Catalase-templated nanozyme-loaded microneedles integrated with polymyxin B for immunoregulation and antibacterial activity in diabetic wounds.

Diabetic wounds are characterized by chronic trauma, with long-term non-healing attributed to persistent inflammation and recurrent bacterial infections. Exacerbation of the inflammatory response is largely due to increased levels of reactive oxygen species (ROS). In this study, catalase (CAT) was used as a biological template to synthesize nanozyme-supported natural enzymes (CAT-Mn(SH)x) using a biomimetic mineralization method. Subsequently, polymyxin B (CAT-Mn(SH)x@PMB) was immobilized on its surface through electrostatic assembly. CAT-Mn(SH)x@PMB demonstrates the ability for slow and sustained release of hydrogen sulfide (H2S). Finally, CAT-Mn(SH)x@PMB loaded microneedles (MNs) substrate were synthesized using polyvinyl alcohol (PVA) and hydroxyethyl methacrylate (HEMA), and named CAT-(MnSH)x@PMB-MNs. It exhibited enhanced enzyme and antioxidant activities, along with effective antibacterial properties. Validation findings indicate that it can up-regulate the level of M2 macrophages and reduce the level of pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Additionally, it promotes angiogenesis and rapid nerve regeneration, thereby facilitating wound healing through its dual anti-inflammatory and antibacterial effects. Hence,this study introduces a time-space tissue-penetrating and soluble microneedle patch with dual anti-inflammatory and antibacterial effects for the treatment of diabetic wounds.

The efficacy and safety of compound kushen injection for adults with esophageal cancer: A meta-analysis of randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Kushen injection (CKI), derived from the traditional Chinese medicine Sophora flavescens, has been widely prescribed to treat a variety of cancers including esophageal cancer (ESCA) in China. AIM OF THE STUDY: This study aimed to evaluate the efficacy and safety of CKI for ESCA systematically. METHODS: The protocol was registered in the PROSPERO database with No. CRD42022320503. PubMed, Embase, the Cochrane Library, Web of Science, CNKI, Wanfang Database, Clinicaltrials, and Chi-CTR were searched to select RCTs that compared CKI with other interventions for ESCA with outcome measures including clinical efficacy, complete response, quality of life (QoL), adverse events (AEs), and serious AEs (SAEs). The Cochrane Risk of Bias 2 (RoB2) tool was used to assess the quality of RCT. The overall effect sizes were estimated with odds ratios (ORs) and 95% confidence intervals (CIs) on binary outcome data. Meta-analyses were conducted to estimate effect sizes. Subgroup and sensitivity analyses on characteristics of RCTs were performed to test the robustness. Publication bias was also detected with different methods. The evidence strength was assessed with the Grading of Recommendation, Assessment, Development, and Evaluation method. RESULTS: This study finally included 35 RCTs with 2491 ESCA patients. The RoB of RCTs was some concern. The effect size of OR was 2.92 (95% CI [2.39, 3.57]) on clinical efficacy, 2.27 (95% CI [1.84, 2.81]) on complete response, 3.71 (95% CI [2.86, 4.80]) on QoL, 0.39 (95% CI [0.30, 0.50]) on AEs, and 0.13 (95% CI [0.07, 0.27]) on SAEs where the statistical significances (P < 0.00001) were found for all outcome measures. These overall effect sizes showed that CKI was more efficacious and safety for ESCA. Moreover, subgroup and sensitivity analyses found consistent results. Most publication bias analyses showed insignificant differences. The evidence strengths were moderate. CONCLUSION: The moderate evidence from this comprehensive PRISMA-compliant meta-analysis suggested that CKI may be a valuable alternative for adult patients with ESCA on its significant efficacy and safety. However, more RCTs of high quality with low RoB, large sample sizes, and long follow-up periods are still warranted to update the ESCA clinical guideline for physicians and policymakers in further study.

Novel compound heterozygous pathogenic variants in the SLC3A1 gene in a Chinese family with cystinuria.

BACKGROUND: Cystinuria is an autosomal recessive disorder characterized by a cystine transport deficiency in the renal tubules due to mutations in two genes: SLC3A1 and SLC7A9. Cystinuria can be classified into three forms based on the genotype: type A, due to mutations in the SLC3A1 gene; type B, due to mutations in the SLC7A9 gene; and type AB, due to mutations in both genes. METHODS: We report a 12-year-old boy from central China with cystine stones. He was from a non-consanguineous family that had no known history of genetic disease. A physical examination showed normal development and neurological behaviors. Whole-exome and Sanger sequencing were used to identify and verify the suspected pathogenic variants. RESULTS: The compound heterozygous variants c.898_905del (p.Arg301AlafsTer6) is located in exon5 and c.1898_1899insAT (p.Asp634LeufsTer46) is located in exon10 of SLC3A1 (NM_000341.4) were deemed responsible for type A cystinuria family. The variant c.898_905del was reported in a Japanese patient in 2000, and the variant c.1898_1899insAT is novel. CONCLUSION: A novel pathogenic heterozygous variant pair of the SLC3A1 gene was identified in a Chinese boy with type A cystinuria, enriching the mutational spectrum of the SLC3A1 gene. We attempted to find a pattern for the association between the genotype of SLC3A1 variants and the manifestations of cystinuria in patients with different onset ages. Our findings have important implications for genetic counseling and the early clinical diagnosis of cystinuria.

Liposomes for Tumor Targeted Therapy: A Review.

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.

Camptothecin Delivery via Tumor-Derived Exosome for Radiosensitization by Cell Cycle Regulation on Patient-Derived Xenograft Mice.

Purpose: While radiotherapy remains the leading clinical treatment for many tumors, its efficacy can be significantly hampered by the insensitivity of cells in the S phase of the cell cycle to such irradiation. Methods: Here, we designed a highly targeted drug delivery platform in which exosomes were loaded with the FDA-approved anti-tumor drug camptothecin (CPT) which is capable of regulating cell cycle. The utilized exosomes were isolated from patient tumors, enabling the personalized treatment of individuals to ensure better therapeutic outcomes. Results: This exosome-mediated delivery strategy was exhibited robust targeted to patient-derived tumor cells in vitro and in established patient-derived xenograft models. By delivering CPT to tumor cells, this nanoplatform was able to decrease cell cycle arrest in the S phase, increasing the frequency of cells in the G1 and G2/M phases such that they were more radiosensitive. Conclusion: This therapeutic approach was able to substantially enhance the sensitivity of patient-derived tumors to ionizing radiation, thereby improving the overall efficacy of radiotherapy without the need for a higher radiation dose.

Development of an Au-anchored Fe Single-atom nanozyme for biocatalysis and enhanced tumor photothermal therapy.

Near-infrared light-induced photothermal therapy (PTT) can achieve effective tumor ablation, but the associated hyperthermic temperatures result in off-target inflammatory damage to proximal tissues. Therefore, killing the tumor at a lower temperature is vital to improving the clinical effect of PTT. In this study, an Au-integrated Fe single-atom nanozyme (FeSAzyme) was developed through the immobilization of an ultrasmall Au nanozyme within a metal-organic framework via an in situ reduction approach. The nanozyme was found to exhibit favorable glucose oxidase- (GOD) like activity and photosensitizing properties to better achieve low-temperature PTT. The Au-carbon nanozyme was able to markedly inhibit tumor growth both in vitro and in vivo due to its GOD-like activity and enhanced photodynamic and photothermal properties. In addition, the integration of the Au nanozyme enhanced the FeSAzyme's peroxidase activity and catalyzed endogenous H2O2 species to generate reactive oxide species, thereby facilitating chemodynamic therapy. Furthermore, its integration markedly enhanced the PTT performance of the FeSAzyme, which achieved pronounced synergistic anti-tumor efficacy. The enzymatic activity and photothermal/photosensitive properties of the Au-FeSAzyme may help to overcome traditional therapeutic limitations, indicating its potential for catalytic cascade nanozymes in biomedical applications.

OShnscc: a novel user-friendly online survival analysis tool for head and neck squamous cell carcinoma based on RNA expression profiles and long-term survival information.

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.

An accessible insight into genetic findings for transplantation recipients with suspected genetic kidney disease.

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.

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

Accurate interpretation of BRCA1/2 variants is critical for risk assessment and precise treatment of breast cancer (BC). Hence, the establishment of an ethnicity-based BRCA1/2 variant database of the Chinese population is of paramount importance. In this study, panel-based sequencing served to detect BRCA1/2 variants in a Chinese multicenter cohort of 21,216 BC patients and 6434 healthy controls. Overall, the percentage of subjects carrying pathogenic variants was 5.5% (1174/21,216) in BC patients and 1.1% (71/6434) in healthy controls. We identified 13 pathogenic variants as high-frequency variants that had a frequency of > 0.45‰ in BC patients (≥ 10 in 21,216 patients), none of which has been reported in Caucasians. Pathogenic BRCA1/2 variants correlated with younger onset age, higher frequencies of bilateral and triple-negative BC (TNBC), invasive carcinomas, high histological grades, and family history of BC and other cancers. Furthermore, the percentage of the subjects carrying VUS was 9.8% (2071/21,216) in BC patients and 6.9% (446/6434) in healthy controls. Based on our cohort study, we unambiguously reclassified 7 out of the 858 VUS resulting in lower VUS ratio in patients (from 9.8 to 7.9%) as well as in healthy control (from 6.9 to 5.3%). We also re-analyzed the 100 variants in 13 exons (2-5 and 15-23) of the BRCA1 genes using a functional assay (saturation genome editing; SGE). 55 of the 59 VUS had distinct status in the SGE study: 24 (43.6%) were pathogenic, and 31 (56.4%) were benign. Strong ethnicity-specific occurrences of pathogenic BRCA1/2 variants were identified in the Chinese population. Hence, the findings provide rationale and sequencing information for the implementation of BRCA1/2 variants tailored to the Chinese population into clinical risk assessment.

Development of MOF "Armor-Plated" Phycocyanin and Synergistic Inhibition of Cellular Respiration for Hypoxic Photodynamic Therapy in Patient-Derived Xenograft Models.

Significant progress has been made in the use of phycocyanin (PC) as a photosensitizer (PS) agent for photodynamic therapy (PDT). The clinical use of PC, however, has been limited by its poor stability, unfavorable pharmacokinetics, limited tumor cell uptake, and the hypoxic nature of the tumor microenvironment. In this study, a novel biomimetic mineralization approach is described for encapsulating PC using zeolitic imidazolate framework-8 (ZIF-8), after which MPEG2000 -COOH is further utilized as an anchor on the ZIF/PC complex in order to yield MPEG2000 -ZIF/PC composites (PMs). These PMs are then used as a stable reinforced PS for PDT, effectively improving the intracellular delivery of this protein PS. In contrast to prior studies that have sought to overcome intratumoral hypoxia via increasing oxygen delivery to the tumor site, the mitochondrial complex I inhibitor papaverine (PPV) is instead utilized to reduce intratumor oxygen consumption in an effort to augment the PDT efficacy of the PMs. It is found that this combination treatment strategy markedly improves the antitumor properties of these PMs both in vitro and in patient-derived xenograft (PDX) models without inducing significant side effects. It is therefore proposed that the "armor-plating" of protein PS agents with ZIF-8 in combination with PPV may be a promising approach to precision medicine-mediated tumor treatment.

Development of a novel oxidative stress-amplifying nanocomposite capable of supplying intratumoral H2O2 and O2 for enhanced chemodynamic therapy and radiotherapy in patient-derived xenograft (PDX) models.

Radiotherapy (RT) is a potent approach to cancer treatment, but the tumor microenvironment (TME) in solid tumors is often highly hypoxic and contains high levels of antioxidant enzymes, thereby reducing the RT efficacy. In this study, we developed an oxidative stress amplifier (termed CFM) capable of self-sufficient H2O2 and O2 delivery that can be used in concert with RT and chemodynamic therapy (CDT) to treat tumors in patient-derived xenograft (PDX) model systems. Upon exposure to the hypoxic and acidic TME, CFM undergoes rapid degradation that results in the release of Fe3+, Ca2+, O2, and H2O2. Glutathione can subsequently reduce Fe3+ to Fe2+, which is then able to react with H2O2via the Fenton reaction to yield high levels of hydroxyl radicals which subsequently damage mitochondria. CaO2-derived O2 also modulates intratumoral hypoxia, while excessive Ca2+ levels within mitochondria result in apoptotic cell death. Altogether, these properties sensitize PDX tumors to RT. Importantly, the Fe, Zn, and Ca generated by CFM degradation are essential elements in humans. Altogether, these properties make this approach to oxidative stress amplification a promising means of amplifying oxidative stress within tumors while overcoming hypoxia-related resistance to RT, thereby providing a framework for the design of potent radiosensitizing therapeutic approaches.

Thymosin alpha-1 blocks the accumulation of myeloid suppressor cells in NSCLC by inhibiting VEGF production.

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.

Frontiers in the COVID-19 vaccines development.

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.

Multi-faceted epigenetic dysregulation of gene expression promotes esophageal squamous cell carcinoma.

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/ß-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.

PEST-containing nuclear protein regulates cell proliferation, migration, and invasion in lung adenocarcinoma.

Lung cancer is the leading cause of cancer-related mortality worldwide. PEST-containing nuclear protein (PCNP) has been found in the nucleus of cancer cells. Whether PCNP plays a role in the growth of lung adenocarcinoma is still unknown. In the present study, the results indicated that the level of PCNP in lung adenocarcinoma tissue was significantly higher than that in corresponding adjacent non-tumor tissue. Over-expression of PCNP promoted the proliferation, migration, and invasion of lung adenocarcinoma cells, while down-regulation of PCNP exhibited opposite effects. PCNP over-expression decreased apoptosis through up-regulating the expression levels of phospho (p)-signal transducers and activators of transcription (STAT) 3 and p-STAT5 in lung adenocarcinoma cells, whereas PCNP knockdown showed opposite trends. PCNP overexpression enhanced autophagy by increasing the expression levels of p-phosphatidylinositol 3-kinase (PI3K), p-Akt, and p-mammalian target of rapamycin (mTOR) in lung adenocarcinoma cells, however an opposite trend was observed in the sh-PCNP group. In addition, overexpression of PCNP showed the tumor-promoting effect on xenografted lung adenocarcinoma, while PCNP knockdown reduced the growth of lung adenocarcinoma via regulating angiogenesis. Our study elucidates that PCNP can regulate the procession of human lung adenocarcinoma cells via STAT3/5 and PI3K/Akt/mTOR signaling pathways. PCNP may be considered as a promising biomarker for the diagnosis and prognosis in patients with lung adenocarcinoma. Furthermore, PCNP can be a novel therapeutic target and potent PCNP inhibitors can be designed and developed in the treatment of lung adenocarcinoma.

Hydrogen Sulfide as a Novel Regulatory Factor in Liver Health and Disease.

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.

Tumour necrosis factor-α-induced protein 8-like 2 is a novel regulator of proliferation, migration, and invasion in human rectal adenocarcinoma cells.

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)-ß-Catenin, and p-glycogen synthase kinase-3ß 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-ß) 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/ß-Catenin and TGF-ß/Smad2/3 signalling pathways. TIPE2 is a potential therapeutic target for the treatment of rectal adenocarcinoma.

Involvement of Glutathione Depletion in Selective Cytotoxicity of Oridonin to p53-Mutant Esophageal Squamous Carcinoma Cells.

Oridonin, a diterpenoid compound isolated from traditional Chinese medicine Rabdosia rubescens, has shown antitumor effects to esophageal cancer. However, its molecular mechanism is not fully understood, which limits its clinical application. In the present study, we used RNA-seq analysis to check the transcriptome changes after oridonin treatment and we found genes controlling the GSH-ROS system were up-regulated, namely SLC7A11, TXNRD1, TRIM16, SRXN1, GCLM, and GCLC. Furthermore, our data suggest that oridonin significantly increased the production of ROS in EC109 and TE1 cells, which can be inhibited by NAC. Interestingly, oridonin can dramatically reduce intracellular GSH levels in TE1 cells in a concentration and time-dependent manner. In addition, cell death caused by oridonin was strongly inhibited by GSH (1 mM), while GSSG (1 mM) had little effect. At the same time, we also found that oridonin showed selective cytotoxicity to esophageal squamous carcinoma cell with p53 mutation since mut-p53 cells had lower SLC7A11 expression, a component of the cystine/glutamate antiporter. We also found that γ-glutamyl cysteine synthetase inhibitor (BSO) synergizes with oridonin to strongly inhibit EC109 cells at a low dose. These results suggested that the antitumor effects of oridonin are based on its -SH reactivity and glutathione depletion. Esophageal squamous carcinoma cells with p53-mutation showed hypersensitivity to oridonin because of the suppression of SLC7A11 expression by p53 mutation.

A recurrent PDGFRB mutation causes familial infantile myofibromatosis.

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 ß (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-ß promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-ß 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-ß in aggressive life-threatening familial forms of the disease.

RAGE mediates podocyte injury in adriamycin-induced glomerulosclerosis.

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.