Mechanism underlying the effect of MnO2 nanosheets for A549 cell chemodynamic therapy.

MnO2 nanosheets (MnO2NSs) were synthesized by one-step method, and MnO2NSs were applied to A549 cell chemodynamic Therapy (CDT). The cytotoxicity, redox ability, and reactive oxygen species production of MnO2NSs have been investigated, and differences in cell metabolism during CDT were determined using liquid chromatography-mass spectrometry (LC-MS/MS). In addition, the metabolites of A549 lung cancer cells affected by MnO2NSs treatment are identified; metabolite differences were identified by PCA, PLS-DA, orthogonal PLS-DA, and other methods; and these differences were analyzed using non-targeted metabolomics. We found that A549 cells which were treated by MnO2NSs have 17 different metabolites and 9 metabolic pathways that varied markedly. Owing to their unique composition, structure, and physicochemical properties, MnO2NSs and their composites have become a favored type of nanomaterial used for CDT in cancer therapy. This work provides insights into the mechanism underlying the effects of MnO2NSs on the tumor microenvironment of A549 lung cancer cells, effectively making up for the deficiency of the study on cellular mechanism of CDT-induced apoptosis of cancer cells. It could aid the development of cancer CDT treatment strategies and help improve the use of nanomaterials in the clinical field.

Progressive pseudorheumatoid dysplasia involving a novel WISP3 mutation and sacroiliac and hip arthritis: A case report and literature review.

INTRODUCTION: Progressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal recessive genetic disease caused by mutations in the Wnt1-inducible signaling pathway protein 3 gene. PPRD is considered a noninflammatory disease, and involvement of the sacroiliac joint and hip arthritis have not been reported previously. PATIENT CONCERNS: We report a case of PPRD in an 11-year-old boy, who presented with bilateral pain and swelling in the knees, elbows, and ankles, and bilateral pain without swelling in the shoulders, wrists, knuckles, and proximal and distal interphalangeal joints for the past 5 years. He had been misdiagnosed with juvenile idiopathic arthritis for more than 6 years. DIAGNOSIS: The correct PPRD diagnosis was made using whole-exome sequencing for Wnt1-inducible signaling pathway protein 3 gene mutations (c.589 + 2T>C and c.721T>G; both mutations have rarely been reported) and magnetic resonance imaging examination; moreover, the latter showed inflammation of the sacroiliac joint and hip joint. INTERVENTION: The patient was administered supplemental calcium, active vitamin D, and glucosamine sulfate. OUTCOME: The patient experienced alleviation of joint pain following treatment initiation; however, joint motion improvement was not obvious. Above all, the long-term use of biologic or targeted synthetic disease-modifying antirheumatic drugs in the future was avoided. CONCLUSION: The findings of the inflammatory aspects in PPRD will enrich our understanding of this rheumatological disease.

Urinary Albumin Levels are Independently Associated with Renal Lesion Severity in Patients with Lupus Nephritis and Little or No Proteinuria.

BACKGROUND Systemic lupus erythematosus (SLE) leads to renal lesions, which may be clinically silent in patients with little or no proteinuria. Early detection of these lesions may improve prognosis, but early markers are controversial. This study aimed to determine renal marker proteins associated with renal lesion severity in patients with lupus nephropathy (LN) and little or no proteinuria. MATERIAL AND METHODS Patients with LN and little or no proteinuria (<0.5 g/24 hours) (n=187) that underwent kidney biopsy were grouped according to: low severity (Class I or II; n=116) versus high severity (Class III, IV, or V; n=71). Disease status was determined according to the SLE disease activity index (SLEDAI). Renal marker proteins (serum ß2-macroglobulin, urinary ß2-macroglobulin, albumin, IgG, and α1-macroglobulin) were measured using radioimmunoassay. RESULTS Compared with the low severity group, patients in the high severity group had higher urinary albumin (11.60±8.94 versus 7.08±10.07 µg/mL, p=0.008) and urinary IgG (13.21±9.35 versus 8.74±8.90 µg/mL, p=0.007) levels. Multivariate conditional logistic regression analysis showed that urinary albumin (odds ratio (OR)=1.417, 95% confidence interval (95% CI): 1.145-1.895, p=0.001) and SLEDAI (OR=2.004, 95% CI: 1.264-3.178, p=0.003) were independently associated with severe renal lesions in these patients. Using an optimal cutoff point of urinary albumin of 7.53 µg/mL resulted in 67% sensitivity and 82% specificity for the detection of high severity renal lesions. CONCLUSIONS Urinary albumin levels and SLEDAI were independently associated with histological severity of renal lesions in patients with LN and little or no proteinuria. These parameters could be used to help select patients for renal biopsy.

Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing.

Moyamoya disease (MMD) is a rare disorder characterized by cerebrovascular occlusion and development of hemorrhage-prone collateral vessels. Approximately 10-12% of cases are familial, with a presumed low penetrance autosomal dominant pattern of inheritance. Diagnosis commonly occurs only after clinical presentation. The recent identification of the RNF213 founder mutation (p.R4810K) in the Asian population has made a significant contribution, but the etiology of this disease remains unclear. To further develop the variant landscape of MMD, we performed high-depth whole exome sequencing of 125 unrelated, predominantly nonfamilial, ethnically diverse MMD patients in parallel with 125 internally sequenced, matched controls using the same exome and analysis platform. Three subpopulations were established: Asian, Caucasian, and non-RNF213 founder mutation cases. We provided additional support for the previously observed RNF213 founder mutation (p.R4810K) in Asian cases (P = 6.01×10(-5)) that was enriched among East Asians compared to Southeast Asian and Pacific Islander cases (P = 9.52×10(-4)) and was absent in all Caucasian cases. The most enriched variant in Caucasian (P = 7.93×10(-4)) and non-RNF213 founder mutation (P = 1.51×10(-3)) cases was ZXDC (p.P562L), a gene involved in MHC Class II activation. Collapsing variant methodology ranked OBSCN, a gene involved in myofibrillogenesis, as most enriched in Caucasian (P = 1.07×10(-4)) and non-RNF213 founder mutation cases (P = 5.31×10(-5)). These findings further support the East Asian origins of the RNF213 (p.R4810K) variant and more fully describe the genetic landscape of multiethnic MMD, revealing novel, alternative candidate variants and genes that may be important in MMD etiology and diagnosis.

Variant priorization and analysis incorporating problematic regions of the genome.

In case-control studies of rare Mendelian disorders and complex diseases, the power to detect variant and gene-level associations of a given effect size is limited by the size of the study sample. Paradoxically, low statistical power may increase the likelihood that a statistically significant finding is also a false positive. The prioritization of variants based on call quality, putative effects on protein function, the predicted degree of deleteriousness, and allele frequency is often used as a mechanism for reducing the occurrence of false positives, while preserving the set of variants most likely to contain true disease associations. We propose that specificity can be further improved by considering errors that are specific to the regions of the genome being sequenced. These problematic regions (PRs) are identified a-priori and are used to down-weight constitutive variants in a case-control analysis. Using samples drawn from 1000-Genomes, we illustrate the utility of PRs in identifying true variant and gene associations using a case-control study on a known Mendelian disease, cystic fibrosis (CF).

BAP1 loss defines a new class of renal cell carcinoma.

The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes, including BAP1. The BAP1 protein, a nuclear deubiquitinase, is inactivated in 15% of clear cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation but not deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10(-5)), [corrected] and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q = 0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.

Genome-scale microRNA and small interfering RNA screens identify small RNA modulators of TRAIL-induced apoptosis pathway.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to death receptors 4/5 and selectively induces caspase-dependent apoptosis. The RNA interference screening approach has led to the discovery and characterization of several TRAIL pathway components in human cells. Here, libraries of synthetic small interfering RNA (siRNA) and microRNAs (miRNA) were used to probe the TRAIL pathway. In addition to known genes, siRNAs targeting CDK4, PTGS1, ALG2, CLCN3, IRAK4, and MAP3K8 altered TRAIL-induced caspase-3 activation responses. Introduction of the miRNAs let-7c, mir-10a, mir-144, mir-150, mir-155, and mir-193 also affected the activation of the caspase cascade. Putative targets of these endogenous miRNAs included genes encoding death receptors, caspases, and other apoptosis-related genes. Among the novel genes revealed in the screen, CDK4 was selected for further characterization. CDK4 was the only member of the cyclin-dependent kinase gene family that bore a unique function in apoptotic signal transduction.

Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/II trials.

PURPOSE: HAb18G/CD147 is a hepatocellular carcinoma (HCC)-associated antigen. We developed iodine (131I) metuximab injection (Licartin), a novel 131I-labeled HAb18G/CD147-specific monoclonal antibody Fab'2 fragment, and evaluated its safety, pharmacokinetics, and clinical efficacy on HCC in Phase I/II trials. METHODS AND MATERIALS: In a Phase I trial, 28 patients were randomly assigned to receive the injection in 9.25-, 18.5-, 27.75-, or 37-MBq/kg doses by hepatic artery infusion. In a multicenter Phase II trial, 106 patients received the injection (27.75 MBq/kg) on Day 1 of a 28-day cycle. Response rate and survival rate were the endpoints. RESULTS: No life-threatening toxic effects were found. The safe dosage was 27.75 MBq/kg. The blood clearance fitted a biphasic model, and its half-life was 90.56-63.93 h. In the Phase II trial, the injection was found to be targeted and concentrated to tumor tissues. Of the 73 patients completing two cycles, 6 (8.22%) had a partial response, 14 (19.18%) minor response, and 43 (58.90%) stable disease. The 21-month survival rate was 44.54%. The survival rate of progression-free patients was significantly higher than that of patients with progressive disease after either one or two cycles (p < 0.0001 or p = 0.0019). CONCLUSION: Iodine (131I) metuximab injection is safe and active for HCC patients.