Target NF-κB p65 for preventing posttraumatic joint contracture in rats.

RelA/p65 is as a crucial component of the nuclear factor κB (NF-κB) signaling pathway that has a significant impact on various fibrotic diseases. However, its role in the fibrosis of tissues surrounding the joint after traumatic injury remains unclear. In this study, rats were divided into three groups: non-operated control (NC) group, p65-siRNA treated (siRNA-p65) group, and negative siRNA treated (siRNA-neg) group. Then, 10 µL (10 nmol) of p65-siRNA was injected into the joint of the siRNA-p65 group. Meanwhile, 10 µL of negative siRNA was administered to the knee joint of the operated siRNA-neg group for comparison. The rats in the NC group did not receive surgery or drug intervention. After 4 weeks of right knee fixation in each group, X-ray measurements revealed significantly reduced degree of knee flexion contracture following p65-siRNA treatment (siRNA-neg: 77.73° ± 2.799°; siRNA-p65: 105.7° ± 2.629°, p < 0.0001). Histopathological examination revealed that the number of dense fibrous connective tissues decreased following p65-siRNA inhibition. Western blot analysis revealed significantly different expression levels of fibrosis-related proteins between the siRNA-p65 and siRNA-neg groups. Immunohistochemical analysis revealed a reduction in the average number of myofibroblasts in the siRNA-p65 group compared with that in the siRNA-neg group. Thus, intra-articular p65-siRNA injection could attenuate fibroblast activation and fibrosis-related protein production, suppress periarticular tissue fibrosis, and prevent joint contracture by downregulating the NF-κB p65 pathway. Statement of clinical significance: Intra-articular injection of p65-siRNA could reduce myofibroblast proliferation and fibrosis-related protein expression by downregulating the NF-κB p65 pathway, inhibit periarticular tissue fibrosis, and prevent joint adhesion, which represents a potential therapy in the prevention of joint fibrosis following traumatic injury.

Novel LDLR variants affecting low density lipoprotein metabolism identified in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disease of lipid metabolism mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Genetic detection of patients with FH help with precise diagnosis and treatment, thus reducing the risk of coronary heart disease (CHD) and other related diseases. The study aimed to identify the causative gene mutations in a Chinese FH family and reveal the pathogenicity and the mechanism of these mutations. METHODS AND RESULTS: Whole exome sequencing was performed in a patient with severe lipid metabolism dysfunction seeking fertility guidance from a Chinese FH family. Two LDLR variants c.1875 C > G (p.N625K; novel variant) and c.1448G > A (p.W483*) were identified in the family. Wildtype and mutant LDLR constructs were established by the site-direct mutagenesis technique. Functional studies were carried out by cell transfection to evaluate the impact of detected variants on LDLR activity. The two variants were proven to affect LDL uptake and binding, resulting in cholesterol clearance reduction to different degrees. According to The American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines, the W483* variant was classified as "Pathogenic", while the N625K variant as "VUS". CONCLUSIONS: Our results provide novel experimental evidence of functional alteration by LDLR variants identified in our study and expand the mutational spectrum of LDLR mutation induced FH.

Study on Integrated Pharmacokinetics of the Component-Based Chinese Medicine of Ginkgo biloba Leaves Based on Nanocrystalline Solid Dispersion Technology.

Background: To improve the dissolution and bioavailability of the component-based Chinese medicine of Ginkgo biloba leaves (GBCCM), a novel nanocrystalline solid dispersion of GBCCM (GBCCM NC-SD) was first prepared. Methods: GBCCM mainly containing high pure flavonoid aglycones (FAs) and terpenoid lactones (TLs) was used as the model drug. PVP K30 and SDS were used as solubilizers, combined stabilizers and carriers, and GBCCM NC-SD was prepared by high-pressure homogenization combined with freeze-dryer. Morphology and crystal characteristic of GBCCM NC-SD were analyzed. The dissolution and bioavailability evaluation were performed to investigate the feasibility of GBCCM NC-SD by in vitro dissolution and in vivo integrated pharmacokinetic models. Results: After homogenizing for 30 cycles under the pressure of 650 bar and freeze-drying, GBCCM NC-SD with uniform quality would be obtained. The particle size, PDI and zeta potential were found to be 335.9 ± 32.8 nm, 0.29 ± 0.02 and -28.4 ± 0.7 mV respectively. Based on charged aerosol detector (CAD) technology, a new chromatographic method for simultaneous detection of eight components in GBCCM was developed. In vitro drug release study showed that the cumulative dissolution of FAs and TLs in GBCCM NC-SD increased from 12.77% to 52.92% (P < 0.01) and 90.91% to 99.21% (P < 0.05) respectively. In comparison with physical mixture of GBCCM and stabilizer (PM), the integrated pharmacokinetics AUC0-t of FAs and TLs in GBCCM NC-SD were significantly increased (P < 0.05), and the T1/2 of TLs was also significantly prolonged (P < 0.05). Conclusion: This study demonstrated that novel GBCCM NC-SD was prepared using Polyvinylpyrrolidone K30 (PVP K30) and Sodium dodecyl sulfate (SDS) as a synergetic stabilizer and also provided a feasible way to improve the dissolution and oral bioavailability of poorly soluble candidate antihypertensive drugs.

Anatomical study for the treatment of proximal humeral fracture through the medial approach.

BACKGROUND: The treatment of complex 3- and 4-part proximal humeral fractures has been controversial due to numerous postoperative complications. With the further study of medial support and blood supply of humeral head, new techniques and conception are developing. The study aims to illustrate the medial approach of the proximal humeral fracture through cadaver autopsy. METHOD: Upper limbs from 19 cadavers have been dissected to expose the shoulder joint. We selected the coracoid process as the bony reference. Vernier caliper will be used to measure the following data, including distance from coracoid process to circumflex brachial artery, distance between anterior humeral circumflex artery (ACHA) and posterior circumflex brachial artery (PCHA) and their diameters. Assessment included the characteristics of the vascular supply around the humeral head, identification of the structures at risk, quality of exposure of the bony structures, and feasibility of fixation. RESULTS: The medial approach is appropriate in 86.84% anatomical patterns. Between the lower part of the shoulder capsule and the insertion of conjoined tendon, the bony surface exposed was limited by the interval between ACHA and PCHA. An interval of 2 to 3 cm (24.29 ± 3.42 mm) was available for medial plate. ACHA (49.35 ± 8.13 mm, 35.14-68.53 mm) and PCHA (49.62 ± 7.82 mm, 37.67-66.76 mm) were about 5 cm away from the coracoid process. Risk structures including ACHA and PCHA originate in common, PCHA originated from the deep brachial artery (DBA), the presence of perforator vessels, musculocutaneous nerve intersects with ACHA, the diameter of PCHA: ACHA < 1.5. In 13.15% anatomical patterns, this risk structure should be taken seriously. CONCLUSION: The medial approach opens a new perspective in the optimal management of complex fractures of proximal humerus. Anatomical research proves that the medial approach is feasible. The interval between ACHA and PCHA is suitable for placement. Anatomical pattern and indication have been discussed, and we hypothesized that ACHA has been destroyed in complex PHFs. With further studies on the anatomy and mechanism of injury, the development of more clinical cases will be an important work of our institution in the future.

Minimally invasive open reduction of greater tuberosity fractures by a modified suture bridge procedure.

BACKGROUND: Most greater tuberosity fractures can be treated without surgery but some have a poor prognosis. The surgical procedures for avulsion fractures of the humeral greater tuberosity include screw fixation, suture anchor fixation, and plate fixation, all of which have treatment-associated complications. To decrease surgical complications, we used a modified suture bridge procedure under direct vision and a minimally invasive small incision to fix fractures of the greater tuberosity of the humerus. AIM: To investigate the clinical efficacy and outcomes of minimally invasive modified suture bridge open reduction of greater tuberosity evulsion fractures. METHODS: Sixteen patients diagnosed between January 2016 and January 2019 with an avulsion-type greater tuberosity fracture of the proximal humerus and treated by minimally invasive open reduction and modified suture bridges with anchors were studied retrospectively. All were followed up by clinical examination and radiographs at 3 and 6 wk, 3, 6 and 12 mo after surgery, and thereafter every 6 mo. Outcomes were assessed preoperatively and postoperatively by a visual analog scale (VAS), the University of California Los Angeles (UCLA) shoulder score, the American Shoulder and Elbow Surgeon score (ASES), and range of motion (ROM) for shoulders. RESULTS: Seven men and nine women, with an average age of 44.94 years, were evaluated. The time between injury and surgery was 1-2 d, with an average of 1.75 d. The mean operation time was 103.1 ± 7.23 min. All patients achieved bone union within 3 mo after surgery. VAS scores were significantly decreased (P = 0.002), and the mean degrees of forward elevation (P = 0.047), mean degrees of abduction (P = 0.035), ASES score (P = 0.092) were increased at 3 wk. The UCLA score was increased at 6 wk (P = 0.029) after surgery. The average degrees of external rotation and internal rotation both improved at 3 mo after surgery (P = 0.012 and P = 0.007, respectively). No procedure-related deaths or incision-related superficial or deep tissue infections occurred. CONCLUSION: Modified suture bridge was effective for the treatment of greater tuberosity evulsion fractures, was easier to perform, and had fewer implants than other procedures.

Biomechanical properties of a novel fixation system for intra-articular distal humerus fractures: a finite element analysis.

BACKGROUND: The traditional strategy for fixing intra-articular distal humerus fractures is double plating placed in an orthogonal configuration, based on posterior approach. With a combined medial and lateral approach, a novel configuration of plating (combined anteromedial and anterolateral plating) has been used. In this study, we investigated the biomechanical properties of the novel plating by comparing it with some traditional strategies. METHODS: Based on the 3D morphology of a healthy subject's humerus, models of three types of intra-articular distal humeral fractures were established using a variety of different internal fixation methods: (a) treatment of a simple intra-articular fracture of the distal humerus with the novel double plate and a traditional orthogonal plate; (b) treatment of a comminuted fracture of the lower distal humerus with the novel double plate, a traditional orthogonal plate and a traditional orthogonal plate combined with distally extended tension screws; (c) treatment of a coronal shear fracture of the distal humerus with the novel double plate, a traditional orthogonal plate and the intra-articular placement of three screws. The material properties of all plates and screws were isotropic and linearly elastic. The Poisson ratio of the implant and bone was 0.3, and the elastic modulus of the implant was 114,000 MPa. The axial loading is 200 N, the bending loading is 30 N and varus rotation is 7.5 Nm in the longitudinal direction. RESULTS: A simple model of intra-articular fracture of the distal humerus (AO C1 type) was established. Under all experimental conditions, the novel double plate showed greater stiffness than the orthogonal double plate. The axial straightening, bending compression and varus torsion increased by 18.00%, 16.00% and 44.00%, respectively. In the model of comminuted fracture of the lower distal humerus, the novel double plate showed the best stiffness under three experimental conditions (163.93 N/mm, 37.97 N/mm, 2697.84 N mm/°), and the stiffness of the traditional orthogonal plate combined with the distally extended tension screws was similar to that of the traditional orthogonal plate (121.21 N/mm, 32.61 N/mm, 1968.50 N mm/°). In the model of coronal shear fracture of the distal humerus, the novel double plate showed the best stiffness under all test conditions (194.17 N/mm, 38.46 N/mm, 2929.69 N mm/°), followed by the traditional plate (153.85 N/mm, 33.33 N/mm, 2650.18 N mm/°), while the stiffness of the three screws was the smallest (115.61 N/mm, 28.30 N/mm, 2180.23 N mm/°). CONCLUSIONS: In terms of biomechanics, compared with other internal fixation methods, the novel combined anteromedial and anterolateral anatomical locking double-plate showed less stress, less displacement and greater stiffness. The novel double-plate method can be used to treat not only simple intra-articular fractures of the humerus but also complex comminuted fractures of the lower distal humerus and coronal shear fractures of the distal humerus, with a better effect than current traditional internal fixation methods.

Revealing Prognosis-Related Pathways at the Individual Level by a Comprehensive Analysis of Different Cancer Transcription Data.

Identifying perturbed pathways at an individual level is important to discover the causes of cancer and develop individualized custom therapeutic strategies. Though prognostic gene lists have had success in prognosis prediction, using single genes that are related to the relevant system or specific network cannot fully reveal the process of tumorigenesis. We hypothesize that in individual samples, the disruption of transcription homeostasis can influence the occurrence, development, and metastasis of tumors and has implications for patient survival outcomes. Here, we introduced the individual-level pathway score, which can measure the correlation perturbation of the pathways in a single sample well. We applied this method to the expression data of 16 different cancer types from The Cancer Genome Atlas (TCGA) database. Our results indicate that different cancer types as well as their tumor-adjacent tissues can be clearly distinguished by the individual-level pathway score. Additionally, we found that there was strong heterogeneity among different cancer types and the percentage of perturbed pathways as well as the perturbation proportions of tumor samples in each pathway were significantly different. Finally, the prognosis-related pathways of different cancer types were obtained by survival analysis. We demonstrated that the individual-level pathway score (iPS) is capable of classifying cancer types and identifying some key prognosis-related pathways.

RETRACTED: Quercetin ameliorates lipopolysaccharide-caused inflammatory damage via down-regulation of miR-221 in WI-38 cells

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Given the comments of Dr Elisabeth Bik regarding this article "… the Western blot bands in all 400+ papers are all very regularly spaced and have a smooth appearance in the shape of a dumbbell or tadpole, without any of the usual smudges or stains. All bands are placed on similar looking backgrounds, suggesting they were copy/pasted from other sources, or computer generated", the journal requested the authors to provide the raw data. However, the authors were not able to fulfil this request and therefore the Editor-in-Chief decided to retract the article.