomerular and tubular damage

BackgroundSystemic lupus erythematosus (SLE) is an immune-mediated disease, due to exposure of self-antigens, through impairment of apoptosis and failure of lymphocytic tolerance. Impaired regulation of the pro- and anti-apoptotic gene products which coordinate programmed cell death may result in autoreactive B and T cells and autoimmunity. Genetically engineered mice that over-express the anti-apoptotic molecule Bcl-2, B cell lymphoma 2 (Bcl2) in B-lymphocytes advance a lupus-like illness. Lupus nephritis (LN) is one of the most serious manifestations of this autoimmune disorder. Glomerulonephritis (GN) is caused by either impaired regulation of apoptosis and/or clearance of apoptotic cells leading to a T cell-mediated autoimmune reaction with initiation of pathological immune complex deposits.ObjectiveTo evaluate the correlation between Bcl2 glomerular and tubular expression and pathological findings and laboratory data in different types of SLE GN.ResultsCompared to the control group, patients with lupus nephritis have significantly higher glomerular, interstitial and tubular expression level (P value < 0.001). BCL2 expression was positively correlated with serum anti-ds-DNA, urine 24-h protein and with the chronicity index. All LN patients had significant glomerular, interstitial and tubular deposits of BCL2, P value < 0.001, P value 0.004, and P value 0.03, respectively.ConclusionThe intrinsic pathway of apoptosis interferes not only with the pathogenesis of lupus glomerulonephritis but also interferes with the pathogenesis of tubulointerstitial lupus nephritis. tubulointerstitial lesions may not only be a result of glomerular injury but also a significant factor in lupus nephritis.

Six years of fluvial response to a large dam removal on the Carmel River, California, USA

AbstractMeasuring river response to dam removal affords a rare, important opportunity to study fluvial response to sediment pulses on a large field scale. We present a before–after/control–impact study of the Carmel River, California, measuring fluvial geomorphic and grain‐size evolution over 8 years, six of which postdated removal of a 32 m‐high dam (one of the largest dams removed worldwide) and included 11 flow events exceeding the 2‐year flood magnitude. We find that the reservoir‐sediment pulse following dam removal was relatively small (97 000 ± 24 000 t over 4 years), owing to deliberate reservoir‐sediment stabilization. Scaled to the size of the Carmel River watershed and compared against long‐term bedrock denudation rates, the post‐dam‐removal sediment release was slightly less than the annualized long‐term sediment export from this basin. New sediment transited &gt;30 km to the river mouth in less than 2 years, assisted by floods 2 and 4 years after dam removal. The sediment pulse fined the downstream riverbed while causing mostly low‐magnitude bed‐elevation changes: commonly 0.5 to 1 m or smaller, occurring as discontinuous sediment patches or interstitial deposits, aside from the filling and subsequent partial scour of deep pools. There was no major geomorphic reset downstream from the dam site. Geomorphic changes were driven almost entirely by flow rather than by the modest increase in sediment supply, in contrast to recent examples from other large dam removals. The relatively minor disturbance caused by dam removal on the Carmel River is likely analogous to many future dam removals: a relatively small sediment pulse after deliberate limitation of reservoir‐sediment erosion, and with an upstream dam remaining in place. Thus, a large dam removal need not lead to major downstream impacts.

Evaluation of contemporary echocardiographic and histomorphology parameters in predicting mortality in patients with endomyocardial biopsy-proven cardiac AL amyloidosis.

This study examined the role of echocardiographic and cardiac histomorphology parameters in predicting mortality in patients with cardiac AL amyloidosis. Patients with endomyocardial biopsy-proven cardiac AL amyloidosis treated at MD Anderson Cancer Center between 6/2011 and 6/2020 were identified. Stored echocardiographic images and endomyocardial biopsy samples were processed for myocardial strain analysis and a detailed histomorphology characterization. Of 43 patients; 44% were women and 63% white. Median age was 65 years; 51% underwent stem cell transplantation (SCT). Thirty patients (70%) died during follow up (median follow up: 4.1 years). Lower LA strain (<13.5%) and absence of SCT as a time-varying covariate were significantly associated with increased risk of death in the multivariate cox regression analysis. Higher LV mass and lower RV tricuspid annular plane systolic excursion were associated with increased odds of having ≥5% interstitial amyloid deposition on biopsy in the multivariate logistic regression analysis. Lower LA strain independently predicted mortality in our cohort, and its performance in the routine assessment of AL amyloidosis may be beneficial. Furthermore, SCT for cardiac AL amyloidosis was associated with improved OS. These findings need to be confirmed by larger studies in the era of contemporary systemic therapies.

Effect of Trichostatin A on Bleomycin Induced Pulmonary Fibrosis in Mice and its Mechanism

To investigate the effect and mechanism of trichostatin A on bleomycin induced pulmonary fibrosis in mice compared with dexamethasone and pirfenidone is the objective of the study. C57 black 6 mice were instilled intranasal bleomycin to establish pulmonary fibrosis model. They were divided into five groups: Control group, model group, dexamethasone group, pirfenidone group and trichostatin A group. Hematoxylin and eosin staining and Masson’s staining was conducted; the expression of related proteins in each group was observed by immunohistochemistry and Western blotting. Hematoxylin and eosin staining and Masson’s staining showed that the lung tissue was damaged in varying degrees, interstitial protein deposition, basal cell hyperplasia and a large number of macrophage infiltration in the alveolar cavity. The lung tissue injury in trichostatin A group was the least. The expression of vimentin, collagen-I, alpha smooth muscle actin and other interstitial proteins in the model group increased significantly, and the expression of above interstitial proteins in each intervention treatment group decreased in varying degrees, especially in trichostatin A group. The expression of suppressor of mothers against decapentaplegic homolog 7 protein decreased significantly in the model group and increased significantly in the trichostatin A group; there was no significant difference in the expression of p38-mitogen-activated protein kinase protein in each group. The expression of interstitial protein messenger RNA such as vimentin, collagen-I and alpha smooth muscle actin peaked on the 14th d after modeling. Trichostatin A could significantly inhibit the progression of pulmonary fibrosis by inhibiting the activity of histone deacetylase 1, while histone deacetylase 1 could activate transforming growth factor beta-1/suppressor of mothers against decapentaplegic pathway, involved in the progression of pulmonary fibrosis. Dexamethasone could not delay or improve pulmonary fibrosis, or even aggravate the progression of pulmonary fibrosis.