Renal cell carcinoma in an adult-onset ESRD patient with nephronophthisis harboring NPHP3 deletion: A case report.

Background: Nephronophthisis (NPHP) is a rare autosomal recessive inherited tubulointerstitial nephropathy, the most prevalent genetic cause of end-stage renal disease (ESRD) in children. Convincing evidence indicated that the overall prevalence of NPHP in adult-onset ESRD is very likely to be an underestimation. Therefore, understanding the genetic background and clinicopathologic features of adult-onset NPHP is warranted. Case presentation: we reported one intriguing case with concurrent NPHP3 c.2694-2_2694-1delAG (splicing) variant and c.1082C > G (p.S361C) variant. A 48-year-old male was admitted to our hospital, complained about renal dysfunction for 10 years, and found right renal space-occupying lesion for 1 week. One of the most interesting clinical features is adult-onset ESRD, which differs from previous cases. Another discovery of this study is that the NPHP harboring NPHP3 deletion may be associated with clear cell renal cell carcinoma. Conclusion: In conclusion, we report two mutations in the NPHP3 gene that cause NPHP with adult-onset ESRD and renal clear cell carcinoma in a Chinese family, enriching the clinical features of NPHP.

Present situation and prospect of immunotherapy for unresectable locally advanced esophageal cancer during peri-radiotherapy.

Four major studies (Checkmate577, Keynote-590, Checkmate649 and Attraction-4) of locally advanced esophageal cancer published in 2020 have established the importance of immunotherapy, represented by anti-programmed death protein (PD)-1 in postoperative adjuvant treatment and advanced first-line treatment of locally advanced or advanced esophageal cancer and esophagogastric junction cancer, from the aspects of proof of concept, long-term survival, overall survival rate and progression-free survival. For unresectable or inoperable nonmetastatic esophageal cancer, concurrent radiotherapy and chemotherapy is the standard treatment recommended by various guidelines. Because its curative effect is still not ideal, it is necessary to explore radical radiotherapy and chemotherapy in the future, and it is considered to be promising to combine them with immunotherapeutic drugs such as anti-PD-1. This paper mainly discusses how to combine radical concurrent radiotherapy and chemotherapy with immunotherapy for unresectable local advanced esophageal cancer.

Erratum: Employing Macrophage-Derived Microvesicle for Kidney-Targeted Delivery of Dexamethasone: An Efficient Therapeutic Strategy against Renal Inflammation and Fibrosis: Erratum.

[This corrects the article DOI: 10.7150/thno.33520.].

Combination of a Novel Genetic Variant in CFB Gene and a Pathogenic Variant in COL4A5 Gene in a Sibling Renal Disease: A Case Report.

Complement factor B (CFB) variants have been described to play a causative role in auto-immune associated C3 glomerulopathy (C3G) and/or atypical hemolytic uremic syndrome (aHUS) by affecting the dysregulations of alternative pathway activation. However, CFB variant concomitant with COL4A5 variant is scarce. Here, we depict two intriguing cases with concurrent novel heterozygosity for CFB c.2054_2057del (p.Ser687Profs∗16) variant and a previous reported COL4A5 c.2999G > T (p.Gly1000Val) variant in a pair of siblings. The clinical feature of either paternal CFB variant or maternal COL4A5 variant is just mild microscopic hematuria. Interestingly, their two children with paternal CFB c.2054_2057del (p.Ser687Profs∗16) variant and maternal COL4A5 c.2999G > T (p.Gly1000Val) variant presented with massive proteinuria, hematuria, and progressive renal failure with poor treatment response. Moreover, complement pathway activation in renal tissue further supports and strengthens the pathogenic role of CFB variant in the development of renal injury in the presence of COL4A5 variant. In conclusion, the rare sibling cases highlight that the extension of genetic analyses in the proband is helpful for the diagnosis and understanding of some family cluster renal diseases.

Treating the primary in low burden metastatic prostate cancer: Where do we stand?

ABSTRACT: On the basis of endocrine therapy for patients with low burden metastatic prostate cancer (LBMP), the clinical efficacy and quality of life were compared between prostate-only directed radiotherapy (PODT) and prostate and metastasis radiotherapy (PMRT).From November 2009 to November 2015, total 91 patients newly diagnosed with LBMP were retrospectively analyzed, of which 52 patients received PODT and 39 patients received PMRT. The biochemical failure free interval (IBF), prostate specific survival (PCSS), and overall survival (OS) time were compared between the 2 groups, and expanded prostate cancer index composite (EPIC) scale was used to evaluate the difference in quality of life between the 2 groups.The median IBF of the PODT group was 31 months, which was significantly lower than the 39 months of the PMRT group (P < .05); the 5-year OS and PCSS were 58.9%, 65.3% in PODT group, and 58.9%, 71.79% in PMRT group, respectively. There was no significant between the 2 groups (P > .05); the side effects of acute radiotherapy in PMRT group were significantly higher than PODT group (P < .05), especially in bone marrow suppression and gastrointestinal reactions; The scores of urinary system function and intestinal system function in PMRT group were significantly higher than PODT group at the end of radiotherapy, 3 months after radiotherapy, and 6 months after radiotherapy (P < .05). The score of sexual function in PMRT group was significantly lower than that in PODT group after radiotherapy (P < .05), and higher than that in PORT group at other follow-up time points (P < .05). The hormone function was decreased at each follow-up time point in 2 groups, and there was no significant difference between the 2 groups (P > .05).Patients with LBMP receiving PMRT can improve IBF, but cannot increase PCSS and OS, and increase the incidence of acute radiation injury.

Multiclass and multiresidue screening of veterinary drugs and pesticides in infant formula using Quadrupole-Orbitrap MS with PRM scan mode.

A multiclass and multiresidue method for screening veterinary drugs and pesticides in infant formula was developed and validated using ultrahigh-performance liquid chromatography coupled to Quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-HRMS). A total of 49 veterinary drugs and pesticides investigated belong to 11 classes including antivirals, anticoccidials, macrolides, pyrethroids, insecticides, sulfonamides, beta-agonists, sedatives, thyreostats, nonsteroidal anti-inflammatory drugs, and other pharmacologically active substances. A generic sample preparation and highly selective acquisition mode of parallel reaction monitoring (PRM) were deliberately incorporated to perform efficient screening analysis. As a result, the screening target concentrations of the analytes varied from 1 to 500 µg/kg with ≤5% of false compliant rate as specified in Decision 2002/657/EC for screening analysis. The average recoveries ranged from 40.7 to 124.9% as well as the relative standard deviations from 4.2 to 26.6%, respectively. The matrix effects and interferences were effectively controlled by integrated application of dispersive solid phase extraction, PRM scan mode, and matrix-matched standard calibration. The proposed method will be helpful to provide applicable strategy for screening residues in infant formula with surveillance purpose.

MicroRNA26a inhibits cisplatin-induced renal tubular epithelial cells apoptosis through suppressing the expression of transient receptor potential channel 6 mediated dynamin-related protein 1.

Acute kidney injury (AKI) is a common adverse reaction of the anticancer drug. Among these chemotherapeutic agents, cisplatin, an effective chemotherapeutic drug, is extensively applied to the treatment of solid tumours, yet various adverse reactions, especially AKI, often limit their use. However, the pathogenesis of AKI caused by cisplatin remains poorly clarified. Therefore, we tested whether microRNAs, which have been certified as key regulators of disease are involved in this process. AKI mouse and HK2 cells were treated with cisplatin. Annexin V/PI staining and cleaved caspase-3 were used to assess apoptosis. Western blot analyses and qRT-PCR were used to evaluate the protein and mRNA level of TRPC6 and DRP1. miR-26a was remarkably decreased in cisplatin-induced AKI and in cisplatin co-cultured HK2 cells. Furthermore, we used a miR-26a mimics in vitro and found that apoptosis was alleviated than that in the control cells. We further verified that miR-26a protected against cisplatin-induced cell apoptosis by acting on transient receptor potential channel 6 (TRPC6) which can regulate the expression of dynamin-related protein 1 (DRP1), thus inhibited the mitochondrial apoptosis pathway. Therefore, the study unveiled that miR-26a/TRPC6/DRP1 is a novel protective pathway in cisplatin-induced AKI and may be targeted for the prevention and treatment of drug-related renal injury. SIGNIFICANCE OF THE STUDY: Our study found that miR-26a was significantly downregulated during cisplatin-induced AKI and during cisplatin co-cultured HK2 cells. Further, in vitro we used miR-26a mimic to intervene cells and found that apoptosis alleviated compared with control group. We further verified that miR-26a protected cisplatin-induced apoptosis by target transient receptor potential channel 6 (TRPC6) which can regulate the expression of dynamic-related protein 1 (DRP1) and inhibit the mitochondrial apoptosis pathway. Thus, miR-26a/TRPC6/DRP1 is a new protective pathway in cisplatin-induced AKI and may be targeted for the prevention and treatment of drug-related acute kidney injury.

Hemophagocytic lymphohistiocytosis complicated by polyserositis: A case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare group of disorders of immune dysregulation characterized by clinical symptoms of severe inflammation. There are basically two types of clinical scenarios: Familial HLH and sporadic HLH. It is thought that the syndrome is implicated in the development of infections, malignancies, and autoimmune diseases. HLH, whether primary or secondary, is characterized by activated macrophages in hematopoietic organs, hepatosplenomegaly, cytopenia, and fever; however, HLH complicated with polyserositis (PS) has never been reported. CASE SUMMARY: We present a case of fever in a 46-year-old previously healthy Chinese woman complicated by pericardial, pleural, and abdomen effusions. She had no contact with sick individuals, recent travel, illicit drug use, or new sexual contacts. She did not consume alcohol or tobacco and lacked a family history of other diseases. Antibiotics were prescribed for suspected infection, and acute liver injury subsequently occurred. Contrast-enhanced computed tomography showed mild pericardial effusion, pleural effusion, hepatosplenomegaly, and a large amount of ascites. A full blood count revealed leukopenia and thrombocytopenia. Increased ferritin and triglyceride levels were observed. The test for Epstein-Barr (EB) virus DNA was positive. This suggests that EB virus replication and EB virus infection existed. Additional studies showed hemophagocytosis in bone marrow biopsy specimens. The patient's condition progressed rapidly. After providing symptomatic support treatment, eliminating immune stimuli, and administering comprehensive cyclosporine and dexamethasone treatment, the patient's condition continued to progress, and the patient's family members decided to stop treatment; the patient subsequently died. CONCLUSION: This case shows the significance of considering HLH as part of the evaluation of unexplained fever and PS of unknown origin.

Employing Macrophage-Derived Microvesicle for Kidney-Targeted Delivery of Dexamethasone: An Efficient Therapeutic Strategy against Renal Inflammation and Fibrosis.

Although glucocorticoids are the mainstays in the treatment of renal diseases for decades, the dose dependent side effects have largely restricted their clinical use. Microvesicles (MVs) are small lipid-based membrane-bound particles generated by virtually all cells. Here we show that RAW 264.7 macrophage cell-derived MVs can be used as vectors to deliver dexamethasone (named as MV-DEX) targeting the inflamed kidney efficiently. Methods: RAW macrophages were incubated with dexamethasone and then MV-DEX was isolated from the supernatants by centrifugation method. Nanoparticle tracking analysis, transmission electron microscopy, western blot and high-performance liquid chromatography were used to analyze the properties of MV-DEX. The LC-MS/MS was applied to investigate the protein compositions of MV-DEX. Based on the murine models of LPS- or Adriamycin (ADR)-induced nephropathy or in-vitro culture of glomerular endothelial cells, the inflammation-targeting characteristics and the therapeutic efficacy of MV-DEX was examined. Finally, we assessed the side effects of chronic glucocorticoid therapy in MV-DEX-treated mice. Results: Proteomic analysis revealed distinct integrin expression patterns on the MV-DEX surface, in which the integrin αLß2 (LFA-1) and α4ß1 (VAL-4) enabled them to adhere to the inflamed kidney. Compared to free DEX treatment, equimolar doses of MV-DEX significantly attenuated renal injury with an enhanced therapeutic efficacy against renal inflammation and fibrosis in murine models of LPS- or ADR-induced nephropathy. In vitro, MV-DEX with about one-fifth of the doses of free DEX achieved significant anti-inflammatory efficacy by inhibiting NF-κB activity. Mechanistically, MV-DEX could package and deliver glucocorticoid receptors to renal cells, thereby, increasing cellular levels of the receptor and improving cell sensitivity to glucocorticoids. Notably, delivering DEX in MVs significantly reduced the side effects of chronic glucocorticoid therapy (e.g., hyperglycemia, suppression of HPA axis). Conclusion: In summary, macrophage-derived MVs efficiently deliver DEX into the inflamed kidney and exhibit a superior capacity to suppress renal inflammation and fibrosis without apparent glucocorticoid adverse effects. Our findings demonstrate the effectiveness and security of a novel drug delivery strategy with promising clinical applications.

Calcium-sensing receptor activation attenuates collagen expression in renal proximal tubular epithelial cells.

316: F1006-F1015, 2019. First published March 6, 2019; doi: 10.1152/ajprenal.00413.2018 .-Experimental studies have shown that pharmacological activation of calcium-sensing receptor (CaSR) attenuates renal fibrosis in some animal models beyond modification of bone and mineral homeostasis; however, its underlying mechanisms remain largely unknown. Since excessive collagen deposition is the key feature of fibrosis, the present study aimed to examine whether CaSR was involved in the regulation of collagen expression in rats with adenine diet-induced renal fibrosis and in profibrotic transforming growth factor (TGF)-ß1-treated renal proximal tubular epithelial cells (PTECs). The results showed that the CaSR agonist cinacalcet significantly attenuated renal collagen accumulation and tubular injury in adenine diet-fed rats. Additionally, the in vitro experiment showed that profibrotic TGF-ß1 significantly increased the expression of collagen and decreased CaSR expression at the mRNA and protein levels in a concentration- and time-dependent manner. Furthermore, the CaSR CRISPR activation plasmid and cinacalcet partially abrogated the upregulation of collagen induced by TGF-ß1 treatment. Blockade of CaSR by the CRISPR/Cas9 KO plasmid or the pharmacological antagonist Calhex231 further enhanced TGF-ß1-induced collagen expression. Mechanistic experiments found that Smad2 phosphorylation and Snail expression were markedly increased in PTECs treated with TGF-ß1, whereas the CaSR CRISPR activation plasmid and cinacalcet substantially suppressed this induction. In summary, this study provides evidence for a direct renal tubular epithelial protective effect of CaSR activation in renal fibrosis, possibly through suppression of collagen expression in PTECs.

CD62P and P10 as predictive markers for assessing the efficacy of hemodialysis in treating end-stage renal disease.

BACKGROUND: CD62P is a platelet α-granule membrane protein, and P10 is a platelet membrane glycoprotein thrombospondin. To better understand the effects of hemodialysis (HD), we have conducted this study to investigate CD62P and P10 in assessing the efficacy of HD in treating patients with end-stage renal disease (ESRD). METHODS: The case group consisted of 111 patients suffering ESRD treated with regular HD and the control group enrolled 117 healthy subjects. Before and after HD treatment, a series of parameters were observed, based on which, CD62P and P10 levels were detected in the patients in two groups before and after HD therapy. The correlation analysis analyzed the correlations of CD62P and P10 markers with serum creatinine (Scr), blood urea nitrogen (BUN), and subjective score; and logistic regression analysis was performed to reveal factors affecting the efficacy of HD. RESULTS: BUN, Scr, serum phosphorus, intact parathyroid hormone (iPTH), fibrinogen, and ß2-microglobulin (ß2-MG) decreased while hemoglobin, albumin, and activated partial thromboplastin time increased in the patients suffering ESRD; patients presented with improvements in subjective symptoms and an increase in dry weight. CD62P and P10 levels were lower in post-treatment patients. CD62P and P10 positively correlated with Scr, BUN and subjective score; post-treatment CD62P and P10 levels, BUN, hemoglobin, albumin, triglyceride, iPTH, ß2-MG, and fibrinogen were correlated with the efficacy of HD. CONCLUSION: CD62P and P10 might be correlated to the efficacy of HD in treating ESRD, in turn providing predictive markers for assessing the ability of HD in treating ESRD.

Artemisinin attenuates tubulointerstitial inflammation and fibrosis via the NF-κB/NLRP3 pathway in rats with 5/6 subtotal nephrectomy.

Artemisinin (Art) is isolated from Artemisia annua L. and known as the most effective antimalaria drugs. Previous studies demonstrated that it could exert an immune-regulatory effect on autoimmune diseases. In this study, we first investigated its potential role in tubulointerstitial inflammation and fibrosis in rats with 5/6 nephrectomy. Subtotal nephrectomized (SNx) rats were orally administered Art (100 mg·kg -1 ·d - 1) for 16 weeks. Blood and urine samples were collected for biochemical examination. Kidney tissues were collected for immunohistochemistry and Western blot analyses. Ang II-induced injury of the human kidney 2 (HK-2) cells was used for in vitro study. It was shown that Art could significantly attenuate the renal function decline in SNx rats compared with control. More importantly, Art treatment significantly reduced the tubulointerstitial inflammation and fibrosis, as demonstrated by the evaluation of renal pathology. Furthermore, Art inhibited the activation of NLRP3 inflammasome and NF-κB in the kidneys. In in vitro study, Art pretreatment could significantly prevent the activation of NLRP3 inflammasome and NF-κB in Ang II-treated HK-2 cells, while BAY11-7082 (an inhibitor of NF-κB) significantly inhibited Ang II-induced NLRP3 inflammasome activation. This study suggested that Art could provide renoprotective role by attenuating the tubulointerstitial inflammation and fibrosis in SNx rats by downregulating the NF-κB/NLRP3 signaling pathway.

Association of lipoprotein(a) and coronary artery disease in 1003 patients with stage 3-5 chronic kidney disease undergoing coronary angiography.

AIM: Lipoprotein(a) [Lp(a)] is considered a risk factor for cardiovascular disease. However, the role of Lp(a) in chronic kidney disease (CKD) patients is not well understood. The aim of this study was to evaluate the association between Lp(a) levels and the presence of coronary artery disease (CAD) and the severity of coronary artery stenosis (CAS) in patients with stage 3-5 CKD. PATIENTS AND METHODS: We retrospectively studied patients who were diagnosed with stage 3-5 CKD and underwent coronary artery angiography in Zhongda Hospital. The Gensini scoring system was used to assess the severity of coronary stenosis. RESULTS: A total of 1003 patients were enrolled in this cross-sectional study, and 776 of these patients were diagnosed with CAD. The Lp(a) levels were significantly higher in the CAD group than the non-CAD group [271.50 (168.00-459.25) vs. 195.00 (131.00-347.00) mg/l, P<0.001]. Multivariate logistic regression analysis showed that the Lp(a) tertiles were associated independently with the presence of CAD [tertile 2 vs. tertile 1 [adjusted odds ratio (OR)=2.063, 95% confidence interval (CI): 1.394-3.053, P<0.001] and tertile 3 vs. tertile 1 (adjusted OR=2.022, 95% CI: 1.345-3.040, P=0.001)]. After adjusting for potential confounders, the Lp(a) levels were associated independently with severe CAS [tertile 2 vs. tertile 1 (adjusted OR=1.603, 95% CI: 1.040-2.472, P=0.033); tertile 3 vs. tertile 1 (adjusted OR=1.743, 95% CI: 1.128-2.693, P=0.012)]. CONCLUSION: Higher Lp(a) levels were associated the presence of CAD and the severe CAS among patients with stage 3-5 CKD independently.

Urinary Exosomes and Exosomal CCL2 mRNA as Biomarkers of Active Histologic Injury in IgA Nephropathy.

IgA nephropathy (IgAN) features variable renal pathology and a heterogeneous clinical course. Our aim was to search noninvasive biomarkers from urinary exosomes for IgAN patients; membrane nephropathy and minimal change disease were included as other glomerulopathy controls. Transmission electron microscopy and nanoparticle tracking analysis confirmed the size and morphology characteristic of urinary exosomes. Exosome markers (Alix and CD63) as well as renal cell markers [aquaporin 2 (AQP2) and nephrin] were detected, which indicate the renal origin of urinary exosomes. Exosome excretion was increased markedly in IgAN patients compared with controls and correlated with levels of proteinuria and tubular injury. More important, urinary exosome excretion correlated with greater histologic activity (mesangial hypercellularity, crescents, and endocapillary hypercellularity). Profiling of the inflammation-related mRNA revealed that exosomal chemokine (C-C motif) ligand 2 (CCL2) was up-regulated in IgAN patients. In a validation study, CCL2 was exclusively highly expressed in IgAN patients compared with healthy controls as well as minimal change disease and membrane nephropathy patients. Also, a correlation between exosomal CCL2 and estimated glomerular filtration rate levels was found in IgAN. Exosomal CCL2 was correlated with tubulointerstitial inflammation and C3 deposition. High CCL2 levels at the time of renal biopsy were associated with subsequent deterioration in renal function. Thus, urinary exosomes and exosomal CCL2 mRNA are promising biomarkers reflecting active renal histologic injury and renal function deterioration in IgAN.

Meta-Analysis of the Relation Between IL10 Promoter Polymorphisms and Autoimmune Liver Disease Risk.

BACKGROUND: Single nucleotide polymorphisms of the IL10 gene have been linked to the occurrence of autoimmune liver disease. METHODS: We performed a meta-analysis to assess the association between three IL10 promoter polymorphisms (rs1800896, rs1800871, and rs1800872) and the risk of autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. RESULTS: In total, 1420 articles were initially identified through database retrieval. After screening, seven eligible articles were ultimately included in the meta-analysis. A fixed-effect model was used for all Mantel-Haenszel statistics due to the absence of large between-study heterogeneity (all I2 < 50%, p > 0.1). No association between any of the studied polymorphisms and risk of autoimmune liver disease was detected in the allele, homozygote, heterozygote, dominant, recessive, or carrier genetic models (passociation > 0.05). Potential publication bias was excluded using Begg's and Egger's tests. Similar negative results were observed in subgroup analyses and in an analysis of the three haplotypes of rs1800896/rs1800871/rs1800872 (G/C/C, A/C/C, and A/T/A). CONCLUSION: Our meta-analysis strongly suggests that the IL10 rs1800896, rs1800871, and rs1800872 polymorphisms are not associated with the risk of autoimmune liver disease.

Complement Factor H Inhibits Anti-Neutrophil Cytoplasmic Autoantibody-Induced Neutrophil Activation by Interacting With Neutrophils.

Our previous study demonstrated that plasma levels of complement factor H (FH) were inversely associated with the disease activity of patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). In addition to serving as an inhibitor of the alternative complement pathway, there is increasing evidence demonstrating direct regulatory roles of FH on several cell types. Here, we investigated the role of FH in the process of ANCA-mediated activation of neutrophils and neutrophil-endothelium interaction. We demonstrated that FH bound to neutrophils by immunostaining and flow cytometry. Interestingly, ANCA-induced activation of neutrophils, including respiratory burst and degranulation, was inhibited by FH. Although FH enhanced neutrophils adhesion and migration toward human glomerular endothelial cells (hGEnCs), it inhibited ANCA-induced activation of neutrophils in the coculture system of hGEnCs and neutrophils. Moreover, the activation and injury of hGEnCs, reflected by the level of endothelin-1 in the supernatant of cocultures, was markedly reduced by FH. However, we found that FH from patients with active AAV exhibited a deficient ability in binding neutrophils and inhibiting ANCA-induced neutrophil activation in fluid phase and on endothelial cells, as compared with that from healthy controls. Therefore, our findings indicate a novel role of FH in inhibiting ANCA-induced neutrophil activation and protecting against glomerular endothelial injury. However, FH from patients with active AAV are deficient in their ability to bind neutrophils and inhibit neutrophil activation by ANCA. It further extends the current understanding of the pathogenesis of AAV, thus providing potential clues for intervention strategies.

A rat model of SHPT with bone abnormalities in CKD induced by adenine and a high phosphorus diet.

The study of parathyroid hyperplasia with bone disease as a critical manifestation of chronic kidney disease-mineral and bone disorders (CKD-MBDs) is challenging due to the lack of a suitable research model. Here, we established a rat model with secondary hyperparathyroidism (SHPT) and bone disease induced by adenine and a high phosphorous diet and analyzed the skeletal characteristics. We performed blood analysis, emission computed tomography (ECT), dual energy X-ray absorptiometry (DEXA), micro-computed tomography (micro-CT), bone histomorphometry, and bone mechanical tests. The CKD rats with SHPT induced by adenine and a high phosphorus diet showed severe abnormalities in calcium and phosphorus metabolism and exhibited parathyroid hyperplasia. The bone mineral density (BMD) of femurs and lumbar vertebrae was significantly lower in the CKD rats than in the control (CTL) rats. The cortical and trabecular bone parameters of femurs showed significant bone loss. In addition, we found decreases in ultimate force, work to failure, stiffness, and elastic modulus in the CKD rats. In conclusion, our findings demonstrated that the CKD rats with SHPT induced by adenine and a high phosphorus diet may serve as a useful model for skeletal analysis in CKD with SHPT.

Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation.

Inflammation is a major contributor to the pathogenesis of ischemic acute kidney injury (AKI), which complicates the post-operative outcomes of large numbers of hospitalized surgical patients. Hydroxychloroquine (HCQ), a well-known anti-malarial drug, is commonly used in clinical practice for its anti-inflammatory actions. However, little is known about its role in renal ischemia/reperfusion (I/R) injury. In the current study, mice were subjected to I/R injury and HCQ was administered for seven days by gavage prior to surgery. In parallel, HK-2 human renal proximal tubule cells were prophylactically treated with HCQ and then were exposed to hypoxia/reoxygenation (H/R). The results showed that HCQ significantly attenuated renal dysfunction evidenced by blunted decreases in serum creatinine and kidney injury molecular-1 expression and the improvement of HK-2 cell viability. Additionally, HCQ markedly reduced macrophage and neutrophil infiltration, pro-inflammatory cytokine production, and NLRP3 inflammasome activation. Mechanistic studies showed that HCQ could inhibit the priming of the NLRP3 inflammasome by down-regulating I/R or H/R-induced NF-κB signaling. Moreover, HCQ reduced cathepsin (CTS) B, CTSD and CTSL activity, and their redistribution from lysosomes to cytoplasm. CTSB and CTSL (not CTSD) were implicated in I/R triggered NLRP3 inflammasome activation. Notably, we found that HCQ attenuated renal injury through downregulation of CTSB and CTSL-mediated NLRP3 inflammasome activation. This study provides new insights into the anti-inflammatory effect of HCQ in the treatment of AKI.

Myeloperoxidase influences the complement regulatory activity of complement factor H.

Objective: The interaction between neutrophils and activation of alternative complement pathway plays a critical role in the pathogenesis of ANCA-associated vasculitis (AAV). MPO, which can be released from ANCA-stimulated neutrophils, was recently demonstrated to be capable of activating the alternative complement pathway. Here we aimed to investigate the interaction between MPO and factor H (FH), a key regulator of the alternative pathway, and its effect on the functional activities of FH. Methods: Detection of FH and MPO on neutrophil extracellular traps (NETs) induced by serum from AAV patients and in kidney biopsies of AAV patients was performed by immunostaining. In vitro binding between MPO and FH was examined by ELISA and surface plasmon resonance. The influence of MPO on the complement regulatory activity of FH was further assessed. Results: FH deposited and co-localized with MPO in NETs. In kidney biopsies from AAV patients, MPO was closely adjacent to FH in glomerular capillaries. We demonstrated that MPO binds to FH with an apparent nanomolar affinity and identified short consensus repeats 1-4 of FH as the major binding sites. In terms of functional analysis, MPO inhibited the interaction between FH and C3b and the decay-accelerating activity of FH. The fluid phase and surface cofactor activities of FH upon C3b inactivation were inhibited by MPO. Conclusion: Our findings indicate that MPO binds to FH and influences the complement regulatory activity of FH. MPO-FH interaction may participate in the pathogenesis of AAV by contributing to activation of the alternative complement pathway.

Cervical cancer treated with reduced-volume intensity-modulated radiation therapy base on Sedlis criteria (NCCN VS RTOG).

OBJECTIVE: This study aimed to evaluate the clinical efficacy of different target volumes in pelvic radiotherapy in postoperative treatment of cervical cancer based on the Sedlis criteria. METHODS: Patients who admitted to our department for post-operative radiotherapy of cervical cancer from December 2001 to December 2011 and met the Sedlis criteria were retrospectively analysed. The incidences of acute and late radiation injuries, and overall, disease-free and tumour-specific survival with reduced-volume pelvic and whole-pelvis radiotherapy were evaluated and compared. RESULTS: A total of 371 patients were included in the study, including 239 receiving whole-pelvis radiotherapy and 132 receiving reduced-volume pelvic radiotherapy. The volume of contours for mean PTV volumes, bilateral femoral heads and small intestine volumes in reduced-volume pelvic radiotherapy were lower than whole-pelvis radiotherapy; the results were similar to the V10, V20, V30, V40 and V45 for pelvic bone marrow and small intestine dose volume (both p < 0.05). The acute radiation injury observed in the two groups was mainly haematologic toxicity and upper and lower gastrointestinal symptoms. The incidences of acute radiation injury, and late radiation injury of gastrointestinal and urinary tracts were both significantly lower with reduced-volume pelvic radiotherapy than with whole-pelvis radiotherapy (both p < 0.05). Moreover, there was no significant difference in the incidence of lower extremity oedema, or 2-year or 5-year overall, disease-free or tumour-specific survival between groups (all p > 0.05). CONCLUSION: Reduced-volume pelvic radiotherapy could relieve acute and late radiation injuries, especially myelosuppression, and did not affect long-term survival. Advanced in knowledge: Our study shows that reduced-volume base on National Comprehensive Cancer Network 2016 is more fit for cervical cancer than others.