Relationship between blood-brain barrier changes and drug metabolism under high-altitude hypoxia: obstacle or opportunity for drug transport?

The blood-brain barrier is essential for maintaining the stability of the central nervous system and is also crucial for regulating drug metabolism, changes of blood-brain barrier's structure and function can influence how drugs are delivered to the brain. In high-altitude hypoxia, the central nervous system's function is drastically altered, which can cause disease and modify the metabolism of drugs in vivo. Changes in the structure and function of the blood-brain barrier and the transport of the drug across the blood-brain barrier under high-altitude hypoxia, are regulated by changes in brain microvascular endothelial cells, astrocytes, and pericytes, either regulated by drug metabolism factors such as drug transporters and drug-metabolizing enzymes. This article aims to review the effects of high-altitude hypoxia on the structure and function of the blood-brain barrier as well as the effects of changes in the blood-brain barrier on drug metabolism. We also hypothesized and explore the regulation and potential mechanisms of the blood-brain barrier and associated pathways, such as transcription factors, inflammatory factors, and nuclear receptors, in regulating drug transport under high-altitude hypoxia.

New strategy for rational use of antihypertensive drugs in clinical practice in high-altitude hypoxic environments.

High-altitude hypoxic environments have critical implications on cardiovascular system function as well as blood pressure regulation. Such environments place patients with hypertension at risk by activating the sympathetic nervous system, which leads to an increase in blood pressure. In addition, the high-altitude hypoxic environment alters the in vivo metabolism and antihypertensive effects of antihypertensive drugs, which changes the activity and expression of drug-metabolizing enzymes and drug transporters. The present study reviewed the pharmacodynamics and pharmacokinetics of antihypertensive drugs and its effects on patients with hypertension in a high-altitude hypoxic environment. It also proposes a new strategy for the rational use of antihypertensive drugs in clinical practice in high-altitude hypoxic environments. The increase in blood pressure on exposure to a high-altitude hypoxic environment was mainly dependent on increased sympathetic nervous system activity. Blood pressure also increased proportionally to altitude, whilst ambulatory blood pressure increased more than conventional blood pressure, especially at night. High-altitude hypoxia can reduce the activities and expression of drug-metabolizing enzymes, such as CYP1A1, CYP1A2, CYP3A1, and CYP2E1, while increasing those of CYP2D1, CYP2D6, and CYP3A6. Drug transporter changes were related to tissue type, hypoxic degree, and hypoxic exposure time. Furthermore, the effects of high-altitude hypoxia on drug-metabolism enzymes and transporters altered drug pharmacokinetics, causing changes in pharmacodynamic responses. These findings suggest that high-altitude hypoxic environments affect the blood pressure, pharmacokinetics, and pharmacodynamics of antihypertensive drugs. The optimal hypertension treatment plan and safe and effective medication strategy should be formulated considering high-altitude hypoxic environments.

The added value of AI-based computer-aided diagnosis in classification of cancer at prostate MRI.

OBJECTIVES: To develop an artificial intelligence (AI) model for prostate segmentation and prostate cancer (PCa) detection, and explore the added value of AI-based computer-aided diagnosis (CAD) compared to conventional PI-RADS assessment. METHODS: A retrospective study was performed on multi-centers and included patients who underwent prostate biopsies and multiparametric MRI. A convolutional-neural-network-based AI model was trained and validated; the reliability of different CAD methods (concurrent read and AI-first read) were tested in an internal/external cohort. The diagnostic performance, consistency and efficiency of radiologists and AI-based CAD were compared. RESULTS: The training/validation/internal test sets included 650 (400/100/150) cases from one center; the external test included 100 cases (25/25/50) from three centers. For diagnosis accuracy, AI-based CAD methods showed no significant differences and were equivalent to the radiologists in the internal test (127/150 vs. 130/150 vs. 125/150 for reader 1; 127/150 vs.132/150 vs. 131/150 for reader 2; all p > 0.05), whereas in the external test, concurrent-read methods were superior/equal to AI-first read (87/100 vs. 71/100, p < 0.001, for reader 2; 79/100 vs. 69/100, p = 0.076, for reader 1) and better than/equal to radiologists (79/100 vs. 72/100, p = 0.039, for reader 1; 87/100 vs. 86/100, p = 1.000, for reader 2). Moreover, AI-first read/concurrent read improved consistency in both internal test (κ = 1.000, 0.830) and external test (κ = 0.958, 0.713) compared to radiologists (κ = 0.747, 0.600); AI-first read method (8.54 s/7.66 s) was faster than readers (92.72 s/89.54 s) and concurrent-read method (29.15 s/28.92 s), respectively. CONCLUSION: AI-based CAD could improve the consistency and efficiency for accurate diagnosis; the concurrent-read method could enhance the diagnostic capabilities of an inexperienced radiologist in unfamiliar situations. KEY POINTS: • For prostate cancer segmentation, the performance of multi-small Vnet displays optimal compared to small Vnet and Vnet (DSCmsvnet vs. DSCsvnet, p = 0.021; DSCmsvnet vs. DSCvnet, p < 0.001). • For prostate gland segmentation, the mean/median DSCs for fine and coarse segmentation were 0.91/0.91 and 0.88/0.89, respectively. Fine segmentation displays superior performance compared to coarse (DSCcoarse vs. DSCfine, p < 0.001). • For PCa diagnosis, AI-based CAD methods improve consistency in internal (κ = 1.000; 0.830) and external (κ = 0.958; 0.713) tests compared to radiologists (κ = 0.747; 0.600); the AI-first read (8.54 s/7.66 s) was faster than the readers (92.72 s/89.54 s) and the concurrent-read method (29.15 s/28.92 s).

Identification of Dezhou donkey muscle development-related genes and long non-coding RNA based on differential expression analysis.

Long non-coding RNAs (lncRNAs) play a critical role in the development of muscles. However, the role of lncRNAs in regulating skeletal muscle development has not been studied systematically in the donkey. In this study, we performed the RNA sequencing for different stages of muscles in donkeys, and investigate their expression profile, which showed that 3215 mRNAs (p-adjust <0.05) and 471 lncRNAs (p-value <0.05) were significantly differently expressed (DE) verified by RT-qPCR. GO and KEGG enrichment analysis indicated that DE genes and target genes of DE lncRNAs were associated with muscle development in the donkey. We also found these four target genes (DCN, ITM2A, MUSTN1, ARRDC2) involved in skeletal muscle growth and development. Combined with transcriptome data, network, and RT-qPCR results showed that four co-expression networks of DCN and lnc-008278, ITM2A and lnc_017247, MUSTN1 and lnc_030153, and ARRDC2 and lnc_033914, which may play an important role in the formation and development of muscle in the donkey.

Effect of Levosimendan on B-type Natriuretic Peptide Levels in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

Objective: This meta-analysis aims to evaluate the effects of levosimendan on B-type natriuretic peptide (BNP) levels in patients with decompensated heart failure and assess the efficacy and safety of levosimendan in treating left heart failure. Methods: Randomized controlled trials (RCTs) were identified through searches in the Chinese Biomedical Literature Database (CBM), Chinese Academic Journal Full Text Database (CNKI), Wanfang Database (CECDB), VIP Chinese Scientific, PubMed, Cochrane Library, and Web of Science. Quality assessment and data extraction were performed for the included studies, and meta-analysis was conducted using Review Manager 5.2 software. Results: The meta-analysis revealed a statistically significant difference in the regulatory effect of levosimendan on BNP levels in patients with stage III heart failure compared to the control group [OR = 2.12, 95% CI (1.22, 3.67), P = .008, I2 = 37%, Z = 2.67]. Additionally, leosimendan showed a significant effect on BNP levels in patients with stage IV heart failure [OR = 1.88, 95% CI (1.27, 2.79), P = .002, I2 = 0%, Z = 3.14], compensatory heart failure [OR=2.97, 95% CI (1.81, 4.86), P < .0001, I2 = 55%, Z = 4.32], and decompensated heart failure [OR = 1.98, 95% CI (1.59, 2.47), P < .00001, I2 = 76%, Z = 6.07]. Conclusions: Levosimendan administration demonstrated improved cardiac function and a significant reduction in plasma BNP levels in patients with decompensated heart failure.

A transcriptional regulatory network of HNF4α and HNF1α involved in human diseases and drug metabolism.

HNF4α and HNF1α are core transcription factors involved in the development and progression of a variety of human diseases and drug metabolism. They play critical roles in maintaining the normal growth and function of multiple organs, mainly the liver, and in the metabolism of endogenous and exogenous substances. The twelve isoforms of HNF4α may exhibit different physiological functions, and HNF4α and HNF1α show varying or even opposing effects in different types of diseases, particularly cancer. Additionally, the regulation of CYP450, phase II drug-metabolizing enzymes, and drug transporters is affected by several factors. This article aims to review the role of HNF4α and HNF1α in human diseases and drug metabolism, including their structures and physiological functions, affected diseases, regulated drug metabolism genes, influencing factors, and related mechanisms. We also propose a transcriptional regulatory network of HNF4α and HNF1α that regulates the expression of target genes related to disease and drug metabolism.

MR Spectroscopy for Detecting Fumarate Hydratase Deficiency in Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome.

Background Noninvasive in vivo detection of fumarate accumulation may help identify fumarate hydratase deficiency in renal cancer related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Purpose To investigate the feasibility of MR spectroscopy (MRS) in detecting elevated fumarate levels in HLRCC-associated renal cancers. Materials and Methods This study included an experimental xenograft mouse model and prospective clinical cohort. First, MRS was performed on patient-derived tumor xenograft models and control models to detect fumarate. Then, consecutive participants with clinical suspicion of HLRCC-associated renal tumors were enrolled. For the detection of fumarate, MRS results were classified as detected, borderline, undetected, or technical failure. The sensitivity, specificity, and accuracy of MRS for diagnosing HLRCC-associated renal cancer were assessed. The signal-to-noise ratio (SNR) of the fumarate peak was calculated and evaluated with receiver operating characteristic curve analysis. Results Fumarate peaks were detected at 6.54 parts per million in all three patient-derived xenograft models. A total of 38 participants (21 men; mean age, 47 years [range, 18-71 years]) with 46 lesions were analyzed. All primary HLRCC-associated renal cancers showed a fumarate peak; among the seven metastatic HLRCC-associated lesions, a fumarate peak was detected in three lesions and borderline in two. When only detected peaks were regarded as positive findings, the sensitivity, specificity, and accuracy of MRS at the lesion level were 69% (nine of 13 lesions), 100% (33 of 33 lesions), and 91% (42 of 46 lesions), respectively. When borderline peaks were also included as a positive finding, the sensitivity, specificity, and accuracy reached 85% (11 of 13 lesions), 88% (29 of 33 lesions), and 87% (40 of 46 lesions), respectively. The SNR of fumarate showed an area under the receiver operating characteristic curve of 0.87 for classifying HLRCC-associated tumors. Conclusion MR spectroscopy of fumarate was sensitive and specific for hereditary leiomyomatosis and renal cell carcinoma-associated tumors. © RSNA, 2022 Online supplemental material is available for this article.

Exposure to High-Altitude Environment Is Associated with Drug Transporters Change: microRNA-873-5p-Mediated Alteration of Function and Expression Levels of Drug Transporters under Hypoxia.

Hypoxia is the main characteristic of a high-altitude environment, affecting drug metabolism. However, so far, the mechanism of microRNA (miRNA) involved in the regulation of drug metabolism and transporters under high-altitude hypoxia is still unclear. This study aims to investigate the functions and expression levels of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein (BCRP), peptide transport 1 (PEPT1), and organic anion-transporting polypeptides 2B1 (OATP2B1) in rats and colon cancer (Caco-2) cells after exposure to high-altitude hypoxia. The protein and mRNA expression of MDR1, MRP2, BCRP, PEPT1, and OATP2B1 were determined by Western blot and qPCR. The functions of MDR1, MRP2, BCRP, PEPT1, and OATP2B1 were evaluated by determining the effective intestinal permeability and absorption rate constants of their specific substrates in rats under high-altitude hypoxia, and uptake and transport studies were performed on Caco-2 cells. To screen the miRNA associated with hypoxia, Caco-2 cells were examined by high throughput sequencing. We observed that the miR-873-5p was significantly decreased under hypoxia and might target MDR1 and pregnane X receptor (PXR). To clarify whether miR-873-5p regulates MDR1 and PXR under hypoxia, Caco-2 cells were transfected with mimics or inhibitors of miR-873-5p and negative control (NC). The function and expression of drug transporters were found to be significantly increased in rats and Caco-2 cells under hypoxia. We found that miR-873-5p regulated MDR1 and PXR expression. Herein, it is shown that miRNA may affect the expression of drug transporter and nuclear receptor under hypoxia. SIGNIFICANCE STATEMENT: This study explores if alterations to the microRNAs (miRNAs), induced by high-altitude hypoxia, can be translated to altered drug transporters. Among miRNAs, which show a significant change in a hypoxic environment, miR-873-5p can act on the multidrug resistance protein 1 (MDR1) gene; however, there are multiple miRNAs that can act on the pregnane X receptor (PXR). This study speculates that the miRNA-PXR-drug transporter axis is important in the physiological disposition of drugs.

Identification of equine herpesvirus 8 in donkey abortion: a case report.

BACKGROUND: Equine herpesvirus-8 (EHV-8) is one of the most economically significant viruses that infect mammals of the genus Equus worldwide, which cause severe respiratory diseases and abortion in horses. However, there is no report of abortion caused by EHV-8 in donkeys. CASE PRESENTATION: The present case report is about a 4-year-old donkey having an abortion and showing a serious respiratory issue on the 296th day of pregnancy. Bacteriological and molecular tests were used to screen possible bacterial/viral pathogens to detect the etiological agent. Salmonella abortus equi, EHV-1, EHV-4, and EAV were all negative in the current study. EHV-8, on the other hand, was the only agent that was isolated and identified. CONCLUSIONS: This was for the first time that EHV-8 had been isolated from a donkey in China. EHV-8 infection can cause abortion in donkeys; therefore, veterinarians and breeders should be aware of it.

Validation of CT radiomics for prediction of distant metastasis after surgical resection in patients with clear cell renal cell carcinoma: exploring the underlying signaling pathways.

OBJECTIVES: To develop a radiomics model using preoperative multiphasic CT for predicting distant metastasis after surgical resection in patients with localized clear cell renal cell carcinoma (ccRCC) and to identify key biological pathways underlying the predictive radiomics features using RNA sequencing data. METHODS: In this multi-institutional retrospective study, a CT radiomics metastasis score (RMS) was developed from a radiomics analysis cohort (n = 184) for distant metastasis prediction. Using a gene expression analysis cohort (n = 326), radiomics-associated gene modules were identified. Based on a radiogenomics discovery cohort (n = 42), key biological pathways were enriched from the gene modules. Furthermore, a multigene signature associated with RMS was constructed and validated on an independent radiogenomics validation cohort (n = 37). RESULTS: The 9-feature-based RMS predicted distant metastasis with an AUC of 0.861 in validation set and was independent with clinical factors (p < 0.001). A gene module comprising 114 genes was identified to be associated with all nine radiomics features (p < 0.05). Four enriched pathways were identified, including ECM-receptor interaction, focal adhesion, protein digestion and absorption, and PI3K-Akt pathways. Most of them play important roles in tumor progression and metastasis. A 19-gene signature was constructed from the radiomics-associated gene module and predicted metastasis with an AUC of 0.843 in the radiogenomics validation cohort. CONCLUSIONS: CT radiomics features can predict distant metastasis after surgical resection of localized ccRCC while the predictive radiomics phenotypes may be driven by key biological pathways related to cancer progression and metastasis. KEY POINTS: • Radiomics features from primary tumor in preoperative CT predicted distant metastasis after surgical resection in patients with localized ccRCC. • CT radiomics features predictive of distant metastasis were associated with key signaling pathways related to tumor progression and metastasis. • Gene signature associated with radiomics metastasis score predicted distant metastasis in localized ccRCC.

First detection and phylogenetic analysis of porcine circovirus 3 in female donkeys with reproductive disorders.

BACKGROUND: PCV3 is a pathogen associated with porcine dermatitis and nephropathy syndrome (PDNS)-like clinical signs, reproductive failure, and cardiac and multiorgan inflammation, which was newly identified in 2016 in sows in USA. Recently, PCV3 has also been identified from several non-porcine species like (cattle, dog, wild boar, deer, mice and ticks). However, PCV3 infection in donkey is not well established. Since 2019, 300 blood samples were collected from female donkey, which was characterized by abortion and sterility, in Liaocheng city of China. RESULTS: In the present study, an investigation of PCV3 in donkey blood samples was undertaken employing by real time PCR. Positive rates of PCV3 in donkeys reach to 21.0 %. In addition, one full-length PCV3 genome sequence was obtained, and it had a highest identity with porcine circovirus 3 PCV3/CN/Nanjing2017 strain and is clustered to PCV3a genotype based on ORF2 sequences. CONCLUSIONS: This is the first report of detection of PCV3 from female donkeys presenting reproductive failure in large-scale donkey farms, China. In addition, the PCV3 strain identified in this study shared the closest relationship with those from porcine, suggesting that PCV3 may be transmitted from pigs to donkeys. Totally, PCV3 infection in donkey should be concerned although the association between it and reproductive failure are not better understood.

Cloning, tissue distribution and functional characterization of the donkey (Equus asinus) oligopeptide transporter 2.

Oligopeptide transporter 2 (PepT2) is an important transporter of oligopeptides. In the present study, we describe the molecular cloning, tissue distribution and functional characterization of a donkey (Equus asinus) PepT2. The cloned cDNA sequence was 2202 bp at full length, encoding a 733 amino acid peptide with a molecular weight of 81.9 kDa and a theoretical pI of 8.92. Bioinformatics analysis showed that the deduced peptide sequence possessed all the characteristic features of PepT2. The expression of PepT2 in the kidney and lung was significantly higher than that observed in the ileum, duodenum, jejunum, spleen, liver, heart and stomach. Functional characterization by heterologous expression in Chinese hamster ovary cells showed that the uptake of ß-Ala-Lys-N-7-amino-4-methylcoumarin-3-acetic acid (ß-Ala-Lys-AMCA) by donkey PepT2-Chinese hamster ovary cells was dependent on time, pH and substrate concentration, with a low Km value of 91.51 ± 14.14 µM and a maximum velocity of 41.37 ± 2.193 pmol/min/mg protein. In the present study, for the first time, the expression and functional characteristics of donkey PepT2 were evaluated, the results of which provide new insights and a better understanding of its crucial role in oligopeptide transport in donkeys.

Combining DWI radiomics features with transurethral resection promotes the differentiation between muscle-invasive bladder cancer and non-muscle-invasive bladder cancer.

PURPOSE: To investigate the value of radiomics features from diffusion-weighted imaging (DWI) in differentiating muscle-invasive bladder cancer (MIBC) from non-muscle-invasive bladder cancer (NMIBC). METHODS: This retrospective study included 218 pathologically confirmed bladder cancer patients (training set: 131 patients, 86 MIBC; validation set: 87 patients, 55 MIBC) who underwent DWI before biopsy through transurethral resection (TUR) between July 2014 and December 2018. Radiomics models based on DWI for discriminating state of muscle-invasive were built using random forest (RF) and all-relevant (AR) methods on the training set and were tested on validation set. Combination models based on TUR data were also built. Discrimination performances were evaluated with the area under the receiver operating characteristic (ROC) curve (AUC), accuracy, sensitivity, specificity, and F1 and F2 scores. Qualitative MRI evaluation based on morphology was performed for comparison. RESULTS: No significant difference was found between RF and AR models. RF model was more sensitive than TUR (0.873 vs 0.655, p = 0.019) for discriminating muscle-invasive bladder cancer. When combining RF with TUR, the sensitivity increased to 0.964, significantly higher than TUR (0.655, p < 0.001), MRI evaluation (0.764, p = 0.006), and the combination of TUR and MRI (0.836, p = 0.046). Combining RF and TUR achieved the highest accuracy of 0.897 and F2 score of 0.946. CONCLUSION: Combining DWI radiomics features with TUR could improve the sensitivity and accuracy in discriminating the presence of muscle invasion in bladder cancer for clinical practice. Multicenter, prospective studies are needed to confirm our results. KEY POINTS: • Twenty-seven to 51% of superficial bladder cancers diagnosed by transurethral resection are upstaged to muscle-invasive at radical cystectomy, suggesting its poor sensitivity for discriminating muscle-invasive bladder cancer. • A small subset of selected all-relevant radiomics features exhibited an equivalent performance compared to that of all the extracted features, confirming that radiomics data contained redundant or irrelevant features and that feature selection should be performed in building radiomics models. • Combining DWI radiomics features with transurethral resection could improve in clinical practice the sensitivity and accuracy for the detection of muscle invasion in bladder cancer.

Effects of long-distance transportation on blood constituents and composition of the nasal microbiota in healthy donkeys.

BACKGROUND: This study aims to determine the effects of transportation on the nasal microbiota of healthy donkeys using 16S rRNA sequencing. RESULTS: Deep nasal swabs and blood were sampled from 14 donkeys before and after 21 hours' long-distance transportation. The values of the plasma hormone (cortisol (Cor), adrenocorticotrophic hormone (ACTH)), biochemical indicators (total protein (TP), albumin (ALB), creatinine (CREA), lactic dehydrogenase (LDH), aspartate transaminase (AST), creatine kinase (CK), blood urea (UREA), plasma glucose (GLU)) and blood routine indices (white blood cell (WBC), lymphocyte (LYM), neutrophil (NEU), red blood cell (RBC), hemoglobin (HGB)) were measured. 16S rRNA sequencing was used to assess the nasal microbiota, including alpha diversity, beta diversity, and phylogenetic structures. Results showed that levels of Cor, ACTH, and heat-shock protein 90 (HSP90) were significantly increased (p < 0.05) after long-distance transportation. Several biochemical indicators (AST, CK) and blood routine indices (Neu, RBC, and HGB) increased markedly (p < 0.05), but the LYM decreased significantly (p < 0.05). Nine families and eight genera had a mean relative abundance over 1%. The predominant phyla in nasal microbiota after and before transportation were Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Transportation stress induced significant changes in terms of nasal microbiota structure compared with those before transportation based on principal coordinate analysis (PCoA) coupled with analysis of similarities (ANOSIM) (p < 0.05). Among these changes, a notably gain in Proteobacteria and loss in Firmicutes at the phylum level was observed. CONCLUSIONS: These results suggest transportation can cause stress to donkeys and change the richness and diversity of nasal microbiota. Further studies are required to understand the potential effect of these microbiota changes on the development of donkey respiratory diseases.

Multiparameter diffusion-weighted imaging for characterizing pathological patterns in lupus nephritis patients: A preliminary study.

BACKGROUND: Microstructural changes of lupus nephritis (LN) kidney such as inflammatory cell infiltration or fibrosis could influence water molecular movement or diffusion, which indicates that diffusion-weighted imaging (DWI) may become a valuable tool in evaluation of this disease. PURPOSE: To explore whether multiparameter diffusion-weighted imaging (mDWI) could contribute to characterize pathological patterns in LN patients. STUDY TYPE: Retrospective. POPULATION: Twenty-two patients with LN. FIELD STRENGTH/SEQUENCE: Multi-b value DWI was performed with a 3.0 T scanner. ASSESSMENT: Apparent diffusion coefficient (ADC)m , perfusion-related diffusion coefficient (Df ), molecular diffusion coefficient (Ds ), perfusion fraction (f), ADCs , α, ADCk , and mean kurtosis (MK) were calculated by monoexponential, biexponential, stretched-exponential, and kurtosis models fits, respectively. STATISTICAL TESTS: Independent sample t-test, Pearson analysis and receiver operating characteristic (ROC). RESULTS: In the whole group, the activity index (AI) correlated significantly with alpha values in the medulla (rho = -0.54, P = 0.03). The chronicity index (CI) correlated significantly with Ds values in the medulla (rho = -0.61, P = 0.02). No significant association was found between any other diffusion parameter and histologic grade with all P > 0.05. For differentiating proliferative LN (Class III or IV) from Class V, the area under the ROC curve (AUC) of alpha in the medulla was 0.833 (P = 0.023). DATA CONCLUSION: mDWI might be used for the characterization of pathological patterns in LN patients. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:1075-1084.

Differentiation of clear cell and non-clear cell renal cell carcinomas by all-relevant radiomics features from multiphase CT: a VHL mutation perspective.

OBJECTIVES: To develop a radiomics model with all-relevant imaging features from multiphasic computed tomography (CT) for differentiating clear cell renal cell carcinoma (ccRCC) from non-ccRCC and to investigate the possible radiogenomics link between the imaging features and a key ccRCC driver gene-the von Hippel-Lindau (VHL) gene mutation. METHODS: In this retrospective two-center study, two radiomics models were built using random forest from a training cohort (170 patients), where one model was built with all-relevant features and the other with minimum redundancy maximum relevance (mRMR) features. A model combining all-relevant features and clinical factors (sex, age) was also built. The radiogenomics association between selected features and VHL mutation was investigated by Wilcoxon rank-sum test. All models were tested on an independent validation cohort (85 patients) with ROC curves analysis. RESULTS: The model with eight all-relevant features from corticomedullary phase CT achieved an AUC of 0.949 and an accuracy of 92.9% in the validation cohort, which significantly outperformed the model with eight mRMR features (seven from nephrographic phase and one from corticomedullary phase) with an AUC of 0.851 and an accuracy of 81.2%. Combining age and sex did not benefit the performance. Five out of eight all-relevant features were significantly associated with VHL mutation, while all eight mRMR features were significantly associated with VHL mutation (false discovery rate-adjusted p < 0.05). CONCLUSIONS: All-relevant features in corticomedullary phase CT can be used to differentiate ccRCC from non-ccRCC. Most subtype-discriminative imaging features were found to be significantly associated with VHL mutation, which may underlie the molecular basis of the radiomics features. KEY POINTS: • All-relevant features in corticomedullary phase CT can be used to differentiate ccRCC from non-ccRCC with high accuracy. • Most RCC-subtype-discriminative CT features were associated with the key RCC-driven gene-the VHL gene mutation. • Radiomics model can be more accurate and interpretable when the imaging features could reflect underlying molecular basis of RCC.

The value of blood oxygen level dependent (BOLD) imaging in evaluating post-operative renal function outcomes after laparoscopic partial nephrectomy.

OBJECTIVES: To assess the ability of renal blood oxygen level dependent (BOLD) MRI metrics to predict post-operative renal function. METHODS: We studied 152 patients who underwent laparoscopic partial nephrectomy (LPN) and renal MRI examination including BOLD. Short-term and long-term renal function was evaluated using the glomerular filtration rate (GFR) derived from renal scintigraphy. Renal function decline was assessed as the absolute decline (AD), percentage decline (PD) and optimal renal function preservation (OP). T2* values were analysed in the renal cortex and medulla ipsilateral and contralateral to the tumour. Clinical characteristics and imaging metrics were evaluated using univariate and multivariate linear regression analyses. Risk factors obtained using BOLD metrics (determined by multivariate regression) were then combined and compared with RENAL scores to predict OP. RESULTS: Increasing warm ischaemia time (WIT), resected and ischaemic volume (RAIV), larger tumour size, higher RENAL score and lower preoperative GFR were short-term risk factors for AD, while increasing WIT and lower preoperative GFR were significant for long-term outcomes. Increasing WIT, RAIV, lower T2* value in the cortex and higher T2* value in the medulla on the ipsilateral side were short-term risk factors for PD, while all of the above factors (except WIT and RAIV) were significant for long-term outcomes. The performance of the combination of T2* values in the cortex and medulla on the ipsilateral side to tumour in predicting OP was better than RENAL score (AUC 0.762 vs 0.634, p = 0.013). CONCLUSIONS: Renal BOLD-MRI metrics could provide useful information to the clinician in predicting post-operative renal function outcomes. KEY POINTS: • Renal fMRI metrics may be useful for prediction of renal functional outcomes and merit further study. • Renal fMRI metrics may reflect degree of baseline disease and ability to tolerate warm ischaemia. • Combination of T2* values was better than RENAL score for predicting OP.

Assessment of response to anti-angiogenic targeted therapy in pulmonary metastatic renal cell carcinoma: R2* value as a predictive biomarker.

PURPOSE: To evaluate the utility of MR R2*-mapping and the optimal time-point for assessing the response of pulmonary metastatic renal cell carcinoma (mRCC) to anti-angiogenic targeted therapy (aATT). MATERIALS AND METHODS: The exploration-sample group and the validation-sample group consisted of 22 and 16 patients. The parameters of MR R2*-mapping, including the R2* value at each time-point (R2*base, R2*1cyc and R2*2cyc) and change between different time-points (R2*(1cyc-base)/base, R2*(2cyc-base)/base and R2*(2cyc-1cyc)/1cyc), were evaluated with a receiver-operating-characteristic analysis, and a cut-off value derived from the clinical outcome was applied to the Kaplan-Meier method to assess the value of R2* mapping and Response-Evaluation-Criteria in Solid Tumours (RECIST) during treatment evaluation. RESULTS: The inter-, intra-observer agreements and inter-scan consistency were excellent (p > 0.80). For the exploration-sample group, the areas under the curve for the parameters of MR R2* mapping were 0.55, 0.60, 0.83, 0.64, 0.88 and 0.83 for R2*base, R2*1cyc, R2*2cyc, R2*(1cyc-base)/base, R2*(2cyc-base)/base and R2*(2cyc-1cyc)/1cyc. For the validation-sample, R2*(2cyc-base)/base better predicted progression-free survival (p = 0.03) than RECIST and other R2* mapping parameters with a lower p value. CONCLUSION: Assessing aATT outcome based on changes in the R2* value between baseline and second treatment is more accurate than assessment at other time-points and assessment based on the RECIST. KEY POINTS: • The inter-scan consistency of R2*-mapping in pulmonary mRCC are excellent. • The intra-/inter-observer agreement of R2* mapping in pulmonary mRCC are excellent. • Using changes in R2* value between baseline/after second-treatment is better than RECIST. • The choice of baseline/after second treatment is better than other time-points.

Characterization of Volatile Compounds in Donkey Meat by Gas Chromatography-Ion Mobility Spectrometry (GC-IMS) Combined with Chemometrics.

Volatile compounds (VOCs) are an important factor affecting meat quality. However, the characteristic VOCs in different parts of donkey meat remain unknown. Accordingly, this study represents a preliminary investigation of VOCs to differentiate between different cuts of donkey meat by using headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) combined with chemometrics analysis. The results showed that the 31 VOCs identified in donkey meat, ketones, alcohols, aldehydes, and esters were the predominant categories. A total of 10 VOCs with relative odor activity values ≥1 were found to be characteristic of donkey meat, including pentanone, hexanal, nonanal, octanal, and 3-methylbutanal. The VOC profiles in different parts of donkey meat were well differentiated using three- and two-dimensional fingerprint maps. Nine differential VOCs that represent potential markers to discriminate different parts of donkey meat were identified by chemometrics analysis. These include 2-butanone, 2-pentanone, and 2-heptanone. Thus, the VOC profiles in donkey meat and specific VOCs in different parts of donkey meat were revealed by HS-GC-IMS combined with chemometrics, whcih provided a basis and method of investigating the characteristic VOCs and quality control of donkey meat.

Newly recognized orbital malformations in kabuki syndrome: A case report.

Kabuki syndrome (KS) is a rare congenital disorder with distinctive characteristics. Herein, we describe a KS patient carrying a novel mutation in the KMT2D gene, c.11785C > T (p.Gln3929*). The patient presented with typical eyelid deformities, including eversion of the lateral lower eyelids, long palpebral fissures, hypertelorism, and medial epicanthus. Orbital computed tomography revealed orbital bone malformation with temporally and inferiorly displaced zygomatic bone. The bilateral orbits were shallow with an enlarged angle between the lateral walls. Zygomatic and maxillary bone dysplasia were also observed. Orbital bone anomalies are thought to be one of the characteristics of KS.