Robust Ultrafast Projection Pipeline for Structural and Angiography Imaging of Fourier-Domain Optical Coherence Tomography.

The current methods to generate projections for structural and angiography imaging of Fourier-Domain optical coherence tomography (FD-OCT) are significantly slow for prediagnosis improvement, prognosis, real-time surgery guidance, treatments, and lesion boundary definition. This study introduced a robust ultrafast projection pipeline (RUPP) and aimed to develop and evaluate the efficacy of RUPP. RUPP processes raw interference signals to generate structural projections without the need for Fourier Transform. Various angiography reconstruction algorithms were utilized for efficient projections. Traditional methods were compared to RUPP using PSNR, SSIM, and processing time as evaluation metrics. The study used 22 datasets (hand skin: 9; labial mucosa: 13) from 8 volunteers, acquired with a swept-source optical coherence tomography system. RUPP significantly outperformed traditional methods in processing time, requiring only 0.040 s for structural projections, which is 27 times faster than traditional summation projections. For angiography projections, the best RUPP variation took 0.15 s, making it 7518 times faster than the windowed eigen decomposition method. However, PSNR decreased by 41-45% and SSIM saw reductions of 25-74%. RUPP demonstrated remarkable speed improvements over traditional methods, indicating its potential for real-time structural and angiography projections in FD-OCT, thereby enhancing clinical prediagnosis, prognosis, surgery guidance, and treatment efficacy.

Smart nanozymes coupled with dynamic magnet field and laser exposures for cancer therapy.

Developing nanozymes for cancer therapy has attracted great attention from researchers. However, enzymes-loaded magnetic particles triggered by both a low-frequency vibrating magnetic field (VMF) and laser for inhibiting tumor growth have never been reported. Herein, we developed a magnetic nanozyme with 3D flower-like nanostructures for cancer therapy. Specifically, the flower-like nanozymes exposed to a VMF could efficiently damage the mitochondrial membrane and cell structure, and inhibit tumor growth through magneto-mechanical force. In parallel, magnetic nanozymes in a weak acid environment containing glucose could generate abundant hydrogen peroxide through glucose oxidase-catalyzed oxidation of glucose, and further significantly promote the Fenton reaction. Interestingly, both glucose oxidase- and Fenton-based catalytic reactions were significantly promoted by the VMF exposure. Flower-like magnetic nanospheres upon a near-infrared laser irradiation could also damage cancer cells and tumor tissues through photothermal effect. The cell-killing efficiency of magnetic nanozymes triggered by the VMF or laser significantly increased in comparison with that of nanozymes without exposures. Mouse tumors grown after injection with magnetic nanozymes was inhibited in a significant way or the tumors disappeared after exposure to a VMF and laser due to the synergistic effect of four major stimuli, viz., magneto-mechanical force, photothermal conversion, improved Fenton reaction, and intratumoral glucose consumption-based starvation effect. This is a great platform that may be suitable for treating many solid tumors.

Oblique lateral interbody fusion with internal fixations in the treatment for cross-segment degenerative lumbar spine disease (L2-3 and L4-5) finite element analysis.

Multi-segmental lumbar degenerative disease, including intersegmental disc degeneration, is found in clinical practice. Controversy still exists regarding the treatment for cross-segment degeneration. Oblique Lateral Interbody Fusion (OLIF) with several internal fixations was used to treat cross-segment lumbar degenerative disease. A whole lumbar spine model was extracted from CT images of the whole lumbar spine of patients with lumbar degeneration. The L2-3 and L4-5 intervertebral spaces were fused with OLIF using modeling software, the Pedicle screws were performed on L2-3 and L4-5, and different internal fixations were performed on L3-4 in Finite Element (FE) software. Among the six 10 Nm moments of different directions, the L3-4 no surgery (NS) group had the relatively largest Range of Motion (ROM) in the whole lumbar spine, while the L2-5 Long segmental fixation (LSF)group had the smallest ROM and the other groups had similar ROM. The ROM in the L1-2 and L5-S1 was relatively close in the six group models, and the articular cartilage stress and disc stress on the L1-2 and L5-S1 were relatively close. In contrast, the L3-4 ROM differed relatively greatly, with the LSF ROM the smallest and the NS ROM the largest, and the L3-4 Coflex (Coflex) group more active than the L3-4 Bacfuse (Bacfuse) group and the L3-4 translaminar facet screw fixation (TFSF) group. The stress on the articular cartilage and disc at L3-4 was relatively greater in the NS disc and articular cartilage, and greater in the Coflex group than in the Bacfuse and TFSF groups, with the greatest stress on the internal fixation in the TFSF group, followed by the Coflex group, and relatively similar stress in the Bacfuse, LSF, and NS groups. In the TFSF group, the stress on the internal fixation was greater than the yield strength among different directional moments of 10 Nm, which means it is unsuitable to be an internal fixation. The LSF group had the greatest overall ROM, which may lead to postoperative low back discomfort. The NS group has the greatest overall ROM, but its increased stress on the L3-4 disc and articular cartilage may lead to accelerated degeneration of the L3-4 disc and articular cartilage. The Coflex and Bacfuse groups had a reduced L3-4 ROM but a greater stress on disc compared to the LSF group, which may lead to disc degeneration in the long term. However, their stress on the articular cartilage was relatively low. Coflex and Bacfuse can still be considered better surgical options.

Brown Sequard syndrome in a patient with Klippel-Feil syndrome following minor trauma: a case report and literature review.

BACKGROUND: There are some cases of Klippel-Feil syndrome with spinal cord injury in clinical work. However, there is no literature report on Brown-Sequard syndrome after trauma. We report a case of Brown-Sequard syndrome following minor trauma in a patient with KFS type III. Her Brown-Sequard syndrome is caused by Klippel-Feil syndrome. CASE PRESENTATION: We found a 38-year-old female patient with KFS in our clinical work. She was unconscious on the spot following a minor traumatic episode. After treatment, her whole body was numb and limb activity was limited. Half an hour later, she felt numb and weak in the right limb and weak in the left limb. She had no previous hypertension, diabetes, or coronary heart disease. After one-month treatment of medication, hyperbaric oxygen, rehabilitation, and acupuncture in our hospital, her muscle strength partially recovered, but the treatment effect was still not satisfactory. Then, she underwent surgical treatment and postoperative comprehensive treatment, and rehabilitation training. She was able to take care of herself with assistance, and her condition improved from grade B to grade D according to the ASIA (ASIA Impairment Scale) classification. CONCLUSION: KFS, also known as short neck deformity, is a kind of congenital deformity characterized by impaired formation and faulty segmentation of the cervical spine, often associated with abnormalities of other organs. The cervical deformity in patients with KFS can alter the overall mechanical activity of the spine, as well as the compensatory properties of the spine for decelerating and rotatory forces, thus increasing the chance of spinal cord injury (SCI) following trauma. Many mechanisms can make patients more susceptible to injury. Increased range of motion of the segment adjacent to the fused vertebral body may lead to slippage of the adjacent vertebral body and altered disc stress, as well as cervical instability. SCI can result in complete or incomplete impairment of motor, sensory and autonomic nervous functions below the level of lesion. This woman presented with symptoms of BSS, a rare neurological disorder with incomplete SCI. Judging from the woman's symptoms, we concluded that previously she had KFS, which resulted in SCI without fracture and dislocation following minor trauma, with partial BSS. After the comprehensive treatment of surgery, hyperbaric oxygen, rehabilitation therapy, and neurotrophic drugs, two years later, we found her symptoms significantly improved, with ASIA Impairment Scale from grade B to grade D, and her ability to perform activities of daily living with aids.

Knockdown of lncRNA NKILA suppresses sevoflurane-induced neuronal cell injury partially by targeting miR-205-5p/ELAVL1 axis.

Sevoflurane (Sev) is a wildly used volatile anesthetic agent that induces neurotoxicity. Long non-coding RNAs (lncRNAs) have been demonstrated to be involved in Sev-induced neuronal injury. Here, we investigated the role of NF-kappaB-interacting lncRNA (NKILA) in Sev-treated human cortical neurons (HCN). From RT-qPCR, Sev dose-dependently increased HCN NKILA transcript expression. Neurotoxicity of Sev was detected using MTT, flow cytometry, Western blotting, and inflammatory mediator assays. Consequently, Sev reduced HCN viability and levels of Bcl-2, SOD, and GSH in HCN, and promoted HCN apoptosis rate and levels of cleaved-caspase-3, Bax, MDA, TNF-α, IL-6, and IL-1ß. Silencing NKILA suppressed Sev-induced above effects. DIANA and starbase databases predicted the potential target relationship between miR-205-5p and NKILA or embryonic lethal abnormal vision-like 1 (ELAVL1); dual-luciferase and RIP confirmed these interactions. NKILA could increase ELAVL1 expression by regulating miR-205-5p. miR-205-5p overexpression and ELAVL1 knockdown could mimic effects of NKILA silencing in Sev-induced HCN. Deleting miR-205-5p and restoring ELAVL1 respectively abolished the neuroprotective effect of NKILA knockdown and miR-205-5p upregulation under Sev anesthesia. In conclusion, Sev induced neuronal cell apoptosis, inflammatory response and oxidative stress through NKILA/miR- 205-5p/ELAVL1 axis and caspase-3 and Bax/Bcl-2 pathway. Inhibiting NKILA might be a potential therapeutic strategy for Sev neurotoxicity.

Associations between TERT Promoter Mutations and Survival in Superficial Spreading and Nodular Melanomas in a Large Prospective Patient Cohort.

Survival outcomes in melanoma and their association with mutations in the telomerase reverse transcriptase gene TERT promoter remain uncertain. In addition, few studies have examined whether these associations are affected by a nearby common germline polymorphism or vary on the basis of melanoma histopathological subtype. We analyzed 408 primary tumors from a prospective melanoma cohort for somatic TERT-124[C>T] and TERT-146[C>T] mutations, the germline polymorphism rs2853669, and BRAFV600 and NRASQ61 mutations. We tested the associations between these variants and clinicopathologic factors and survival outcomes. TERT-124[C>T] was associated with thicker tumors, ulceration, mitoses (>0/mm2), nodular histotype, and CNS involvement. In a multivariable model controlling for the American Joint Committee on Cancer stage, TERT-124[C>T] was an independent predictor of shorter recurrence-free survival (hazard ratio = 2.58, P = 0.001) and overall survival (hazard ratio = 2.47, P = 0.029). Patients with the germline variant and TERT-124[C>T]-mutant melanomas had significantly shorter recurrence-free survival than those lacking either or both sequence variants (P < 0.04). The impact of the germline variant appeared to be more pronounced in superficial spreading than in nodular melanoma. No associations were found between survival and TERT-146[C>T], BRAF, or NRAS mutations. These findings strongly suggest that TERT-124[C>T] mutation is a biomarker of aggressive primary melanomas, an effect that may be modulated by rs2853669.

O-alkyl and o-benzyl hesperetin derivative-1L attenuates inflammation and protects against alcoholic liver injury via inhibition of BRD2-NF-κB signaling pathway.

Alcoholic liver injury (ALI) is a major risk factor for alcoholic liver disease, characterized by excessive inflammatory response and abnormal liver dysfunction. Previous studies have indicated that O-alkyl and o-benzyl hesperetin derivative-1 L (HD-1 L) has anti-inflammatory and hepato-protective effects in CCl4-induced liver injury. However, its effect on ALI and underlying mechanism has not been elucidated. This study was designed to evaluate the protective effects of HD-1 L on alcoholic liver injury and reveal the underlying mechanisms. ALI model was established in male C57BL/6 J mice (aged 6-8 weeks) by Gao-Binge protocol. The mice were received different doses of HD-1 L (25 mg/kg, 50 mg/kg, 100 mg/kg) by daily intragastric administration, respectively. Liver function and inflammation were measured. Mechanism underlying the anti-inflammatory and hepato-protective effect of HD-1 L were studied in RAW264.7 cells. In alcoholic liver injury mice, HD-1 L effectively improved the liver pathology, and remarkably reduced the levels of alanine transaminase (ALT), aspartate transaminase (AST), triglyceride (TG) and total cholesterol (T-CHO) in serum. Moreover, HD-1 L markedly suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro. Our results showed that HD-1 L decreased the activity of Bromodomain-containing Protein 2 (BRD2) and inhibited expression of BRD2 in vivo and in vitro. Furthermore, HD-1 L further alleviated alcohol-induced inflammation after blocking BRD2 with inhibitor (JQ1) or BRD2 small interfering (si)-RNA in RAW264.7 cells. Besides, HD-1 L failed to effectively exert its anti-inflammatory effects after over expression of BRD2. In addition, HD-1 L significantly inhibited the phosphorylation and activation of NF-κB-P65 mediated by BRD2. In conclusion, HD-1 L alleviated liver injury and inflammation mainly by inhibiting BRD2-NF-κB signaling pathway, and HD-1 L may be a potential anti-inflammatory compound in treatment of alcoholic liver disease.

Prediction of Clinically Significant Cancer Using Radiomics Features of Pre-Biopsy of Multiparametric MRI in Men Suspected of Prostate Cancer.

BACKGROUND: Texture features based on the spatial relationship of pixels, known as the gray-level co-occurrence matrix (GLCM), may play an important role in providing the accurate classification of suspected prostate cancer. The purpose of this study was to use quantitative imaging parameters of pre-biopsy multiparametric magnetic resonance imaging (mpMRI) for the prediction of clinically significant prostate cancer. METHODS: This was a prospective study, recruiting 200 men suspected of having prostate cancer. Participants were imaged using a protocol-based 3T MRI in the pre-biopsy setting. Radiomics parameters were extracted from the T2WI and ADC texture features of the gray-level co-occurrence matrix were delineated from the region of interest. Radical prostatectomy histopathology was used as a reference standard. A Kruskal-Wallis test was applied first to identify the significant radiomic features between the three groups of Gleason scores (i.e., G1, G2 and G3). Subsequently, the Holm-Bonferroni method was applied to correct and control the probability of false rejections. We compared the probability of correctly predicting significant prostate cancer between the explanatory GLCM radiomic features, PIRADS and PSAD, using the area under the receiver operation characteristic curves. RESULTS: We identified the significant difference in radiomic features between the three groups of Gleason scores. In total, 12 features out of 22 radiomics features correlated with the Gleason groups. Our model demonstrated excellent discriminative ability (C-statistic = 0.901, 95%CI 0.859-0.943). When comparing the probability of correctly predicting significant prostate cancer between explanatory GLCM radiomic features (Sum Variance T2WI, Sum Entropy T2WI, Difference Variance T2WI, Entropy ADC and Difference Variance ADC), PSAD and PIRADS via area under the ROC curve, radiomic features were 35.0% and 34.4% more successful than PIRADS and PSAD, respectively, in correctly predicting significant prostate cancer in our patients (p < 0.001). The Sum Entropy T2WI score had the greatest impact followed by the Sum Variance T2WI. CONCLUSION: Quantitative GLCM texture analyses of pre-biopsy MRI has the potential to be used as a non-invasive imaging technique to predict clinically significant cancer in men suspected of having prostate cancer.

Prostate Cancer Gleason Score From Biopsy to Radical Surgery: Can Ultrasound Shear Wave Elastography and Multiparametric Magnetic Resonance Imaging Narrow the Gap?

OBJECTIVES: To investigate the impact of ultrasound shear wave elastography (USWE) and multiparametric magnetic resonance imaging (mpMRI) in predicting a change in biopsy-assigned Gleason Score (GS) after radical surgery for localised prostate cancer (PCa). METHOD: A total of 212 men opting for laparoscopic radical prostatectomy (LRP) between September 2013 and June 2017 were recruited into this study. All the participants had 12-core transrectal ultrasound (TRUS) biopsies and imaging using USWE and mpMRI before radical surgery. The predictive accuracy for imaging modalities was assessed in relation to upgrading and downgrading of PCa GS between the biopsies and radical prostatectomy using Student's t-test and multivariable logistic regression analyses. A decision analysis curve was constructed assessing the impact of nomogram on clinical situations using different thresholds of upgrading probabilities. RESULTS: Most GS 6 diseases on biopsies were upgraded on radical surgery (37/42, 88.1%). Major downgrading was seen in GS 8 category of disease (14/35; 37.1%), whereas no alteration was observed in GS 7 on biopsies in most men (55/75; 73.3%). In univariate analysis, higher preoperative prostate-specific antigen (PSA) (p = 0.001), higher prostate-specific antigen density (PSAD) (p = 0.002), stiffer USWE lesions (p = 0.009), and higher prostate imaging-reporting and data system (PIRADS) (p = 0.002) on mpMRI were significant predictors of upgrading. In multivariate logistic regression analyses, only PSA (p = 0.016) and USWE-measured tissue stiffness (p = 0.029) showed statistical significance in predicting upgrading. CONCLUSIONS: Measurement of tissue stiffness using USWE in clinically localised PCa can predict upgrading of GS and has the potential to improve patient management options.

Discovery of 7-O-1, 2, 3-triazole hesperetin derivatives as multi-target-directed ligands against Alzheimer's disease.

The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase, anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC50 = 3.08 ± 0.29 µM) and exhibited good anti-neuroinflammatory activity (IC50 = 2.91 ± 0.47 µM) against NO production through remarkably blocking the NF-κB signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 µM concentration. Furthermore, possessing significant self-mediated Aß1-42 aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8. In the bi-directional transport assay, a8 exhibited a blood-brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents.

The ROC of Cox proportional hazards cure models with application in cancer studies.

With recent advancement in cancer screening and treatment, many patients with cancers are identified at early stage and clinically cured. Importantly, uncured patients should be treated timely before the cancer progresses to advanced stages for which therapeutic options are rather limited. It is also crucial to identify uncured subjects among patients with early-stage cancers for clinical trials to develop effective adjuvant therapies. Thus, it is of interest to develop statistical predictive models with as high accuracy as possible in predicting the latent cure status. The receiver operating characteristic curve (ROC) and the area under the ROC curve (AUC) are among the most widely used statistical metrics for assessing predictive accuracy or discriminatory power for a dichotomous outcome (cured/uncured). Yet the conventional AUC cannot be directly used due to incompletely observed cure status. In this article, we proposed new estimates of the ROC curve and its AUC for predicting latent cure status in Cox proportional hazards (PH) cure models and transformation cure models. We developed explicit formulas to estimate sensitivity, specificity, the ROC and its AUC without requiring to know the patient cure status. We also developed EM type estimates to approximate sensitivity, specificity, ROC and AUC conditional on observed data. Numerical studies were used to assess their finite-sample performance of the proposed methods. Both methods are consistent and have similar efficiency as shown in our numerical studies. A melanoma dataset was used to demonstrate the utility of the proposed estimates of the ROC curve for the latent cure status. We also have developed an [Formula: see text] package called [Formula: see text] to efficiently compute the proposed estimates.

Design and synthesis of 7-O-1,2,3-triazole hesperetin derivatives to relieve inflammation of acute liver injury in mice.

Based on the previous research results of our research group, to further improve the anti-inflammatory activity of hesperetin, we substituted triazole at the 7-OH branch of hesperetin. We also evaluated the anti-inflammatory activity of 39 new hesperetin derivatives. All compounds showed inhibitory effects on nitric oxide (NO) and inflammatory factors in lipopolysaccharide-induced RAW264.7 cells. Compound d5 showed a strong inhibitory effect on NO (half maximal inhibitory concentration = 2.34 ± 0.7 µM) and tumor necrosis factor-α, interleukin (IL)-1ß, and (IL-6). Structure-activity relationships indicate that 7-O-triazole is buried in a medium-sized hydrophobic cavity that binds to the receptor. Compound d5 can also reduce the reactive oxygen species production and significantly inhibit the expression of inducible NO synthase and cyclooxygenase-2 through the nuclear factor-κB signaling pathway. In vivo results indicate that d5 can reduce liver inflammation in mice with acute liver injury (ALI) induced by CCI4. In conclusion, d5 may be a candidate drug for treating inflammation associated with ALI.

Inhibitory activity of medicinal mushroom Ganoderma lucidum on colorectal cancer by attenuating inflammation.

The medicinal mushroom Ganoderma lucidum (GL, Reishi or Lingzhi) exhibits an inhibitory effect on cancers. However, the underlying mechanism of the antitumor activity of GL is not fully understood. In this study, we characterized the gene networks regulated by a commercial product of GL containing a mixture of spores and fruiting bodies namely "GLSF", in colorectal carcinoma. We found that in vitro co-administration of GLSF extract at non-toxic concentrations significantly potentiated growth inhibition and apoptosis induced by paclitaxel in CT26 and HCT-15 cells. GLSF inhibited NF-κB promoter activity in HEK-293 cells but did not affect the function of P-glycoprotein in K562/DOX cells. Furthermore, we found that when mice were fed a modified diet containing GLSF for 1 month prior to the CT26 tumor cell inoculation, GLSF alone or combined with Nab-paclitaxel markedly suppressed tumor growth and induced apoptosis. RNA-seq analysis of tumor tissues derived from GLSF-treated mice identified 53 differentially expressed genes compared to normal tissues. Many of the GLSF-down-regulated genes were involved in NF-κB-regulated inflammation pathways, such as IL-1ß, IL-11 and Cox-2. Pathway enrichment analysis suggested that several inflammatory pathways involving leukocyte migration and adhesion were most affected by the treatment. Upstream analysis predicted activation of multiple tumor suppressors such as α-catenin and TP53 and inhibition of critical inflammatory mediators. "Cancer" was the major significantly inhibited biological effect of GLSF treatment. These results demonstrate that GLSF can improve the therapeutic outcome for colorectal cancer through a mechanism involving suppression of NF-κB-regulated inflammation and carcinogenesis.

Predicting the Performance of Concurrent Systematic Random Biopsies during Image Fusion Targeted Sampling of Multi-Parametric MRI Detected Prostate Cancer. A Prospective Study (PRESET Study).

The study was aimed to develop a predictive model to identify patients who may benefit from performing systematic random biopsies (SB) in addition to targeted biopsies (TB) in men suspected of having prostate cancer. A total of 198 patients with positive pre-biopsy MRI findings and who had undergone both TB and SB were prospectively recruited into this study. The primary outcome was detection rates of clinically significant prostate cancer (csPCa) in SB and TB approaches. The secondary outcome was net clinical benefits of SB in addition to TB. A logistic regression model and nomogram construction were used to perform a multivariate analysis. The detection rate of csPCa using SB was 51.0% (101/198) compared to a rate of 56.1% (111/198) for TB, using a patient-based biopsy approach. The detection rate of csPCa was higher using a combined biopsy (64.6%; 128/198) in comparison to TB (56.1%; 111/198) alone. This was statistically significant (p < 0.001). Age, PSA density and PIRADS score significantly predicted the detection of csPCa by SB in addition to TB. A nomogram based on the model showed good discriminative ability (C-index; 78%). The decision analysis curve confirmed a higher net clinical benefit at an acceptable threshold.

Identification of novel CDK 9 inhibitors based on virtual screening, molecular dynamics simulation, and biological evaluation.

AIMS: Cyclin-dependent kinase 9 (CDK9) is a member of the CDK subfamily and plays a major role in the regulation of transcriptional elongation. It has attracted widespread attention as a therapeutic target for cancer. Here, we aimed to explore novel CDK 9 inhibitors by using a hybrid virtual screening strategy. MAIN METHODS: A hybrid virtual screening strategy was constructed with computer-aided drug design (CADD). First, compounds were filtered in accordance with Lipinski's rule of five and adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Second, a 3D-QSAR pharmacophore model was built and used as a 3D query to screen the obtained hit compounds. Third, the hit compounds were subjected to molecular docking studies. Fourth, molecular dynamics (MD) simulations were performed on CDK9 in complex with the final hits to examine the structural stability. Finally, CDK9 kinase biochemical assay was performed to identify the biological activity of the hit compounds. KEY FINDINGS: Seven hit compounds were screened out. These hit compounds showed drug-like properties in accordance with Lipinski's rule of five and ADMET. Complexes involving the six hit compounds bound to CDK9 exhibited good structural stability in the MD simulation. Furthermore, these six hit compounds had strong inhibitory activity against CDK9 kinase. In particular, hit 3 showed the most promising activity with the percentage of 71%. SIGNIFICANCE: The six hit compounds may be promising novel CDK9 inhibitors, and the hybrid virtual screening strategy designed in this study provides an important reference for the design and synthesis of novel CDK9 inhibitors.

Quantitative analysis of the correlation between preoperative cervical degeneration and postoperative heterotopic ossification after cervical disc replacement: minimum 10-year follow-up data.

OBJECTIVE: The authors aimed to identify factors that may be useful for quantifying the amount of degenerative change in preoperative patients to identify ideal candidates for cervical disc replacement (CDR) in patients with a minimum of 10 years of follow-up data. METHODS: During the period from December 2003 to August 2008, 54 patients underwent CDR with a Bryan cervical disc prosthesis performed by the same group of surgeons, and all of the patients in this group with at least 10 years of follow-up data were enrolled in this retrospective analysis of cases. Postoperative bone formation was graded in radiographic images by using the McAfee classification for heterotopic ossification. Preoperative degeneration was evaluated in radiographs based on a quantitative scoring system. After univariate analysis, the authors performed multifactor logistic regression analysis to identify significant factors. To determine the cutoff points for the significant factors, a receiver operating characteristic (ROC) curve analysis was conducted. RESULTS: Study patients had a mean age of 43.6 years and an average follow-up period of 120.3 months. The patients as a group had a 68.2% overall incidence of bone formation. Based on univariate analysis results, data for patient sex, disc height, and the presence of anterior osteophytes and endplate sclerosis were included in the multivariate analysis. According to the analysis results, the identified independent risk factors for postoperative bone formation included disc height, the presence of anterior osteophytes, and endplate sclerosis, and according to a quantitative scoring system for degeneration of the cervical spine based on these variables, the ROC curve indicated that the optimal cutoff scores for these risk factors were 0.5, 1.5, and 1.5, respectively. CONCLUSIONS: Among the patients who were followed up for at least 10 years after CDR, the incidence of postoperative bone formation was relatively high. The study results indicate that the degree of degeneration in the target level before surgery has a positive correlation with the incidence of postoperative ossification. Rigorous indication criteria for postoperative ossification should be applied in patients for whom CDR may be a treatment option.

Prediction of prostate cancer Gleason score upgrading from biopsy to radical prostatectomy using pre-biopsy multiparametric MRI PIRADS scoring system.

An increase or 'upgrade' in Gleason Score (GS) in prostate cancer following Transrectal Ultrasound (TRUS) guided biopsies remains a significant challenge to overcome. to evaluate whether MRI has the potential to narrow the discrepancy of histopathological grades between biopsy and radical prostatectomy, three hundred and thirty men treated consecutively by laparoscopic radical prostatectomy (LRP) between July 2014 and January 2019 with localized prostate cancer were included in this study. Independent radiologists and pathologists assessed the MRI and histopathology of the biopsies and prostatectomy specimens respectively. A multivariate model was constructed using logistic regression analysis to assess the ability of MRI to predict upgrading in biopsy GS in a nomogram. A decision-analysis curve was constructed assessing impact of nomogram using different thresholds for probabilities of upgrading. PIRADS scores were obtained from MRI scans in all the included cases. In a multivariate analysis, the PIRADS v2.0 score significantly improved prediction ability of MRI scans for upgrading of biopsy GS (p = 0.001, 95% CI [0.06-0.034]), which improved the C-index of predictive nomogram significantly (0.90 vs. 0.64, p < 0.05). PIRADS v2.0 score was an independent predictor of postoperative GS upgrading and this should be taken into consideration while offering treatment options to men with localized prostate cancer.

Design, Synthesis and Investigation of the Potential Anti-Inflammatory Activity of 7-O-Amide Hesperetin Derivatives.

To develop new anti-inflammatory agents, a series of 7-O-amide hesperetin derivatives was designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. All compounds showed inhibitory effect on LPS-induced NO production. Among them, 7-O-(2-(Propylamino)-2-oxoethyl)hesperetin (4d) and 7-O-(2-(Cyclopentylamino)-2-oxoethyl)hesperetin (4k) with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC50 = 19.32 and 16.63 µM, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) than indomethacin and celecoxib at 10 µM. The structure-activity relationships (SARs) suggested that the 7-O-amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound 4d could also significantly suppress the expression of inducible nitric oxide synthase enzymes (iNOS) and cyclooxygenase-2 (COX-2), through the nuclear factor-kappa B (NF-κB) signaling pathway.

Prediction of Postprostatectomy Biochemical Recurrence Using Quantitative Ultrasound Shear Wave Elastography Imaging.

Objectives: To determine the prognostic significance of tissue stiffness measurement using transrectal ultrasound shear wave elastography in predicting biochemical recurrence following radical prostatectomy for clinically localized prostate cancer. Patients and Methods: Eligible male patients with clinically localized prostate cancer and extraperitoneal laparoscopic radical prostatectomy between November 2013 and August 2017 were retrospectively selected. Information of potential biochemical recurrence predictors, including imaging (ultrasound shear wave elastography and magnetic resonance imaging), clinicopathological characteristics, and preoperative prostate specific antigen (PSA) levels were obtained. Recurrence-free survival (Kaplan-Meier curve) and a multivariate model were constructed using Cox regression analysis to evaluate the impact of shear wave elastography as a prognostic marker for biochemical recurrence. Results: Patients experienced biochemical recurrence in an average of 26.3 ± 16.3 months during their follow-up. A cutoff of 144.85 kPa for tissue stiffness measurement was estimated for recurrence status at follow-up with a sensitivity of 74.4% and a specificity of 61.7%, respectively (p < 0.05). In univariate analysis, shear wave elastography performed well in all preoperative factors compared to biopsy Gleason Score, PSA and magnetic resonance imaging; in multivariate analysis with postoperative pathological factors, shear wave elastography was statistically significant in predicting postoperative biochemical recurrence, which improved the C-index of predictive nomogram significantly (0.74 vs. 0.70, p < 0.05). Conclusions: The study revealed that quantitative ultrasound shear wave elastography-measured tissue stiffness was a significant imaging marker that enhanced the predictive ability with other clinical and histopathological factors in prognosticating postoperative biochemical recurrence following radical prostatectomy for clinically localized prostate cancer.

4-Methylcoumarin-[5,6-g]-hesperetin attenuates inflammatory responses in alcoholic hepatitis through PPAR-γ activation.

4-Methylcoumarin-[5,6-g]-hesperetin (4-MCH) is a hesperidin derivative produced by the structural modification of hesperetin. Alcoholic hepatitis (AH) is the origin of many serious liver diseases that are accompanied by hepatic inflammation. In this study, we detected the anti-inflammatory activity of 4-MCH in EtOH fed mice and examined the potential molecular mechanism of this activity. We found that 4-MCH suppressed the release of inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in primary liver macrophages isolated from mice and in EtOH-treated RAW264.7 cells. In addition, we showed that the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) was down-regulated in vivo and in vitro in AH. Furthermore, 4-MCH acted as an activator of PPAR-γ, which could therefore ameliorate the inhibitory effects of EtOH on the expression of PPAR-γ. The impairment of PPAR-γ function (T0070907 or PPAR-γ siRNA treatment) resulted in greater inflammation than that in the control group. Conversely, over-expression of PPAR-γ further reduced the release of inflammatory cytokines from EtOH-stimulated RAW264.7 cells. Additional investigations showed that 4-MCH significantly inhibited the phosphorylation of p65. Collectively, these results indicate that 4-MCH alleviated the inflammatory reaction through PPAR-γ activation via the NF-κB-p65 signaling pathway, which regulates the expression of IL-6 and TNF-α in AH.