Use of machine learning-based integration to develop a monocyte differentiation-related signature for improving prognosis in patients with sepsis.

BACKGROUND: Although significant advances have been made in intensive care medicine and antibacterial treatment, sepsis is still a common disease with high mortality. The condition of sepsis patients changes rapidly, and each hour of delay in the administration of appropriate antibiotic treatment can lead to a 4-7% increase in fatality. Therefore, early diagnosis and intervention may help improve the prognosis of patients with sepsis. METHODS: We obtained single-cell sequencing data from 12 patients. This included 14,622 cells from four patients with bacterial infectious sepsis and eight patients with sepsis admitted to the ICU for other various reasons. Monocyte differentiation trajectories were analyzed using the "monocle" software, and differentiation-related genes were identified. Based on the expression of differentiation-related genes, 99 machine-learning combinations of prognostic signatures were obtained, and risk scores were calculated for all patients. The "scissor" software was used to associate high-risk and low-risk patients with individual cells. The "cellchat" software was used to demonstrate the regulatory relationships between high-risk and low-risk cells in a cellular communication network. The diagnostic value and prognostic predictive value of Enah/Vasp-like (EVL) were determined. Clinical validation of the results was performed with 40 samples. The "CBNplot" software based on Bayesian network inference was used to construct EVL regulatory networks. RESULTS: We systematically analyzed three cell states during monocyte differentiation. The differential analysis identified 166 monocyte differentiation-related genes. Among the 99 machine-learning combinations of prognostic signatures constructed, the Lasso + CoxBoost signature with 17 genes showed the best prognostic prediction performance. The highest percentage of high-risk cells was found in state one. Cell communication analysis demonstrated regulatory networks between high-risk and low-risk cell subpopulations and other immune cells. We then determined the diagnostic and prognostic value of EVL stabilization in multiple external datasets. Experiments with clinical samples demonstrated the accuracy of this analysis. Finally, Bayesian network inference revealed potential network mechanisms of EVL regulation. CONCLUSIONS: Monocyte differentiation-related prognostic signatures based on the Lasso + CoxBoost combination were able to accurately predict the prognostic status of patients with sepsis. In addition, low EVL expression was associated with poor prognosis in sepsis.

Fate Determination Role of Erythropoietin and Romiplostim in the Lineage Commitment of Hematopoietic Progenitors.

Erythropoietin (EPO) and thrombopoietin (TPO) have long been known to promote erythropoiesis and megakaryopoiesis, respectively. However, the fate-changing role of EPO and TPO on megakaryocyte-erythroid progenitors (MEPs) to develop along the erythroid versus megakaryocyte lineage remains unclear. We have previously shown that EPO may have a fate-changing role because EPO treatment could induce progenitor cells depletion and result in EPO resistance. Therefore, we hypothesize that a combination of romiplostim, a TPO receptor agonist that could stimulate the expansion of progenitors, with EPO can treat EPO resistance. Using rats with anemia due to chronic kidney disease, we demonstrated that romiplostim synergized with EPO to promote red blood cells production whereas EPO inhibited platelet production in a dose-dependent manner to reduce the risk of thrombosis. Corroborating findings from in vivo, in vitro experiments demonstrated that romiplostim expanded hematopoietic stem cells and stimulated megakaryopoiesis whereas EPO drove the progenitors toward an erythroid fate. We further developed a novel pharmacokinetic-pharmacodynamic model to quantify the effects of EPO and romiplostim on megakaryopoiesis and erythropoiesis simultaneously. The modeling results demonstrated that EPO increased the differentiation rate of MEPs into burst-forming unit-erythroid cells up to 22-fold, indicating that the slight increase of MEPs induced by romiplostim could be further amplified and recruited by EPO to promote erythropoiesis. The data herein support that romiplostim in combination with EPO can treat EPO resistance. SIGNIFICANCE STATEMENT: This study clarified that erythropoietin (EPO) drives the fate of megakaryocyte-erythroid progenitors (MEPs) toward the erythroid lineage, thus reducing their megakaryocyte (MK) lineage commitment, whereas romiplostim, a thrombopoietin receptor agonist, stimulates megakaryopoiesis through the MK-committed progenitor and MEP bifurcation pathways simultaneously. These findings support an innovative combination of romiplostim and EPO to treat EPO-resistant anemia because the combination therapy further promotes erythropoiesis compared to EPO monotherapy and inhibits platelet production compared to romiplostim monotherapy.

Metabolomics and integrated network pharmacology analysis reveal Tricin as the active anti-cancer component of Weijing decoction by suppression of PRKCA and sphingolipid signaling.

Currently, conventional methods of treating non-small cell lung cancer (NSCLC) have many disadvantages. An alternative effective therapy with minimal adverse reactions is urgently needed. Weijing decoction (WJD), which is a classic ancient Chinese herbal prescription, has been used successfully to treat pulmonary system diseases containing lung cancer in the clinic. However, the key active component and target of Weijing decoction are still unexplored. Therefore, for the first time, our study aims to investigate the pharmacological treatment mechanism of Weijing decoction in treating NSCLC via an integrated model of network pharmacology, metabolomics and biological methods. Network pharmacology results conjectured that Tricin is a main bioactive component in this formula which targets PRKCA to suppress cancer cell growth. Metabolomics analysis demonstrated that sphingosine-1-phosphate, which is regulated by sphingosine kinase 1 and sphingosine kinase 2, is a differential metabolite in plasma between the WJD-treated group and the control group, participating in the sphingolipid signaling. In vitro experiments demonstrated that Tricin had vital effects on the proliferation, pro-apoptosis, migration and colony formation of Lewis lung carcinoma cells. Through a series of validation assays, Tricin inhibited the tumor growth mainly by suppressing PRKCA/SPHK/S1P signaling and antiapoptotic signaling. On the other hand, Weijing formula could inhibit the tumor growth and prolong the survival time. A high dosage of Tricin was much more potent in animal experiments. In conclusion, we confirmed that Weijing formula and its primary active compound Tricin are promising alternative treatments for NSCLC patients.

Feasibility and efficacy of microwave ablation for treating breast fibroadenoma.

BACKGROUND: To investigate the safety, efficacy, and follow-up outcomes of microwave ablation (MWA) in patients with breast fibroadenoma. METHODS: An institutional review board-approved this study of patients treated with MWA for breast fibroadenoma from October 2017 to March 2019. Clinical features of patients and breast fibroadenoma were analyzed. At follow-up all patients received physical examination and ultrasound imaging. RESULTS: In total, 171 patients with 271 lesions were enrolled. The mean lesion diameter was 1.35 ± 0.47 cm. The results revealed differential lesion states, including stability, enlargement, reduction, and complete regression, at 1-6, 6-12, and >12 months of follow-up. The size was reduced in 22.14% (31/140), 26.36% (29/110), and 36.36% (16/44) of the lesions at 1-6, 6-12, and >12 months of follow-up, respectively. The proportion of lesions with complete regression was 24.29% (34/140) at 1-6 months, 45.45% (50/110) at 6-12 months, and 40.91% (18/44) at >12 months of follow up. There was no significant relationship between the curative effect and age, lesion location, and blood flow in patients with breast fibroadenoma after MWA (p > .05), but there was statistically significant relationship with lesion diameter (categorized as <1.5 cm and ≥1.5 cm) (p < .05). CONCLUSIONS: The current evidence indicates that MWA is a safe and effective method for treating breast fibroadenoma. Nevertheless, further large-scale prospective trials and well-designed future studies are warranted to validate our findings.

Seasonal variations of epidermal biophysical properties in Kunming, China: A self-controlled cohort study.

BACKGROUND: Epidermal biophysical properties can be affected by many factors, including body site, age, gender, ethnicity, disease, temperature, humidity, and ultraviolet (UV) radiation. Information about variation of epidermal biophysical properties with seasons is still limited. In the present study, we determined seasonal variation of epidermal biophysical properties of women in Kunming, China. MATERIALS AND METHODS: A total of 72 women, aged 22.96 ± 2.11 years, were enrolled in this study. Transepidermal water loss rates (TEWL), stratum corneum (SC) hydration, sebum content, melanin index (MI), erythema index (EI), and L*a* values were measured on the right cheek and the right forearm, using a non-invasive skin physiological instrument in the spring, summer, autumn, and winter in Kunming, China. RESULTS: On the cheek, TEWL, SC hydration, sebum, MI, and L*a* values varied greatly with seasons (P < .05). SC hydration, sebum, MI, and a*value peaked in the summer, but went lowest in winter. In contrast, TEWL and L*value went lowest in summer but peaked in winter. Similarly, SC hydration, MI, and L*value also varied with seasons on the forearm (P < .05). In addition, SC hydration, sebum, MI, EI, and a*value of the cheek were higher than that of the forearm (P < .001), but L*values of the cheek were lower than that of the forearm (P < .001). There were no correlations among TEWL and MI, EI, and L*a*values in any season (P > .05). CONCLUSIONS: Both epidermal permeability barrier function, sebum, and skin pigment in healthy women vary seasons in Kunming, China.

FOXO1 and FOXO3a sensitize non-small-cell lung cancer cells to cisplatin-induced apoptosis independent of Bim.

Low sensitivity to chemotherapy has been a major challenge in the treatment of non-small-cell lung cancer (NSCLC). It is of great clinical significance to discover its mechanisms to improve cell sensitivity to chemotherapeutic drugs. The forkhead box subfamily O (FOXO) transcriptional factors are downstream factors of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway and are reported to play pro-apoptotic roles in a variety of cells including NSCLC cells. But their roles and mechanisms in mediating cell response to chemotherapy remain to be discovered. We proposed that FOXO1 and FOXO3a may increase the sensitivity of NSCLC cells to cisplatin. Moreover, we presumed that LY294002, an inhibitor of the PI3K/AKT pathway, may enhance the cytotoxic effects of cisplatin through upregulating FOXO1 and FOXO3a. In the present study, we found that cisplatin initially increased the expressions and nuclear accumulation of FOXO1 and FOXO3a in NSCLC. Knockdown of FOXO1 and FOXO3a significantly decreased the cell sensitivity to cisplatin in vitro and in vivo. Moreover, inhibition of FOXO1 and FOXO3a attenuated cisplatin-induced cell apoptosis independent of Bim, a pro-apoptotic protein downstream of the FOXOs. Moreover, LY294002 synergistically increased the cytotoxic effects of cisplatin. Mechanistically, LY294002 increased the expressions and nuclear accumulation of FOXO1 and FOXO3a. Knockdown of FOXO1 and FOXO3a abrogated the enhancing effect of LY294002 on cisplatin. Taken together, our results suggested that FOXO1 and FOXO3a sensitize NSCLC cells to cisplatin and mediate the enhancing effects of LY294002 on cisplatin.

Image Representation Method Based on Relative Layer Entropy for Insulator Recognition.

Deep convolutional neural networks (DCNNs) with alternating convolutional, pooling and decimation layers are widely used in computer vision, yet current works tend to focus on deeper networks with many layers and neurons, resulting in a high computational complexity. However, the recognition task is still challenging for insufficient and uncomprehensive object appearance and training sample types such as infrared insulators. In view of this, more attention is focused on the application of a pretrained network for image feature representation, but the rules on how to select the feature representation layer are scarce. In this paper, we proposed a new concept, the layer entropy and relative layer entropy, which can be referred to as an image representation method based on relative layer entropy (IRM_RLE). It was designed to excavate the most suitable convolution layer for image recognition. First, the image was fed into an ImageNet pretrained DCNN model, and deep convolutional activations were extracted. Then, the appropriate feature layer was selected by calculating the layer entropy and relative layer entropy of each convolution layer. Finally, the number of the feature map was selected according to the importance degree and the feature maps of the convolution layer, which were vectorized and pooled by VLAD (vector of locally aggregated descriptors) coding and quantifying for final image representation. The experimental results show that the proposed approach performs competitively against previous methods across all datasets. Furthermore, for the indoor scenes and actions datasets, the proposed approach outperforms the state-of-the-art methods.

Broadband dielectric properties of honey: effects of temperature.

Dielectric properties of jujube honey were investigated at 298-358 K by broadband dielectric measurements. Four relaxation processes were observed and analyzed, which are caused by long range correlation of density fluctuation, cooperative motions of molecules, rotational polarization of bound water and collective reorientation of free water, respectively. The results of temperature dependence of dielectric parameters show that with increasing temperature, the interaction among the molecules e.g. water, fructose and glucose molecules etc. weaken, and the honey gradually forms a complete sugar solution. At a given temperature, the penetration depth at 27 MHz is much greater than that at 915 MHz and 2.45 GHz. And based on the calculated penetration depth, dielectric heating at 27 MHz seems to has more advantages for large volume of materials.

Inhibitory effects of flavonoids on P-glycoprotein in vitro and in vivo: Food/herb-drug interactions and structure-activity relationships.

Flavonoids are a class of polyphenol antioxygen, despite various known biological activities and therapeutic potential, scattered but not much is known about their interactions with drug transporters. P-glycoprotein (P-gp) as a cellular defense mechanism by effluxing its substrates has been widely investigated. The aim of this study was to investigate the inhibitory effects of 75 flavonoids on P-gp in vitro and in vivo and to illuminate the structure-activity relationships of flavonoids with P-gp. Five flavonoids, including tangeretin, sinensetin, isosinensetin, sciadopitysin and oroxylin A exhibited significant inhibition on P-gp in MDR1-MDCKIIcells, which reduced the P-gp-mediated efflux of paraquat and taxol and consequently increased their cell toxicity. In addition, co-administration of digoxin with five flavonoids increased the AUC0-t of digoxin in different extents in rats, from 19.84% to 81.51%. Molecular docking assays elucidated the inhibitory effect of flavonoids might be related to Pi interactions, but not hydrogen bonds. The pharmacophore model suggested the hydrophobic groups in B benzene ring may play a vital role in the potency of flavonoids inhibition on P-gp. Taken together, our findings would provide the basis for a reliable assessment of the potential risks of flavonoid-containing food/herb-drug interactions in humans.

Correction to: Perceptions of traditional Chinese medicine for chronic disease care and prevention: a cross-sectional study of Chinese hospital-based health care professionals.

Following publication of the original article [1], the author reported that the funding information was missing from the original article.

Perceptions of traditional Chinese medicine for chronic disease care and prevention: a cross-sectional study of Chinese hospital-based health care professionals.

BACKGROUND: In China, demands for disease prevention and health care and the prevalence of chronic non-communicable diseases have increased. TCM and general hospitals are increasingly utilizing TCM strategies for chronic non-communicable disease care and prevention. This study aimed to investigate health care professionals' (HCPs') perceptions of TCM for prevention, their TCM knowledge, and their abilities to provide such services in TCM and general hospitals. METHODS: This cross-sectional study investigated Chinese medicine hospitals and Chinese medicine departments in general hospitals in five Chinese cities. A self-designed questionnaire used to study 400 HCPs focused on basic demographic data, the demand for and effects of TCM for prevention and treatment, and their perceptions of such service implementation. The data analysis included chi-squared tests and descriptive and multi-factor analyses. RESULTS: The 335 HCP respondents comprised 230 (68.7%) females and 105 (31.3%) males, 75.5% of whom overall had knowledge of TCM preventive and health care services. Respondents older than 40 years (28.6%) had greater knowledge of and satisfaction with TCM for preventive and health care services than younger respondents. Moreover, 97.7% of the older respondents were clearly willing to provide TCM preventive services for chronic diseases, 67.8% of whom indicated that their hospitals already provided TCM for prevention and treatment. According to the chi-squared test results, the TCM service characteristics in hospitals, hospital outlooks regarding TCM and TCM development in hospitals were the primary factors affecting the respondents' perceptions of TCM for chronic disease care and prevention. The multivariate analysis showed high satisfaction as significantly associated with older providers and those with lengthier work experience, particularly among those who worked in hospitals that provided typical TCM services and had positive attitudes towards TCM. CONCLUSION: The study HCPs had relatively satisfactory knowledge of and positive attitudes towards TCM for chronic disease care and prevention and would use it in practice. Their perceptions and satisfaction levels correlated closely with the successful application of TCM for preventive care and treatment in hospitals. While the use of TCM for prevention and treatment was well developed in some hospitals, further improvements are warranted.

Catanionic lipid nanosystems improve pharmacokinetics and anti-lung cancer activity of curcumin.

Novel catanionic lipid nanosystems (CLNs) incorporating curcumin (CCM) were developed, and improvements in pharmacokinetics and enhanced anti-lung cancer activity were observed. CCM was present in a lipid matrix surrounded by cationic, anionic and zwitterionic surfactants, forming the core-shell nanosystems. Compared with free CCM, the CCM-CLNs had much higher oral and intravenous bioavailabilities due to enhanced absorption and reduced clearance. The CCM-CLNs exhibited greater cytotoxicity in Lewis lung cancer (LLC) cells, which might have been due to increased antiproliferative, proapoptotic and anti-invasive activities and induction of cell cycle arrest. The CCM-CLNs increased the antitumor efficacy of CCM and decreased the tumor growth rate in tumor-bearing mice. This is the first report of induction of apoptosis in LLC cells by CCM through the PI3K/Akt/FoxO1/Bim signaling pathway. Catanionic lipid nanocarriers show promise for the therapeutic delivery of insoluble anti-tumor drugs.

A metal (Co)-organic framework-based chemiluminescence system for selective detection of L-cysteine.

A metal (Co)-Organic Framework (Co-MOF) was first found to catalyze the chemiluminescence (CL) of luminol. On the basis of X-ray photoelectron spectroscopy, powder X-ray diffraction, CL spectral, UV-visible absorption spectral, and electron spin resonance (ESR) spectral studies, as well as the research of the influence of various free radical scavengers, a possible CL mechanism was proposed. The enhanced CL might be attributed to the formation of a peroxide analogous complex between the oxygen-related radicals and the active metal site of the Co-MOF material. The established Co-MOF-luminol CL system was successfully applied to determine L-cysteine (CySH), based on the selective and sensitive enhancing effect of CySH on this CL system. Under the optimized conditions, CySH was selectively detected in the range 0.1-10 µM with a detection limit of 18 nM. This novel CL system obviously gives impetus to the new research field of metal-organic frameworks (MOFs) in chemiluminescence.

Aggregation behavior and electrical properties of amphiphilic pyrrole-tailed ionic liquids in water, from the viewpoint of dielectric relaxation spectroscopy.

The self-aggregation behavior of amphiphilic pyrrole-tailed imidazolium ionic liquids (Py(CH2)12mim⁺Br⁻: Py = pyrrole, mim = methylimidazolium) in water is investigated by dielectric spectroscopy from 40 Hz to 110 MHz. Dielectric determination shows that the critical micelle concentration (CMC) is 8.5 mM, which is lower than that for traditional ionic surfactants. The thermodynamic parameter of the micellization, the Gibbs free energy ΔG, was calculated for Py(CH2)12mim⁺Br⁻ and compared to those of the corresponding C(n)mim⁺Br⁻ (n = 12, 14). It was found that the main driven forces of the Py(CH2)12mim⁺Br⁻ aggregation were hydrophobic interaction and π-π interactions among the adjacent Py groups. Further, the structure of aggregation was speculated theoretically that Py groups partially insert into the alkyl chains and the staggered arrangement in micelles is formed. When the concentration of Py(CH2)12mim⁺Br⁻ is higher than CMC, two remarkable relaxations which originated from diffusion of counterions and interfacial polarization between the micelles and solution, were observed at about 1.3 MHz and 55 MHz. The relaxation parameters representing the real properties of the whole system were obtained by fitting the experimental data with Cole-Cole equation. A dielectric model characterizing the structure and electrical properties of spherical micelles was proposed by which the conductivity, permittivity and the volume fraction of micelles as well as electrical properties of solution were calculated from the relaxation parameters. An intriguingly high permittivity of about 150 for the micelle was found to be a direct consequence of the strong orientational order of water molecules inside the core of micelle, and essentially is attributed to the special structure of the micelle. Furthermore, the calculation of the interfacial electrokinetic parameters of the micelles, i.e., the surface conductivity, surface charge density and zeta potential, were also achieved based on the relaxation parameters and phase parameters from higher frequency relaxation. On the basis of the results obtained, the aggregation behaviours and interfacial electrokinetic properties of the special micelles are discussed.

Associations between contrast-enhanced ultrasound features and WHO/ISUP grade of clear cell renal cell carcinoma: a retrospective study.

BACKGROUND: Clear cell renal cell carcinoma (CCRCC) comprises 70%-80% of RCCs. The World Health Organization/International Society of Urology Pathology (WHO/ISUP) classification is the most important prognostic factor for CCRCC. By evaluating the variations of tumor microvascular density, contrast-enhanced ultrasound (CEUS) can noninvasively predict the WHO/ISUP grade of CCRCC, and provide the appropriate treatment plan before clinical operation. METHODS: In this study, we used CEUS features to analyze 116 CCRCC cases and assess the value of correlation between each indicator and CCRCC WHO/ISUP grading. RESULTS: When compared to high-grade (WHO/ISUP grade III/IV) tumors, low-grade (WHO/ISUP grade I/II) tumors had reduced relative peak intensity (ΔPI) (P = 0.021), relative area under the curve (ΔAUC) (P = 0.019). However, the frequency of incomplete pseudocapsule (P = 0.021) was significantly higher in high-grade tumors. A cut-off value of mean diameter > 5.5 cm, ΔPI > 304 × 10-3, ΔAUC > 350 × 10-3 allowed identification of high-grade tumors with an area under the curve (AUC) of 74.6%, 71.7%, 70.7%, respectively (95% confidence interval). CONCLUSIONS: The features of CEUS are effective for differentiating high-grade tumors from low-grade tumors, thus CEUS can be considered an acceptable method for the preoperative assessment of tumor grade.

Blocking Palmitoylation of Apelin Receptor Alleviates Morphine Tolerance in Neuropathic Cancer Pain.

Neuropathic cancer pain (NCP) is an important symptom in patients with cancer. However, significant analgesic tolerance and other side effects critically hamper the administration of morphine. Protein palmitoylation mediated by the DHHC family may be involved in the glial activation and inflammatory responses underlying organ failure. In this study, we investigated the key role of protein palmitoylation in cancer pain and sought to target palmitoylation to suppress morphine tolerance. We found that long-term use of morphine led to the accumulation of the morphine metabolite, morphine-3-glucuronide, in vivo and activated ERK1/2 and microglia to release inflammatory factors through the apelin receptor APLNR. Palmitoyltransferase ZDHHC9 was upregulated in NCP, and APLNR was palmitylated to protect it from lysosomal degradation and to maintain its stability. We also designed competitive inhibitors of APLNR palmitoylation to inhibit the development of NCP, release of inflammatory factors, and attenuation of morphine tolerance. Therefore, targeting APLNR palmitoylation in combination with morphine is a potent method for cancer pain treatment. Our data provide a basis for the future clinical use of related drugs combined with morphine for the treatment of cancer-related pain.

Development of stemness-related signature to optimize prognosis prediction and identify XMD8-85 as a novel therapeutic compound for glioma.

Glioma is a highly invasive and aggressive type of brain cancer with poor treatment response. Stemness-related transcription factors form a regulatory network that sustains the malignant phenotype of gliomas. We conducted an integrated analysis of stemness-related transcription factors using The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets, established the characteristics of stemness-related transcription factors, including Octamer-Binding Protein 4 (OCT4), Meis Homeobox 1 (MEIS1), E2F Transcription Factor 1 (E2F1), Transcription Factor CP2 Like 1 (TFCP2L1), and RUNX Family Transcription Factor 1 (RUNX1). The characteristic of stemness-related transcription factors was identified as an independent prognostic factor for glioma patients. Patients in the high-risk group have a worse prognosis than those in the low-risk group. The glioma microenvironment in the high-risk group exhibited a more active immune status. Single-cell level analysis revealed that stem cell-like cells exhibited stronger intercellular communication than glioma cells. Meanwhile, patients in different risk stratification exhibited varying sensitivities to immunotherapy and small molecule drug therapy. XMD8-85 was more effective in the high-risk group, and its antitumor effects were validated both in vivo and in vitro. Our results indicate that this prognostic feature will assist clinicians in predicting the prognosis of glioma patients, guiding immunotherapy and personalized treatment, as well as the potential clinical application of XMD8-85 in glioma treatment, and helping to develop effective treatment strategies.

Predictive Model of CK7 Expression in Patients With Clear Cell Renal Cell Carcinoma by Combined Multimodal Ultrasound Diagnostic Techniques: A Retrospective Study.

OBJECTIVE: The aim of the work described here was to develop and validate a predictive model for cytokeratin 7 (CK7) expression in clear cell renal cell carcinoma (ccRCC) patients by combining multimodal ultrasound diagnostic techniques. METHODS: This retrospective study enrolled 157 surgically confirmed ccRCC patients. All patients underwent pre-operative multimodal ultrasound diagnostic examinations, including B-mode ultrasound (US), color Doppler flow imaging (CDFI) and contrast-enhanced ultrasound (CEUS). The patients were randomly divided into a training group (103 cases) and a testing group (54 cases). Univariate and multivariate logistic regression analyses were performed in the training group to identify independent indicators associated with CK7 positivity. These indicators were included in the predictive model. Receiver operating characteristic (ROC) curves and calibration curves were used to evaluate the model's discriminative ability and accuracy. Decision curve analysis (DCA) and nomogram visualization were used to assess the clinical utility of the predictive model. RESULTS: Univariate logistic regression analysis revealed that US and CDFI observations were not correlated with CK7 expression and could not predict it. Multivariate logistic regression analysis identified age (odds ratio [OR] = 0.953, 95% confidence interval [CI]: 0.909-0.999), wash-in pattern (OR = 0.180, 95% CI: 0.063-0.513) and enhancement homogeneity (OR = 11.610, 95% CI: 1.394-96.675) as independent factors related to CK7 positivity in ccRCC. Incorporating these variables into the predictive model resulted in areas under the receiver operating characteristic curve of 0.812 (95% CI: 0.711-0.913) for the training group and 0.792 (95% CI: 0.667-0.924) for the testing group. The calibration curve and DCA revealed that the model had good accuracy and clinical utility of the model. CONCLUSION: The combination of multimodal ultrasound diagnostic techniques in constructing a predictive model for CK7 expression in ccRCC patients has significant predictive value.

Linking phenotype to kinase: identification of a novel benzoxaborole hinge-binding motif for kinase inhibition and development of high-potency rho kinase inhibitors.

Benzoxaboroles are a novel class of drug-like compounds that have been rich sources of novel inhibitors for various enzymes and of new drugs. While examining benzoxaborole activity in phenotypic screens, our attention was attracted by the (aminomethylphenoxy)benzoxaborole family, which potently inhibited Toll-like receptor-stimulated cytokine secretion from leukocytes. After considering their structure-activity relationships and the central role of kinases in leukocyte biology, we performed a kinome-wide screen to investigate the members of the (aminomethylphenoxy)benzoxaborole family. This technique identified Rho-activated kinase (ROCK) as a target. We showed competitive behavior, with respect to ATP, and then determined the ROCK2-drug cocrystal structure. The drug occupies the ATP site in which the oxaborole moiety provides hydrogen bond donors and acceptors to the hinge, and the aminomethyl group interacts with the magnesium/ATP-interacting aspartic acid common to protein kinases. The series exhibits excellent selectivity against most of the kinome, with greater than 15-fold selectivity against the next best member of the AGC protein kinase subfamily. Medicinal chemistry efforts with structure-based design resulted in a compound with a Ki of 170 nM. Cellular studies revealed strong enzyme inhibition rank correlation with suppression of intracellular phosphorylation of a ROCK substrate. The biochemical potencies of these compounds also translated to functional activity, causing smooth muscle relaxation in rat aorta and guinea pig trachea. The series exhibited oral availability and one member reduced rat blood pressure, consistent with ROCK's role in smooth muscle contraction. Thus, the benzoxaborole moiety represents a novel hinge-binding kinase scaffold that may have potential for therapeutic use.

Structure-activity relationships of 6-(aminomethylphenoxy)-benzoxaborole derivatives as anti-inflammatory agent.

A series of novel 6-(aminomethylphenoxy)benzoxaborole analogs was synthesized for the investigation of the structure-activity relationship of the inhibition of TNF-alpha, IL-1beta, and IL-6, from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compounds 9d and 9e showed potent activity against all three cytokines with IC50 values between 33 and 83nM. Chloro substituted analog 9e (AN3485) is considered to be a promising lead for novel anti-inflammatory agent with a favorable pharmacokinetic profile.