Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.

Large-scale foundation model on single-cell transcriptomics.

Large pretrained models have become foundation models leading to breakthroughs in natural language processing and related fields. Developing foundation models for deciphering the 'languages' of cells and facilitating biomedical research is promising yet challenging. Here we developed a large pretrained model scFoundation, also named 'xTrimoscFoundationα', with 100 million parameters covering about 20,000 genes, pretrained on over 50 million human single-cell transcriptomic profiles. scFoundation is a large-scale model in terms of the size of trainable parameters, dimensionality of genes and volume of training data. Its asymmetric transformer-like architecture and pretraining task design empower effectively capturing complex context relations among genes in a variety of cell types and states. Experiments showed its merit as a foundation model that achieved state-of-the-art performances in a diverse array of single-cell analysis tasks such as gene expression enhancement, tissue drug response prediction, single-cell drug response classification, single-cell perturbation prediction, cell type annotation and gene module inference.

Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma.

BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide. METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1. RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9). CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).

Animal-SNPAtlas: a comprehensive SNP database for multiple animals.

Single-nucleotide polymorphisms (SNPs) as the most important type of genetic variation are widely used in describing population characteristics and play vital roles in animal genetics and breeding. Large amounts of population genetic variation resources and tools have been developed in human, which provided solid support for human genetic studies. However, compared with human, the development of animal genetic variation databases was relatively slow, which limits the genetic researches in these animals. To fill this gap, we systematically identified ∼ 499 million high-quality SNPs from 4784 samples of 20 types of animals. On that basis, we annotated the functions of SNPs, constructed high-density reference panels and calculated genome-wide linkage disequilibrium (LD) matrixes. We further developed Animal-SNPAtlas, a user-friendly database (http://gong_lab.hzau.edu.cn/Animal_SNPAtlas/) which includes high-quality SNP datasets and several support tools for multiple animals. In Animal-SNPAtlas, users can search the functional annotation of SNPs, perform online genotype imputation, explore and visualize LD information, browse variant information using the genome browser and download SNP datasets for each species. With the massive SNP datasets and useful tools, Animal-SNPAtlas will be an important fundamental resource for the animal genomics, genetics and breeding community.

lncRNASNP v3: an updated database for functional variants in long non-coding RNAs.

Long non-coding RNAs (lncRNAs) act as versatile regulators of many biological processes and play vital roles in various diseases. lncRNASNP is dedicated to providing a comprehensive repository of single nucleotide polymorphisms (SNPs) and somatic mutations in lncRNAs and their impacts on lncRNA structure and function. Since the last release in 2018, there has been a huge increase in the number of variants and lncRNAs. Thus, we updated the lncRNASNP to version 3 by expanding the species to eight eukaryotic species (human, chimpanzee, pig, mouse, rat, chicken, zebrafish, and fruitfly), updating the data and adding several new features. SNPs in lncRNASNP have increased from 11 181 387 to 67 513 785. The human mutations have increased from 1 174 768 to 2 387 685, including 1 031 639 TCGA mutations and 1 356 046 CosmicNCVs. Compared with the last release, updated and new features in lncRNASNP v3 include (i) SNPs in lncRNAs and their impacts on lncRNAs for eight species, (ii) SNP effects on miRNA-lncRNA interactions for eight species, (iii) lncRNA expression profiles for six species, (iv) disease & GWAS-associated lncRNAs and variants, (v) experimental & predicted lncRNAs and drug target associations and (vi) SNP effects on lncRNA expression (eQTL) across tumor & normal tissues. The lncRNASNP v3 is freely available at http://gong_lab.hzau.edu.cn/lncRNASNP3/.

Effects of geniposide on innate immunity and antiviral activity of Scyllaparamamosain.

In this study, we examined the impact of geniposide on the innate immunity of the mud crab Scylla paramamosain, specifically in relation to WSSV infection. Through the use of in vitro cell culture experiments, we assessed the effects of geniposide on various parameters of hemocyte activity in S. paramamosain. Our findings revealed that high doses of geniposide inhibited hemocyte growth, with an optimal dose of 100 mg/kg determined. Additionally, we observed that geniposide increased the total hemocyte counts in S. paramamosain following WSSV infection. Geniposide also enhanced the enzymatic activities in hemolymph following treatment. The enzymes affected by geniposide encompassed ACP (acid phosphatase), POD (phenol oxidase catalase), PO (phenoloxidase), SOD (superoxide dismutase), CAT (catalase), and LZM (lysozyme). Furthermore, the activities of ACP, POD, PO, and LZM were also observed to increase subsequent to infection with WSSV. Notably, geniposide was found to enhance the phagocytosis of V. alginolyticus within the hemocytes. Geniposide can reduce hemocyte apoptosis rates after treatment, as well as hemocytes infected with WSSV. Furthermore, geniposide treatment significantly up-regulated the expression level of Myosin, but expression levels of Astakine, C-type lectin (CTL), STAT, JAK, proPO, minichromosome maintenance protein (MCM7), caspase-3 and crustin were down-regulated in the hemocytes. Additionally, geniposide treatment inhibited WSSV replication in hemocytes of S. paramamosain, and enhanced the survival rates of mud crabs following WSSV infection. These experimental results provide evidence that geniposide can improve the immune response by regulating humoral immunity and cellular immunity, and enhance pathogen resistance in S. paramamosain.

Independent association between IVC filter placement and VTE risk in patients with upper gastrointestinal bleeding and isolated distal DVT: A retrospective cohort study.

BACKGROUND: The placement of inferior vena cava (IVC) filters often emerges as an alternative preventative measure against pulmonary embolism in patients with upper gastrointestinal (GI) bleeding and isolated distal deep vein thrombosis (DVT). We aimed to investigate the association of IVC filter placement and the incidence of venous thromboembolism (VTE) recurrence in this patient population. METHODS: We performed a retrospective cohort study including 450 patients with upper GI bleeding and isolated distal DVT. Propensity score matching using logistic regression was conducted to mitigate potential selection bias. Logistic regression models and additional sensitivity analyses were conducted to estimate the association between IVC filter implantation and VTE recurrence. Interaction and stratified analyses were also performed according to the background covariates. RESULTS: Patients who underwent IVC filter placement were significantly younger than patients in the surveillance group (55.8 ± 9.0 vs 58.4 ± 11.2 years, p = 0.034). Patients in the IVC filter group demonstrated a higher distal thrombus burden. The VTE recurrence composite was significantly higher in patients who underwent IVC filter placement (44.1% [45/102] vs 25% [87/348], p < 0.001). Unmatched crude logistic regression analysis identified a significant association between IVC filter placement and VTE recurrence composite (OR = 2.37; 95% CI, 1.50-3.75). Sensitivity analyses yielded congruent outcomes. CONCLUSION: This study revealed an increased risk of VTE recurrence among patients receiving IVC filter placement, suggesting that IVC filter placement may not be suitable as a primary treatment for patients with upper GI bleeding and isolated distal DVT.

Development and validation of peritumoral vascular and intratumoral radiomics to predict pathologic complete responses to neoadjuvant chemotherapy in patients with triple-negative breast cancer.

BACKGROUND: To develop and validate a peritumoral vascular and intratumoral radiomics model to improve pretreatment predictions for pathologic complete responses (pCRs) to neoadjuvant chemoradiotherapy (NAC) in patients with triple-negative breast cancer (TNBC). METHODS: A total of 282 TNBC patients (93 in the primary cohort, 113 in the validation cohort, and 76 in The Cancer Imaging Archive [TCIA] cohort) were retrospectively included. The peritumoral vasculature on the maximum intensity projection (MIP) from pretreatment DCE-MRI was segmented by a Hessian matrix-based filter and then edited by a radiologist. Radiomics features were extracted from the tumor and peritumoral vasculature of the MIP images. The LASSO method was used for feature selection, and the k-nearest neighbor (k-NN) classifier was trained and validated to build a predictive model. The diagnostic performance was assessed using the ROC analysis. RESULTS: One hundred of the 282 patient (35.5%) with TNBC achieved pCRs after NAC. In predicting pCRs, the combined peritumoral vascular and intratumoral model (fusion model) yields a maximum AUC of 0.82 (95% confidence interval [CI]: 0.75, 0.88) in the primary cohort, a maximum AUC of 0.67 (95% CI: 0.57, 0.76) in the internal validation cohort, and a maximum AUC of 0.65 (95% CI: 0.52, 0.78) in TCIA cohort. The fusion model showed improved performance over the intratumoral model and the peritumoral vascular model, but not significantly (p > 0.05). CONCLUSION: This study suggested that combined peritumoral vascular and intratumoral radiomics model could provide a non-invasive tool to enable prediction of pCR in TNBC patients treated with NAC.

Post-discharge nutritional management for patients with coronary heart disease and frailty: a qualitative study.

BACKGROUND: Frail elderly patients experience physiological function and reserve depletion, leading to imbalances in their internal environment, which increases the risk of coronary heart disease recurrence and malnutrition. However, the majority of these patients, who primarily have a low level of education and lack self-management skills, face difficulties actively dealing with obstacles during the transition period after their discharge from hospitalization. Therefore, it is necessary to understand and discuss in depth the nutrition management experience of discharged elderly patients with coronary heart disease and frailty (ages 65-80 years old) and to analyze the promoting and hindering factors that affect scientific diet behavior during the discharge transition period. METHODS: Fifteen elderly patients with coronary heart disease and frailty who had been discharged from the hospital for 6 months were interviewed using a semistructured method. The directed content analysis approach to descriptive research was used to extract topics from the interview content. RESULTS: All participants discussed the problems in health nutrition management experience of discharged. Five topics and ten subtopics were extracted, such as ①Weak perceptions and behaviors towards healthy eating (personal habit solidification, negative attitudes towards nutrition management), ②Lack of objective factors for independently adjusting dietary conditions (reliance on subjective feelings, times of appetite change), ③Personal hindrance factors (memory impairment, deficiencies in self-nutrition management), ④Expected external support (assistance care support, ways to obtain nutritional information), ⑤Lack of continuous nutrition management (interruption of professional guidance, avoidance of medical treatment behavior). CONCLUSIONS: Nutrition management after discharge places a burden on elderly patients with coronary heart disease and frailty. According to the patients' physical conditions, we should develop a diet support system that is coordinated by individuals, families and society.

Animal-eRNAdb: a comprehensive animal enhancer RNA database.

Enhancer RNAs (eRNAs) are a class of non-coding RNAs transcribed from enhancers. As the markers of active enhancers, eRNAs play important roles in gene regulation and are associated with various complex traits and characteristics. With increasing attention to eRNAs, numerous eRNAs have been identified in different human tissues. However, the expression landscape, regulatory network and potential functions of eRNAs in animals have not been fully elucidated. Here, we systematically characterized 185 177 eRNAs from 5085 samples across 10 species by mapping the RNA sequencing data to the regions of known enhancers. To explore their potential functions based on evolutionary conservation, we investigated the sequence similarity of eRNAs among multiple species. In addition, we identified the possible associations between eRNAs and transcription factors (TFs) or nearby genes to decipher their possible regulators and target genes, as well as characterized trait-related eRNAs to explore their potential functions in biological processes. Based on these findings, we further developed Animal-eRNAdb (http://gong_lab.hzau.edu.cn/Animal-eRNAdb/), a user-friendly database for data searching, browsing and downloading. With the comprehensive characterization of eRNAs in various tissues of different species, Animal-eRNAdb may greatly facilitate the exploration of functions and mechanisms of eRNAs.

Orthogonal genome-wide screens of bat cells identify MTHFD1 as a target of broad antiviral therapy.

Bats are responsible for the zoonotic transmission of several major viral diseases, including those leading to the 2003 SARS outbreak and likely the ongoing COVID-19 pandemic. While comparative genomics studies have revealed characteristic adaptations of the bat innate immune system, functional genomic studies are urgently needed to provide a foundation for the molecular dissection of the viral tolerance in bats. Here we report the establishment of genome-wide RNA interference (RNAi) and CRISPR libraries for the screening of the model megabat, Pteropus alecto. We used the complementary RNAi and CRISPR libraries to interrogate P. alecto cells for infection with two different viruses: mumps virus and influenza A virus, respectively. Independent screening results converged on the endocytosis pathway and the protein secretory pathway as required for both viral infections. Additionally, we revealed a general dependence of the C1-tetrahydrofolate synthase gene, MTHFD1, for viral replication in bat cells and human cells. The MTHFD1 inhibitor, carolacton, potently blocked replication of several RNA viruses, including SARS-CoV-2. We also discovered that bats have lower expression levels of MTHFD1 than humans. Our studies provide a resource for systematic inquiry into the genetic underpinnings of bat biology and a potential target for developing broad-spectrum antiviral therapy.

Examining the Effect of Entrepreneurial Leadership on Nursing Team Creativity in New Hospitals: A Structural Equation Model.

METHODS: This cross-sectional study sampled 833 nurses from 2 new hospitals in Guizhou Province, China. They completed a questionnaire on entrepreneurial leadership, nursing team creativity, innovation climate, creative self-efficacy, team psychological safety, and knowledge sharing. Data were analyzed using structural equation modeling. RESULTS: Entrepreneurial leadership positively influenced nursing team creativity. Innovation climate, creative self-efficacy, team psychological safety, and knowledge sharing mediated the relationship between entrepreneurial leadership and nursing team creativity in new hospitals. CONCLUSIONS: This study confirmed the significant role of innovation climate, creative self-efficacy, team psychological safety, and knowledge sharing in mediating the relationship between entrepreneurial leadership and nursing team creativity through empirical analysis.

Small Molecules Promote the Rapid Generation of Dental Epithelial Cells from Human-Induced Pluripotent Stem Cells.

Human-induced pluripotent stem cells (hiPSCs) offer a promising source for generating dental epithelial (DE) cells. Whereas the existing differentiation protocols were time-consuming and relied heavily on growth factors, herein, we developed a three-step protocol to convert hiPSCs into DE cells in 8 days. In the first phase, hiPSCs were differentiated into non-neural ectoderm using SU5402 (an FGF signaling inhibitor). The second phase involved differentiating non-neural ectoderm into pan-placodal ectoderm and simultaneously inducing the formation of oral ectoderm (OE) using LDN193189 (a BMP signaling inhibitor) and purmorphamine (a SHH signaling activator). In the final phase, OE cells were differentiated into DE through the application of Purmorphamine, XAV939 (a WNT signaling inhibitor), and BMP4. qRT-PCR and immunostaining were performed to examine the expression of lineage-specific markers. ARS staining was performed to evaluate the formation of the mineralization nodule. The expression of PITX2, SP6, and AMBN, the emergence of mineralization nodules, and the enhanced expression of AMBN and AMELX in spheroid culture implied the generation of DE cells. This study delineates the developmental signaling pathways and uses small molecules to streamline the induction of hiPSCs into DE cells. Our findings present a simplified and quicker method for generating DE cells, contributing valuable insights for dental regeneration and dental disease research.

Diverting the 5-exo-Trig Oxypalladation to Formally 6-endo-Trig Fluorocycloetherification Product through 1,2-O/Pd(IV) Dyotropic Rearrangement.

Pd-catalyzed cyclizative functionalization of γ-hydroxyalkenes affords tetrahydrofuran derivatives via a key 5-exo-trig oxypalladation step. Herein, we report a palladium(II)-catalyzed, Selectfluor-mediated formal 6-endo-trig fluorocycloetherification of γ-hydroxyalkenes for the synthesis of functionalized tetrahydropyrans. Mechanistically, an σ-alkyl-Pd(II) intermediate resulting from the 5-exo-trig oxypalladation process is isolated and characterized by X-ray crystallographic analysis. Its oxidation with Selectfluor to Pd(IV) triggers the chemoselective 1,2-O/Pd(IV) dyotropic rearrangement affording, after C-F bond-forming reductive elimination, the tetrahydropyrans with concurrent generation of a tertiary carbon-fluorine bond. The occurrence of this 1,2-positional interchange is further evidenced by trapping the rearranged quaternary C(sp3)-Pd bond by an internal nucleophile that is materialized by the development of a Pd(II)-catalyzed oxidative bis-heterocyclization of alkenes.

Special issue "The advance of solid tumor research in China": Prognosis prediction for stage II colorectal cancer by fusing computed tomography radiomics and deep-learning features of primary lesions and peripheral lymph nodes.

Currently, the prognosis assessment of stage II colorectal cancer (CRC) remains a difficult clinical problem; therefore, more accurate prognostic predictors must be developed. In our study, we developed a prognostic prediction model for stage II CRC by fusing radiomics and deep-learning (DL) features of primary lesions and peripheral lymph nodes (LNs) in computed tomography (CT) scans. First, two CT radiomics models were built using primary lesion and LN image features. Subsequently, an information fusion method was used to build a fusion radiomics model by combining the tumor and LN image features. Furthermore, a transfer learning method was applied to build a deep convolutional neural network (CNN) model. Finally, the prediction scores generated by the radiomics and CNN models were fused to improve the prognosis prediction performance. The disease-free survival (DFS) and overall survival (OS) prediction areas under the curves (AUCs) generated by the fusion model improved to 0.76 ± 0.08 and 0.91 ± 0.05, respectively. These were significantly higher than the AUCs generated by the models using the individual CT radiomics and deep image features. Applying the survival analysis method, the DFS and OS fusion models yielded concordance index (C-index) values of 0.73 and 0.9, respectively. Hence, the combined model exhibited good predictive efficacy; therefore, it could be used for the accurate assessment of the prognosis of stage II CRC patients. Moreover, it could be used to screen out high-risk patients with poor prognoses, and assist in the formulation of clinical treatment decisions in a timely manner to achieve precision medicine.

SOX9 and HMGB3 co-operatively transactivate NANOG and promote prostate cancer progression.

BACKGROUND: The homeodomain-containing transcription factor NANOG is overexpressed in prostate adenocarcinoma (PCa) and predicts poor prognosis. The SOX family transcription factor SOX9, as well as the transcription co-activator HMGB3 of the HMGB family, are also overexpressed and may play pivotal roles in PCa. However, it is unknown whether SOX9 and HMGB3 interact with each other, or if they regulate NANOG gene transcription. METHODS: We identified potential SOX9 responsive elements in NANOG promoter, and investigated if SOX9 regulated NANOG transcription in co-operation with HMGB3 by experimental analysis of potential SOX9 binding sites in NANOG promoter, reporter gene transcription assays with or without interference or artificial overexpression of SOX9 and/or HMGB3, and protein-binding assays of SOX9-HMGB3 interaction. Clinicopathologic and prognostic significance of SOX9-HMGB3 overexpression in PCa was analyzed. RESULTS: SOX9 activated NANOG gene transcription by preferentially binding to a highly conserved consensus cis-regulatory element (-573 to -568) in NANOG promoter, and promoted the expression of NANOG downstream oncogenic genes. Importantly, HMGB3 functioned as a partner of SOX9 to co-operatively enhance transactivation of NANOG by interacting with SOX9, predominantly via the HMG Box A domain of HMGB3. Overexpression of SOX9 and/or HMGB3 enhanced PCa cell survival and cell migration and were significantly associated with PCa progression. Notably, Cox proportional regression analysis showed that co-overexpression of both SOX9 and HMGB3 was an independent unfavorable prognosticator for both CRPC-free survival (relative risk [RR] = 3.779，95% confidence interval [CI]: 1.159-12.322, p = 0.028) and overall survival (RR = 3.615，95% CI: 1.101-11.876, p = 0.034). CONCLUSIONS: These findings showed a novel SOX9/HMGB3/NANOG regulatory mechanism, deregulation of which played important roles in PCa progression.

RNF34 functions in immunity and selective mitophagy by targeting MAVS for autophagic degradation.

Viral infection triggers the formation of mitochondrial antiviral signaling protein (MAVS) aggregates, which potently promote immune signaling. Autophagy plays an important role in controlling MAVS-mediated antiviral signaling; however, the exact molecular mechanism underlying the targeted autophagic degradation of MAVS remains unclear. Here, we investigated the mechanism by which RNF34 regulates immunity and mitophagy by targeting MAVS. RNF34 binds to MAVS in the mitochondrial compartment after viral infection and negatively regulates RIG-I-like receptor (RLR)-mediated antiviral immunity. Moreover, RNF34 catalyzes the K27-/K29-linked ubiquitination of MAVS at Lys 297, 311, 348, and 362 Arg, which serves as a recognition signal for NDP52-dependent autophagic degradation. Specifically, RNF34 initiates the K63- to K27-linked ubiquitination transition on MAVS primarily at Lys 311, which facilitates the autophagic degradation of MAVS upon RIG-I stimulation. Notably, RNF34 is required for the clearance of damaged mitochondria upon viral infection. Thus, we elucidated the mechanism by which RNF34-mediated autophagic degradation of MAVS regulates the innate immune response, mitochondrial homeostasis, and infection.

AKR1B10 Is a New Sensitive and Specific Marker for Fumarate Hydratase-Deficient Renal Cell Carcinoma.

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare and distinct subtype of renal cancer caused by FH gene mutations. FH negativity and s-2-succinocysteine (2SC) positivity on immunohistochemistry can be used to screen for FH-deficient RCC, but their sensitivity and specificity are not perfect. The expression of AKR1B10, an aldo-keto reductase that catalyzes cofactor-dependent oxidation-reduction reactions, in RCC is unclear. We compared AKR1B10, 2SC, and FH as diagnostic biomarkers for FH-deficient RCC. We included genetically confirmed FH-deficient RCCs (n = 58), genetically confirmed TFE3 translocation RCCs (TFE3-tRCC) (n = 83), clear cell RCCs (n = 188), chromophobe RCCs (n = 128), and papillary RCCs (pRCC) (n = 97). AKR1B10, 2SC, and FH were informative diagnostic markers. AKR1B10 had 100% sensitivity and 91.4% specificity for FH-deficient RCC. The nonspecificity of AKR1B10 was shown in 26.5% of TFE3-tRCCs and 21.6% of pRCCs. 2SC showed 100% sensitivity and 88.9% specificity. However, nonspecificity for 2SC was evident in multiple RCCs, including pRCC, TFE3-tRCC, clear cell RCCs, and chromophobe RCCs. FH was 100% specific but 84.5% sensitive. AKR1B10 served as a highly sensitive and specific diagnostic biomarker. Our findings suggest the value of combining AKR1B10 and 2SC to screen for FH-deficient RCC. AKR1B10+/2SC+/FH- cases can be diagnosed as FH-deficient RCC. Patients with AKR1B10+/2SC+/FH+ are highly suspicious of FH-deficient RCC and should be referred for FH genetic tests.

A systematic comparison of normalization methods for eQTL analysis.

Expression quantitative trait loci (eQTL) analysis has been widely used in interpreting disease-associated loci through correlating genetic variant loci with the expression of specific genes. RNA-sequencing (RNA-Seq), which can quantify gene expression at the genome-wide level, is often used in eQTL identification. Since different normalization methods of gene expression have substantial impacts on RNA-seq downstream analysis, it is of great necessity to systematically compare the effects of these methods on eQTL identification. Here, by using RNA-seq and genotype data of four different cancers in The Cancer Genome Atlas (TCGA) database, we comprehensively evaluated the effect of eight commonly used normalization methods on eQTL identification. Our results showed that the application of different methods could cause 20-30% differences in the final results of eQTL identification. Among these methods, COUNT, Median of Ratio (MED) and Trimmed Mean of M-values (TMM) generated similar results for identifying eQTLs, while Fragments Per Kilobase Million (FPKM) or RANK produced more differential results compared with other methods. Based on the accuracy and receiver operating characteristic (ROC) curve, the TMM method was found to be the optimal method for normalizing gene expression data in eQTLs analysis. In addition, we also evaluated the performance of different pairwise combinations of these methods. As a result, compared with single normalization methods, the combination of methods can not only identify more cis-eQTLs, but also improve the performance of the ROC curve. Overall, this study provides a comprehensive comparison of normalization methods for identifying eQTLs from RNA-seq data, and proposes some practical recommendations for diverse scenarios.

Pretreatment Multiparametric MRI-Based Radiomics Analysis for the Diagnosis of Breast Phyllodes Tumors.

BACKGROUND: Preoperative pathological grading assessment is important for patients with breast phyllodes tumors (PTs). PURPOSE: To develop and validate a clinical-radiomics model based on multiparametric MRI and clinical information for the pretreatment differential diagnosis of PTs. STUDY TYPE: Retrospective. POPULATION: A total of 216 patients with PTs, 133 in the training cohort (55 benign PTs [BPTs] and 78 borderline/malignant PTs [BMPTs]) and 83 in the validation cohort (28 BPTs and 55 BMPTs). FIELD STRENGTH/SEQUENCE: 1.5 T and 3 T; T2-weighted imaging (T2WI), precontrast T1-weighted imaging (T1WI) and dynamic contrast-enhanced T1-weighted imaging (DCE-T1WI). ASSESSMENT: A total of 3138 radiomics features were computed to decode the imaging phenotypes of PTs. To build the classification models, the following workflow was followed: minimum-maximum scaling normalization method, recursive feature elimination based on ridge regression (Ridge-RFE), synthetic minority oversampling technique, and support vector machine classifier. We established several models based on the statistically significant features (Ridge-RFE selected) of each sequence to distinguish BPTs from BMPTs, including precontrast T1WI model, DCE-T1WI phase 1 model, T1WI feature fusion model, T2WI model, T1WI + T2WI model, clinical feature model, conventional MRI characteristics model, and combined clinical-radiomics model. STATISTICAL TESTS: Univariate analysis was utilized to compare variables between the BPT and BMPT groups. The receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic performance of these models. RESULTS: In the training cohort, the clinical-radiomics model had excellent diagnostic efficiency, with an area under ROC (AUC) of 0.91 ± 0.02 (95% CI: 0.87-0.94). In the validation cohort, the AUCs were 0.79 ± 0.05 (95% CI: 0.70-0.87) for the combined model and 0.77 ± 0.05 (95% CI: 0.67-0.85) for the radiomics model. DATA CONCLUSION: Compared with conventional MRI characteristics, radiomics features extracted from multiparametric MRI are helpful for improving the accuracy of differentiating the pathological grades of PTs preoperatively. The model based on radiomics and clinical information is expected to become a potential noninvasive tool for the assessment of PTs grades. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.