TgMIC6 inhibition of autophagy is partially responsible for the phenotypic differences between Chinese 1 Toxoplasma gondii strains.

Chinese1 is the predominant Toxoplasma gondii lineage in China, and significant phenotypic differences are observed within the lineage. WH3 and WH6 are two representative strains of Chinese 1, which exhibit divergent virulence and pathogenicity in mice. However, virulence determinants and their modulating mechanisms remain elusive. A global genome expression analysis of the WH3 and WH6 transcriptional profiles identified microneme secretory protein 6 (MIC6), which may be associated with the phenotypic difference observed in WH3. In the present study, the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome-editing technique was used to generate a T. gondii microneme secretory protein (TgMIC6) knockout in WH3. Wild-type mice and different mouse and human cell lines were infected with the WH3, WH3-Δmic6, and WH6 strains. The survival rate of mice, related cytokine levels in serum, and the proliferation of parasites were observed. These results suggested that TgMIC6 is an important effector molecule that determines the differential virulence of WH3 in vivo and in vitro. Furthermore, MIC6 may enhance WH3 virulence via inhibition of host cell autophagy and activation of key molecules in the epidermal growth factor receptor (EGFR)-Akt-mammalian target of rapamycin (mTOR) classical autophagy pathway. CD40L was cleared in vivo by i.p injection of CD40L monoclonal antibody, and it was found that the virulence of WH3-Δmic6 to mice was restored to a certain extent in the absence of CD40L. This study elucidates the virulence determinants and immune escape strategies of Toxoplasma gondii in China. Moreover, these data will aid the development of effective strategies for the prevention and control of toxoplasmosis.

Exosomes Derived from Adipose Mesenchymal Stem Cells Promote Regeneration of Injured Liver in Minipigs.

Hepatic ischemia/reperfusion injury (IRI) is an important factor affecting liver regeneration and functional recovery postoperatively. Many studies have suggested that mesenchymal stem cells (MSCs) contribute to hepatic tissue repair and functional recovery through paracrine mechanisms mediated by exosomes. Minipigs exhibit much more similar characteristics of the liver to those of humans than rodents. This study aimed to explore whether exosomes from adipose-derived MSCs (ADSCs-exo) could actively promote liver regeneration after hepatectomy combined with HIRI in minipigs and the role they play in the cell proliferation process. This study also compared the effects and differences in the role of ADSCs and ADSCs-exo in the inflammatory response and liver regeneration. The results showed that ADSCs-exo suppressed histopathological changes and reduced inflammatory infiltration in the liver; significantly decreased levels of ALT, TBIL, HA, and the pro-inflammatory cytokines TNF-α, IL-6, and CRP; increased levels of the anti-inflammatory cytokine IL-10 and the pro-regeneration factors Ki67, PCNA, CyclinD1, HGF, STAT3, VEGF, ANG1, ANG2; and decreased levels of the anti-regeneration factors SOCS3 and TGF-ß. These indicators above showed similar changes with the ADSCs intervention group. Indicating that ADSCs-exo can exert the same role as ADSCs in regulating inflammatory responses and promoting liver regeneration. Our findings provide experimental evidence for the possibility that ADSCs-exo could be considered a safe and effective cell-free therapy to promote regeneration of injured livers.

Comparison of Novel 3D-printed Stepped Porous Metal Cones and Metaphyseal Sleeves for Reconstruction of Severe Knee Bone Defects: Short-term Clinical Outcomes.

OBJECTIVE: Both porous metal cones and metaphyseal sleeves are excellent implants for reconstructing severe bone defects in the knee joint, but they both exhibit design limitations. The porous metal cone, especially, has significant room for improvement in its shape design. The existing porous metal cones often feature a conical external surface with a relatively small taper, potentially compromising both rotational and axial stability. To improve both axial and rotational stability in porous metal cones, we developed a 3D-printed stepped porous metal cone. This study aimed to assess the short-term clinical outcome of the 3D-printed stepped porous metal cone and to compare it with the clinical outcome of patients who underwent revision total knee arthroplasty (rTKA) with the metaphyseal sleeves during the same period. METHOD: Patients who underwent total knee arthroplasty revision with metaphyseal bone defect reconstruction from 2019 to 2021 were retrospectively analyzed. A total of 61 patients were enrolled in the study, including 15 patients using 3D-printed stepped porous metal cones and 46 patients using metaphyseal metal sleeves. Thirty patients using metaphyseal sleeves were screened by propensity score matching method and compared with those using stepped cones. Analysis included the American Knee Society Score, the Hospital for Special Surgery knee score, the Western Ontario and McMaster Universities Arthritis index, the Short Form 12 (SF-12) health survey, and radiographic assessment with a mean follow-up of 28.5 ± 8.3 months. To conduct comparative analyses, unpaired Student's t-tests were employed for continuous variables, while categorical variables were analyzed using the appropriate Fisher exact or chi-squared test. RESULTS: In this study, the survival rates of both the stepped cone and metaphyseal sleeve were 100%. There was no statistically significant difference in postoperative knee function scores between the two groups (p > 0.05). However, patients in the cone group had significantly higher mental component summary scores on the SF-12 scale (p < 0.05) and higher increases in mean postoperative physical component summary scores than patients in the sleeve group (p < 0.05). In addition, patients in the cone group experienced fewer intraoperative and postoperative complications compared to the sleeve group. CONCLUSION: The 3D-printed stepped porous metal cone can effectively reconstruct bone defects in complex rTKA and provide satisfactory early clinical and radiographic results. The 3D-printed stepped cone provides a more stable structure similar to the sleeve while maintaining the original benefits of the cone making it a promising choice for rTKA.

Metaphyseal Metal Sleeves for Reconstruction of Severe Knee Bone Defects: Excellent Survival Rate at a Mean Follow-Up of 6.4 Years.

OBJECTIVE: Management of bone loss in complex primary and revision total knee arthroplasty is key to the surgeries. Metaphyseal metal sleeves have been increasingly used recently to reconstruct severe knee metaphyseal bone defects. This study aimed to investigate the outcomes of the metaphyseal sleeve reconstructing Anderson Orthopedic Research Institute (AORI) type II and type III bone defects of knee joint. METHODS: From 2014 to 2019, a total of 44 knees were enrolled in this clinical retrospective study after the screening, including seven cases of primary TKA and 37 cases of revision TKA. The types of bone defects involved in this study were AORI types II and III, and did not involve AORI type I bone defects. Patients' knee function preoperatively and postoperatively as well as quality of life were recorded and analyzed. Analysis included the American Knee Society Score (KSS), hospital for special surgery knee score (HSS), the Western Ontario and McMaster Universities (WOMAC) index, the Short Form 12 (SF-12) health survey, visual analogue scale score, and radiographic assessment with a mean follow-up of 6.4 years. Paired t-tests were used to determine the significance of changes in clinical scores and knee mobility. RESULTS: A mean follow-up of 77.2 (±17.6, standard deviation [SD]) months was performed, and none of the patients underwent knee revision for infection or aseptic loosening. At the last follow-up, the KSS knee score changed statistically from 37.1 (±19.7) preoperatively to 86.5 (±13.6, SD, p < 0.001) postoperatively and the KSS function score from 32.7 (±24.0) preoperatively to 78.3 (±15.6, SD, p < 0.001) postoperatively. The knee mobility improved from a mean of preoperative 72.61° (±33.42°, SD) to 108.52° (±24.15°, SD, p < 0.001). Postoperative radiographs showed that the host bone was tightly integrated with the metaphyseal metal sleeve, and there was no obvious translucent line formation around the sleeve. Of the patients, 86.4% had a postoperative satisfaction score ≥8 (10-point scale). CONCLUSION: At the mean follow-up of 6.4 years, the survival rate of the metaphyseal sleeves was 100%. Metaphyseal sleeves combined with cementless stems is an excellent and viable option for reconstruction of AORI type II and type III bone defects of the knee.

Application of three-dimensional cell culture technology in screening anticancer drugs.

The drug development process involves a variety of drug activity evaluations, which can determine drug efficacy, strictly analyze the biological indicators after the drug action, and use these indicators as the preclinical drug evaluation criteria. At present, most of the screening of preclinical anticancer drugs mainly relies on traditional 2D cell culture. However, this traditional technology cannot simulate the tumor microenvironment in vivo, let alone reflect the characteristics of solid tumors in vivo, and has a relatively poor ability to predict drug activity. 3D cell culture is a technology between 2D cell culture and animal experiments, which can better reflect the biological state in vivo and reduce the consumption of animal experiments. 3D cell culture can link the individual study of cells with the study of the whole organism, reproduce in vitro the biological phenotype of cells in vivo more greatly, and thus predict the activity and resistance of anti-tumor drugs more accurately. In this paper, the common techniques of 3D cell culture are discussed, with emphasis on its main advantages and application in the evaluation of anti-tumor resistance, which can provide strategies for the screening of anti-tumor drugs.

Exosomes from adipose-derived mesenchymal stem cells can attenuate liver injury caused by minimally invasive hemihepatectomy combined with ischemia-reperfusion in minipigs by modulating the endoplasmic reticulum stress response.

AIMS: Hepatic ischemia-reperfusion injury (IRI) impairs postoperative recovery of liver function after liver resection or transplantation. It is crucial to minimize liver injury during surgery in order to improve patient survival and quality of life. The aim of this study was to explore the therapeutic efficacy of exosomes from adipose-derived mesenchymal stem cells (ADSCs-exo) against hepatectomy combined with IRI injury and compare that with the effect of adipose-derived mesenchymal stem cells (ADSCs). MAIN METHOD: Minimally invasive hemihepatectomy combined with hepatic IRI was established in minipigs. A single dose of ADSCs-exo, ADSCs or PBS was injected through the portal vein. The histopathological features and function of the liver, and the oxidative stress levels, endoplasmic reticulum (ER) ultrastructure and ER stress (ERS) response were analyzed pre- and postoperatively. KEY FINDINGS: ADSCs-exo alleviated the histopathological injuries and ultrastructural changes in the ER, and significantly improved ALP, TP and CAT levels. Furthermore, ADSCs-exo treatment also downregulated ERS-related factors such as GRP78, ATF6, IRE1α/XBP1, PERK/eIF2α/ATF4, JNK and CHOP. The therapeutic effects of ADSCs-exo and ADSCs were similar. SIGNIFICANCE: Intravenous administration of a single dose of ADSCs-exo is a novel cell-free therapeutic approach to improve surgery-related liver injury. Our findings provide evidence of the paracrine effect of ADSCs and an experimental basis for treating liver injury with ADSCs-exo instead of ADSCs.

A combination of acidic electrolyzed water with modified atmosphere packaging improves quality of jujube during cold storage by enhancing antioxidant activity.

This study aimed to investigate the effects of a combination of acidic electrolyzed water (AEW) and modified atmosphere packaging (MAP) on the quality of jujube stored at 1 ± 0.5°C for 40 days. Jujube was treated with AEW + MAP, AEW, and MAP, respectively, to identify an appropriate preservation method based on the changes of quality indicators, activities of antioxidant enzymes and nonenzymatic antioxidant systems, malondialdehyde (MDA) content, and cell membrane permeability. Results showed that the combined treatment maintained higher storage quality of jujube than the other three treatments. The combined treatment significantly suppressed softening, weight, and color loss and maintained total soluble solid and titratable acidity. Moreover, the combined treatment improved antioxidant capacity showing high levels of nonenzymatic antioxidant systems (ascorbic acid and 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity), and the activities of antioxidant enzymes (ascorbate peroxidase, superoxide dismutase, and catalase). These effects remarkably suppressed the increase of MDA level and cell membrane permeability, thereby inhibiting oxidative damage and alleviating quality deterioration. Furthermore, kinetic model indicated that AEW + MAP decreased rate constant of quality deterioration. Principal component analysis also showed that AEW + MAP treatment alleviated quality deterioration, with higher comprehensive score than other treatments. In summary, AEW + MAP was an effective preservation method to maintain storage quality and delay postharvest senescence of jujube. PRACTICAL APPLICATION: In this study, a combination of acidic electrolyzed water (AEW) with modified atmosphere packaging (MAP) has been found to have effective preservation effects on jujube. AEW + MAP treatment improved quality of jujube during cold storage mainly by enhancing antioxidant capacity. The combined treatment may provide a new preservation technology for jujube.

ADSCs-exo attenuates hepatic ischemia-reperfusion injury after hepatectomy by inhibiting endoplasmic reticulum stress and inflammation.

Hepatic ischemia-reperfusion (I/R) injury commonly occurs during liver surgery. Exosomes from adipose-derived stem cells (ADSCs-exo) induce a hepatoprotective effect during hepatic I/R injury. This study aimed to investigate the possible mechanism by which ADSCs-exo attenuates hepatic I/R injury in rats. Rats were randomly divided into four groups: Sham, I30R + PH, ADSCs, and ADSCs-exo groups. Liver tissues were collected immediately after 24 h of reperfusion for further analyses. The content of inflammatory factors in liver tissue was detected using enzyme-linked immunosorbent assay. The pathological changes in liver tissue were analyzed using HE staining. Transmission electron microscopy was used to visualize the ultrastructural changes of hepatocytes. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to detect the expression of endoplasmic reticulum stress (ERS)-related genes and proteins. Liver histomorphology and hepatocyte ultrastructure changes improved after ADSCs-exo treatment. Moreover, ADSCs-exo treatment significantly downregulated tumor necrosis factor-α, interleukin-1ß (IL-1ß), and IL-6 levels while upregulating IL-10 levels. Western blot analysis suggested that the protein expressions of GRP78, p-PERK, p-eIF2α, p-IRE1α, XBP1s, ATF-6, ATF-4, CHOP, p-JNK, cleaved-Caspase-3, cleaved Caspase-9, and cleaved Caspase-12 significantly decreased after ADSCs-exo treatment. RT-qPCR results demonstrated that mRNA expression of GRP78, IRE1α, XBP1, ATF-6, ATF-4, CHOP, JNK, Caspase-3, Caspase-9, and Caspase-12 markedly reduced after ADSCs-exo treatment. In conclusion, ADSCs-exo protects against hepatic I/R injury after hepatectomy by inhibiting ERS and inflammation. Therefore, ADSCs-exo can be considered as a viable option for the treatment of hepatic I/R injury.

HMGB1/RAGE axis accelerates the repair of HUVECs injured by pathological mechanical stretching via promoting bFGF expression.

AIM: During hypertension-induced endothelial dysfunction, periodic mechanical stretching (MS) activates related inflammatory pathways and leads to endothelial damage, but the underlying mechanisms remain unknown. The present study aimed to determine the injury of HUVECs caused by overstretching and the role of HMGB1-RAGE pathway in HUVECs after injury. MAIN METHODS AND KEY FINDINGS: Human umbilical vein endothelial cells (HUVECs) were cultured and seeded in BioFlex™ plates (six wells). Cells were exposed to 5% (physiological state) and 20% (pathological state) mechanical stretch at 1 Hz for 12 or 24 h in a Flexcell-5000™, with unstretched cells serving as controls. It was found that excessive MS can inhibit cell viability, proliferation, and tube-forming ability resulting in disordered cell arrangement and orientation, slowing cell migration. All these changes cause endothelial damage compared to physiological MS. Endothelial cells (ECs) promote cell migration and self-repair after injury by increasing the High-mobility group box 1 (HMGB1) expression. Experiments and protein prediction networks have shown that HMGB1 can also promote the expression of downstream protein bFGF by binding to receptor for advanced glycation end products (RAGE). Interestingly, VEGF protein expression did not change significantly during this repair process, implying that bFGF replaces the role of VEGF in vascular endothelial repair. SIGNIFICANCE: The present study demonstrates that in the context of endothelial injury caused by excessive MS, the HMGB1/RAGE/bFGF pathway is activated and promotes endothelial repair after injury. Therefore, understanding these mechanisms will help find new therapies for diseases such as hypertension, atherosclerosis, and aneurysm formation.

The application of custom-made 3D-printed titanium augments designed through surgical simulation for severe bone defects in complex revision total hip arthroplasty.

BACKGROUND: With the development of radiology and three-dimensional (3D) printing technology, custom-made 3D-printed titanium augments have been more widely used. However, the radiological and clinical outcomes of custom-made augments lack reports. To better understand the clinical effect of using 3D-printed titanium augments and the significance of accurate placement, the aim of this study was to assess the outcomes when using custom-made 3D-printed titanium augments and to validate the idea that surgical simulation should be done before designing custom-made augments. METHODS: A retrospective review was conducted on 31 surgical simulations and revision total hip arthroplasties using custom-made 3D-printed titanium augments. The safe zone, cup position, and hip rotation center were measured on anteroposterior radiographs. Clinical outcomes were assessed with a mean 21.1 months of follow-up. RESULTS: All patients were positioned within the safe zone, and none of the acetabular cups nor the custom-made augments had any evidence of migration at the latest follow-up. A strong correlation was found between the planned cup position and the postoperative position. The average vertical position of the center of rotation was significantly increased from 3.55 cm to 2.35 cm. The mean Harris Hip Score was increased from 40.81 preoperatively to 65.46 postoperatively. Complications included gait abnormality, groin pain, fracture of the greater trochanter, and partial palsy of the sciatic nerve. However, patient satisfaction reached 92.3%. CONCLUSION: Surgical simulations help to design custom-made augments accurately and improve surgical plans. Acetabular components supported with custom-made 3D-printed augments is a useful method to bridge severe bone deficiencies. In this study, both the radiologic results and clinical outcomes were favorable. LEVEL OF EVIDENCE: Level 4.

The optimal screw-hole positions of the eccentric revision cup based on a morphological study.

BACKGROUND: Bridging bone defects in revision total hip arthroplasty is a challenge to orthopedic surgeons. The eccentric revision cup is a progression of jumbo cup. Our aim is to confirm the optimal screw-hole positions of the eccentric revision cup by morphological measurements of three-dimensional pelvic reconstruction. METHODS: Eighty CT images were converted to virtual three-dimensional bones. After simulating the surgery procedure, all available screw holes were inserted with the screws in virtual. By measuring the length of the screw in the pelvic bone, we determined the rich bone stock area. Then the screw holes were designed according to the characteristics of bone stock distribution. The peripheral screw-hole cluster and inner screw-hole cluster were studied respectively. RESULTS: For peripheral screw-hole cluster, five screw holes were evenly distributed between point A and point B in the thicker rim. For inner screw-hole cluster, screw hole 1 and screw hole 2 are the recommended inner screw holes. CONCLUSION: The eccentric revision cup has inherited the strengths of jumbo cup besides several unique advantages, including using the peripheral screws enhancing primary stability; decreasing the shift of hip rotation center and restoring biomechanical function; reducing the risk of dislocation because of the smaller head-cup differences; increasing the contact area between the outer cup and the host bone while maintaining a normal inclination of the inner cup. In this study, we confirmed the optimal screw-hole positions of the eccentric revision cup by surgical simulation and morphological measurement. However, biomechanical tests are still being further explored.

Core Decompression with Local Administration of Zoledronate and Enriched Bone Marrow Mononuclear Cells for Treatment of Non-Traumatic Osteonecrosis of Femoral Head.

OBJECTIVE: To investigate the efficacy and safety of core decompression (CD) with local administration of zoledronate and enriched bone marrow mononuclear cells (BMMCS) for the treatment of non-traumatic osteonecrosis of femoral head (ONFH). METHODS: A total of 17 patients (30 hips) diagnosed with stage II and III ONFH according to the 2019 revised Association for Research on Osseous Circulation (ARCO) staging criteria from 2012 to 2014 were retrospectively reviewed. The patients received the following therapy: the BMMCs and zoledronate were injected into the necrotic zone, respectively, along with CD. The mean age of the patients was 36.8 years; 14 were men and three were women. All patients included had non-traumatic ONFH and a minimum follow-up of 5 years, which ended when total hip arthroplasty (THA) was performed. Imaging modalities, including plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI) were taken pre- and postoperatively. Harris hip score (HHS) was used to evaluate the functional outcomes of femoral head necrosis. Kaplan-Meier analysis was adopted to determine the probability of survivorship with THA as the end point in this series of patients. The correlation between radiological progression or THA and related risk factors were further analyzed. All complications were recorded. RESULTS: With THA as the follow-up endpoint, All patients were followed up for an average of 69.1 ± 20.5 months (range, 18-95 months). Preoperative imaging found six hips (20%) at ARCO stage II, 14 hips (46.7%) at stage IIIA, 10 hips (33.3%) at stage IIIB. Fourteen hips (46.7%) shown progression radiologically, while six hips (20%) underwent TKA among these patients with hip preservation. The cumulative survival was 80% (95% CI, 0.608-905) at 5 years with THA as the end point. HHS improved from 63.3 ± 8.7 preoperatively to 74.6 ± 20.6 postoperatively (P = 0.000). Radiological progression was found to be associated with ARCO stage, Japanese Investigation Committee (JIC) type, and corticosteroid exposure (P = 0.047; P = 0.012; P = 0.031). However, no correlation was found between conversion to THA and the known risk factors. No major complication was reported, with only four patients complaining about general weakness and muscle soreness, and all disappeared within 2-3 days. CONCLUSIONS: The novel treatment modality could relieve pain, delay the progression of collapse, which might be an effective and safe method for hip preservation of early and mid-term ONFH. However, the effect of this method may be related to ARCO stage, JIC type, and corticosteroid exposure.

Factors influencing knee valgus alignment in Crowe type IV hip dysplasia after total hip arthroplasty.

BACKGROUND: Valgus deformity of the knee remains a complaint after total hip arthroplasty (THA) among some patients with Crowe type IV hip dysplasia. We aimed to identify the knee alignment in these patients before and after surgery, and to explore the factors contributing to postoperative knee valgus alignment. MATERIALS AND METHODS: We retrospectively reviewed a series of Crowe type IV patients who received THA between February 2010 and May 2019 in our hospital. The patients' medical data were collected from the hospital information system. On both preoperative and postoperative full limb length standing radiographs, the following parameters were measured: hip-knee-ankle angle (HKA), mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle, anatomical tibiofemoral angle, anatomical lateral distal femoral angle, femoral neck-shaft angle, pelvic obliquity, limb length, height and lateral distance of hip center, and femoral offset. Univariate and multivariate binary logistic regression were used to identify the factors influencing postoperative knee valgus alignment. RESULTS: A total of 64 Crowe type IV patients (87 hips) were included in the study. Overall, HKA improved from 176.54 ± 3.52° preoperatively to 179.45 ± 4.31° at the last follow-up. Those hips were subdivided into non-valgus group (≥ 177.0°, n = 65) and valgus group (< 177.0°, n = 22) according to postoperative HKA. Only postoperative mLDFA was a significant factor in the multivariate regression model. CONCLUSIONS: The postoperative mLDFA is a major factor related to knee valgus alignment after THA, which combines the preoperative anatomy and surgical reconstruction. Other factors previously published were found to have no significance. LEVEL OF EVIDENCE: III.

Exosomes from adipose-derived mesenchymal stem cells alleviate liver ischaemia reperfusion injury subsequent to hepatectomy in rats by regulating mitochondrial dynamics and biogenesis.

Hepatic ischaemia reperfusion injury (HIRI) is a major factor leading to liver dysfunction after liver resection and liver transplantation. Adipose-derived mesenchymal stem cells (ADSCs) have potential therapeutic effects on HIRI. Exosomes derived from ADSCs (ADSCs-exo) have been widely studied as an alternative of ADSCs therapy. Thus, the aim of this study was to evaluate the potential protective effect and related mechanism of ADSCs-exo on HIRI subsequent to hepatectomy. Rats were randomly divided into four groups: Sham, I30R+PH, ADSCs and ADSCs-exo group. After 24 h of reperfusion, liver and serum of the rats were immediately collected. ADSCs-exo improved liver function, inhibited oxidative stress and reduced apoptosis of hepatocytes in HIRI subsequent to hepatectomy in rats. ADSCs-exo significantly promoted the recovery of mitochondrial function, markedly increased the content of ATP in the liver tissue, and improved the ultrastructure of mitochondria in hepatocytes. Moreover, ADSCs-exo significantly increased the expression of OPA-1, MFN-1 and MFN-2 proteins related to mitochondrial fusion, while DRP-1 and Fis-1 mRNA and protein expression associated with mitochondrial fission were significantly decreased after the treatment with ADSCs-exo. In addition, ADSCs-exo significantly increased the expression of PGC-1α, NRF-1 and TFAM genes and proteins related to mitochondrial biogenesis. ADSCs-exo improves liver function induced by HIRI subsequent to hepatectomy in rats and maintains mitochondrial homeostasis by inhibiting mitochondrial fission, promoting mitochondrial fusion and promoting mitochondrial biogenesis. Therefore, ADSCs-exo may be considered as a potential promising alternative to ADSCs in the treatment of HIRI subsequent to hepatectomy.

Optimal intervention time of ADSCs for hepatic ischemia-reperfusion combined with partial resection injury in rats.

AIMS: Hepatic ischemia reperfusion injury (HIRI) is a complication of liver surgery and liver transplantation. Adipose-derived stem cells (ADSCs) can inhibit oxidative stress and inflammation through a paracrine effect. This study aimed to determine the optimal time window of ADSCs transplantation to restore liver function after HIRI. MAIN METHODS: A rat model of hepatic ischemia reperfusion combined with partial hepatectomy (HIR/PH) was established. The animals were injected intravenously with 2 × 106 rat ADSCs 2 h before, immediately after, or 6 h after surgery. Liver tissues and blood samples were collected for routine histological and biochemical assays. The molecular changes were analyzed by qRT-PCR and western blotting. KEY FINDINGS: ADSCs significantly improved liver tissue structure and decreased the levels of AST, ALT and ALP, which was indicative of functional recovery. In addition, transplantation of ADSCs immediately after operation decreased the levels of inflammation-related cytokines such as TNF-α, IL-1ß and IL-6, and significantly increased the activity of antioxidant enzymes. At the same time, the expression of MDA was decreased. Mechanistically, ADSCs activated the Keap1/Nrf2 pathway in the injured liver. Transplantation of ADSCs pre- and 6 h post-operation did not significantly affect some indices such as mRNA and protein expression of HO-1, and protein expression of NQO1. SIGNIFICANCE: Transplanting ADSCs immediately after surgery accelerated tissue repair and functional recovery of the liver by activating the Keap1/Nrf2 pathway, which inhibited hepatic inflammation and oxidative stress, and restored the hepatic microenvironment.

Three-Dimensional Distribution of Bone-Resorption Lesions in Osteonecrosis of the Femoral Head Based on the Three-Pillar Classification.

OBJECTIVE: To investigate three-dimensional distribution of bone-resorptive lesions based on the three-pillar classification and its effect on the disease progression of osteonecrosis of the femoral head (ONFH). METHODS: A total of 194 femoral head CT images from 117 patients diagnosed with ARCO stage II and III ONFH were retrospectively reviewed from April 2014 to February 2019. Three-dimensional structures of the femoral head and the bone-resorptive lesions were reconstructed. Using the three-pillar classification and coronal plane of the femoral head, we divided each femoral head into six regions to observe the location characteristics of bone-resorption lesions, and explore the destruction of different areas of the femoral head by the bone-resorptive lesions. Then the hips were divided into two groups based on whether they contained bone-resorption lesions and compared the difference of stage II and stage III between the two groups. RESULTS: The regional distribution revealed 39 (27.27%), 55 (38.46%), six (4.20%), 23 (16.08%), 17 (11.89%) and three (2.10%) bone-resorptive lesions in regions I, II, III, IV, V and VI respectively. The lateral pillar, AL (I + IV), contained 44.76% of the lesions, central pillar, C (II + V), 48.95%, and medial pillar, M (III + VI), 6.29%. Moreover, there were 81.82% bone-resorption lesions in anterolateral pillar, AL (I + II + IV), and 18.18% in posteromedial pillar, PM (III + V + VI). In all ONFH hips, the lateral pillar of 81(88.04%) femoral heads were affected, the central pillar of 84 (91.30%) femoral heads were affected, and the medical pillar of 29 (31.52%) femoral heads were affected. The ratio of ARCO stage III in the group with bone-resorption lesions was significantly higher than that of the group without bone-resorption lesions (76.09% vs 30.39%, P < 0.001). CONCLUSIONS: This study demonstrated that the bone-resorption lesions are mainly distributed in the lateral and central pillar of the femoral head, and the two pillars of the femoral head are usually involved by bone-resorption lesions. Furthermore, the ratio of ARCO stage III in the group with bone-resorption lesions was significantly higher than that of the group without bone-resorption lesions, suggesting that the bone-resorption lesions might accelerate the progression of ONFH.

RPN2 Predicts Poor Prognosis and Promotes Bladder Cancer Growth and Metastasis via the PI3K-Akt Pathway.

BACKGROUND: Ribophorin II (RPN2) is a highly conserved glycoprotein involved in the N-linked glycosylation of multiple proteins. RPN2 was reported to be associated with malignant phenotype in several tumors. However, the function of RPN2 in bladder cancer (BCa) remains unclear. METHODS: Expression of RPN2 in BCa and adjacent tissues was compared by bioinformatics analysis, immunohistochemistry, and Western blotting. qRT-PCR was performed to explore the correlation between RPN2 expression and various clinical features in 38 patients. We assessed the effects of RPN2 on the biological activity of BCa both in vitro and in vivo, and explored its potential mechanisms based on gene set enrichment analysis (GSEA). RESULTS: We found that RPN2 was highly expressed in human BCa compared with normal adjacent tissues. There was a significant positive correlation between higher RPN2 mRNA levels and tumor T stage, lymph node (LN) metastasis and the degree of pathological differentiation in 38 patients with BCa. We further demonstrated that RPN2 silencing inhibited the growth and metastasis of BCa both in vitro and in vivo. Western blotting revealed that RPN2 knockdown suppressed epithelial-mesenchymal transition (EMT) and inhibited the PI3K-Akt pathway. CONCLUSION: These data suggest that RPN2 functions as an oncogene to promote tumor development and is a promising prognostic factor and therapeutic target in BCa.

Local administration of zoledronic acid prevents traumatic osteonecrosis of the femoral head in rat model.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a refractory disease due to its unclear pathomechanism. Neither conservative treatment nor surgical treatment during the early stage of ONFH achieves satisfactory results. Therefore, this study aims to explore the available evidence on the effect of zoledronic acid on early-stage ONFH. METHODS: For groups were established:the Normal group, model group, Normal saline group(NS group) and zoledronic acid-treated group. The blood supply to the femoral head of animals in the model group and zoledronic acid-treated group was interrupted via a surgical procedure, and zoledronic acid was then locally administered to the femoral head. Four weeks after surgery, all the hips were harvested and evaluated by micro-CT and histopathology(H&E staining, TRAP staining, Toluidine blue staining and masson staining). RESULTS: The values of BMD, BS/BV and Tb.Th in the Normal group and zoledronic acid-treated group were significantly higher than those in the model group and NS group (p â€‹< â€‹0.05). The outcome of H&E staining, Toluidine blue staining and masson staining were consistent with that of micro-CT. CONCLUSION: The local administration of zoledronic acid in the femoral head had positive effects on the bone structure of the femoral head in a modified rat model of traumatic ONFH and offered a promising therapeutic strategy during the early stage of ONFH. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This article could provide a choice for treating patients who have osteonecrosis of femora head and can be the basic research for advanced development over this disease.

The Variation of the Pelvis in Unilateral Crowe Type IV Developmental Dysplasia of the Hip.

OBJECTIVE: To investigate variation of the pelvis in unilateral Crowe type IV developmental dysplasia of the hip (DDH) and analyze the reliability of pelvic landmarks. METHODS: We retrospectively received preoperative anteroposterior pelvic radiographs for 89 adult patients with unilateral Crowe type IV DDH at our institution between September 2008 and May 2019. Forty-eight patients without a false acetabulum was type IVA and 41 with a false acetabulum was type IVB. The heights of the ilium, acetabulum, and ischium areas in affected and unaffected sides were measured. The ratios of the three areas in entire pelvis are calculated. The discrepancies of bilateral iliac crest, inferior sacroiliac articulation, teardrop, and ischial tuberosity on the bisector of the pelvis were also measured. RESULTS: The mean heights of the ilium, acetabulum, ischium areas in the affected side were 74.4, 88.6, and 37.0 mm, respectively, in type IVA group and 77.7, 83.5, and 37.8 mm, respectively, in type IVB group. The heights in the unaffected side were 82.1, 84.6, and 43.8 mm, respectively, in type IVA group and 84.6, 82.0, and 44.0 mm, respectively, in type IVB group. The ratios of the ilium, acetabulum, ischium areas in affected side of Crowe type IVA group were 0.37, 0.44, and 0.19, respectively, and the ratios in unaffected side were 0.39, 0.40, and 0.21, respectively. The ratios in affected side of Crowe type IVB group were 0.39, 0.42, and 0.19, respectively, and the ratios in unaffected side were 0.40, 0.39, and 0.21, respectively. The discrepancies of bilateral iliac crest, inferior sacroiliac articulation, teardrop, and ischial tuberosity on the line of the bisector of the pelvis in Crowe type IVA group were 5.6, 5.2, 2.0, and 7.1 mm, respectively. Those in Crowe type IVB group were 8.1, 3.5, 3.5, and 4.9 mm, respectively. CONCLUSIONS: Pelvic asymmetry was a common occurrence in unilateral Crowe type IV DDH in adults. Furthermore, it should be reliable to use teardrop as pelvic landmark to balance leg length discrepancy in preoperative planning.

Pseudotumor and repeated dislocation after total hip arthroplasty with ceramic-on-metal bearing: a case report.

Pseudotumor is a rare complication following total hip arthroplasty (THA) with ceramic-on-metal (CoM) bearings. There is still in controversy about the using of CoM bearings when conducting surgery. We reported a case of a 47-year-old woman who underwent cementless CoM bearing THA because of left Crowe type III dislocation of the hip (DDH) in December 2009. One year after THA, she presented at our hospital complaining of crunching noise, pain, and decreased level of function. A revision surgery was performed because of left hip instability in December 2010, we adjusted the excessive anteversion of stem and replaced the head by using the long-neck ceramic head. In February 2019, she was admitted to our hospital complaining of repeated dislocation and fracture of greater trochanter. During the re-revision surgery, a pseudotumor and grey synovial sac were revealed. The metal liner was replaced with a ceramic liner and the greater trochanter was reattached using the Cable-Ready system. Clinical outcome was successful at 6 months postoperatively. This case vividly demonstrated CoM bearing should be avoided in THA. The pseudotumor highly destructed the periprosthetic soft tissues and the bone, which leaded to dislocation and periprosthetic fracture. The surgeon should be aware of the complication so that prompt diagnosis and treatment can be performed.