Curcumin Inhibits the Growth of Hepatocellular Carcinoma via the MARCH1-mediated Modulation of JAK2/STAT3 Signaling.

BACKGROUND: Curcumin has been reported to have anti-hepatocellular carcinoma (HCC) effects, but the underlying mechanism is not well known. OBJECTIVES: To investigate whether membrane-associated RING-CH 1 (MARCH1) is involved in the curcumin-induced growth suppression in HCC and its underlying molecular mechanism. A few recent patents for curcumin for cancer are also reviewed in this article. METHODS: The effect of curcumin on growth inhibition of HCC cells was analyzed through in vitro and in vivo experiments, and the expression levels of MARCH1, Bcl-2, VEGF, cyclin B1, cyclin D1, and JAK2/STAT3 signaling molecules were measured in HCC cells and the xenograft tumors in nude mice. Cell transfection with MARCH1 siRNAs or expression plasmid was used to explore the role of MARCH1 in the curcumin-induced growth inhibition of HCC cells. RESULTS: Curcumin inhibited cell proliferation, promoted apoptosis, and arrested the cell cycle at the G2/M phase in HCC cells with the decrease of Bcl-2, VEGF, cyclin B1, and cyclin D1 expression as well as JAK2 and STAT3 phosphorylation, resulting in the growth suppression of HCC cells. MARCH1 is highly expressed in HCC cells, and its expression was downregulated after curcumin treatment in a dose-dependent manner. The knockdown of MARCH1 by siRNA decreased the phosphorylation levels of JAK2 and STAT3 and inhibited the growth of HCC cells. In contrast, opposite results were observed when HCC cells overexpressed MARCH1. A xenograft tumor model in nude mice also showed that curcumin downregulated MARCH1 expression and decelerated the growth of transplanted HCC with the downregulation of JAK2/STAT3 signaling and functional molecules. The ADC value of MRI analysis showed that curcumin slowed down the progression of HCC. CONCLUSION: Our results demonstrated that curcumin may inhibit the activation of JAK2/STAT3 signaling pathway by downregulating MARCH1 expression, resulting in the growth suppression of HCC. MARCH1 may be a novel target of curcumin in HCC treatment.

Tendon Repair and Regeneration Using Bioinspired Fibrillation Engineering That Mimicked the Structure and Mechanics of Natural Tissue.

Replicating the controlled nanofibrillar architecture of collagenous tissue represents a promising approach in the design of tendon replacements that have tissue-mimicking biomechanics─outstanding mechanical strength and toughness, defect tolerance, and fatigue and fracture resistance. Guided by this principle, a fibrous artificial tendon (FAT) was constructed in the present study using an engineering strategy inspired by the fibrillation of a naturally spun silk protein. This bioinspired FAT featured a highly ordered molecular and nanofibrillar architecture similar to that of soft collagenous tissue, which exhibited the mechanical and fracture characteristics of tendons. Such similarities provided the motivation to investigate FAT for applications in Achilles tendon defect repair. In vitro cellular morphology and expression of tendon-related genes in cell culture and in vivo modeling of tendon injury clearly revealed that the highly oriented nanofibrils in the FAT substantially promoted the expression of tendon-related genes combined with the Achilles tendon structure and function. These results provide confidence about the potential clinical applications of the FAT.

The effect of ultrasound-guided acupotomy and Juanbi decoction on lumbar disc herniation: A randomized controlled trial.

BACKGROUND: Acupotomy as well as Juanbi decoction has been used in the treatment of lumbar disc herniation. However, there is no study on ultrasound-guided acupotomy combined with Juanbi decoction in the treatment of lumbar disc herniation. METHOD: This study was supported by the Sichuan Provincial Administration of Traditional Chinese Medicine [grant number: 2020LC0163] and the Science and Technology Department of Sichuan Province [grant number: 2022YFS0418]. This study was 3 center, open, randomized, controlled trial, and was carried out from December 2020 to December 2022. A total of 60 eligible patients with LDH were split into group A and group B at random. The group B received Juanbi Decoction 3 times daily for 2 weeks along with an acupotomy assisted by ultrasound. The acupotomy was administered once a week. The same protocol was used with the group A, but the Juanbi Decoction was replaced with normal saline. OBSERVATION INDEX: Visual analogue scale (VAS) score on 1 day and 1 week after treatment, VAS score, Japanese orthopedic association low back pain score(JOA) rate, Oswestry Disability Index (ODI), and low back outcome scale (LBOS) at 1, 3, 6, and 12 months after treatment in 2 groups. RESULTS: There were no significant differences in general information, VAS score before treatment, JOA, ODI, and LBOS between the 2 groups (P > .05). Intra-group comparison: VAS score, JOA rate, ODI, and LBOS were compared before and after treatment in both groups, and the differences were statistically significant (P < .05). There were significant differences in VAS and LBOS between the 2 groups at 3 and 6 months after treatment, and there were statistically significant differences in ODI and JOA rates at 3, 6, and 12 months after treatment between the 2 groups. CONCLUSION: Acupotomy aided by ultrasound combined with Juanbi Decoction significantly relieves lumbar pain and can improve lumbar function in patients with LDH, and the clinical efficacy lasts for about 6 months.

Mid-Term Outcomes of Cemented or Uncemented Total Hip Arthroplasty for Failed Proximal Femoral Nail Antirotation Following Intertrochanteric Femur Fractures: A Retrospective Observational Study.

Introduction: The aim of this retrospective study was to assess the clinical outcomes of cemented or uncemented total hip arthroplasty (CTHA or UTHA) following prior failed proximal femoral nail antirotation (PFNA) fixation in patients with intertrochanteric femur fractures (IFFs). Materials and methods: Data from 244 patients with IFFs who experienced a conversion of PFNA to CTHA (n = 120) or to UTHA (n = 124) due to screw cut-out, mal/nonunion, or osteonecrosis during 2008-2018 were retrospectively analyzed. Follow-up occurred 1, 3, 6, and 12 months postoperatively and yearly thereafter. The primary outcome was the incidence of orthopedic complications; the secondary outcome was the Harris hip score (HHS). Results: The median follow-up was 60 months (range, 50-67 months). The incidences of orthopedic complications were 10% in the PFNA to CTHA group and 19.3% in the PFNA to UTHA group (P = .040). Significant differences were also observed regarding the incidence of prosthesis revision (1.7% for PFNA to CTHA vs 7.2% for PFNA to UTHA, P = .036). From the three years after conversion surgery to the final follow-up, significant differences were detected in HHS between groups (each P < .05). At the final follow-up, a statistically significant difference was detected in the HHS (79.54±18.85 for PFNA to CTHA vs. 75.26±18.27 for PFNA to UTHA, P = .014). Conclusion: The results of the study may demonstrate a significant statistical advantage with respect to the orthopedic complication rate and HHS in favor of CTHA compared to UTHA in patients with failed PFNA.

Long-term survival of hybrid total hip replacement for prior failed proximal femoral nail antirotation: a retrospective study with a median 10-year follow-up.

BACKGROUND: Hybrid total hip replacement (THR) is commonly used in the management of proximal femur fractures in elderly individuals. However, in the context of the revision, the literature on hybrid THR is limited, and differences in the long-term survival outcomes reported in the literature are obvious. This retrospective study aimed to evaluate the long-term survival of hybrid THR for failed proximal femoral nail antirotation (PFNA) in elderly individuals aged ≥ 75 years. METHODS: An observational cohort of 227 consecutive individuals aged ≥ 75 years who experienced hybrid THRs following prior primary PFNAs was retrospectively identified from the Joint Surgery Centre, the First Affiliated Hospital, Sun Yat-sen University. Implant survival was estimated using the Kaplan-Meier method. The primary end point was the implant survivorship calculated using the Kaplan-Meier method with revision for any reason as the end point; secondary end points were the function score measured using the modified Harris Hip Score (mHHS) and the incidence of main orthopaedic complications. RESULTS: In total, 118 individuals (118 THRs) were assessed as available. The median follow-up was 10 (3-11) years. The 10-year survivorship with revision for any reason as the endpoint was 0.914 (95% confidence interval [CI], 0.843-0.960). The most common indication for revision was aseptic loosening (70.0%), followed by periprosthetic fracture (30.0%). At the final follow-up, the median functional score was 83.6 (79.0-94.0). Among the 118 patients included in this study, 16 experienced 26 implant-related complications. The overall incidence of key orthopaedic complications was 13.5% (16/118). CONCLUSION: For patients aged ≥ 75 years old with prior failed PFNAs, hybrid THR may yield satisfactory long-term survival, with good functional outcomes and a low rate of key orthopaedic complications.

Myricetin Induces Autophagy and Cell Cycle Arrest of HCC by Inhibiting MARCH1-Regulated Stat3 and p38 MAPK Signaling Pathways.

Myricetin is a type of natural flavonol known for its anticancer activity. However, the molecular mechanism of myricetin in anti-hepatocellular carcinoma (HCC) is not well defined. Previous studies indicated that downregulation of membrane-associated RING-CH finger protein 1 (MARCH1) contributed to the treatment of a variety of cancers. Whether the anticancer property of myricetin is associated with MARCH1 expression remains to be investigated. This research explored the anti-HCC mechanism of myricetin. Our results indicate that myricetin induces autophagy and arrests cell cycle at the G2/M phase to suppress the proliferation of HCC cells by downregulating MARCH1. Myricetin reduces MARCH1 protein in Hep3B and HepG2 cells. Interestingly, myricetin upregulates the MARCH1 mRNA level in Hep3B cells but downregulates it in HepG2 cells. The knockdown of MARCH1 by siRNAs (small interfering RNAs) decreases the phosphorylated p38 MAPK (p-p38 MAPK) and Stat3 (p-Stat3), and inhibits HCC cell viability. Moreover, myricetin inhibits p38 MAPK and Stat3 signaling pathways by downregulating MARCH1 to repress HCC growth both in vitro and in vivo. Bafilomycin A1 (BafA1), an autophagy inhibitor, has synergetic effect with myricetin to inhibit HCC growth. Taken together, our results reveal that myricetin inhibits the proliferation of HCC cells by inhibiting MARCH1-regulated p38 MAPK and Stat3 signaling pathways. This research provides a new molecular mechanism for myricetin in anti-HCC and suggests that targeting MARCH1 could be a novel treatment strategy in developing anticancer therapeutics.

Injectable Mussel-Inspired highly adhesive hydrogel with exosomes for endogenous cell recruitment and cartilage defect regeneration.

In the early stage of osteoarthritis (OA), cartilage degradation in the surface region leads to superficial cartilage defect. However, enhancing the regeneration of cartilage defect remains a great challenge for existing hydrogel technology because of the weak adhesion to wet tissue. In the present study, an injectable mussel-inspired highly adhesive hydrogel with exosomes was investigated for endogenous cell recruitment and cartilage defect regeneration. The hydrogel with high bonding strength to the wet surface was prepared using a crosslinked network of alginate-dopamine, chondroitin sulfate, and regenerated silk fibroin (AD/CS/RSF). Compared with commercial enbucrilate tissue adhesive, the AD/CS/RSF hydrogel provided a comparative lap shear strength of 120 kPa, with a similar gelation time and a higher capacity for maintaining adhesive strength. The AD/CS/RSF/EXO hydrogel with encapsulated exosomes recruited BMSCs migration and inflation, promoted BMSCs proliferation and differentiation. Most importantly, the AD/CS/RSF/EXO hydrogel accelerated cartilage defect regeneration in situ, and extracellular matrix remodeling after injection in rat patellar grooves. The exosomes released by the hydrogels could recruit BMSCs into the hydrogel and neo-cartilage via the chemokine signaling pathway. Our findings reveal an injectable and adhesive hydrogel for superficial cartilage regeneration, which is a promising approach for minimally treating cartilage defect with arthroscopic assistance.

Sinomenine Suppresses Development of Hepatocellular Carcinoma Cells via Inhibiting MARCH1 and AMPK/STAT3 Signaling Pathway.

Promotion of apoptosis and suppression of proliferation in tumor cells are popular strategies for developing anticancer drugs. Sinomenine (SIN), a plant-derived alkaloid, displays antitumor activity. However, the mechanism of action of SIN against hepatocellular carcinoma (HCC) is unclear. Herein, several molecular technologies, such as Western Blotting, qRT-PCR, flow cytometry, and gene knockdown were applied to explore the role and mechanism of action of SIN in the treatment of HCC. It was found that SIN arrests HCC cell cycle at G0/G1 phase, induces apoptosis, and suppresses proliferation of HCC cells via down-regulating the expression of membrane-associated RING-CH finger protein 1 (MARCH1). Moreover, SIN induces cell death and growth inhibition through AMPK/STAT3 signaling pathway. MARCH1 expression was silenced by siRNA to explore its involvement in the regulation of AMPK/STAT3 signaling pathway. Silencing MARCH1 caused down-regulation of phosphorylation of AMPK, STAT3 and decreased cell viability and function. Our results suggested that SIN inhibits proliferation and promotes apoptosis of HCC cells by MARCH1-mediated AMPK/STAT3 signaling pathway. This study provides new support for SIN as a clinical anticancer drug and illustrates that targeting MARCH1 could be a novel treatment strategy in developing anticancer therapeutics.

Nivolumab plus ipilimumab versus nivolumab in individuals with treatment-naive programmed death-ligand 1 positive metastatic soft tissue sarcomas: a multicentre retrospective study.

BACKGROUND: Currently, the choice of treatment for individuals with metastatic soft tissue sarcomas (MSTS) presents a significant challenge to clinicians. The aim of this retrospective study was to assess the efficacy and safety of nivolumab plus ipilimumab (NPI) versus nivolumab alone (NIV) in individuals with treatment-naive programmed death-ligand 1 (PD-L1) positive MSTS. METHODS: Prospectively maintained databases were reviewed from 2013 to 2018 to assess individuals with treatment-naive PD-L1 MSTS who received NPI (nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every 2 weeks) or NIV (3 mg/kg every 2 weeks) until disease progression, withdrawal, unendurable [AEs], or death. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: The median follow-up was 16.0 months (IQR 14.4-18.5) after targeted intervention. The median OS was 12.2 months (95% confidence interval [CI], 6.1-13.7) and 9.2 months (95% CI, 4.2-11.5) for the NPI and NIV groups, respectively (hazard ratio [HR] 0.49, 95% CI, 0.33-0.73; p=0.0002); the median PFS was 4.1 months (95% CI, 3.2-4.5) and 2.2 months (95% CI, 1.1-3.4) for the NPI and NIV groups, respectively (HR 0.51, 95% CI, 0.36-0.71; p< 0.0001). Key grade 3-5 AEs occurred more frequently in the NPI group than in the NIV group (94 [72.9%] for NPI vs. 35 [27.1%], p< 0.001). CONCLUSIONS: For treatment-naive PD-L1 positive MSTS, NPI seems to be less tolerated but has a greater survival advantage than NIV as the primary therapy.

Conversion from a failed proximal femoral nail anti-rotation to a cemented or uncemented total hip arthroplasty device: a retrospective review of 198 hips with previous intertrochanteric femur fractures.

BACKGROUND: At present, it is unclear which device (uncemented or cemented total hip arthroplasty [UTA or CTA, respectively]) is more suitable for the conversion of a failed proximal femoral nail anti-rotation (PFNA). The aim of this review was to assess the outcomes of failed PFNAs converted to a UTA or CTA device in elderly individuals with intertrochanteric femoral fractures (IFFs). METHODS: Two hundred fifty-eight elderly individuals (258 hips) with IFFs who underwent a conversion to a UTA or CTA device following failed PFNAs during 2007-2017 were retrospectively identified from the China Southern Medical Centre (CSMC) database. The primary endpoint was the Harris Hip Score (HHS); secondary endpoint was the key orthopaedic complication rate. RESULTS: The median follow-up was 65 months (60-69 months). Significant distinctions were observed (87.26 ± 16.62 for UTA vs. 89.32 ± 16.08 for CTA, p = 0.021; 86.61 ± 12.24 for symptomatic UTA vs. 88.68 ± 13.30 for symptomatic CTA, p = 0.026). A significant difference in the overall key orthopaedic complication rate was detected (40.8% [40/98] vs. 19.0% [19/100], p = 0.001). Apparent distinctions were detected in terms of the rate of revision, loosening, and periprosthetic fracture (11.2% for UTA vs 3.0% for CTA, p = 0.025; 13.2% for UTA vs 5.0% for CTA, p = 0.043; 10.2% for UTA vs 3.0% for CTA, p = 0.041, respectively). CONCLUSION: For elderly individuals with IFFs who suffered a failed PFNA, CTA devices may have a noteworthy advantage in regard to the revision rate and the rate of key orthopaedic complications compared with UTA devices, and CTA revision should be performed as soon as possible, regardless of whether these individuals have symptoms.

Favourable clinical outcomes following cemented arthroplasty after metal-on-metal total hip replacement: a retrospective study with a mean follow-up of 10 years.

BACKGROUND: Given the unexpected high rate of failure following metal-on-metal total hip replacement (MoM-THR), it is expected that more MoM-THR patients will experience revision. The long-term outcomes regarding the primary MoM-THR revised to cemented THR (CTHR) remain controversial. The purpose of this retrospective review was to evaluate the long-term outcomes of patients who underwent conversion from MoM-THR to CTHR. METHODS: A total of 220 patients (220 hips) who underwent a conversion of primary MoM-THR to CTHR from March 2006 to October 2016 were retrospectively reviewed. The primary outcomes were the functional outcomes assessed using the Harris hip scores (HHS) and major radiographic outcomes. Follow-ups occurred at 3 months, 6 months, 1 year, 2 years, and then every two years after revision. RESULTS: Mean follow-up was 10.1 years (5-13 years). Distinct improvements were detected in the mean HHS between the preoperative and last follow-up analysis (62.35[±8.49] vs. 84.70[±14.68], respectively, p < 0.001). The key orthopaedic complication rate was 18.2% (27/148). Seven (4.7%) cases experienced a CTHR failure at a mean of 3.4 (±1.2) years after revision MoM-THR, mostly attributed to recurrent dislocation. CONCLUSION: CTHR might yield an acceptable functional score and a low rate of the key orthopaedic complications.

Conversion to hemi-shoulder arthroplasty or reverse total shoulder arthroplasty after failed plate osteosynthesis of proximal humerus fractures: a retrospective study.

OBJECTIVE: To assess the clinical outcomes of hemi-shoulder arthroplasty (HSA) versus reverse total shoulder arthroplasty (RTSA) following failed plate osteosynthesis of proximal humerus fractures in elderly patients. METHODS: This retrospective study identified all patients that had a documented failed plate osteosynthesis of proximal humeral fractures treated with revision HSA or RTSA. Follow-up occurred at 1, 3, 6 and 12 months after surgery and every year thereafter. The primary outcomes were the American Shoulder and Elbow Surgeons (ASES) scores, Simple Shoulder Test (SST) scores, visual analogue scale (VAS) pain scores and the University of California, Los Angeles Shoulder Rating Scale (UCLA SRS) scores. The secondary outcome was the rate of major complications. RESULTS: A total of 126 patients (126 shoulders) were enrolled in the study. At the final follow-up, the RTSA group had significantly greater improvements in ASES, SST and UCLA SRS scores than the HSA group. The RTSA group had significantly larger decreases in the VAS pain score compared with the HSA group. The rate of major complications was significantly higher in the HSA group than in the RTSA group (44.4% versus 27.5%, respectively). CONCLUSION: RTSA provided superior functional outcomes compared with HSA, with a lower rate of major complications after a follow-up period of at least 5 years.

Mid-term outcomes of uncemented or cemented arthroplasty revision following metal-on-metal total hip arthroplasty failure: a retrospective observational study.

OBJECTIVE: To retrospectively compare the mid-term outcomes of uncemented or cemented total hip arthroplasty (THA) revision for prior primary metal-on-metal (MoM) THA failure. METHODS: Data from 278 patients (278 hips) who underwent uncemented THA (UTHA) or cemented THA (CTHA) for prior primary MoM-THA failure from 2006 to 2016 were retrospectively analysed. Follow-up was performed 6 months, 1 year, 2 years, and then every 2 years after conversion. The mean follow-up time was 96 months (range, 64-128 months). The primary endpoint was the modified Harris hip score (HHS). The secondary endpoint was the major orthopaedic complication rate. RESULTS: The HHS showed significantly greater differences in the CTHA than UTHA group 12 months after conversion. From the 12th month after conversion to the final follow-up, CTHA yielded better functional outcomes than UTHA. There were significant differences between the UTHA and CTHA groups in the rates of re-revision (14.4% vs. 4.9%, respectively), aseptic loosening (17.3% vs. 6.8%, respectively), and periprosthetic fracture (11.5% vs. 3.9%, respectively). CONCLUSION: CTHA has more advantages than UTHA in terms of improving functional outcomes and decreasing the major orthopaedic complication rate.

Resveratrol inhibits the malignant progression of hepatocellular carcinoma via MARCH1-induced regulation of PTEN/AKT signaling.

Resveratrol is a common, naturally occurring polyphenol confirmed with inhibited the cellular effects of carcinogenesis. However, the molecular mechanism underlying resveratrol's action against hepatocellular carcinoma (HCC) is still unclear. In addition, MARCH1 promotes the initiation and progression of HCC, but it is unclear whether resveratrol exerts antitumor efforts by regulating MARCH1 expression. This study determined the molecular mechanisms underlying the antitumor effects of resveratrol in HCC. Resveratrol induced apoptosis and inhibited the proliferation, migration, and invasion of HCC cell lines (HepG2 and Hep3B). In addition, it inhibited MARCH1 and phospho-protein kinase B (p-AKT) expression but upregulated the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) dose-dependently both in vitro and in vivo. MARCH1 knockdown by small interfering RNA (siRNA) also increased PTEN expression. Meanwhile, MK2206 (an AKT inhibitor) and bisperoxovanadium (BPV; a PTEN inhibitor) combined with resveratrol decreased MARCH1 expression more than the single-treatment HCC group. These results suggested that resveratrol affects the biological characteristics of HCC via downregulation of MARCH1 expression.

Cisplatin-based chemotherapy with or without bevacizumab for Chinese postmenopausal women with advanced cervical cancer: a retrospective observational study.

BACKGROUND: The purpose of this study was to assess the efficacy and safety of cisplatin-based chemotherapy with or without bevacizumab (BEV) in Chinese women with advanced cervical cancer (ACC). METHODS: For this observational study, we analysed the data of 316 Chinese women with ACC who were treated at the Henan provincial people's hospital between Jan 1, 2014, and Dec 31, 2018, with cisplatin-based chemotherapy plus BEV (CB) or cisplatin-based chemotherapy alone (CA) until disease progression, unacceptable toxicity, or death. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS); the secondary endpoint was the occurrence of adverse events (AEs). RESULTS: A total of 264 patients with ACC were included in the assessment (CB, n = 130 and CA, n = 134). At a median follow-up of 38 months (IQR 36-40), the median OS in the CB cohort was significantly longer than that in the CA cohort (hazard ratio [HR] 1.21, 95% confidence interval[CI] 1.14-1.73; p = 0.002); additionally, the median PFS was 345 days (95% CI, 318-372) for CB and 261 days (95% CI, 165-357) for CA(HR 1.61, 95% CI 1.12-2.17; p = 0.000). Significant differences were noted between groups in terms of thrombosis/embolism, neutropenia, and febrile neutropenia. CONCLUSIONS: In Chinese women with ACC, cisplatin-based chemotherapy plus BEV is associated with improved survival compared to cisplatin-based chemotherapy alone. This finding suggests a positive survival benefit of anti-angiogenesis therapy in this population.

Long-term follow-up outcomes for patients undergoing primary total hip arthroplasty with uncemented versus cemented femoral components: a retrospective observational study with a 5-year minimum follow-up.

BACKGROUND: This retrospective analysis compared the long-term outcomes for patients with a femoral neck fracture (AO/OTA type 31B) treated with a primary unilateral total hip arthroplasty with uncemented or cemented femoral components (UTHA or CTHA, respectively). METHODS: We conducted a retrospective cohort study using the South China Hip Arthroplasty Database. We identified 422 patients with femoral neck fracture (AO/OTA type 31B) who were previously treated with primary unilateral UTHA or CTHA between 2007 and 2015, with follow-up until 2019. Follow-up occurred 1, 3, 6 and 12 months postoperatively and yearly thereafter. The primary outcome was the Harris hip score (HHS). The secondary outcome was the orthopaedic complication rate. RESULTS: In total, 324 patients (UTHA n = 160, mean age 68.61 ± 7.49 years; CTHA n = 164, mean age 68.75 ± 7.04 years) were evaluated for study eligibility. The median follow-up was 73.3 months (range, 11.6-89.2 months). At the final follow-up, HHS was 74.09 ± 6.23 vs 79.01 ± 10.21 (UTHA vs CTHA, p = 0.012). Significant differences were detected in the incidence of prosthetic revision, loosening, and periprosthetic fracture between the UTHA and CTHA groups (7.5% for UTHA vs 1.8% for CTHA, p = 0.015; 17.5% for UTHA vs 8.5% for CTHA, p = 0.016; 11.9% for UTHA vs 4.9% for CTHA, p = 0.021, respectively). CONCLUSION: In this setting, CTHA demonstrated superiority to UTHA by improving functional outcomes and decreasing complication rates.

Downregulation of B7-H4 suppresses tumor progression of hepatocellular carcinoma.

B7-H4, as a member of the B7 superfamily, was overexpressed in various types of cancers. However, the effects of B7-H4 on the aggressiveness of HCC and the underlying mechanisms have not yet been fully explored. For this purpose, B7-H4 expression was detected by Flow cytometry and Western blotting, it was highly expressed in several HCC cell lines but not in normal LO2 cell line. Knockdown B7-H4 expression induced HCC cells apoptosis by flow cytometry and colony formation assays and increased several apoptosis-related proteins, including survivin, cleaved caspase-3, cleaved caspase-7, and Bax, while the pro-growth protein survivin was reduced. Then the proliferation and cell cycle were suppressed after treated by siB7-H4. Moreover, the level of B7-H4 was significantly correlated with cell migration. In vivo, intra-tumor injection of siRNA targeting B7-H4 can significantly inhibited the growth of HepG2 cells in nude mice. Finally, regions of interest were manually traced on T1WI, T2WI, DWI and ADC of MR images. ADC values were increased in HCC xenografts after B7-H4 siRNA treatment. These data indicated that downregulation of B7-H4 suppressed the proliferation and migration and promoted apoptosis in vitro and in vivo. Blocking the B7-H4 channel might be a potential therapeutic strategy for HCC.

Role of Tim-3 in Decidual Macrophage Functional Polarization During Abnormal Pregnancy With Toxoplasma gondii Infection.

Vertical transmission of the intracellular parasite Toxoplasma gondii (T. gondii) can lead to devastating consequences during gestation. Tim-3, a negative immune regulator, is constitutively expressed on decidual macrophages, but its specific role during T. gondii infection has not yet been explored. In the present study, we discovered that Tim-3 plays an important role in the abnormal pregnancy due to T. gondii infection using Tim-3-/- pregnant mice and anti-Tim-3 neutralizing antibody treated human decidual macrophages. The results showed that abnormal pregnancy outcomes were more prevalent in Tim-3-/- infected pregnant mice than in wild-type infected pregnant mice. Tim-3 expression in decidual macrophages was significantly down-regulated after T. gondii infection both in vitro and in vivo. Tim-3 down-regulation by T.gondii infection could strengthen M1 activation and weaken M2 tolerance by changing the M1 and M2 membrane molecule expression, arginine metabolic enzymes synthesis, and cytokine secretion profiles of decidual macrophages. Moreover, Tim-3 down-regulation by T.gondii infection led to PI3K-AKT phosphorylation inhibition, downstream transcription factor C/EBPß expression, and SOCS1 activation, which resulted in enzymes synthesis regulation and cytokines secretion. Our study demonstrates that Tim-3 plays an indispensable role in the adverse pregnancy outcomes caused by T. gondii infection.

OGR1 mediates the inhibitory effects of acidic environment on proliferation and angiogenesis of endothelial progenitor cells.

Ovarian cancer G-protein-coupled receptor 1 (OGR1), an acid-sensitive receptor, plays a key proton-sensing role through stimulation of inositol phosphate formation. Avascular necrosis of the femoral head is characterized by apoptosis of bone cells mainly resulting from deficient local blood perfusion, eventually leading to acidification with disruption of endothelial progenitor cells' (EPCs) function. However, whether EPCs express OGR1 has not been demonstrated. This study attempted to whether OGR1 mediates the effects of acid on proliferation, migration, and angiogenesis in EPCs. FITC-UEA-I and Dil-Ac-LDL double-staining methods were used to identify EPCs. Expression of OGR1 was analyzed by RT-PCR (reverse transcription PCR) and western blot after incubation in media ranging in pH, cell counting kit-8 and cell cycle analysis were used to analyze proliferation and cell cycle distribution. Scratch test, transwell migration assay, and tube formation experiments were performed to analyze migration and vascularization of EPCs after silencing OGR1 with small interfering RNA (siRNA). The result show EPCs were positive for FITC-UEA-I and Dil-Ac-LDL double-staining and expressed OGR1. The expression of OGR1 increased gradually with decreased pH and was highest in pH 6.4 medium. Incubation in pH 6.4 medium inhibited proliferation of EPCs and caused cell cycle arrest. Silencing of OGR1 using siRNA partially reversed the effect of acidic environment on EPCs. Migration and angiogenesis of EPCs were inhibited in pH 6.4 medium, and silencing of OGR1 partially reversed this effect. The results demonstrated expression of OGR1 in EPCs, and the OGR1 mediated the effects of acidic environment on proliferation, migration, and angiogenesis of EPCs.

Apoptotic bodies from endplate chondrocytes enhance the oxidative stress-induced mineralization by regulating PPi metabolism.

This study aimed to investigate the role of apoptotic bodies (Abs) from the oxidative stressed endplate chondrocytes in regulating mineralization and potential mechanisms. Endplate chondrocytes were isolated from rats and treated with H2O2 to induce oxidative stress. The calcium deposition for matrix mineralization in the cells was examined by histological staining. The expression levels of calcification-related genes in individual groups of cells were determined by quantitative real time-PCR (qRT-PCR). Subsequently, extracellular vesicles (EVs) were purified and characterized. The effect of treatment with H2O2 and/or Abs on the mineralization, extracellular PPi metabolism and related gene expression were determined. Oxidative stress significantly increased the mineralization and promoted the generation of main Abs from endplate chondrocytes. Abs were effectively endocytosed by endplate chondrocytes and co-localized with collagen (COL)-II in the cytoplasm, which enhanced the mineralization, alkaline phosphatase (ALP), osteocalcin (OCN), Runt-related transcription factor 2 (RUNX2) and COL-I expression in endplate chondrocytes. Furthermore, treatment either H2O2 or Abs significantly decreased PPi, but increased Pi production and treatment with both further enhancing the changes in endplate chondrocytes. Similarly, treatment either H2O2 or Abs significantly decreased the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and ankylosis protein (ANK) expression and ENPP1 promoter activity, but increased the tissue-nonspecific alkaline phosphatase (TNAP) expression and TNAP promoter activity in endplate chondrocytes. Oxidative stress promoted the generation of Abs, which might enhance the oxidative stress-mediated mineralization in endplate chondrocytes by regulating the PPi metabolism.