Curcumin analogue NL04 inhibits spinal cord central sensitization in rats with bone cancer pain by inhibiting NLRP3 inflammasome activation and reducing IL-1ß production.

The management and therapy of bone cancer pain (BCP) remain formidable clinical challenges. Curcumin and its analogues have been shown to have anti-inflammatory and analgesic properties. In the present study, we investigated the efficacy of curcumin analogue NL04 (NL04) in modulating inflammation in spinal dorsal horn (SDH), thereby exploring its potential to reduce central sensitization of BCP in a rat model. Differing doses of NL04 and curcumin were administered intrathecally either once (on day 12 of BCP) or over seven consecutive days (from day 6-12 of BCP). Results indicated that the ED50 for NL04 and curcumin ameliorating BCP-induced mechanical hyperalgesia is 49.08 µg/kg and 489.6 µg/kg, respectively. The analgesic effects at various doses of NL04 lasted between 4 and 8 h, with sustained administration over a week maintaining pain relief for 1-4 days, while also ameliorating locomotor gait via gait analysis and reducing depressive and anxiety-like behaviors via open-field and light-dark transition tests. The analgesic effects at various doses of curcumin lasted 4 h, with sustained administration over a week maintaining pain relief for 0-2 days. ELISA, Western blotting, qPCR, and immunofluorescence assays substantiated that intrathecal administration of NL04 on days 6-12 of BCP dose-dependently lowered spinal IL-1ß and IL-18 levels and significantly reduced the expression of IKKß genes and proteins, as well as the downstream cleavage of the trans-Golgi network (TGN). Whole-cell patch-clamp results demonstrated that NL04 inhibits potassium ion efflux in rat primary spinal neurons. Thus, NL04 exhibits significant analgesic effects in a BCP rat model by downregulating IKKß expression and inhibiting neuronal potassium ion efflux, which, in turn, suppresses the activation of NLRP3 inflammasomes and reduces IL-1ß production, potentially ameliorating pain management in BCP.

Efficacy and Safety of Different Doses of Rivaroxaban and Risk Factors for Bleeding in Elderly Patients with Venous Thromboembolism: A Real-World, Multicenter, Observational, Cohort Study.

INTRODUCTION: Venous thromboembolism (VTE) consists of deep vein thrombosis (DVT) and pulmonary embolism (PE). Rivaroxaban is a direct oral anticoagulant (DOAC) inhibiting activated coagulation factor X (FXa), and exerts several advantages in the treatment of VTE compared to conventional therapy. However, the efficacy and safety of rivaroxaban in elderly patients with VTE was still poorly understood. METHODS: The study was carried out using an observational and non-interventional approach. A total of 576 patients aged ≥ 60 years with newly diagnosed VTE were included in the study. All patients received rivaroxaban with recommended treatment duration of ≥ 3 months for secondary prevention. In addition, 535 elderly patients with various diseases except VTE were included in the study in a retrospective and randomized way. RESULTS: The total bleeding rate was 12.2% (70/576). Major bleeding and non-major clinically relevant (NMCR) bleeding occurred in 4 (0.69%) patients and 5 (0.87%) patients, respectively. The rate of recurrent VTE was 5.4%. The mean level of D-dimers was increased by 467.2% in the elderly patients with VTE compared with the elderly patients without VTE. The elderly patients with VTE receiving rivaroxaban at a dose of 10 mg once daily (n = 134) had lower risk for bleeding (3.7% vs 14.7%; P = 0.001) and a similar rate of recurrent VTE (4.5% vs 5.7%; P = 0.596) as compared to the elderly patients with VTE receiving rivaroxaban at higher doses including 15 mg once daily and 20 mg once daily (n = 442). In addition, age, concomitant aspirin, hemoglobin, activated partial thromboplastin time (APTT), and rivaroxaban doses were independent predictive factors for bleeding events. CONCLUSIONS: The study suggested that a dose of 10 mg once daily should be the priority in elderly patients with VTE receiving long-term rivaroxaban anticoagulation therapy in view of reduced bleeding risk.

Exploring the Alternative Conformation of a Known Protein Structure Based on Contact Map Prediction.

The rapid development of deep learning-based methods has considerably advanced the field of protein structure prediction. The accuracy of predicting the 3D structures of simple proteins is comparable to that of experimentally determined structures, providing broad possibilities for structure-based biological studies. Another critical question is whether and how multistate structures can be predicted from a given protein sequence. In this study, analysis of tens of two-state proteins demonstrated that deep learning-based contact map predictions contain structural information on both states, which suggests that it is probably appropriate to change the target of deep learning-based protein structure prediction from one specific structure to multiple likely structures. Furthermore, by combining deep learning- and physics-based computational methods, we developed a protocol for exploring alternative conformations from a known structure of a given protein, by which we successfully approached the holo-state conformations of multiple representative proteins from their apo-state structures.

Quantitative differentiation of malignant and benign thyroid nodules with multi-parameter diffusion-weighted imaging.

BACKGROUND: The value of conventional magnetic resonance imaging in the differential diagnosis of thyroid nodules is limited; however, the value of multi-parameter diffusion-weighted imaging (DWI) in the quantitative evaluation of thyroid nodules has not been well determined. AIM: To determine the utility of multi-parametric DWI including mono-exponential, bi-exponential, stretched exponential, and kurtosis models for the differentiation of thyroid lesions. METHODS: Seventy-nine patients (62 with benign and 17 with malignant nodules) underwent multi-b value diffusion-weighted imaging of the thyroid. Multiple DWI parameters were obtained for statistical analysis. RESULTS: Good agreement was found for diffusion parameters of thyroid nodules. Malignant lesions displayed lower diffusion parameters including apparent diffusion coefficient (ADC), the true diffusion coefficient (D), the perfusion fraction (f), the distributed diffusion coefficient (DDC), the intravoxel water diffusion heterogeneity (α) and kurtosis model-derived ADC (Dapp), and higher apparent diffusional kurtosis (Kapp) than benign entities (all P < 0.01), except for the pseudodiffusion coefficient (D*) (P > 0.05). The area under the ROC curve (AUC) of the ADC(0 and 1000) was not significantly different from that of the ADC(0 and 2000), ADC(0 to 2000), ADC(0 to 1000), D, DDC, Dapp and Kapp (all P > 0.05), but was significantly higher than the AUC of D*, f and α (all P < 0.05) for differentiating benign from malignant lesions. CONCLUSION: Multiple DWI parameters including ADC, D, f, DDC, α, Dapp and Kapp could discriminate benign and malignant thyroid nodules. The metrics including D, DDC, Dapp and Kapp provide additional information with similar diagnostic performance of ADC, combination of these metrics may contribute to differentiate benign and malignant thyroid nodules. The ADC calculated with higher b values may not lead to improved diagnostic performance.

Suffrutines A and B Inhibit the Expression of Inflammatory Mediators in LPS-Induced RAW264.7 Cells by Suppressing the NF-κB Signaling Pathway.

Flueggea suffruticosa is a traditional Chinese medicine that has been commonly used for the treatment of inflammatory ailments, including rheumatism and lumbago. Suffrutines A and suffrutines B are a pair of novel E,E and Z,E isomeric indolizidine alkaloids isolated from the roots of F. suffruticosa. However, their anti-inflammatory activity has not been reported thus far. The aim of this study was to investigate the inhibitory effect of inflammatory mediators and possible mechanisms of suffrutines A and B in lipopolysaccharide-induced RAW264.7 cells. Results showed that suffrutines A and B could remarkably inhibit the production of nitric oxide, prostaglandin E2, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 in lipopolysaccharide-induced RAW264.7 cells. Further evaluation demonstrated that compared with suffrutines A, suffrutines B could more significantly inhibit the phosphorylation of IKKα/ß, the degradation of IκBα, and the nuclear translocation of the p65 and p52 subunits in the canonical and non-canonical nuclear factor-κB pathways. Therefore, suffrutines B exhibited more potent inhibitory activity on inflammatory mediators than suffrutines A.

PremPLI: a machine learning model for predicting the effects of missense mutations on protein-ligand interactions.

Resistance to small-molecule drugs is the main cause of the failure of therapeutic drugs in clinical practice. Missense mutations altering the binding of ligands to proteins are one of the critical mechanisms that result in genetic disease and drug resistance. Computational methods have made a lot of progress for predicting binding affinity changes and identifying resistance mutations, but their prediction accuracy and speed are still not satisfied and need to be further improved. To address these issues, we introduce a structure-based machine learning method for quantitatively estimating the effects of single mutations on ligand binding affinity changes (named as PremPLI). A comprehensive comparison of the predictive performance of PremPLI with other available methods on two benchmark datasets confirms that our approach performs robustly and presents similar or even higher predictive accuracy than the approaches relying on first-principle statistical mechanics and mixed physics- and knowledge-based potentials while requires much less computational resources. PremPLI can be used for guiding the design of ligand-binding proteins, identifying and understanding disease driver mutations, and finding potential resistance mutations for different drugs. PremPLI is freely available at https://lilab.jysw.suda.edu.cn/research/PremPLI/ and allows to do large-scale mutational scanning.

Idiopathic mesenteric phlebosclerosis: clinical and CT imaging characteristics.

BACKGROUND: The aim of our study was to evaluate the clinical characteristics and computed tomography (CT) imaging findings of idiopathic mesenteric phlebosclerosis (IMP). METHODS: From January 2013 to May 2019, the clinical data of 10 patients diagnosed with IMP were analyzed retrospectively. Computed tomography angiography (CTA) and colonoscopy were performed in all 10 patients. All CT imaging findings were evaluated by three radiologists, including the form and distribution of calcification, the bowel's thickness, and the surrounding fat gap. The calcification score was calculated according to the extent of the involved mesenteric veins. The colonic wall thickness was defined as the average value of the thickest and thinnest regions of the intestinal wall. The correlation between the calcification scores and the colonic wall thickness was analyzed using Spearman's correlation analysis. RESULTS: All 10 patients were male with an average age of 59.6 years (range, 51-83 years). The average smoking index was 712 (range, 0-1,800). Among them, 7 patients had a history of long-term excessive daily intake of medicinal liquor or Chinese herbal medicine. Clinical symptoms of abdominal pain, diarrhea, bloating, and nausea were found. Colonoscopy showed dark purple discolorations of the edematous mucosa, engorged blood vessels, extensive erosion, ulceration, and multi-focal nodular surface in all patients. CT demonstrated colonic wall thickening, calcification along the mesenteric vein, and blurry surrounding fat gap in all 10 patients. Mesenteric venous calcification involved the terminal ileum, the ascending and transverse colon in all patients, and the descending colon and sigmoid colon's involvement in two patients. A total of 33 segments of the intestinal wall were involved. The median calcification score was 6 points, the mean thickness of the colonic wall was 10.73±3.22 mm, and there was no significant correlation (P=0.782) between calcification score and thickness of the colonic wall. CONCLUSIONS: The main features of IMP are mesenteric venous calcification, colonic wall thickness, and pericolic fat stranding, and there is no correlation between calcification score and colonic wall thickness. Therefore, CT imaging combined with colonoscopy can improve the diagnostic accuracy of IMP.

PremPS: Predicting the impact of missense mutations on protein stability.

Computational methods that predict protein stability changes induced by missense mutations have made a lot of progress over the past decades. Most of the available methods however have very limited accuracy in predicting stabilizing mutations because existing experimental sets are dominated by mutations reducing protein stability. Moreover, few approaches could consistently perform well across different test cases. To address these issues, we developed a new computational method PremPS to more accurately evaluate the effects of missense mutations on protein stability. The PremPS method is composed of only ten evolutionary- and structure-based features and parameterized on a balanced dataset with an equal number of stabilizing and destabilizing mutations. A comprehensive comparison of the predictive performance of PremPS with other available methods on nine benchmark datasets confirms that our approach consistently outperforms other methods and shows considerable improvement in estimating the impacts of stabilizing mutations. A protein could have multiple structures available, and if another structure of the same protein is used, the predicted change in stability for structure-based methods might be different. Thus, we further estimated the impact of using different structures on prediction accuracy, and demonstrate that our method performs well across different types of structures except for low-resolution structures and models built based on templates with low sequence identity. PremPS can be used for finding functionally important variants, revealing the molecular mechanisms of functional influences and protein design. PremPS is freely available at https://lilab.jysw.suda.edu.cn/research/PremPS/, which allows to do large-scale mutational scanning and takes about four minutes to perform calculations for a single mutation per protein with ~ 300 residues and requires ~ 0.4 seconds for each additional mutation.

Circular RNA GLIS2 promotes colorectal cancer cell motility via activation of the NF-κB pathway.

Circular RNAs (circRNAs) are a newly discovered type of biological molecule that belongs to the noncoding RNA family. Abundant evidence has shown that circRNAs are involved in the progression of various cancers. However, the particular functions of circRNAs in colorectal cancer (CRC) remain elusive. In this study, we investigated the differentially expressed circRNAs in three pairs of cancer tissue and adjacent normal tissue of CRC. We revealed that circGLIS2 expression was higher in CRC tissue and cell lines. Gain-and-loss function assays showed that circGLIS2 was involved in the regulation of cell migration. Moreover, overexpressing circGLIS2 in CRC cells activated the NF-κB pathway and induced pro-inflammatory chemokine production, which evoked tumor-associated inflammation through recruiting leukocytes. In turn, when the cancer cells were exposed to the supernatant of circGLIS2 overexpressed cancer cells, they were endowed with the ability of migration and chemokines production. Furthermore, the rescue assay confirmed that circGLIS2 activated NF-κB signaling and promoted cell migration by sponging miR-671. Overall, our study reveals that circGLIS2, acting as a potential oncogene, maintains the abnormal activation state of the NF-κB signaling pathway via the miR-671 sponge mechanism in CRC cells. This study provides a scientific basis for targeting circGLIS2 in colorectal cancer interventions.

PremPRI: Predicting the Effects of Missense Mutations on Protein-RNA Interactions.

Protein-RNA interactions are crucial for many cellular processes, such as protein synthesis and regulation of gene expression. Missense mutations that alter protein-RNA interaction may contribute to the pathogenesis of many diseases. Here, we introduce a new computational method PremPRI, which predicts the effects of single mutations occurring in RNA binding proteins on the protein-RNA interactions by calculating the binding affinity changes quantitatively. The multiple linear regression scoring function of PremPRI is composed of three sequence- and eight structure-based features, and is parameterized on 248 mutations from 50 protein-RNA complexes. Our model shows a good agreement between calculated and experimental values of binding affinity changes with a Pearson correlation coefficient of 0.72 and the corresponding root-mean-square error of 0.76 kcal·mol-1, outperforming three other available methods. PremPRI can be used for finding functionally important variants, understanding the molecular mechanisms, and designing new protein-RNA interaction inhibitors.

Imaging Features of Sclerosing Angiomatoid Nodular Transformation in Spleen.

PURPOSE: The purpose of this study was to evaluate the features of sclerosing angiomatoid nodular transformation (SANT) in spleen on the imaging of computed tomography (CT) and magnetic resonance (MR). MATERIALS AND METHODS: From July 2006 to April 2017, 12 patients with SANT confirmed by pathology were evaluated in a retrospective study. Eight patients were with CT imaging only, 2 patients were with MR imaging only, and 2 patients were with both CT and MR. Three professional senior radiologists analyzed the imaging features on CT and MR. The main characteristic analysis included size, margin, density, signal intensity, and enhancement pattern. The significant enhancement was defined as the degree of enhancement of lesion that is higher than the surrounding spleen parenchyma, and the mild enhancement was defined as the degree of enhancement of lesion that is lower than the surrounding spleen parenchyma. RESULTS: All the 12 patients (5 men, 7 women; mean age, 45.8 years; age range, 21-62 years) presented as single lesion without special clinical symptoms. The range of lesions on diameter was from 25 to 80 mm. On CT images, 9 (90%) of 10 presented as hypodense in comparison with the parenchyma of spleen, 1 (10%) of 10 presented as isodense, and calcification was observed in 4 (40%) of 10 cases. On MR images, 4 (100%) of 4 manifested heterogeneous hypointensity on in-phase sequence and 3 (75%) of 4 performed as isointensity on out-of-phase sequence of T1-weighted. On the sequences of T2-weighted and diffusion-weighted image, 4 (100%) of 4 showed hypointensity. On CT and MR enhancement images, the number of significant enhancement and mild enhancement was 2 and 10, respectively. Seven (58%) of 12 showed progressive enhancement with the pattern of "spoke-wheel." CONCLUSIONS: Imaging features on CT and MR have a high diagnostic value for SANT, especially when CT combined with MR examination.

Copper-Catalyzed C-H Carbamoyloxylation of Aryl Carboxamides with CO2 and Amines at Ambient Conditions.

A copper-catalyzed, 8-aminoquinoline-assisted, one-pot three-component coupling of aryl carboxamides, CO2, and amines has been developed. This protocol proceeds smoothly in the presence of inexpensive CuI and MnO2 at room temperature under atmospheric CO2 pressure, leading to simultaneous construction of C-O and C-N bonds. The reaction displays a broad substrate scope, high functional group tolerance, and excellent monoselectivity, providing an operationally simple method for the synthesis of various O-aryl carbamates.

Copper-catalyzed intramolecular cross dehydrogenative coupling approach to coumestans from 2'-hydroxyl-3-arylcoumarins.

A copper-catalyzed intramolecular cross dehydrogenative C-O coupling reaction of 2'-hydroxyl-3-arylcoumarins was developed. This protocol provided a facile and efficient strategy for the construction of natural coumestans and derivatives in moderate to high yields. This transformation exhibited good functional group compatibility and was amenable to substrates with free phenolic hydroxyl groups.

Reduced-gliotoxin induces ROS-mediated anoikis in human colorectal cancer cells.

Reduced-gliotoxin is a small molecule derived from the secondary metabolites of marine fungi; compared to other gliotoxin analogues, it exhibits potent anticancer effects. However, the molecular basis of the death of colorectal cancer (CRC) cells induced by reduced-gliotoxin is unclear. Thus, the aim of this study was to investigate the potency of reduced-gliotoxin against CRC cells and to elucidate the underlying mechanisms. Cell morphology, flow cytometric analysis and western bolt analysis were performed to examine the functions and mechanisms of cell death induced by reduced-gliotoxin. Our findings demonstrated that reduced-gliotoxin triggered rapid cell detachment and induced anoikis in CRC cells. Mechanistically, our data indicated that the anoikis induced by reduced-gliotoxin was associated with the disruption of integrin-associated cell detachment and multiple signaling pathways. Furthermore, reduced-gliotoxin induced the excessive production of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP), resulting in the activation of both endogenous and exogenous apoptotic pathways and eventually, in the apoptosis of CRC cells. The blockage of ROS generation with N-acetylcysteine (NAC) attenuated the anoikis induced by reduced-gliotoxin. Taken together, these results suggest that reduced-gliotoxin may prove to be a potential candidate in the treatment of CRC.

[Therapeutic feasibility of percutaneous puncture and chemical neurolysis of thoracic sympathetic nerve block in palmar hyperhidrosis under the guidance of computed tomograph].

OBJECTIVE: To explore the therapeutic feasibility of percutaneous puncture and neurolytic thoracic sympathetic nerve block under the guidance of computed tomograph (CT). METHODS: From September 2009 to August 2010, 23 cases with primary palmar hyperhidrosis underwent percutaneous puncture and neurolytic thoracic sympathetic nerve block at our hospital. The puncture of thoracic sympathetic nerve was guided by CT through the gap of T3-4. The screen showed the direction of needle and the location of needle tip at the upper joint of costal head beside T3 body and outside of costal pleura. A mixed injection of 1% lidocaine and 30% iohexol was administered. On CT, lidocaine was found to cover the area where the thoracic sympathetic nerve was located. And after several minutes, the patient's palms turned warm and dry from cool and wet without the onset of Horner's syndrome. Then 2.5 ml of absolute alcohol was injected to block the thoracic sympathetic nerve. RESULTS: CT could guide the needle to the right position. And the injectate spreaded to the site of thoracic sympathetic nerve. At 5 min after anesthetic injection, the palmar temperature raised an average of 2.86°C and the amplitude of pulse rose over 55%. Palmar hyperhidrosis was cured in 19 patients by one attempt and 4 patients required a second block with absolute alcohol. No complication occurred and there were 2 patients with tendency of recurrence during a follow-up period of 8 - 18 months. CONCLUSION: The CT-guided therapy of percutaneous puncture and chemical neurolysis of thoracic sympathetic nerve block is both feasible and efficacious for palmar hyperhidrosis.

[Selective percutaneous dorsal root ganglion radiofrequency thermocoagulation guided by CT scanning in treatment of post-herpetic neuralgia].

OBJECTIVE: To present the experience in a technique used to treat intractable postherpetic neuralgia (PHN)-percutaneous dorsal root ganglion (DGR) radiofrequency thermocoagulation guided by CT scanning. METHODS: Sixteen PHN patients underwent puncture of radiohealing needle into the superior 1/3 of the corresponding intervertebral foramen guided by CT. Electric stimulation test and impedance test were conducted to confirm the right spot. Radiofrequency heat coagulation therapy under the condition of 90 degrees C 90 s was performed for 3 cycles. Then mixture of betamethasone and lidocain was injected and the needle was pulled out. CT was conducted to observe if pneumothorax occurred. The patients were followed up for 2-16 months. RESULTS: Radiofrequency thermocoagulation was performed on 45 target dorsal root ganglia in 16 PHN patients with the effect of immediate disappearance of hyperalgesia. Remaining spontaneous pain was seen in 5 cases, however, with decreases of attack frequency and severity. The visual analogue pain scale score was decreased from 7-9 before the procedure to 2-3 after the procedure. No relapse was found during the follow-up. CONCLUSION: Selective percutaneous DRG radiofrequency thermocoagulation guided by CT scanning is effective in treatment of PHN.