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Head and neck squamous cell carcinoma (HNSCC), as the most common type (90%) of head and neck cancer, includes various epithelial malignancies that arise in the nasal cavity, oral cavity, pharynx, and larynx. In 2020, approximately 878 ‍ 000 new cases and 444 000 deaths linked to HNSCC occurred worldwide (Sung et al., 2021). Due to the associated frequent recurrence and metastasis, HNSCC patients have poor prognosis with a five-year survival rate of 40%-50% (Jou and Hess, 2017). Therefore, novel prognostic biomarkers need to be developed to identify high-risk HNSCC patients and improve their disease outcomes.

Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

Novel corona virus caused pneumonia first reported in December, 2019 in Wuhan, China was later named COVID-19. Due to its special pathogenicity, COVID-19 transmitted with high speed beyond borders and has significantly affected normal life. Currently, no specific drugs, treatment or vaccines are available. Vaccine development for COVID-19 is a highly complex process involving viral genomic studies, identification of target for vaccine, vaccine design, manufacturing, storage and distribution, preclinical and clinical safety and efficacy studies. The high levels of efforts and global collaboration at this scale is unprecedented. The World Health Organization (WHO) has documented 160 different COVID-19 vaccine candidates as of July 13, 2020 with 26 currently on clinical evaluation while 137 vaccines on preclinical evaluation. COVID-19 vaccine efforts mark the first use of mRNA-type vaccines ever evaluated. Numerous research organizations have successfully initiated clinical evaluation of COVID-19 vaccines. This review aims to summarize the advances and challenges for COVID-19 vaccines development.

Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to delineate the methylome landscape and characterize the oncogenic drivers of esophageal squamous cell carcinoma (ESCC). We found 98% of CpGs are hypomethylated across the ESCC genome. Hypo-methylated regions are enriched in areas with heterochromatin binding markers (H3K9me3, H3K27me3), while hyper-methylated regions are enriched in polycomb repressive complex (EZH2/SUZ12) recognizing regions. Altered methylation in promoters, enhancers, and gene bodies, as well as in polycomb repressive complex occupancy and CTCF binding sites are associated with cancer-specific gene dysregulation. Epigenetic-mediated activation of non-canonical WNT/β-catenin/MMP signaling and a YY1/lncRNA ESCCAL-1/ribosomal protein network are uncovered and validated as potential novel ESCC driver alterations. This study advances our understanding of how epigenetic landscapes shape cancer pathogenesis and provides a resource for biomarker and target discovery., The epigenetic landscape of esophageal squamous cell carcinoma (ESCC) at genome-wide high resolution is incompletely studied. Here, the authors performed an integrated multi-omics analysis of ESCC and non-tumor tissues to define the genome-wide methylome landscape and epigenetic alterations to uncover oncogenic drivers of ESCC.

Cell organelles play crucial roles in the normal functioning of an organism, therefore the disruption of their operation is associated with diseases and in some cases death. Thus, the detection and monitoring of the activities within these organelles are of great importance. Several probes based on graphene oxide, small molecules, and other nanomaterials have been developed for targeting specific organelles. Among these materials, organelle-targeted fluorescent probes based on carbon dots have attracted substantial attention in recent years owing to their superior characteristics, which include facile synthesis, good photostability, low cytotoxicity, and high selectivity. The ability of these probes to target specific organelles enables researchers to obtain valuable information for understanding the processes involved in their functions and/or malfunctions and may also aid in effective targeted drug delivery. This review highlights recently reported organelle-specific fluorescent probes based on carbon dots. The precursors of these carbon dots are also discussed because studies have shown that many of the intrinsic properties of these probes originate from the precursor used. An overview of the functions of the discussed organelles, the types of probes used, and their advantages and limitations are also provided. Organelles such as the mitochondria, nucleus, lysosomes, and endoplasmic reticulum have been the central focus of research to date, whereas the Golgi body, centrosome, vesicles, and others have received comparatively little attention. It is therefore the hope of the authors that further studies will be conducted in an effort to design probes with the ability to localize within these less studied organelles so as to fully elucidate the mechanisms underlying their function.

Liposomes, the most widely studied nano-drug carriers in drug delivery, are sphere-shaped vesicles consisting of one or more phospholipid bilayers. Compared with traditional drug delivery systems, liposomes exhibit prominent properties that include targeted delivery, high biocompatibility, biodegradability, easy functionalization, low toxicity, improvements in the sustained release of the drug it carries and improved therapeutic indices. In the wake of the rapid development of nanotechnology, the studies of liposome composition have become increasingly extensive. The molecular diversity of liposome composition, which includes long-circulating PEGylated liposomes, ligand-functionalized liposomes, stimuli-responsive liposomes, and advanced cell membrane-coated biomimetic nanocarriers, endows their drug delivery with unique physiological functions. This review describes the composition, types and preparation methods of liposomes, and discusses their targeting strategies in cancer therapy.

Determining the etiology of end-stage renal disease (ESRD) constitutes a great challenge in the context of renal transplantation. Evidence is lacking on the genetic findings for adult renal transplant recipients through exome sequencing (ES). Adult patients on kidney transplant waitlist were recruited from 2017 to 2019. Trio-ES was conducted for the families who had multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early onset or extrarenal features. Pathogenic variants were confirmed in 62 from 115 families post sequencing for 421 individuals including 195 health family members as potential living donors. Seventeen distinct genetic disorders were identified confirming the priori diagnosis in 33 (28.7%) families, modified or reclassified the clinical diagnosis in 27 (23.5%) families, and established a diagnosis in two families with ESRD of unknown etiology. In 14.8% of the families, we detected promising variants of uncertain significance in candidate genes associated with renal development or renal disease. Furthermore, we reported the secondary findings of oncogenes in 4.4% of the patients and known single-nucleotide polymorphisms associated with pharmacokinetics in our cohort to predict the drug levels of tacrolimus and mycophenolate. The diagnostic utility of the genetic findings has provided new clinical insight in most families that help with preplanned renal transplantation.

Background: Significant advances have been made in recent years to utilize natural enzymes with antioxidant properties for the treatment of acute kidney injury (AKI). However, these enzymes have limited clinical utility due to their limited cellular uptake, poor pharmacokinetic properties, and suboptimal stability. We prepared a novel biomimetic mineralization approach to overcome these limitations.Results: Catalase (CAT) and superoxide dismutase (SOD) were encapsulated in a zeolitic imidazolate framework-8 (ZIF-8), then this SOD@CAT@ZIF-8 complex was anchored with MPEG2000-COOH to yield an MPEG2000-SOD@CAT@ZIF-8 (PSCZ) composite. This composite was then utilized as a stable tool with antioxidant properties for the integrated cascade-based treatment of AKI, remarkably improved intracellular enzyme delivery. The PSCZ composite showed a significantly relieve ability of H2O2 induced ROS and prevented apoptosis in HEK293 cells. In vivo, this composite showed a protective effect in the cisplatin-induced AKI mouse model. In addition, PSCZ treatment mitigated renal dysfunction and histological injury, like tubulointerstitial infiltration. RNA sequencing results further confirmed the protective effect of PSCZ and the potential molecular mechanism was revealed. PSCZ treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and inflammatory infiltration of renal tubules. Moreover, PSCZ administration regulated renal injury via the p53 signaling pathway. These renoprotective effects of PSCZ treatment were more potent in CP-AKI mice than those of SOD or CAT alone. This dual-enzyme-embedded metal-organic framework was able to scavenge reactive oxygen species synergistically and effectively. Conclusion: PSCZ can remarkably improve intracellular enzyme delivery, and it can be used as a stable tool with antioxidant properties for the integrated cascade-based treatment of AKI. The ZIF-8-based “armor plating” represents an effective means of shielding enzymes with improved therapeutic utility to guide the precision medicine-based treatment of AKI.

Additional file 8: Table S5. 55 VUS detected in our study with distinct status in the Findlay et al. study.

Additional file 6: Table S3. Clinical characteristics of BC patients with pathogenic BRCA1/2 variants carriers and non-pathogenic variants carrier.

Additional file 5: Figure S2. Comparison of clinical characteristics of BC patients with pathogenic BRCA1/2 variants and BC patients with benign BRCA1/2 variants/VUS. a. The distribution of age at diagnosis between pathogenic BRCA1/2 variants carriers and benign BRCA1/2 variants/VUS carriers. b. The distribution of BMI between pathogenic BRCA1/2 variants carriers and benign BRCA1/2 variants/VUS carriers. c. The distribution of histology between pathogenic BRCA1/2 variants carriers and benign BRCA1/2 variants/VUS carriers. d. The distribution of subtype between pathogenic BRCA1/2 variants carriers and benign BRCA1/2 variants/VUS carriers. e. The distribution of tumor size between pathogenic BRCA1/2 variants carriers and benign BRCA1/2 variants/VUS carriers. f. The distribution of histological grade between pathogenic BRCA1/2 variants carriers and benign BRCA1/2 variants/VUS carriers. g. The distribution of lymph modes status between pathogenic BRCA1/2 variants carriers and benign BRCA1/2 variants/VUS carriers. h. The distribution of location of cancer between pathogenic BRCA1/2 variants carriers and benign BRCA1/2 variants/VUS carriers. i. The distribution of family history of breast cancer between pathogenic BRCA1/2 variants carriers and benign BRCA1/2 variants/VUS carriers. j. The distribution of family history of other cancer between pathogenic BRCA1/2 variants carriers and benign BRCA1/2 variants/VUS carriers.

Additional file 3: Table S1. Distribution of 3-tier-classified variants in BCs and HCs.

Additional file 7: Table S4. Variants detected in our study whose clinical significance were benign but conflicting interpretations of pathogenicity in ClinVar.

Additional file 4: Table S2. Carrier frequency of pathogenic variants in BCs and HCs.

Additional file 1: Figure S1. Schematic representation of the study and major results. Clinical samples from Chinese breast cancer patients (BCs; n = 21,216) and healthy controls (HCs; n = 6434) were subjected to an amplicon-based next-generation sequencing of the BRCA1/2 genes. A total of n = 17,420 BCs and n = 5890 HCs were implemented in the clinical analysis in a 3-tier classification system to determine pathogenic variants (n = 1245) and variants of uncertain significance (VUS; n = 2517) of the BRCA1/2 genes. The repartition of the pathogenic variants with respect to frameshifts, stop-codon gains, splicing variants, missense mutations, and start-codon losses are depicted on the right. The 48 moderate-frequency pathogenic variants (detected in ≥ 5 BC patients) represented 39.8% of all pathogenic variants. Reclassification of VUS allowed to reduce the VUS ratio from 9.1 to 6.8%. The data demonstrate a high level of ethnicity-specific BRCA1/2 germline mutations in the Chinese population compared to the Caucasian group.

Additional file of Prevalence and reclassification of BRCA1 and BRCA2 variants in a large, unselected Chinese Han breast cancer cohort

Fiber metal laminates (FMLs) are a novel type of structural material that has been extensively applied in the aerospace field. These laminates are sandwich-type composite materials that comprise alternate metal and fiber-reinforced resin layers. Because of the structural characteristics of the material, it has high-impact resistance from the metal layer and increased fracture toughness and excellent fatigue and damage tolerance properties from the fiber layer. To further develop and apply this new composite material, it is essential to understand the research status on the stress analysis of each component in FMLs and the tensile strength properties of FMLs. Therefore, in this study, the current research status on the residual stress and applied stress of the component materials in FMLs and the tensile strength of the laminates is summarized. The relationship between the applied stress of each layer and the remote stress of laminates and the relationship between the tensile properties of laminates and the component material properties in laminates are clarified. Additionally, the theoretical basis and direction of development of the related models are analyzed and studied. Consequently, all of the above are aimed at laying a foundation for further investigations of the laminate theory and for the improvement of the theoretical research system.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel coronavirus causing an outbreak of COVID-19 globally in the past six months. A relatively higher divergence on the spike protein of SASR-CoV-2 enables it to transmit across species efficiently. We particularly believe that the adaptive mutations of the receptor-binding domain (RBD) of spike protein in SARS-CoV-2 might be essential to its high transmissibility among humans. Thus here we collected 2,142 high-quality genome sequences of SARS-CoV-2 from 160 regions in over 50 countries and reconstructed their phylogeny, and also analyzed the interaction between the polymorphisms of spike protein and human ACE2 (hACE2). Phylogenetic analysis of SARS-CoV-2 and coronavirus in other hosts show SARS-CoV-2 is highly possible originated from Bat-CoV (RaTG13) found in horseshoe bat and a recombination event may occur on the spike protein of Pangolin-CoV to imbue it the ability to infect humans. Moreover, compared to the S gene of SARS-CoV-2, it is more conserved in the direct-binding sites of RBD and we noticed that spike protein of SARS-CoV-2 may under a consensus evolution to adapt to human hosts better. 3,860 amino acid mutations in spike protein RBD (T333-C525) of SARS-CoV-2 were simulated and their stability and affinity binding to hACE2 (S19-D615) were calculated. Our analysis indicates SARS-CoV-2 could infect humans from different populations with no preference, and a higher divergence in the spike protein of SARS-CoV-2 at the early stage of this pandemic may be a good indicator that could show the pathway of SARS-CoV-2 transmitting from the natural reservoir to human beings.

Hydrogen sulfide (H2S), a colorless gas smelling of rotten egg, has long been recognized as a toxic gas and environment pollutant. However, increasing evidence suggests that H2S acts as a novel gasotransmitter and plays important roles in a variety of physiological and pathological processes in mammals. H2S is involved in many hepatic functions, including the regulation of oxidative stress, glucose and lipid metabolism, vasculature, mitochondrial function, differentiation, and circadian rhythm. In addition, H2S contributes to the pathogenesis and treatment of a number of liver diseases, such as hepatic fibrosis, liver cirrhosis, liver cancer, hepatic ischemia/reperfusion injury, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, hepatotoxicity, and acute liver failure. In this review, the biosynthesis and metabolism of H2S in the liver are summarized and the role and mechanism of H2S in liver health and disease are further discussed.

Objective: To present a case of adult-onset familial diabetes mellitus in which a genetic etiology typical for neonatal diabetes was identified.Methods: We conducted whole-exome and Sanger sequencing, assessed clinical presentation and family history, and performed a literature review.Results: A 40-year-old, thin woman presented with a 10-year history of mildly elevated fasting glucose and A1C levels. Her mother had diabetes mellitus since her 40s and is on insulin, and her daughter presented with diabetes mellitus at age 21. The patient and her daughter underwent whole-exome sequencing and were found to have a mutation in the KCNJ11 gene, c.G685A, p.E229K. This mutation is known to be associated with neonatal presentation of diabetes mellitus, which neither of these family members had a history of. Given her known mutation and postprandial hyperglycemia, a trial of low-dose sulfonylurea was initiated in the daughter but failed due to hypoglycemia. She was found to have a CYP2C9 genotype associated with poor oral drug clearance.Conclusion:KCNJ11 mutation should be screened for in patients and families meeting criteria for maturity-onset diabetes of the young, even without evidence of neonatal onset in the family. Furthermore, even though sulfonylurea therapy is successful in the majority of patients with KCNJ11 mutations, there may be a role for other interacting environmental or genetic modifiers, such as CYP2C9 geno-type, that affect sulfonylurea metabolism. Those patients who have delayed onset of disease and milder courses may be less ideal candidates for this treatment.Abbreviations: BMI = body mass index;KATP = ATP-sensitive potassium channel;MODY = maturity-onset diabetes of the young;NDM = neonatal diabetes mellitus

Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to characterize the oncogenic drivers of esophageal squamous cell carcinoma (ESCC). We found 98% of CpGs are hypomethylated across the ESCC genome and two-thirds occur in long non-coding (lnc)RNA regions. DNA methylation and epigenetic heterogeneity both coincide with chromosomal topological alterations. Gene body methylation, polycomb repressive complex occupancy, and CTCF binding sites associate with cancer-specific gene regulation. Epigenetically-mediated activation of non-canonical WNT signaling and the lncRNAESCCAL-1were validated as potential ESCC driver alterations. Gene-specific cancer driver roles of epigenetic alterations and heterogeneity are identified.

Background Thymosin alpha-1 (TA) has been reported to inhibit tumor growth as an immunomodulator. However, its mechanism of action in immunosuppressive cells is unclear. The purpose of this study was to investigate whether TA can reshape the immune microenvironment by inhibiting the function of myeloid-derived suppressor cells (MDSCs) in non-small cell lung carcinoma (NSCLC). Methods The effects of TA on peripheral blood monocytic MDSCs (M-MDSCs) in patients with NSCLC and on the apoptosis and migration of M-MDSCs were studied. A mouse subcutaneous xenograft tumor model was constructed, and the effect of TA on M-MDSC migration was evaluated. Quantitative real-time PCR, Western blotting, flow cytometry and immunohistochemistry were used to examine the mechanism by which TA affects M-MDSCs. Results TA not only promoted the apoptosis of M-MDSCs by reducing the Bcl-2/BAX ratio but also and more importantly inhibited the migration of MDSCs to the tumor microenvironment by suppressing the production of vascular endothelial growth factor (VEGF) through the downregulation of hypoxia-inducible factor (HIF)-1α in tumor cells. Conclusions TA may have a novel antitumor effect mediated by decreasing M-MDSC accumulation in the tumor microenvironment through reduced VEGF production.

Tumour necrosis factor‐α‐induced protein 8‐like 2 (TIPE2) is a tumour suppressor in many types of cancer. However, the mechanism of action of TIPE2 on the growth of rectal adenocarcinoma is unknown. Our results showed that the expression levels of TIPE2 in human rectal adenocarcinoma tissues were higher than those in adjacent non‐tumour tissues. Overexpression of TIPE2 reduced the proliferation, migration, and invasion of human rectal adenocarcinoma cells and down‐regulation of TIPE2 showed reverse effects. TIPE2 overexpression increased apoptosis through down‐regulating the expression levels of Wnt3a, phospho (p)‐β‐Catenin, and p‐glycogen synthase kinase‐3β in rectal adenocarcinoma cells, however, TIPE2 knockdown exhibited reverse trends. TIPE2 overexpression decreased autophagy by reducing the expression levels of p‐Smad2, p‐Smad3, and transforming growth factor‐beta (TGF‐β) in rectal adenocarcinoma cells, however, TIPE2 knockdown showed opposite effects. Furthermore, TIPE2 overexpression reduced the growth of xenografted human rectal adenocarcinoma, whereas TIPE2 knockdown promoted the growth of rectal adenocarcinoma tumours by modulating angiogenesis. In conclusion, TIPE2 could regulate the proliferation, migration, and invasion of human rectal adenocarcinoma cells through Wnt/β‐Catenin and TGF‐β/Smad2/3 signalling pathways. TIPE2 is a potential therapeutic target for the treatment of rectal adenocarcinoma.

Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor β (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-β promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-β as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-β in aggressive life-threatening familial forms of the disease.

Diabetic nephropathy ensues from events involving earliest changes in the glomeruli and podocytes, followed by accumulation of extracellular matrix in the mesangium. Postulated mechanisms include roles for vascular endothelial growth factor (VEGF), produced by podocytes and contributing to enhanced excretion of urinary albumin and recruitment/activation of inflammatory cells, and transforming growth factor-beta (TGF-beta), elicited largely from mesangial cells and driving production of extracellular matrix. RAGE, a receptor for advanced glycation endproducts (AGEs) and S100/calgranulins, displays enhanced expression in podocytes of genetically diabetic db/db mice by age 13 weeks. RAGE-bearing podocytes express high levels of VEGF by this time, in parallel with enhanced recruitment of mononuclear phagocytes to the glomeruli; events prevented by blockade of RAGE. By age 27 weeks, soluble RAGE-treated db/db mice displayed diminished albuminuria and glomerulosclerosis, and improved renal function. Diabetic homozygous RAGE null mice failed to develop significantly increased mesangial matrix expansion or thickening of the glomerular basement membrane. We propose that activation of RAGE contributes to expression of VEGF and enhanced attraction/activation of inflammatory cells in the diabetic glomerulus, thereby setting the stage for mesangial activation and TGF-beta production; processes which converge to cause albuminuria and glomerulosclerosis.

CYP1A2 is a major cytochrome P-450 isoform in the liver and the olfactory mucosa but is essentially not expressed in other tissues. A nuclear factor 1 (NF-1) -like element was identified in the proximal promoter region of rat, mouse, rabbit, and human CYP1A2 genes through data base analysis. In vitro DNase I footprinting with a -211 to +81 probe from the rat CYP1A2 gene and nuclear extracts from rat liver and olfactory mucosa revealed a single protected region corresponding to the NF-1-like element at -129 to -111. Protein binding to this NF-1-like element was tissue-selective and was confirmed by in vivo footprinting in native chromatin from rat liver. Multiple DNA-binding complexes were detected in gel-shift assays using the CYP1A2 NF-1-like element and nuclear extracts from liver and olfactory mucosa, all of which were supershifted in the presence of an anti-NF1 antibody. The NF-1-like element was essential for transcriptional activity of the CYP1A2 gene in an in vitro transcription assay using nuclear extracts from the two tissues. Thus, members of the NF-1 family of transcription factors may play an important role in the tissue-selective expression of the CYP1A2 gene in the liver and olfactory mucosa.

Objective To investigate the potential association of plastin 3 ( PLS3 ) expression levels in the blood with disease severity in spinal muscular atrophy (SMA). Design Measurement of PLS3 messenger RNA levels in the blood of patients with types I, II, and III SMA. Setting Pediatric Neuromuscular Clinical Research Network SMA Natural History study. Participants A cohort of 88 patients of both sexes who had SMA. Main Outcome Measures Levels of PLS3 messenger RNA in relation to SMA type and SMN2 copy number. Results Prepubertal female and younger male ( PLS3 expression than did postpubertal female and older male (≥11 years) patients, respectively ( P ≤ .001). Expression of PLS3 in male patients did not correlate with SMA clinical type or SMN2 copy number in either age group ( P > .10). In postpubertal female patients, PLS3 expression was greatest in patients with type III SMA, was intermediate in patients with type II SMA, and was lowest in patients with type I SMA. Expression of PLS3 correlated with SMA type, SMN2 copy number, and the gross motor function measure only in postpubertal female patients. Conclusion The PLS3 gene may be an age- and/or puberty-specific and sex-specific modifier of SMA.

In the kidney, the receptor for advanced glycation end products (RAGE) is principally expressed in the podocyte at low levels, but is upregulated in both human and mouse glomerular diseases. Because podocyte injury is central to proteinuric states, such as the nephrotic syndrome, the murine adriamycin nephrosis model was used to explore the role of RAGE in podocyte damage. In this model, administration of the anthracycline antibiotic adriamycin provokes severe podocyte stress and glomerulosclerosis. In contrast to wild-type animals, adriamycin-treated RAGE-null mice were significantly protected from effacement of the podocyte foot processes, albuminuria, and glomerulosclerosis. Administration of adriamycin induced rapid generation of RAGE ligands, and treatment with soluble RAGE protected against podocyte injury and glomerulosclerosis. In vitro, incubation of RAGE-expressing murine podocytes with adriamycin stimulated AGE formation, and treatment with RAGE ligands rapidly activated nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, via p44/p42 MAP kinase signaling, and upregulated pro-fibrotic growth factors. These data suggest that RAGE may contribute to the pathogenesis of podocyte injury in sclerosing glomerulopathies such as focal segmental glomerulosclerosis.