Resolvin D1 alleviates apoptosis triggered by endoplasmic reticulum stress in IPEC-J2 cells.

BACKGROUND: Resolvin D1 (RvD1), a specialized pro-resolving lipid mediator (SPM), is derived from docosahexaenoic acid (DHA). It plays a key role in actively resolving inflammatory responses, which further reduces small intestinal damage. However, its regulation of the apoptosis triggered by endoplasmic reticulum (ER) stress in intestinal epithelial cells is still poorly understood. The intestinal porcine epithelial cells (IPEC-J2) were stimulated with tunicamycin to screen an optimal stimulation time and concentration to establish an ER stress model. Meanwhile, RvD1 (0, 1, 10, 20, and 50 nM) cytotoxicity and its impact on cell viability and the effective concentration for reducing ER stress and apoptosis were determined. Finally, the effects of RvD1 on ER stress and associated apoptosis were furtherly explored by flow cytometry analysis, AO/EB staining, RT-qPCR, and western blotting. RESULTS: The ER stress model of IPEC-J2 cells was successfully built by stimulating the cells with 1 µg/mL tunicamycin for 9 h. Certainly, the increased apoptosis and cell viability inhibition also appeared under the ER stress condition. RvD1 had no cytotoxicity, and its concentration of 1 nM significantly decreased cell viability inhibition (p= 0.0154) and the total apoptosis rate of the cells from 14.13 to 10.00% (p= 0.0000). RvD1 at the concentration of 1 nM also significantly reduced the expression of glucose-regulated protein 78 (GRP-78, an ER stress marker gene) (p= 0.0000) and pro-apoptotic gene Caspase-3 (p= 0.0368) and promoted the expression of B cell lymphoma 2 (Bcl-2, an anti-apoptotic gene)(p= 0.0008). CONCLUSIONS: Collectively, the results shed light on the potential of RvD1 for alleviating apoptosis triggered by ER stress, which may indicate an essential role of RvD1 in maintaining intestinal health and homeostasis.

Multiomics of HER2-low triple-negative breast cancer identifies a receptor tyrosine kinase-relevant subgroup with therapeutic prospects.

To provide complementary information and reveal the molecular characteristics and therapeutic insights of HER2-low breast cancer, we performed this multiomics study of hormone receptor-negative (HR-) and HER2-low breast cancer, also known as HER2-low triple-negative breast cancer (TNBC), and identified 3 subgroups: basal-like, receptor tyrosine kinase-relevant (TKR), and mesenchymal stem-like. These 3 subgroups had distinct features and potential therapeutic targets and were validated in external data sets. Interestingly, the TKR subgroup (which exists in both HR+ and HR- breast cancer) had activated HER2 and downstream MAPK signaling. In vitro and in vivo patient-derived xenograft experiments revealed that pretreatment of the TKR subgroup with a tyrosine kinase inhibitor (lapatinib or tucatinib) could inhibit HER2 signaling and induce accumulated expression of nonfunctional HER2, resulting in increased sensitivity to the sequential HER2-targeting, Ab-drug conjugate DS-8201. Our findings identify clinically relevant subgroups and provide potential therapeutic strategies for HER2-low TNBC subtypes.

Costal Cartilage Graft Repair Osteochondral Defect in a Mouse Model.

OBJECTIVE: Osteochondral defects develop into osteoarthritis without intervention. Costal cartilage can be utilized as an alternative source for repairing osteochondral defect. Our previous clinical study has shown the successful osteochondral repair by costal cartilage graft with integration into host bone bed. In this study, we investigate how cartilaginous graft adapt to osteochondral environment and the mechanism of bone-cartilage interface formation. DESIGN: Costal cartilage grafting was performed in C57BL/6J mice and full-thickness osteochondral defect was made as control. 3D optical profiles and micro-CT were applied to evaluate the reconstruction of articular cartilage surface and subchondral bone as well as gait analysis to evaluate articular function. Histological staining was performed at 2, 4, and 8 weeks after surgery. Moreover, costal cartilage from transgenic mice with fluorescent markers were transplanted into wild-type mice to observe the in vivo changes of costal chondrocytes. RESULTS: At 8 weeks after surgery, 3D optical profiles and micro-CT showed that in the graft group, the articular surface and subchondral bone were well preserved. Gait analysis and International Cartilage Repair Society (ICRS) score evaluation showed a good recovery of joint function and histological repair in the graft group. Safranin O staining showed the gradual integration of graft and host tissue. Costal cartilage from transgenic mice with fluorescent markers showed that donor-derived costal chondrocytes turned into osteocytes in the subchondral area of host femur. CONCLUSION: Costal cartilage grafting shows both functional and histological repair of osteochondral defect in mice. Graft-derived costal chondrocytes differentiate into osteocytes and contribute to endochondral ossification.

Follicular unit extraction megasession treatment of high-grade androgenetic alopecia in Asians: Introducing novel principles for surgical design.

BACKGROUND: Male androgenetic alopecia (MAGA) has been one of the most common reasons for hair consultation, which affects more than half of men under the age of 50. Recently, follicular unit extraction (FUE) megasession has been an attractive treatment option for patients with severe AGA. However, compared with hair transplant surgery by traditional FUE or follicular unit transplantation (FUT), a megasession lacks a suitable surgical design solution for Asian high-grade AGA patients. Therefore, we introduced novel principles for surgical design into FUE megasession for Asians. OBJECTIVE: The goal was to investigate the naturalness of hair, patient and doctor satisfaction level, and safety assessment of FUE megasession with the specific surgical design, to explore a novel technique for an efficient, satisfactory, and safe FUE megasession procedure. METHODS: Thirty-six Asian male patients with AGA in Hamilton Grade V-VI were enrolled in the research. All participants underwent FUE megasession treatment with the specific surgical design. The investigators observed the patients' general conditions, surgical information, naturalness of hair, and patient and doctor satisfaction level and adverse reactions. RESULTS: Before surgery, the average age of patients was 36.8 ± 9.6 years, and average duration of disease was 8.3 ± 3.8 years. During surgery, we harvested an average of 3705 ± 383 grafts. Recipient density ranged from 30 FUs/cm2 to 50 FUs/cm2 , and the total operation time was 10.6 ± 0.9 h. After surgery, patient-rated Likert score for naturalness of hair was as high as 4.72, and the doctor rated 4.61. Patient satisfaction score was up to 4.64, and the doctor scored 4.75. No serious side effects occurred in the study. CONCLUSION: FUE megasession with the introduced surgical design is a satisfactory treatment option for patients with high-grade AGA in Asians, with few side effects. The application of the novel design method can effectively lead to relatively natural density and appearance in one operation. Due to its remarkable effect, high satisfaction level, and few postoperative complications, FUE megasession with the introduced surgical design has great potential for Asian high-grade AGA patients.

Arthroscopic repair of degenerative medial meniscus tears in patients aged over 45 years resulted in favorable clinical outcomes and low clinical failure rates at a minimum 2-year follow-up.

PURPOSE: This study aimed to investigate clinical and radiological results of arthroscopic repair for isolated medial degenerative meniscus tears (DMTs) in patients over 45 years old at a minimum 2-year follow-up. METHODS: From 2013 to 2017, patients aged over 45 years with isolated medial DMT refractory to conservative management or with true mechanical symptoms who had undergone arthroscopic repair were retrospectively reviewed. Arthroscopic meniscus repair was performed using all-inside or all-inside and inside-out technique in combination with bone marrow venting procedure. Tear patterns were classified according to arthroscopic findings. Magnetic resonance imaging (MRI) and outcome evaluations, including Lysholm score, Tegner activity score, and International Knee Documentation Committee (IKDC) score, were evaluated preoperatively and at the final follow-up. International Cartilage Repair Society grades of the medial compartments and MRI signal at tear sites were assessed preoperatively and at the final follow-up. A grade 0 to 2 signal at the repair site suggested a healed meniscus, whereas a grade 3 signal suggested an unhealed meniscus. Clinical failure was determined according to Barrett criteria. RESULTS: Twenty-seven patients (mean age, 57.7 ± 7.4 years) were enrolled. The mean follow-up was 52.0 ± 15.6 months. Among tear patterns, 48% were complex tears, 30% were horizontal tears, and 22% were other patterns. The mean Lysholm score and IKDC score significantly improved from 53 ± 25 to 89 ± 15 (p < 0.001) and 34 ± 24 to 72 ± 15 (p < 0.001) at the final follow-up, respectively. The median Tegner activity score significantly improved from 1 (range 1-4) to 4 (range 2-7, p < 0.001). Three (11%) patients were considered clinical failures, and five patients (19%) had cartilage lesion progression. At the final follow-up, MRI showed grade 0 in one (4%) patient, grade 1 in nine (33%) patients, grade 2 in six (22%) patients, and grade 3 in eleven (41%) patients. CONCLUSION: Arthroscopic repair of isolated medial DMT refractory to conservative management or with true mechanical symptoms in patients aged over 45 years had good to excellent clinical outcomes with low clinical failure rates, despite unhealed menisci being observed on MRI in 41% of patients at a mean 4.3-year follow-up. Arthroscopic repair could be a treatment option for these patients. LEVEL OF EVIDENCE: IV.

Novel evidence for the prognostic impact of ß-blockers in solid cancer patients receiving immune checkpoint inhibitors.

OBJECTIVE: Cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has made encouraging achievements in both clinical trials and real-world studies. The ß-blockers, as common concomitant medications in clinical practice, have been suggested to exert anti-cancer effects in various human malignancies. This study aimed to clarify the prognostic impact of ß-blockers in solid cancer patients receiving ICI therapy. METHOD: A systematic literature review and meta-analysis was firstly performed based on databases including PubMed, Cochrane Library, Web of Science, Embase, and Clinicaltrials.gov before August 1th 2022. The association of ß-blocker use with overall survival (OS) or progression-free survival (PFS) was determined using the hazard ratios (HRs) coupled with 95% confidence intervals (CIs). Then, a retrospective study enrolling 194 patients was performed to validate the results of the meta-analysis. RESULTS: A total of 11 studies enrolling 10,156 patients were included in the meta-analysis. The pooled analysis demonstrated ß-blocker use was not significantly correlated with either OS (HR = 0.97(0.85-1.11)) or PFS (HR = 0.98(0.90-1.06)). Similar results were also observed in the subgroup analysis stratified by cancer type, age, sample size and ICI therapy, except for the OS (HR = 0.61(0.45-0.83)) and PFS (HR = 0.65(0.44-0.96)) in the studies with sample size less than 200. The retrospective study indicated no significant correlation between ß-blocker use and the clinical outcome in the entire cohort and lung cancer subgroup. However, ß-blocker use was found to be significantly associated with better objective response to ICI-based therapy in the entire cohort (odds ratio (OR) = 0.42(0.19-0.94), p = 0.036) and lung cancer subgroup (OR = 0.25(0.08-0.83), p = 0.024). CONCLUSION: Although both our up-to-date meta-analysis and retrospective study suggested ß-blocker use has no significant impact on the overall prognosis of solid cancer patients receiving ICIs, ß-blocker use may be associated with improved anti-cancer efficacy of ICIs. Considering study limitations, more clinical validations and mechanism investigations are of great necessity for clarifying the role of ß-blockers in ICI-based therapy.

Axial Stress Measurement of Steel Tubes Using Ultrasonic Guided Waves.

Axially loaded steel tubes are widely used as primary structural members in civil engineering structures. In this paper, a stress measurement method for axially loaded steel tubes is developed based on the linear relationship between the group velocity of guided waves in the steel tube and the stress of the steel tube. The propagation modes of guided waves in a typical steel tube are analyzed using semi-analytical finite element method. A torsional mode T(0,1) is adopted to conduct the measurement. Experiments are carried out to calibrate the linear relationship between the group velocity of guided waves in a steel tube and the stress of the steel tube. The calibrated linear relationship is verified by another round of experiments on the same steel tube specimen. There is an average error of 8.2% between the stresses predicted by the calibrated linear equation and those obtained from strain gauges. Via this study, the guided wave-based stress measurement method has been successfully extended to axially loaded steel tubes.

Copy number amplification of ENSA promotes the progression of triple-negative breast cancer via cholesterol biosynthesis.

Copy number alterations (CNAs) are pivotal genetic events in triple-negative breast cancer (TNBC). Here, our integrated copy number and transcriptome analysis of 302 TNBC patients reveals that gene alpha-endosulfine (ENSA) exhibits recurrent amplification at the 1q21.3 region and is highly expressed in TNBC. ENSA promotes tumor growth and indicates poor patient survival in TNBC. Mechanistically, we identify ENSA as an essential regulator of cholesterol biosynthesis in TNBC that upregulates the expression of sterol regulatory element-binding transcription factor 2 (SREBP2), a pivotal transcription factor in cholesterol biosynthesis. We confirm that ENSA can increase the level of p-STAT3 (Tyr705) and activated STAT3 binds to the promoter of SREBP2 to promote its transcription. Furthermore, we reveal the efficacy of STAT3 inhibitor Stattic in TNBC with high ENSA expression. In conclusion, the amplification of ENSA at the 1q21.3 region promotes TNBC progression and indicates sensitivity to STAT3 inhibitors.

Breast Cancer Vaccines: Disappointing or Promising?

Breast cancer has become the most commonly diagnosed cancer globally. The relapse and metastasis of breast cancer remain a great challenge despite advances in chemotherapy, endocrine therapy, and HER2 targeted therapy in the past decades. Innovative therapeutic strategies are still critically in need. Cancer vaccine is an attractive option as it aims to induce a durable immunologic response to eradicate tumor cells. Different types of breast cancer vaccines have been evaluated in clinical trials, but none has led to significant benefits. Despite the disappointing results at present, new promise from the latest study indicates the possibility of applying vaccines in combination with anti-HER2 monoclonal antibodies or immune checkpoint blockade. This review summarizes the principles and mechanisms underlying breast cancer vaccines, recapitulates the type and administration routes of vaccine, reviews the current results of relevant clinical trials, and addresses the potential reasons for the setbacks and future directions to explore.

Age-related accumulation of advanced oxidation protein products promotes osteoclastogenesis through disruption of redox homeostasis.

Enhanced osteoclastogenesis is one of the major causes of age-related bone loss. Aging is accompanied by accumulation of advanced oxidation protein products (AOPPs). However, whether AOPPs accumulation contributing to the osteoclastogenesis with aging remains unclear. Here, we showed that AOPPs accumulation was associated with the enhanced osteoclastogenesis and deterioration of bone microstructure in aged mice. In vitro, AOPPs directly induced osteoclastogenesis by interaction with receptor activator of nuclear factor κ B (RANK) and the receptor for advanced glycation end products (RAGE) in the primary bone marrow monocytes. Bindings of AOPPs to RANK and RAGE were able to activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, trigger generation of reactive oxygen species, then induce phosphorylation of mitogen-activated protein kinases and c-fos, upregulation of the nuclear factor of activated T cell c1, eventually induce bone marrow monocytes to differentiate into mature osteoclasts. Chronic exposure to AOPPs enhanced osteoclastogenesis and bone loss in mice, which could be alleviated by NADPH oxidase inhibitor apocynin. Local injection of AOPPs into subperiosteal area induced bone resorption at the site of administration, which was similar to the effect of RANK ligand. Together, these results suggested that AOPPs could serve as a novel regulator of osteoclastogenesis and AOPPs accumulation might play an important role in the development of age-related bone loss.

Prognostic Effect of Microenvironment Phenotype in Triple-Negative Breast Cancer: Biomarker Analysis of a Prospective Trial.

Background: The microenvironment of triple-negative breast cancer (TNBC) can be divided into three clusters based on bioinformatics-based immunogenomic analysis: the "immune-desert" cluster, the "innate immune-inactivated" cluster, and the "immune-inflamed" cluster. The immune-inflamed cluster is considered as "hot tumor" while the other two are considered as "cold tumor". Methods: To investigate the prognostic effect of microenvironment phenotypes on TNBC, we compared relapse-free survival (RFS) of different phenotypes in 100 patients with RNA sequencing-based expression data from the PATTERN trial (NCT01216111, published in JAMA Oncol 2020), which indicated a superior efficacy of adjuvant paclitaxel-plus-carboplatin regimen compared to the regimen of cyclophosphamide/epirubicin/fluorouracil followed by docetaxel for TNBC. We also analyzed the efficacy of the two regimens for different immune phenotypes to explore potential treatment strategies. Results: No significant difference in RFS was observed between the "hot tumor" and the "cold tumor" (hazard ratio [HR] = 0.68, 95% confidence interval [CI] 0.28-1.66, P = 0.40). However, the "hot tumor" subtype was associated with significantly longer RFS in node-positive patients (HR = 0.27, 95%CI 0.07-0.97, P = 0.03). Consistently, a similar trend to improved RFS of the "hot tumor" phenotype was detected in patients with stage pT2-3 tumors (HR = 0.29, 95%CI 0.06-1.30, P = 0.08). Furthermore, no significant difference in RFS between the two treatment arms was observed in patients with "hot tumor" (HR = 0.39, 95% CI 0.08-2.01, P = 0.24) or "cold tumor" (HR = 1.05, 95% CI 0.39-2.82, P = 0.92). Conclusion: The microenvironment phenotype in TNBC might have prognostic significance to patients with a high risk of recurrence. The association of the microenvironment phenotypes with the efficacy of adjuvant chemotherapy for TNBC remains to be further studied.

Non-anatomic repair of medial meniscus posterior root tears to the posterior capsule provided favourable outcomes in middle-aged and older patients.

PURPOSE: To describe a non-anatomic arthroscopic all-inside repair technique for middle-aged and older patients with medial meniscus posterior root tears (MMPRTs) and to evaluate the short- to mid-term clinical and radiologic results. The hypothesis was that this procedure would yield good clinical outcome results and structural healing in middle- and older-aged patients. METHODS: This was a retrospective study evaluating patients who had undergone MMPRT repair by suturing the meniscal root directly to the capsule, rather than by the transtibial technique, between 2013 and 2016. This all-inside repair technique was performed for patients with type II MMPRTs who were over 40 years old. Exclusion criteria included tibial osteotomy due to malalignment, concomitant multiple-ligament injuries and follow-up time less than 2 years. The Lysholm score, Tegner activity score and International Knee Documentation Committee (IKDC) score were evaluated preoperatively and at the final follow-up. Medial meniscal extrusion, the International Cartilage Repair Society (ICRS) grades of the medial compartment, and the healing status of the medial meniscus root were assessed on magnetic resonance imaging preoperatively and at the final follow-up. RESULTS: Twenty-nine patients (mean age 61.7 ± 7.9) were included; the mean follow-up duration was 46.2 ± 7.9 months. The mean Lysholm score significantly improved from 33.7 ± 20.9 preoperatively to 81.7 ± 19.9 at the final follow-up (p < 0.001), the median Tegner activity score improved from 1.0 (range 1-4) to 3.0 (range 2-4, p < 0.001), and the mean IKDC score improved from 20.1 ± 16.4 to 69.6 ± 16.2 (p < 0.001). On MRI, 9 (31%) cases had complete healing; 17 (59%) had partial healing; and 3 (10%) had failed healing (ICCs ≥ 0.92). Mean meniscal extrusion significantly increased from 2.3 ± 1.7 mm preoperatively to 3.5 ± 1.5 mm postoperatively (p < 0.001, ICCs ≥ 0.92). CONCLUSION: Non-anatomic arthroscopic all-inside repair of MMPRTs to the posterior capsule yielded good to excellent clinical results and a high rate of healing in the medial meniscus root on MRI in middle-aged and older patients at short- to mid-term follow-up, despite increased meniscal extrusion. This method is an alternative to the transtibial pullout repair technique for treating MMPRTs in middle- and older-aged patients. LEVEL OF EVIDENCE: Level IV.

Association Between a Tri-allelic Polymorphism in the Estrogen Metabolism Oxidoreductase NRH:Quinone Oxidoreductase 2 Gene and Risk of Breast Cancer by Molecular Subtype.

Background: We hypothesized that NRH:quinone oxidoreductase 2 (NQO2) is a candidate susceptibility gene for breast cancer because of its known enzymatic activity on estrogen-derived quinones. A tri-allelic polymorphism in the NQO2 gene might be associated with the risk of luminal-like breast cancer. Methods: In this case-control study, 2,865 women were recruited, including 1,164 patients with pathologically confirmed breast cancer and 1,701 cancer-free controls. The tri-allelic genetic polymorphism (I-29, I-16, and D alleles) was genotyped by a polymerase chain reaction and restriction fragment length polymorphism (RFLP)-based assay. Because the I-16 allele frequency is rare (approximately 1.0%), individuals carrying the I-16 allele were excluded from the analysis. Breast cancer subtypes were classified according to ER, PR, HER2, and grade. Results: In the association analysis of allele, an increased risk of breast cancer is associated with I-29 allele [82.5% in case group and 79.0% in the control group; odds ratio (OR), 1.25; 95% CI, 1.09-1.43, compared with D allele, p = 0.0015]. In the association analysis of genotype, the I-29-containing genotype was significantly correlated with breast cancer under a dominant model (adjusted OR, 1.31, 95% CI, 1.12-1.54, p = 0.001). Moreover, in the subtype analysis, there was a significant association of the I-29/D polymorphism with luminal-like breast cancer (adjusted OR, 1.54, 95% CI, 1.22-1.94, p = 0.001 for luminal-A disease; adjusted OR, 1.37, 95% CI, 1.06-1.76, p = 0.014 for luminal-B disease) but not with HER2-enriched or triple-negative subtypes. Conclusion: The tri-allelic polymorphism in the NQO2 gene is associated with breast cancer risk, especially for the luminal-like subtype. Our findings provide a new piece of molecular epidemical evidence supporting the hypothesis that estrogen and its metabolites are carcinogens of luminal-like breast cancer. Further external validation studies are needed.

Carboxymethyl chitosan based redox-responsive micelle for near-infrared fluorescence image-guided photo-chemotherapy of liver cancer.

High-efficient vectors for the co-delivery of photosensitizers and chemotherapeutics were urgently needed for the combination therapy. In this work, a redox-responsive micelle (PCL-SS-CMC-GA) was prepared for the co-delivery of doxorubicin (DOX) and pheophorbide A (PHA). Poly-ε-caprolactone was linked to carboxymethyl chitosan through a disulfide bond, which was easily broken in the reductive solution to release the payloads. The charge conversion property and glycyrrhetinic acid (GA) targeting ligand of the micelles effectively extended the average residence time (up to 18 times) in circulation and improved their intracellular uptake by HepG2 cells. The micelles exhibited an enhanced tumor accumulation and near infrared (NIR) imaging performance. More interestingly, this nanoplatform could fully exert the synergistic effect of DOX and PHA to improve the inhibition efficiency (with an inhibitory rate of 80.5 %) in vivo. With impressive photo-chemo theranostic and NIR imaging capability, PCL-SS-CMC-GA@DOX/PHA showed great potential in image-guided treatment of liver cancer.

Identification of the rhizospheric microbe and metabolites that led by the continuous cropping of ramie (Boehmeria nivea L. Gaud).

Continuous cropping lowers the production and quality of ramie (Boehmeria nivea L. Gaud). This study aimed to reveal the metagenomic and metabolomic changes between the healthy- and obstacle-plant after a long period of continuous cropping. After 10 years of continuous cropping, ramie planted in some portions of the land exhibited weak growth and low yield (Obstacle-group), whereas, ramie planted in the other portion of the land grew healthy (Health-group). We collected rhizosphere soil and root samples from which measurements of soil chemical and plant physiochemical properties were taken. All samples were subjected to non-targeted gas chromatograph-mass spectrometer (GS/MS) metabolome analysis. Further, metagenomics was performed to analyze the functional genes in rhizospheric soil organisms. Based on the findings, ramie in Obstacle-group were characterized by shorter plant height, smaller stem diameter, and lower fiber production than that in Health-group. Besides, the Obstacle-group showed a lower relative abundance of Rhizobiaceae, Lysobacter antibioticus, and Bradyrhizobium japonicum, but a higher relative abundance of Azospirillum lipoferum and A. brasilense compared to the Health-group. Metabolomic analysis results implicated cysteinylglycine (Cys-Gly), uracil, malonate, and glycerol as the key differential metabolites between the Health- and Obstacle-group. Notably, this work revealed that bacteria such as Rhizobia potentially synthesize IAA and are likely to reduce the biotic stress of ramie. L. antibioticus also exerts a positive effect on plants in the fight against biotic stress and is mediated by metabolites including orthophosphate, uracil, and Cys-Gly, which may serve as markers for disease risk. These bacterial effects can play a key role in plant resistance to biotic stress via metabolic and methionine metabolism pathways.

Effect of fire needle for ganglion cysts: A protocol of systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Ganglion cysts (GCs) are tumor-like lesions that often occur in the soft tissues, which are mostly caused by the degeneration of mucin produced by the joint capsule and tendon sheath on the carpal dorsal joints of extremities. GCs may appear asymptomatic as benign tumors, but some patients also seek treatment because of the pain caused by these fluid-filled cysts. As a kind of complementary and alternative therapy, there have been some studies published in China which have proved that the fire needle has a better therapeutic effect on ganglion cyst. The purpose of this systematic review is to evaluate the efficacy of fire needle in the treatment of GCs. METHODS: PubMed, EMBASE, the Cochrane Library, Chinese National Knowledge Infrastructure, Chinese VIP Information, Wanfang Database, and Chinese Biomedical Literature Database were searched by 2 reviewers from the inception until August 2020. The original study that randomised control trials of fire needle for GCs will be selected and is not limited by country or language. In addition, researches in progress, the reference lists and the citation lists of identified publications will be retrieved similarly. Study selection, data extraction, and assessment of the quality will be performed independently by 2 reviewers who have been trained prior to data extraction. A meta-analysis will be conduct if the quantity and quality of the original studies included are satisfactory; otherwise, a descriptive analysis will be conducted. Review Manager V5.4: (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) software will be using for data synthesis and assessment the risk of bias according by Cochrane Handbook. RESULT: This study will provide a comprehensive review of current evidence for the treatment of fire needle on GCs. CONCLUSION: The conclusion of this study will provide a judging basis that whether the treatment of GCs with fire needle is effective. INPLASY REGISTRATION NUMBER: INPLASY202080032.

Chitosan based pH-responsive polymeric prodrug vector for enhanced tumor targeted co-delivery of doxorubicin and siRNA.

The co-delivery of chemotherapeutic drugs and siRNA has gained increasing attentions owing to the enhanced antitumor efficacy over single administration. In this work, a chitosan-based pH-responsive prodrug vector was developed for the co-delivery of doxorubicin (DOX) and Bcl-2 siRNA. The accumulation of fabricated nanoparticles in hepatoma cells was enhanced by glycyrrhetinic acid receptor-mediated endocytosis. The cumulative release amount of the encapsulated DOX and siRNA reached 90.2 % and 81.3 % in 10 h, respectively. More strikingly, this nanoplatform can efficiently integrate gene- and chemo-therapies with a dramatically enhanced tumor inhibitory rate (88.0 %) in vivo. This co-delivery system may provide the latest strategy to meet the needs of combination therapies for tumors, offering safe and efficient improvements to the synergistic antitumor efficacy of gene-chemotherapies.

Advanced oxidation protein products increase TNF-α and IL-1ß expression in chondrocytes via NADPH oxidase 4 and accelerate cartilage degeneration in osteoarthritis progression.

Interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, in particular, control the degeneration of articular cartilage, making them prime targets for osteoarthritis (OA) therapeutic strategies. Advanced oxidation protein products (AOPPs) are prevalent in numerous diseases. Our previous work demonstrates that intra-articular injections of AOPPs accelerate regression of cartilage in OA models. Whether AOPPs exist in the course of OA and their effects on TNF-α and IL-1ß expression in chondrocytes are still unclear. This study confirmed that AOPPs levels in human synovial fluid were positively associated with severity of OA. We also found AOPPs deposition in articular cartilage in anterior cruciate ligament transection (ACLT) induced rodent OA models. AOPPs increased expression of TNF-α and IL-1ß in chondrocytes in vitro, which was inhibited by pre-treatment with SB202190 (p38-MAPK inhibitor) or apocynin (NADPH oxidase inhibitor) or NOX4 knockdown by siRNAs. Subsequently, we further verified in vivo that exogenous injection of AOPPs in OA mice up-regulated expression of TNF-α and IL-1ß in cartilage, which was blocked by treatment with apocynin. In parallel, apocynin attenuated articular cartilage degeneration resulting in substantially lower OARSI scores. Specifically, apocynin reduced NOX4, p-P38, TNF-α and IL-1ß and increased collagen II and glycosaminoglycan (GAG). This study demonstrated that AOPPs increased expression of TNF-α and IL-1ß in chondrocytes via the NADPH oxidase4-dependent and p38-MAPK mediated pathway, and accelerated cartilage degeneration in OA progression. These findings suggest an endogenous pathogenic role of AOPPs in OA progression. Targeting AOPPs-triggered cellular mechanisms might be a promising therapeutic option for patients with OA.

Hydroxytyrosol promotes autophagy by regulating SIRT1 against advanced oxidation protein product­induced NADPH oxidase and inflammatory response.

Advanced oxidation protein products (AOPPs) can trigger NADPH oxidase (NOX) and lead to the production of reactive oxygen species (ROS) in the pathophysiology of rheumatoid arthritis (RA). Hydroxytyrosol (HT) is a phenolic composite in olive oil that has antioxidant and anti­inflammatory effects and enhances autophagy. Early research has revealed that HT can activate the silent information regulator 1 (SIRT1) pathway to induce autophagy and alleviate the cartilage inflammatory response caused by H2O2. However, whether HT can attenuate AOPP­induced NOX and inflammatory responses remains to be elucidated. The present study aimed to investigate how HT can alleviate the damage caused by AOPPs. In cell experiments, chondrocytes were pre­stimulated with HT and then exposed to AOPPs. First, it was found that HT promoted autophagy through the SIRT1 pathway, increased the expression of autophagy­related proteins including microtubule­associated protein 1 light chain 3, autophagy related (ATG)5 and ATG7, and decreased the expression of P62. Furthermore, HT reduced the expression of NOX, which was affected by AOPPs in chondrocytes through the SIRT1 pathway. Finally, the expression of inflammatory cytokines caused by AOPPs was downregulated following HT treatment. In conclusion, it was found that HT reduced the expression of NOX and inhibited the inflammatory response caused by AOPPs in chondrocytes through the SIRT1 pathway.