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.

Cost-effectiveness of Different Intra-articular Drug Injections on Wrist and/or Elbow Compromise in Patients With Established Rheumatoid Arthritis: Short-term Results of an Open Observational Evaluation.

BACKGROUND: Intra-articular (IA) injections are an integral part of the management of rheumatoid arthritis (RA). However, there are few reports regarding the association between drug effectiveness and cost. OBJECTIVES: The aim of this study was to assess the cost-effectiveness of various combinations of IA injections of betamethasone, hyaluronic acid (HA) or etanercept for oligoarthritis in RA. METHODS: Seventy RA patients were assigned to 4 groups according to the IA injection drug(s): betamethasone alone, betamethasone + etanercept, betamethasone + HA, or etanercept alone. Data for the following were collected before and after IA injection: erythrocyte sedimentation rate, C-reactive protein (CRP), disease activity score in 28 joints calculated with CRP, and patient global visual analog scale. In addition, power Doppler ultrasonography and gray-scale ultrasonography scores were obtained for synovitis, and passive range of motion of joints was measured. RESULTS: Sixty-eight RA patients completed the trial. Compared with patients given etanercept alone, the visual analog scale, power Doppler ultrasonography, and gray-scale ultrasonography scores of each of the other groups were significantly better at each time point. At 1 month, the passive range of motion of joints in patients given betamethasone + HA was significantly better than that of each of the other groups. Synovial hyperplasia improved significantly in all groups, but less so in those given etanercept alone. All other clinical parameters of the 4 groups were similar. The costs per joint for the betamethasone-alone, betamethasone + etanercept, betamethasone + HA, and etanercept-alone groups were, respectively, $7.55, $181.77, $42.68, and $174.22. CONCLUSIONS: Intra-articular injection of betamethasone alone was the most cost-effective treatment for oligoarthritis of RA. Betamethasone combined with HA injection resulted in the best improvement in joint function.

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.

GSH responsive AuNRs@TFF nanotheranostic for NIR-II photoacoustic imaging-guided CDT/PTT synergistic cancer therapy.

Gold nanorods (AuNRs) are important photothermal therapeutic agents; however, a single therapy does not achieve satisfactory outcomes, and the synthesis process often leads to the adsorption of cetyltrimethylammonium bromide on the surface of AuNRs, which reduces its biocompatibility. Natural polyphenols are abundant in natural plants and have good biocompatibility. The metal-polyphenol network is formed by the coordination of metal ions and polyphenols, which has good drug loading, surface adhesion, and biocompatibility. In this study, the metal-polyphenol network structure formed by a transition metal (iron) and natural polyphenol tannic acid was used to modify the surface of gold nanorods (AuNRs@TF). Additionally, the surfaces of AuNRs were modified using the targeted functional molecule mercapto folic acid (AuNRs@TFF). The constructed composite nanomaterials AuNRs@TFF has good biocompatibility and tumor targeting ability. Tannic acid­iron degrades in the tumor microenvironment and releases iron ions that catalyze the Fenton reaction, thereby facilitating chemodynamic therapy. The good photo-thermal ability of AuNRs generate good photoacoustic signals to facilitate photoacoustic imaging mediation and enhances photothermal and chemodynamic therapy performance. This study expands on the application of AuNRs in the field of nanomedicine. The simple and effective design of AuNRs@TFF provides a strategy for the development of synergistic therapeutic agents for photothermal therapy and chemodynamic therapy.

Hyaluronic acid modified Cu/Mn-doped metal-organic framework nanocatalyst for chemodynamic therapy.

Chemodynamic therapy (CDT) is a new method for cancer treatment that produces highly toxic reactive oxygen species (ROS) in the tumor microenvironment to induce cancer cell apoptosis or necrosis. However, the therapeutic effect of CDT is often hindered by intracellular H2O2deficiency and the activity of antioxidants such as glutathione (GSH). In this study, a nano-catalyst HCM was developed using a self-assembled Cu/Mn-doped metal-organic framework, and its surface was modified with hyaluronic acid to construct a tumor-targeting CDT therapeutic agent with improved the efficiency and specificity. Three substances HHTP (2, 3, 6, 7, 10, 11-hexahydroxybenzophenanthrene), Cu2+, and Mn2+were shown to be decomposed and released under weakly acidic conditions in tumor cells. HHTP produces exogenous H2O2in the presence of oxygen to increase the H2O2content in tumors, Cu2+reduces GSH content and generates Cu+in the tumor, and Cu+and Mn2+catalyze H2O2to produce ∙OH in a Fenton-like reaction. Together, these three factors change the tumor microenvironment and improve the efficiency of ROS production. HCM showed selective and efficient cytotoxicity to cancer cells, and could effectively inhibit tumor growthin vivo, indicating a good CDT effect.

A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome.

The transforming growth factor ß (TGF-ß) family of growth factors are key regulators of mammalian development and their dysregulation is implicated in human disease, notably, heritable vasculopathies including Marfan (MFS, OMIM #154700) and Loeys-Dietz syndromes (LDS, OMIM #609192). We described a syndrome presenting at birth with distal arthrogryposis, hypotonia, bifid uvula, a failure of normal post-natal muscle development but no evidence of vascular disease; some of these features overlap with MFS and LDS. A de novo mutation in TGFB3 was identified by exome sequencing. Several lines of evidence indicate the mutation is hypomorphic suggesting that decreased TGF-ß signaling from a loss of TGFB3 activity is likely responsible for the clinical phenotype. This is the first example of a mutation in the coding portion of TGFB3 implicated in a clinical syndrome suggesting TGFB3 is essential for both human palatogenesis and normal muscle growth.

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.

[Role and mechanism of endoplasmic reticulum stress response induced by wear particles in osteolysis].

OBJECTIVE: To analyze the role of endoplasmic reticulum stress response in the development of osteoblast apoptosis and osteolysis in osteolytic bone tissue, and to explore the causes of artificial joint loosening, so as to provide new ideas and theoretical basis for the prevention and treatment of artificial joint loosening. METHODS: The animal model of osteolysis induced by wear particles was established by mouse skull, and randomly divided into 4 groups, 7 rats in each group:group 1, blank control group;group 2, wear particles tial6v4 nano alloy powder (TiNPs) group;group 3, endoplasmic reticulum stress response positive control (TiNPs+Tg) group; group 4, endoplasmic reticulum stress response inhibitor (TiNPs+4-PBA) group. The pathological changes of osteolysis were observed by toluidine blue staining, HE staining and ALP staining;the expression of endoplasmic reticulum stress response marker protein was detected by Western Blotting;the apoptosis of osteoblasts in osteolytic skull tissue was detected by TUNEL and Caspase-3 immunohistochemistry. RESULTS: Wear particles TiNPs can induce osteolysis in vitro, aggravate the infiltration of inflammatory cells and inhibit the differentiation and maturation of osteoblasts. At the same time, wear particles can also up regulate the markers of endoplasmic reticulum stress response and promote the apoptosis of osteoblasts in osteolytic bone tissue. After adding 4-PBA, an inhibitor of endoplasmic reticulum stress (4-PBA), on the basis of wear particles TiNPs, the symptoms of osteolysis were significantly relieved, bone erosion and inflammatory infiltration were significantly reduced, the differentiation and maturation of osteoblasts were improved, the number of apoptotic osteoblasts decreased sharply, and the expression of endoplasmic reticulum stress marker protein gradually decreased. CONCLUSION: Endoplasmic reticulum stress is involved in the formation of osteolysis and plays an important role in the occurrence and development of osteolysis. At the same time, endoplasmic reticulum stress can be used as a new therapeutic target to provide new ideas and methods for clinical reversal or treatment of osteolysis and aseptic loosening.

Application and preliminary validation of the hip inflammation MRI scoring system (HIMRISS) in spondyloarthritis.

AIMS: Spondyloarthritis (SpA) is an inflammatory rheumatic disease and hip involvement often results in severe deformities and functional impairment. Magnetic resonance imaging (MRI) is a powerful imaging tool for detecting early hip lesions in SpA. The aims of this study are to apply the hip inflammation MRI scoring system (HIMRISS) in SpA patients and to evaluate its reproducibility and validity. METHODS: Four readers new to HIMRISS (two radiologists and two rheumatologists) scored the MRI scans obtained from a total of 55 SpA patients with hip lesions in two separate exercises (33 patients in exercise 1 and 22 patients in exercise 2). After the training and review process for exercise 1, these well-trained readers with expertise in the HIMRISS method scored the scans obtained from 22 patients and evaluated the association between HIMRISS and clinical activity of SpA, including Ankylosing Spondylitis Disease Activity Score (ASDAS), laboratory features, Bath Ankylosing Spondylitis Disease Activity Index and Harris hip scores. RESULTS: HIMRISS is a reliable MRI scoring method for bone merrow lesions (BML) and synovitis in SpA. After 2 training exercises, the reliability improved from 0.67 to 0.90. The reliability for detecting femoral BML, acetabular BML, and synovitis effusion was very good after the 2 exercises (overall intraclass correlation coefficient = 0.73, 0.84 and 0.88, respectively). The clinical correlations between HIMRISS and ASDAS were most significant, and the correlations were closer to summed bilateral HIMRISS scores than just the worse side. HIMRISS was found to be an excellent tool for the early diagnosis of inflammation before the occurrence of structural damage, which was not significantly reflected in the systemic diagnosis. CONCLUSION: HIMRISS offers a reliable MRI scoring method for hip joint in SpA, and it is beneficial for early detection and fast quantification in disease activity assessment.

The Ratio of Plasma and Urinary 8-oxo-Gsn Could Be a Novel Evaluation Index for Patients with Chronic Kidney Disease.

Nucleic acid oxidation plays an important role in the pathophysiology progress of a variety of diseases. 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGsn) and 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn), which originate from DNA and RNA oxidation, were the most widely used indicators for oxidative stress. The study investigated the relation between 8-oxo-dGsn, 8-oxo-Gsn, and CKD. 146 patients with CKD were divided into five disease stages, and their fasting blood and morning urine were collected. The levels of 8-oxo-dGsn and 8-oxo-Gsn in plasma and urine were quantified by LC-MS/MS. The ratio of urinary 8-oxo-Gsn to creatinine increased from stages 1 to 4 corresponding to the increased severity of CKD, but it decreased in stage 5. And plasma 8-oxo-Gsn gradually increased with the decline of renal function. In particular, the increased ratio of plasma and urine 8-oxo-Gsn in stage 5 exceeded the concentration of creatinine. This trend was similar to the estimated glomerular filtration rate (eGFR), which indicates that 8-oxo-Gsn could be an appropriate indicator for renal function. Our finding indicates that as the disease progresses, RNA oxidation is increased. The significant increase in the ratio of plasma and urinary 8-oxo-Gsn is a novel evaluation index of end-stage renal disease.

Levels of 8-oxo-dGsn and 8-oxo-Gsn in random urine are consistent with 24 h urine in healthy subjects and patients with renal disease.

Oxidatively generated damage to nucleic acids may play an important role in the pathophysiological processes of a variety of diseases. 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGsn) and 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) are oxidatively generated products of DNA and RNA, respectively. Our previous studies have suggested that the amounts of 8-oxo-dGsn and 8-oxo-Gsn in urine were considerably higher than other body fluid or tissue. The aim of this study was to investigate whether 8-oxo-dGsn and 8-oxo-Gsn levels in random urine samples are consistent with those in 24 h urine samples in healthy subjects and patients with renal disease. A total of 16 healthy subjects and 104 renal disease patients were enrolled in this study, and their random and 24 h urine samples were collected. The levels of urinary 8-oxo-dGsn and 8-oxo-Gsn were quantified by LC-MS/MS and corrected by creatinine. Regardless of healthy subjects or renal disease patients, the levels of oxidised nucleosides in random urine samples were consistent with 24 h urine samples. Regardless of the age bracket, there is no significant difference between random samples and 24 h urine samples. In conclusion, 8-oxo-dGsn and 8-oxo-Gsn levels in random urine samples could replace those in 24 h urine samples, and were considered as the representative of the level of systemic oxidative stress for the whole day.

Improved annotation of the insect vector of citrus greening disease: biocuration by a diverse genomics community.

Database URL: https://citrusgreening.org/.

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.

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.

Achieving high-sensitivity for clinical applications using augmented exome sequencing.

BACKGROUND: Whole exome sequencing is increasingly used for the clinical evaluation of genetic disease, yet the variation of coverage and sensitivity over medically relevant parts of the genome remains poorly understood. Several sequencing-based assays continue to provide coverage that is inadequate for clinical assessment. METHODS: Using sequence data obtained from the NA12878 reference sample and pre-defined lists of medically-relevant protein-coding and noncoding sequences, we compared the breadth and depth of coverage obtained among four commercial exome capture platforms and whole genome sequencing. In addition, we evaluated the performance of an augmented exome strategy, ACE, that extends coverage in medically relevant regions and enhances coverage in areas that are challenging to sequence. Leveraging reference call-sets, we also examined the effects of improved coverage on variant detection sensitivity. RESULTS: We observed coverage shortfalls with each of the conventional exome-capture and whole-genome platforms across several medically interpretable genes. These gaps included areas of the genome required for reporting recently established secondary findings (ACMG) and known disease-associated loci. The augmented exome strategy recovered many of these gaps, resulting in improved coverage in these areas. At clinically-relevant coverage levels (100 % bases covered at ≥20×), ACE improved coverage among genes in the medically interpretable genome (>90 % covered relative to 10-78 % with other platforms), the set of ACMG secondary finding genes (91 % covered relative to 4-75 % with other platforms) and a subset of variants known to be associated with human disease (99 % covered relative to 52-95 % with other platforms). Improved coverage translated into improvements in sensitivity, with ACE variant detection sensitivities (>97.5 % SNVs, >92.5 % InDels) exceeding that observed with conventional whole-exome and whole-genome platforms. CONCLUSIONS: Clinicians should consider analytical performance when making clinical assessments, given that even a few missed variants can lead to reporting false negative results. An augmented exome strategy provides a level of coverage not achievable with other platforms, thus addressing concerns regarding the lack of sensitivity in clinically important regions. In clinical applications where comprehensive coverage of medically interpretable areas of the genome requires higher localized sequencing depth, an augmented exome approach offers both cost and performance advantages over other sequencing-based tests.

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).

Characterization of the Asian Citrus Psyllid Transcriptome.

The Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Psyllidae) is a vector for the causative agents of Huanglongbing, which threatens citrus production worldwide. This study reports and discusses the first D. citri transcriptomes, encompassing the three main life stages of D. citri, egg, nymph and adult. The transcriptomes were annotated using Gene Ontology (GO) and insecticide-related genes within each life stage were identified to aid the development of future D. citri insecticides. Transcriptome assemblies and other sequence data are available for download at the International Asian Citrus Psyllid Genome Consortium website [http://psyllid.org/download] and at NCBI [http://www.ncbi.nlm.nih.gov/bioproject/29447].

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.