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.

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.

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.

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 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.

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.

MARCH1 encourages tumour progression of hepatocellular carcinoma via regulation of PI3K-AKT-ß-catenin pathways.

Membrane-associated RING-CH-1 (MARCH1) is a membrane-anchored E3 ubiquitin ligase that is involved in a variety of cellular processes. MARCH1 was aberrantly expressed as a tumour promoter in ovarian cancer, but the signalling about the molecular mechanism has not yet been fully illuminated. Here, we first determined that MARCH1 was obviously highly expressed in human hepatocellular carcinoma samples and cells. In addition, our findings demonstrated that the proliferation, migration and invasion of hepatocellular carcinoma were suppressed, but the apoptosis was increased, as a result of MARCH1 knockdown by either siRNA targeting MARCH1 or pirarubicin treatment. Conversely, the proliferation, migration and invasion of hepatocellular carcinoma were obviously accelerated, and the apoptosis was decreased, by transfecting the MARCH1 plasmid to make MARCH1 overexpressed. Moreover, in vivo, the results exhibited a significant inhibition of the growth of hepatocellular carcinoma in nude mice, which were given an intra-tumour injection of siRNA targeting MARCH1. Furthermore, our study concluded that MARCH1 functions as a tumour promoter, and its role was up-regulated the PI3K-AKT-ß-catenin pathways both in vitro and in vivo. In summary, our work determined that MARCH1 has an important role in the development and progression of hepatocellular carcinoma and may be used as a novel potential molecular therapeutic target in the future treatment of hepatocellular carcinoma.

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.

Capecitabine plus bevacizumab versus capecitabine in maintenance treatment for untreated characterised KRAS exon 2 wild-type metastatic colorectal cancer: a retrospective analysis in Chinese postmenopausal women.

BACKGROUND: Capecitabine plus bevacizumab (CAP-B) maintenance treatment after 6 cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOXB) has demonstrated clinical activity and failure to compromise quality of life in patients with metastatic colorectal cancer (MCC) in a previous phase 3 CAIRO3 study. The objective of this study is to evaluate the efficacy and safety of CAP-B versus CAP in maintenance treatment after 6-cycle CAPOXB induction therapy in Chinese postmenopausal women with untreated characterised KRAS exon 2 wild-type MCC. METHODS: During 2012-2016, prospectively maintained databases were reviewed to evaluate cohorts with untreated characterised KRAS exon 2 wild-type MCC and stable disease or better after 6-cycle CAPOXB induction treatment. After induction treatment, all patients received either CAP-B or capecitabine (CAP) as maintenance treatment. Median progression-free survival (mPFS) and median overall survival (mOS) were the primary endpoints. Safety was the secondary endpoint. RESULTS: A total of 263 women with untreated characterised KRAS exon 2 wild-type MCC and stable disease or better after 6-cycle CAPOXB induction treatment were included for the evaluation of efficacy and safety (CAP-B-treated cohort, n = 130 and CAP-treated cohort, n = 133). The mPFS was 11.5 months (95% confidence interval [CI], 5.6-17.4) and 9.2 months (95% CI, 3.6-14.8) for the CAP-B-treated and CAP-treated cohorts, respectively (HR 0.54, 95% CI 0.32~0.85; P = 0.013). The mOS was 16.2 months (95% CI, 11.4-18.7) and 12.4 months (95% CI, 10.6-15.5) for the CAP-B- and CAP-treated cohorts, respectively (HR 0.72, 95% CI 0.51~0.94; P = 0.022). The CAP-B-treated cohort experienced significantly more grade 3 or 4 diarrhoea (P < 0.001) than the CAP-treated cohort. CONCLUSIONS: CAP-B maintenance treatment after 6-cycle CAPOX-B in Chinese postmenopausal women with untreated KRAS exon 2 wild-type MCC is poorer tolerated but has a more modest, if any, benefit compared with that of CAP maintenance treatment.

Secalonic Acid-F, a Novel Mycotoxin, Represses the Progression of Hepatocellular Carcinoma via MARCH1 Regulation of the PI3K/AKT/ß-catenin Signaling Pathway.

Liver cancer is a very common and significant health problem. Therefore, powerful molecular targeting agents are urgently needed. Previously, we demonstrated that secalonic acid-F (SAF) suppresses the growth of hepatocellular carcinoma (HCC) cells (HepG2), but the other anticancer biological functions and the underlying mechanism of SAF on HCC are unknown. In this study, we found that SAF, which was isolated from a fungal strain in our lab identified as Aspergillus aculeatus, could inhibit the progression of hepatocellular carcinoma by targeting MARCH1, which regulates the PI3K/AKT/ß-catenin and antiapoptotic Mcl-1/Bcl-2 signaling cascades. First, we confirmed that SAF reduced the proliferation and colony formation of HCC cell lines (HepG2 and Hep3B), promoted cell apoptosis, and inhibited the cell cycle in HepG2 and Hep3B cells in a dose-dependent manner. In addition, the migration and invasion of HepG2 and Hep3B cells treated with SAF were significantly suppressed. Western blot analysis showed that the level of MARCH1 was downregulated by pretreatment with SAF through the regulation of the PI3K/AKT/ß-catenin signaling pathways. Moreover, knockdown of MARCH1 by small interfering RNAs (siRNAs) targeting MARCH1 also suppressed the proliferation, colony formation, migration, and invasion as well as increased the apoptotic rate of HepG2 and Hep3B cells. These data confirmed that the downregulation of MARCH1 could inhibit the progression of hepatocellular carcinoma and that the mechanism may be via PI3K/AKT/ß-catenin inactivation as well as the downregulation of the antiapoptotic Mcl-1/Bcl-2. In vivo, the downregulation of MARCH1 by treatment with SAF markedly inhibited tumor growth, suggesting that SAF partly blocks MARCH1 and further regulates the PI3K/AKT/ß-catenin and antiapoptosis Mcl-1/Bcl-2 signaling cascade in the HCC nude mouse model. Additionally, the apparent diffusion coefficient (ADC) values, derived from magnetic resonance imaging (MRI), were increased in tumors after SAF treatment in a mouse model. Taken together, our findings suggest that MARCH1 is a potential molecular target for HCC treatment and that SAF is a promising agent targeting MARCH1 to treat liver cancer patients.

Decidual macrophage M1 polarization contributes to adverse pregnancy induced by Toxoplasma gondii PRU strain infection.

Recent evidence indicates that macrophages at the maternal-fetal interface adapt to a phenotype characterized by alternative activation (M2 polarization) and exhibit immunosuppressive functions that favor the maintenance of pregnancy. The bias of M2 decidual macrophages toward M1 has been clinically linked to pregnancy-related complications, such as preeclampsia and preterm delivery. The aim of this study was to investigate the effect of Toxoplasma gondii PRU strain infection on the bias of decidual macrophage polarization and its contribution to adverse pregnancy outcomes. A mouse model with adverse pregnancy outcome was established by infection with T. gondii PRU strain and the expression levels of functional molecules in decidual macrophages of mice were measured. The results showed that T. gondii infection caused seriously adverse pregnancy outcome in mice. The placentae of infected mice showed obvious congestion and inflammatory cell infiltration. The expression of CD206, MHC-II, and arginase-1 considered as M2 markers was decreased in decidual macrophages after T. gondii infection, whereas the expression of CD80, CD86, iNOS, and cytokines TNF-α and IL-12 considered as M1 markers was increased. Furthermore, iNOS-positive expression was observed in the decidua basalis of infected mice. Our results indicated that T. gondii infection was responsible for the bias of M2 decidual macrophages toward M1, which changes the immunosuppressive microenvironment at the maternal-fetal interface and contributes to adverse pregnancy outcomes.

Comparing the vascular thromboembolic events following arteriovenous fistula in Chinese population with end-stage renal diseases receiving Clopidogrel versus Beraprost sodium therapy: a retrospective cohort study.

BACKGROUND: To assess the time to first on-study vascular thromboembolic events (VTEs) of clopidogrel (CL) or beraprost sodium (BPS) in Chinese population with end-stage renal disease (ESRD) treated with arteriovenous fistula (AVF) surgery. METHODS: From Jan 2009 to May 2015, 346 ESRD cases suffering an AVF surgery and undergoing oral administration of 75 mg CL (initial dose of 300 mg), 1 time/day, for 4 weeks or 40 µg BPS, 3 times/day, for 4 weeks were retrospectively assessed. The primary outcome was time to first on-study VTE. RESULTS: In total, 222 ESRD cases (CL, n = 112; BPS, n = 110) were assessed, with a median follow-up time of 38.1 months (range, 37-40 months). The mean time to first on-study VTE was 1.2 weeks (0.5-2.3) and 1.8 weeks (1.2-3.8) for CL and BPS, respectively (HR 0.27, 95% CI 0.16-1.45; P = 0.00). An increased incidence of VTEs was found during the 1th-month follow-up, with rates of 14.2 and 5.5% for CL and BPS, respectively (P = 0.03). The difference persisted over time, with rates of 24.1 and 11.8% at final follow-up, respectively (P = 0.02). CONCLUSION: CL with an increased risk of VTEs tended to have a VTE within the 1st month after cessation compared with BPS.

Erlotinib versus gefitinib for brain metastases in Asian patients with exon 19 EGFR-mutant lung adenocarcinoma: a retrospective, multicenter study.

BACKGROUND: The purpose of this study was to compare clinical outcomes of Erlotinib versus Gefitinib in the treatment of Asian patients with exon 19 EGFR-mutant lung adenocarcinoma and newly diagnosed brain metastases. METHODS: Consecutive Asian patients with exon 19 EGFR-mutant lung adenocarcinoma and newly diagnosed brain metastases were identified and initially received peroral administration of 150 mg/d erlotinib or 250 mg/d gefitinib during 2009-2015. Overall survival (OS) was the primary endpoint. Progression-free survival (PFS) was the second endpoint. RESULTS: The cohort consisted of 227 Asian patients (erlotinib-treated cohort: n = 112, mean age = 58.5 years [SD: 20.13]; gefitinib-treated cohort: n = 115, mean age = 58.4 years [SD: 19.52]). In a multivariate analysis controlling for age, sex and time span of smoking history, significant difference was detected in the 36-month OS between erlotinib and gefitinib groups (58.3% vs. 49.1%, p = 0.012). There was also significant difference in the 36-month PFS between erlotinib and gefitinib groups (64% vs. 53%, p = 0.013). CONCLUSION: For Asian patients with exon 19 EGFR-mutant lung adenocarcinoma and brain metastases, erlotinib was associated with a significantly longer OS and a more prolonged PFS and compared with gefitinib.

Denosumab versus zoledronic acid for preventing symptomatic skeletal events in Asian postmenopausal women with oestrogen-receptor-positive advanced breast cancer: an outcome analyses with a mean follow-up of 3 years.

BACKGROUND: The purpose of this study was to evaluate the efficacy of denosumab or zoledronic acid (ZA) using symptomatic skeletal events (SSEs) as the primary endpoint in Asian postmenopausal women with oestrogen-receptor-positive advanced breast cancer. METHODS: Asian postmenopausal women with oestrogen-receptor-positive advanced breast cancer receiving subcutaneous denosumab 120 mg Q4W, or intravenous ZA 4 mg Q4W until the primary analysis cut-off date were retrospectively analysed in the Hong Kong Practice-Based Cancer Research Center(HKCRC) from March 2011 to March 2013. The time to first on-study SSE that was assessed either clinically or through routine radiographic scans was the primary endpoint. RESULTS: 242 patients received denosumab or ZA treatment (n = 120, mean age of 64.9 years (SD 3.01) and n = 122, 65.4 years (3.44), respectively). The median times to first on-study SSE were 14.7 months (12.9-45.6) and 11.7 months (9.9-45.6) for denosumab and ZA, respectively (hazard ratio, HR 0.44, 95% CI 0.71-2.95; p = 0·0002). Compared with the ZA group, denosumab-treated patients had a significantly delayed time to first SSE (HR 0.65 [95% CI 0.29-1.45], p < 0.0001). An increased incidence of SSE was found in the 16-month follow-up with rates of 2.1 and 10.7% for denosumab and ZA, respectively (P = 0.033). The difference persisted with time with rates of 8.3 and 17.2% at the final follow-up, respectively (P < 0.05). CONCLUSION: In postmenopausal women aged ≥60 years with oestrogen-receptor-positive advanced breast cancer, denosumab significantly reduced the risk of developing SSEs compared with ZA. The findings of this pilot trial justify a larger study to determine whether the result is more generally applicable to a broader population.

Conversion to total hip arthroplasty after failed proximal femoral nail antirotations or dynamic hip screw fixations for stable intertrochanteric femur fractures: a retrospective study with a minimum follow-up of 3 years.

BACKGROUND: Conversion to total hip arthroplasty (CTHA) is a relatively common procedure after a failed dynamic hip screw (DHS) or proximal femoral nail anti-rotation (PFNA) fixation of intertrochanteric fractures, but there have been far fewer reports specifically describing the long-term results of CTHA after failed treatments of stable intertrochanteric fractures with DHS or PFNA. The aim of the present study was to compare the clinical and radiological outcomes of CTHA after failed PFNA or DHS fixations of stable intertrochanteric fractures after a minimum follow-up of 3 years. METHODS: Between January 2005 and April 2014, we retrospectively reviewed 142 active elderly patients treated at our institution (a single institution study). A total of 72 patients (72 hips; 41 women, 31 men; mean age 76.9 years old; range 60-92 years old) who underwent conversion of a failed PFNA to a THA were compared with 70 patients (70 hips; 36 women, 34 men; mean age 75.0 years old; range 60-90 years old) who underwent CTHA after a failed DHS fixation. The mean follow-up periods were 48 (range 43-52) and 48 (range 44-52) months for the DHS and PFNA groups, respectively. Clinical and radiologic evaluations were performed on all patients. The primary outcome was the Harris Hip Score (HHS). The secondary outcomes were the complication rates. RESULTS: The Harris Hip Score (HHS) improved from 50.61 ± 3.23 preoperatively to 85.28 ± 4.45 at the last follow-up in the PFNA group and from 51.46 ± 3.90 to 84.50 ± 4.34 in the DHS group, with no significant differences noted between the groups at each follow-up (P > 0.05). However, the complication rate in the converted DHS patients was significantly higher (42.9%) than that in the converted PFNA patients (20.8%; P = 0.003). Thirty-seven PFFs (2.4%) occurred during a mean follow-up of 44.4 months. The incidence of periprosthetic fractures was found to be significantly higher (P = 0.021) for the DHS group (15.7%) than for the PFNA group (4.2%). CONCLUSIONS: CTHA after failed DHS fixations of stable intertrochanteric fractures might be associated with a significantly higher complication rate than CTHA after failed PFNA fixations. Therefore, PFNA patients with stable intertrochanteric fractures may be more suitable for CTHA.

Recombinant human endostatin inhibits TNF-alpha-induced receptor activator of NF-κB ligand expression in fibroblast-like synoviocytes in mice with adjuvant arthritis.

Bone loss is a critical pathology responsible for the functional disability in patients with rheumatoid arthritis (RA). It is well known that receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) plays a crucial role in bone loss in RA. The purpose of this study was to determine whether recombinant human endostatin (rh-endostatin) mediates bone erosion in RA by regulation of RANKL expression in an experimental model of RA, consisting of mice with adjuvant-induced arthritis (AA). Cultured AA fibroblast-like synoviocytes (FLSs) obtained from these mice were induced by tumor necrosis factor-α (TNF-α) combined with or without rh-endostatin. The levels of RANKL and osteoprotegerin (OPG) mRNA, soluble and membrane-bound proteins were assessed by real-time PCR, ELISA, and Western blotting. Western blotting and the luciferase reporter assay were used to study related signaling pathways. Rh-endostatin inhibited RANKL mRNA expression, soluble and membrane-bound protein expression in AA FLSs but not in CD4+ T cells. However, OPG expression and secretion was not affected by rh-endostatin in AA FLSs. Molecular analysis demonstrated that rh-endostatin significantly inhibited TNF-α-induced MAPK and AP-1 signaling pathways. Moreover, rh-endostatin attenuated TNF-α-induced NF-κB signaling by suppressing the phosphorylation level of inhibitor kappaBα (IκBα) and nuclear translocation of NF-κB p65 in FLSs from mice with AA. These results provide the first evidence that rh-endostatin inhibits TNF-α-induced RANKL expression in AA FLSs.

The Cytotoxic Effect of the Benzene Metabolite Hydroquinone is Mediated by the Modulation of MDR1 Expression via the NF-κB Signaling Pathway.

BACKGROUND/AIMS: Benzene is a toxic chemical whose leukemogenic effects have been studied for decades. The mechanisms of benzene-induced toxicity and leukemogenicity are not fully understood, although the involvement of several pathways has been suggested, including oxidative stress, DNA damage, cell cycle regulation and programmed cell death. In the present study, we investigated the effect of hydroquinone (HQ), a major benzene metabolite, on the viability of bone marrow derived mesenchymal stem cells (BMSCs) and explored the underlying mechanisms. METHODS: First, we study the the effect of HQ on BMSCs cell viability, apoptosis and the expressions of MDR1 and NF-κB. Then we investigate the MDR1 on cell viability and cell apoptosis for BMSCs under HQ treatment. Finally, we studied the impact of nuclear factor κB (NF-κB) on the expression of MDR1. RESULTS: Our results showed that HQ decreased cell viability and promoted cell apoptosis of BMSCs, as determined by the MTT assay and flow cytometry. Western blotting and quantitative PCR showed that HQ downregulated the expression of the MDR1 gene by inhibiting the activation and nuclear translocation of the transcription factor NF-κB. Overexpression of MDR1 attenuated the inhibitory effect of HQ on cell viability in BMSC. CONCLUSION: The results of the present study suggest the involvement of the multidrug resistance membrane transporter MDR1 and the NF-κB pathway in the cytotoxicity of benzene and its metabolites. Further studies are necessary to clarify the role of the pathways involved and the crosstalk between them in mediating the effects of HQ in bone marrow progenitor cells.

IL-10 regulate decidual Tregs apoptosis contributing to the abnormal pregnancy with Toxoplasma gondii infection.

This study aims to investigate whether IL-10 regulate decidual Treg cells apoptosis to reverse the abnormal pregnancy outcomes with Toxoplasma gondii (T. gondii) infection. Recombinant mouse IL-10 (rIL-10) treatment and IL-10 deficiency (IL-10(-/-)) abnormal pregnancy animal models with T. gondii infection were established. Apoptosis related molecules cleaved Caspase-3 and Caspase-8 in decidual Treg cells were examined using flow cytometry. The levels of cleaved Caspase-3 and Caspase-8 in decidual Treg cells were up-regulated with T. gondii infection. Compared to infected group, the expressions of cleaved Caspase-3 and Caspase-8 in decidual Treg cells were down-regulated in rIL-10-treated group, while up-regulated in infected IL-10(-/-) group. In addition, pregnant outcomes were improved in rIL-10-treated group, while worse in IL-10(-/-) group compared to infected group. These findings revealed that IL-10 reduced the decidual Treg cells apoptosis contributing to improving adverse pregnant outcomes following T. gondii infection.

Adoptive transfer of Treg cells counters adverse effects of Toxoplasma gondii infection on pregnancy.

Acute infection with Toxoplasma gondii (T. gondii) during pregnancy is associated with adverse outcomes. The mechanisms that cause this phenomenon are not clear. Regulatory T cells (Tregs) are involved in maternal tolerance, and here we observed a decrease in the absolute numbers of CTLA-4(+) Tregs and PD-1(+) Tregs in spleen and at the fetal-maternal interface in T. gondii-infected mice. Our results suggest that T. gondii induces apoptosis of Tregs. Additionally, we found that the expression of CTLA-4 and PD-1 on Tregs at fetal-maternal interface were higher than on spleen cells from normal pregnant mice. Therefore, we adoptively transferred Tregs from fetal-maternal interface or from spleens of normal pregnant mice into infected pregnant mice. Pregnancy outcomes were improved when Tregs were transferred from the fetal-maternal interface but not from the spleen. The mechanism appears to be through up-regulation of the number of CTLA-4(+) Tregs and PD-1(+) Tregs and correction of the imbalance between tolerant cytokines (IL-10, TGF-ß) and inflammatory cytokines (IFN-γ). Our data indicate that Tregs at fetal-maternal interface express high levels of inhibitory molecules that play a vital immuno-protective role during pregnancy.

Molecular actions of ovarian cancer G protein-coupled receptor 1 caused by extracellular acidification in bone.

Extracellular acidification occurs under physiologic and pathologic conditions, such as exercise, ischemia, and inflammation. It has been shown that acidosis has various adverse effects on bone. In recent years there has been increasing evidence which indicates that ovarian cancer G protein-coupled receptor 1 (OGR1) is a pH-sensing receptor and mediates a variety of extracellular acidification-induced actions on bone cells and other cell types. Recent studies have shown that OGR1 is involved in the regulation of osteoclast differentiation, survival, and function, as well as osteoblast differentiation and bone formation. Moreover, OGR1 also regulates acid-induced apoptosis of endplate chondrocytes in intervertebral discs. These observations demonstrate the importance of OGR1 in skeletal development and metabolism. Here, we provide an overview of OGR1 regulation ofosteoclasts, osteoblasts, and chondrocytes, and the molecular actions of OGR1 induced by extracellular acidification in the maintenance of bone health.