A novel explainable online calculator for contrast-induced AKI in diabetics: a multi-centre validation and prospective evaluation study.

BACKGROUND: In patients undergoing percutaneous coronary intervention (PCI), contrast-induced acute kidney injury (CIAKI) is a frequent complication, especially in diabetics, and is connected with severe mortality and morbidity in the short and long term. Therefore, we aimed to develop a CIAKI predictive model for diabetic patients. METHODS: 3514 patients with diabetes from four hospitals were separated into three cohorts: training, internal validation, and external validation. We developed six machine learning (ML) algorithms models: random forest (RF), gradient-boosted decision trees (GBDT), logistic regression (LR), least absolute shrinkage and selection operator with LR, extreme gradient boosting trees (XGBT), and support vector machine (SVM). The area under the receiver operating characteristic curve (AUC) of ML models was compared to the prior score model, and developed a brief CIAKI prediction model for diabetes (BCPMD). We also validated BCPMD model on the prospective cohort of 172 patients from one of the hospitals. To explain the prediction model, the shapley additive explanations (SHAP) approach was used. RESULTS: In the six ML models, XGBT performed best in the cohort of internal (AUC: 0.816 (95% CI 0.777-0.853)) and external validation (AUC: 0.816 (95% CI 0.770-0.861)), and we determined the top 15 important predictors in XGBT model as BCPMD model variables. The features of BCPMD included acute coronary syndromes (ACS), urine protein level, diuretics, left ventricular ejection fraction (LVEF) (%), hemoglobin (g/L), congestive heart failure (CHF), stable Angina, uric acid (umol/L), preoperative diastolic blood pressure (DBP) (mmHg), contrast volumes (mL), albumin (g/L), baseline creatinine (umol/L), vessels of coronary artery disease, glucose (mmol/L) and diabetes history (yrs). Then, we validated BCPMD in the cohort of internal validation (AUC: 0.819 (95% CI 0.783-0.855)), the cohort of external validation (AUC: 0.805 (95% CI 0.755-0.850)) and the cohort of prospective validation (AUC: 0.801 (95% CI 0.688-0.887)). SHAP was constructed to provide personalized interpretation for each patient. Our model also has been developed into an online web risk calculator. MissForest was used to handle the missing values of the calculator. CONCLUSION: We developed a novel risk calculator for CIAKI in diabetes based on the ML model, which can help clinicians achieve real-time prediction and explainable clinical decisions.

Photodynamic therapy based on porphyrin-based metal-organic frameworks.

Porphyrins and their derivatives have excellent photophysical and electrochemical properties, which have attracted great interest in the fields of catalysis, biosensing, gas storage, solar cells, biomedicine, etc. However, the inherent limitations, such as self-quenching, weak absorption at biological spectral windows and poor photochemical stability, severely hinder their applications in biomedicine, especially in the field of photodynamic therapy (PDT). In recent years, metal-organic frameworks (MOFs) have received increasing attention as a class of hybrid porous coordination polymers assembled from metal ions/secondary building units (SBUs) and organic linkers. By introducing porphyrins into MOFs via the encapsulation in the pores as well as grafting on the surface to form porphyrin@MOFs or using porphyrins as organic linkers to construct porphyrin-MOFs, not only the unique properties of porphyrins and MOFs are combined, but also the limitations of porphyrins are overcome and their applications are facilitated in the biomedicine field. This article reviews important synthetic strategies of forming porphyrin-based MOFs (including porphyrin@MOFs and porphyrin-MOFs), which focuses on the recent research achievements and progress in PDT and tumor therapy fields. Furthermore, by carefully designing the composition of MOFs (such as the modification of organic linkers), MOFs could respond to the tumor microenvironment for on-demand treatment. In addition, some other strategies, including chemotherapy, photothermal therapy (PTT) and the latest cancer immunotherapy, are also combined in the review. Finally, the challenges and prospects in biomedical applications of this class of emerging materials are discussed.

High-quality genome assembly and pan-genome studies facilitate genetic discovery in mung bean and its improvement.

Mung bean is an economically important legume crop species that is used as a food, consumed as a vegetable, and used as an ingredient and even as a medicine. To explore the genomic diversity of mung bean, we assembled a high-quality reference genome (Vrad_JL7) that was ∼479.35 Mb in size, with a contig N50 length of 10.34 Mb. A total of 40,125 protein-coding genes were annotated, representing ∼96.9% of the genetic region. We also sequenced 217 accessions, mainly landraces and cultivars from China, and identified 2,229,343 high-quality single-nucleotide polymorphisms (SNPs). Population structure revealed that the Chinese accessions diverged into two groups and were distinct from non-Chinese lines. Genetic diversity analysis based on genomic data from 750 accessions in 23 countries supported the hypothesis that mung bean was first domesticated in south Asia and introduced to east Asia probably through the Silk Road. We constructed the first pan-genome of mung bean germplasm and assembled 287.73 Mb of non-reference sequences. Among the genes, 83.1% were core genes and 16.9% were variable. Presence/absence variation (PAV) events of nine genes involved in the regulation of the photoperiodic flowering pathway were identified as being under selection during the adaptation process to promote early flowering in the spring. Genome-wide association studies (GWASs) revealed 2,912 SNPs and 259 gene PAV events associated with 33 agronomic traits, including a SNP in the coding region of the SWEET10 homolog (jg24043) involved in crude starch content and a PAV event in a large fragment containing 11 genes for color-related traits. This high-quality reference genome and pan-genome will provide insights into mung bean breeding.

Pulmonary hypertension due to left heart disease with pulmonary arterial wedge pressure ≤15 mm Hg.

BACKGROUND: Pulmonary hypertension due to left heart disease (PH-LHD) is the most prevalent type of pulmonary hypertension (PH). The hemodynamic diagnostic standard of pulmonary arterial wedge pressure (PAWP) >15 mm Hg that is traditionally recommended by guidelines is being challenged. METHODS: To address this problem, we analyzed the data of 154 patients with PH-LHD admitted to our center from April 2013 to March 2018. Pharmacological or nonpharmacological treatment of underlying left heart disease was offered to all 154 patients. RESULTS: In total, there were 24 patients (15.6%) with PAWP ≤15 mm Hg. Comparison of echocardiography and right heart catheterization parameters between the two groups (PAWP >15 mm Hg and PAWP ≤15 mm Hg) showed that the group with PAWP ≤15 mm Hg had smaller left ventricular diameter, higher cardiac output, lower pressure and higher oxygen saturation in the pulmonary artery, right atrium, right ventricle, and superior vena cava. No significant difference was found regarding dilated cardiomyopathy, diabetes mellitus, hypertension, atrial fibrillation, and left heart valvular disease, but a significant difference was found for coronary heart disease (higher morbidity in group with PAWP ≤15 mm Hg) between the two groups. CONCLUSION: We found that 15.6% of the patients with PH-LHD under pharmacological or nonpharmacological treatment had PAWP ≤15 mm Hg. These results suggest that the diagnostic criterion of PAWP and the characteristics for this group of patients should be further investigated.

Machine learning for the diagnosis of pulmonary hypertension.

Objective This paper aims to investigate whether machine learning (ML) can be used to predict the state of pulmonary hypertension (PH), including pre-capillary and post-capillary, from echocardiographic data.Methods Two hundred and seventy-five patients with PH who underwent both echocardiography and right heart catheterization were included in the study. Mean pulmonary artery pressure, pulmonary artery wedge pressure measured by right heart catheterization were used as criteria for judging pre-capillary PH and post-capillary PH. Thirteen echocardiographic indicators were used to predict whether the PH was pre-capillary or post-capillary. Nine ML models were used to make predictions. Accuracy was used as the primary reference standard, and the performance of classification model is observed in conjunction with area under curve (AUC), specificity (Sp), sensitivity (Se), Positive Prediction Value (PPV), Negative Prediction Value (NPV), Positive Likelihood Ratio (PLR) and Negative Likelihood Ratio (NLR) and other assessment protocols.Results By comparing the accuracy (ACC), recall rate (Recall) and other model effect evaluation index of the classification under the nine ML models, it can be found that the ML model can effectively identify the pre-capillary PH and the post-capillary PH. LogitBoost performed best in nine ML models (ACC=0.87, Recall=0.83, F1score=0.85, AUC=0.87, Se=0.90, NPV=0.88, PPV=0.87, PLR=8.61 and NLR=0.18, AUC=0.83), it showed good results in identification of the pre-capillary PH (ACC=0.83, Recall=0.87, F-score=0.85); Post-vascular PH (ACC=0.90, Recall=0.88, F-score=0.89). Decision Tree (ACC=0.75, Recall=0.77, F1score=0.78, AUC=0.75, Se=0.72, NPV=0.78, PPV=0.77, PLR=3.66 and NLR=0.29, AUC=0.79) performed worst, and the accuracy of the other seven models was greater than 0.82.Conclusion The classification results of the nine ML models in this paper indicate that the ML method can effectively identify the pre-capillary PH and post-capillary PH from echocardiographic data. Compared with medical diagnosis, ML methods can distinguish between pre-capillary PH and the post-capillary PH under non-invasive conditions.

Two Novel er1 Alleles Conferring Powdery Mildew (Erysiphe pisi) Resistance Identified in a Worldwide Collection of Pea (Pisum sativum L.) Germplasms.

Powdery mildew caused by Erysiphe pisi DC. severely affects pea crops worldwide. The use of resistant cultivars containing the er1 gene is the most effective way to control this disease. The objectives of this study were to reveal er1 alleles contained in 55 E. pisi-resistant pea germplasms and to develop the functional markers of novel alleles. Sequences of 10 homologous PsMLO1 cDNA clones from each germplasm accession were used to determine their er1 alleles. The frame shift mutations and various alternative splicing patterns were observed during transcription of the er1 gene. Two novel er1 alleles, er1-8 and er1-9, were discovered in the germplasm accessions G0004839 and G0004400, respectively, and four known er1 alleles were identified in 53 other accessions. One mutation in G0004839 was characterized by a 3-bp (GTG) deletion of the wild-type PsMLO1 cDNA, resulting in a missing valine at position 447 of the PsMLO1 protein sequence. Another mutation in G0004400 was caused by a 1-bp (T) deletion of the wild-type PsMLO1 cDNA sequence, resulting in a serine to leucine change of the PsMLO1 protein sequence. The er1-8 and er1-9 alleles were verified using resistance inheritance analysis and genetic mapping with respectively derived F2 and F2:3 populations. Finally, co-dominant functional markers specific to er1-8 and er1-9 were developed and validated in populations and pea germplasms. These results improve our understanding of E. pisi resistance in pea germplasms worldwide and provide powerful tools for marker-assisted selection in pea breeding.

Comparison of arterial stiffness indices measured by pulse wave velocity and pulse wave analysis.

OBJECTIVE: Arterial stiffness indices measured by pulse wave velocity and pulse wave analysis have been widely studied in different populations. Only a few small studies have been reported regarding these two measurement methods. Therefore, the aim of our study was to compare the arterial stiffness indices measured by pulse wave velocity and pulse wave analysis in a randomly selected Chinese population. METHODS: A total of 4285 subjects were recruited from Gaoyou County, Jiangsu Province, China. There were 2017 (47.1%) participants with hypertension. Pulse wave velocity was assessed by using a VP-1000 Automatic Arteriosclerosis Measurement System. Large artery elasticity and small artery elasticity were measured by pulse wave analysis with an HDI/PulseWave CR-2000 Research CardioVascular Profiling System using the modified Windkessel model. RESULTS: Brachial-ankle pulse wave velocity, large artery elasticity and small artery elasticity were all significantly associated with the Framingham risk score (r = 0.588, -0.387, -0.448; p < .001). Brachial-ankle pulse wave velocity was correlated with both large artery elasticity (r = -0.486, p < .001) and small artery elasticity (r = -0.455, p < .001). In the receiver operating characteristic analysis, brachial-ankle pulse wave velocity [0.834, 95% confidence interval (0.821-0.845)] had a significantly larger area under the curve than both large artery elasticity [0.701, (0.684-0.715)] and small artery elasticity [0.696, (0.678-0.709)]. CONCLUSION: Brachial-ankle pulse wave velocity is significantly correlated with both large artery elasticity and small artery elasticity. The brachial-ankle pulse wave velocity measurement has a better predictive value for hypertension than the large artery elasticity and small artery elasticity measurements. What is new? We investigated the associations between brachial-ankle pulse wave velocity, large artery elasticity and small artery elasticity and compared the values of these indices for predicting hypertension for the first time in a randomly selected large population. What is relevant? Brachial-ankle pulse wave velocity was closely associated with large artery elasticity and small artery elasticity. The brachial-ankle pulse wave velocity measurement was a sensitive test for predicting hypertension in the study population when compared to large artery elasticity and small artery elasticity readings. SUMMARY: The present study confirms that brachial-ankle pulse wave velocity is significantly correlated with small and large arterial compliance and is a superior method of diagnosing hypertension compared to large artery elasticity and small artery elasticity.

Brachial-ankle pulse wave velocity compared with mean arterial pressure and pulse pressure in risk stratification in a Chinese population.

BACKGROUND: Brachial-ankle pulse wave velocity (baPWV) can be easily measured in an observer-independent way, but lacks robust population-based validation in terms of fatal combined with nonfatal outcomes. METHOD: To address this issue, we studied 4251 Chinese randomly recruited Gaoyou County (54.1% women; mean age, 52.1). RESULTS: In the whole study population, mean values were 102.4 mmHg for mean arterial pressure (MAP), 51.1 mmHg for pulse pressure, and 14.8 m/s for baPWV. Over 4.4 years (median), 74 participants experienced a fatal or nonfatal cardiovascular event and 44 a stroke. In multivariable-adjusted Cox regression, standardized hazard ratios expressing the risk of a composite cardiovascular endpoint were 1.77 (95% confidence interval, 1.43-2.20), 1.37 (1.14-1.64) and 1.50 (1.26-1.78) for MAP, PP and baPWV, respectively; the corresponding hazard ratios for stroke were 1.82 (1.39-2.38), 1.39 (1.12-1.74) and 1.53 (1.25-1.89). baPWV did not add to the prediction of cardiovascular events or stroke by MAP (hazard ratios for baPWV, 1.25 and 1.27, respectively; P ≥ 0.053) but refined models including PP (hazard ratios, 1.42 and 1.45; P ≤ 0.0033). The optimized baPWV threshold, obtained by maximizing Youden's index (16.7 m/s), increased the integrated discrimination improvement over and beyond MAP (+1.27%; P = 0.021) and PP (+1.37%; P = 0.038) for the cardiovascular outcome, but not stroke, and increased the net reclassification improvement for both endpoints (≥42.2%; P ≤ 0.004). CONCLUSION: With fatal and nonfatal cardiovascular and cerebrovascular endpoints as outcome, baPWV marginally increases risk stratification over and beyond MAP, but is a better predictor than PP. A threshold of 16.7 m/s might be used in Chinese populations.

The combinatory effects of PPAR-γ agonist and survivin inhibition on the cancer stem-like phenotype and cell proliferation in bladder cancer cells.

Strategies for peroxisome proliferator-activated receptor (PPAR) activation or survivin inhibition have potential for cancer therapy. However, whether the combination of these two approaches can be developed as a rational regimen with enhanced efficiency in the inhibition of tumor cells remains to be determined. In this study, the combinatory effect of PPAR-γ agonist and survivin inhibition on bladder cancer cells was investigated. T24 and 5637 cells were treated with 15d-PGJ(2) to determine whether 15d-PGJ(2) had an inhibitory effect. Cell viability and proliferation were analyzed and efficiency of survivin siRNAs was assessed using western blot analysis. The results showed that, in the human bladder cancer cell lines T24 and 5637, the natural PPAR-γ ligand 15d-PGJ(2) significantly decreased cell proliferation and loci formation. The increase in the proportion of apoptotic cells was observed in the cells 48 h after 15d-PGJ(2) treatment. Furthermore, 15d-PGJ(2) substantially inhibited the levels of stemness-related genes in these cells. The ability of sphere formation was markedly suppressed in the cells treated with 15d-PGJ(2). More importantly, the downregulation of survivin with siRNAs significantly enhanced the 15d-PGJ(2)-mediated induction of cell apoptosis and inhibition of sphere formation. Accordingly, we also found that survivin inhibition significantly enhanced 15d-PGJ(2)-induced production of reactive oxygen species (ROS) in bladder cancer cells. Taken together, these findings suggest that the combination of 15d-PGJ(2) and survivin inhibition play a potentially role in the therapeutical manipulation of bladder cancer.

Growth arrest and DNA damage 45G down-regulation contributes to Janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma.

UNLABELLED: Growth arrest and DNA damage 45G (GADD45G), a stress sensor with multiple implications in various biological processes, is down-regulated in a broad spectrum of cancers. However, little is known about the biological effects of GADD45G on hepatocellular carcinoma (HCC) cells and the related mechanisms. In the present study, we found that GADD45G was commonly down-regulated in oncogene-transformed mouse liver cells and in human and mouse HCC. Ectopic expression of GADD45G robustly elicited senescence in HCC cells and suppressed tumor growth in vivo. Furthermore, GADD45G-induced senescence occurred in HCC cells independently of p53, p16(INK4a) (p16), and retinoblastoma (Rb). Instead, the prompt inhibition of Janus kinase 2 (Jak2), tyrosine kinase 2 (Tyk2), and signal transducer and activator of transcription 3 (Stat3) activation was observed in cells undergoing senescence. Impairment of Jak-Stat3 activation caused by GADD45G expression was associated with activation of SH2 domain-containing protein tyrosine phosphatase-2 (Shp2). Expression of constitutively activated Stat3 or human telomerase reverse transcriptase (hTERT), as well as knockdown of Shp2f, efficiently counteracted GADD45G-induced senescence. More important, in clinical HCC specimens, we found that GADD45G expression was inversely correlated with phosphorylated Stat3 expression in tumor cells and disease progression. CONCLUSION: GADD45G functions as a negative regulator of the Jak-Stat3 pathway and inhibits HCC by inducing cellular senescence. The decrease or absence of GADD45G expression may be a key event for tumor cells or premalignant liver cells to bypass cellular senescence.

Inhibition of oxidative stress-elicited AKT activation facilitates PPARγ agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells.

Emerging evidence suggests that tumor-initiating cells (TICs) are the most malignant cell subpopulation in tumors because of their resistance to chemotherapy or radiation treatment. Targeting TICs may be a key innovation for cancer treatment. In this study, we found that PPARγ agonists inhibited the cancer stem cell-like phenotype and attenuated tumor growth of human hepatocellular carcinoma (HCC) cells. Reactive oxygen species (ROS) initiated by NOX2 upregulation were partially responsible for the inhibitory effects mediated by PPARγ agonists. However, PPARγ agonist-mediated ROS production significantly activated AKT, which in turn promoted TIC survival by limiting ROS generation. Inhibition of AKT, by either pharmacological inhibitors or AKT siRNA, significantly enhanced PPARγ agonist-mediated inhibition of cell proliferation and stem cell-like properties in HCC cells. Importantly, in nude mice inoculated with HCC Huh7 cells, we demonstrated a synergistic inhibitory effect of the PPARγ agonist rosiglitazone and the AKT inhibitor triciribine on tumor growth. In conclusion, we observed a negative feedback loop between oxidative stress and AKT hyperactivation in PPARγ agonist-mediated suppressive effects on HCCs. Combinatory application of an AKT inhibitor and a PPARγ agonist may provide a new strategy for inhibition of stem cell-like properties in HCCs and treatment of liver cancer.

c-MYC overexpression overrides TAK1 dependency in efficient tumorigenicity of AKT-transformed cells.

Transforming growth factor activated kinase 1 (TAK1) provides prosurvival signals in various types of cells, and emerging evidence indicates that targeting TAK1 is a promising means to eliminate certain types of cancer cells. Here, we show that TAK1 is required for efficient tumorigenicity of AKT-transformed cells. TAK1 inhibition accelerates cell apoptosis of AKT-transformed cells in anchorage-independent cell growth accompanying by the downregulation of Mcl-1 and Bcl-2 expression. On the contrary, the tumorigenicity of c-Myc-transformed cells is not significantly affected by TAK1 inhibition. Moreover, AKT-transformed cells with c-Myc overexpression tolerate TAK1 inhibition in anchorage-independent growth and tumorigenicity in vivo. Together, our results provide evidence that TAK1-dependency in the tumorigenicity of AKT-transformed cells can be alleviated by c-Myc overexpression. These findings suggest that dual-targeting TAK1 and c-Myc might be a rational therapeutic strategy for treatment of certain types of cancer.