Is Prior Nonoperative or Operative Treatment of Dysplasia of the Hip Associated With Poorer Results of Periacetabular Osteotomy?

BACKGROUND: Understanding the implications of either nonoperative or operative treatment of developmental dysplasia of the hip (DDH) performed before periacetabular osteotomy (PAO) is critical to counseling patients and their families. There are limited studies, however, on PAO for the treatment of residual DDH after surgical intervention during childhood, and even less information about PAO after prior nonoperative treatment. QUESTIONS/PURPOSES: We analyzed patients who had undergone PAO for DDH and asked: Did patients with prior childhood treatment (either operative or nonoperative) (1) improve less in modified Harris hip score (mHHS), 12-item International Hip Outcome Tool (iHOT-12) score, or WOMAC score; (2) demonstrate more severe preoperative deformities; and (3) receive less complete radiographic correction and have more frequent complications than did patients whose hips had not undergone prior treatment? We also asked: (4) Were there subgroup differences among patients with DDH treated nonoperatively versus operatively before PAO in these same functional and radiographic parameters? METHODS: Between January 2011 and December 2020, a total of 90 PAOs were performed in 82 patients who had prior surgical or nonsurgical treatment. Of those, 3 patients (3 hips) with neuromuscular diseases were excluded, 4 patients (5 hips) were excluded for having received treatment after childhood, 7 hips that had undergone bilateral PAOs were excluded, and another 4 patients (4 hips) were lost to follow-up before the minimum study period of 2 years, leaving 71 patients (71 hips) for analysis (the previous treatment group). Among these, 32 patients had a history of previous surgery (the previous surgery group), and 39 patients had prior nonsurgical treatment (such as a Pavlik harness, closed reduction, spica casting) (the previous nonoperative group). During the same period, 1109 PAOs were performed in 956 patients who had no history of previous hip treatment. Following a 1:2 ratio, 142 patients (142 hips) were selected as the control group by matching for age (within 2 years difference), year of surgery (same year), and follow-up time (within 1-year difference). The patient characteristics for both the previous treatment group and the control group exhibited comparability, with mean ± SD follow-up durations of 49 ± 23 months and 48 ± 19 months, respectively. Within the previous 5 years, 3 patients (8%) in the previous nonoperative group, 4 patients (13%) in the previous surgery group, and 15 patients (11%) in the control group had not attended follow-up visits. We compared hip function and radiographic results between the two groups and performed a subgroup analysis between the previous surgery group and the previous nonoperative group. Hip function was assessed using the mHHS questionnaire, the WOMAC, and the iHOT-12 with attention to the minimum clinically important differences of these tools. The threshold values for clinically important improvement were 9.6 points, 13 points, and 16.1 points for the mHHS, iHOT-12, and WOMAC, respectively. Radiographic measurements included the lateral center-edge angle (LCEA), anterior center-edge angle (ACEA), Tönnis angle, acetabulum-head index, and acetabular wall index. We also evaluated Tönnis osteoarthritis grade and femoral head deformity. Occurrences of adverse radiographic events such as posterior column fracture, nonunion, stress fractures, insufficient coverage or overcoverage, acetabular protrusion, and progression of osteoarthritis were recorded. RESULTS: We found no clinically important differences in magnitude of improvement between the previous treatment group and the control group in terms of mHHS (mean ± SD 10 ± 12 versus 12 ± 12; p = 0.36), iHOT-12 (25 ± 18 versus 26 ± 19; p = 0.51), or WOMAC score (12 ± 12 versus 15 ± 19; p = 0.17). Preoperative deformity in the previous treatment group was more severe than in the control group (mean ± SD LCEA -1° ± 9° versus 5° ± 8°; ACEA -8° ± 18° versus 1° ± 14°; Tönnis angle 31° ± 7° versus 27° ± 7°; acetabulum-head index 56% ± 13% versus 61% ± 8%; all p < 0.001). In the previous treatment group, a higher percentage of patients exhibited flattening or irregularity of the femoral head compared with the control group (52% versus 9%; p < 0.001), and there was also a higher proportion of patients with Tönnis grade 1 or above (51% versus 42%; p < 0.001). Although there were still differences in LCEA, ACEA, and Tönnis angle between the two groups at the last follow-up, the differences were small, and the mean values were within the normal range. The previous treatment group had a higher risk of intraoperative posterior column fracture (14% and 5%; p = 0.02), insufficient acetabular coverage (20% and 8%; p = 0.01), and progression of osteoarthritis (17% and 8%; p = 0.04) compared with the control group. Subgroup analysis revealed no clinically important differences in magnitude of improvement between the previous surgery group and the previous nonoperative group in terms of mHHS (10 ± 14 versus 10 ± 11; p = 0.91), iHOT-12 (22 ± 21 versus 27 ± 14; p = 0.26), or WOMAC score (12 ± 14 versus 12 ± 11; p = 0.94). Apart from a higher proportion of patients who presented with arthritis (72% versus 34%; p = 0.01) and a smaller anterior wall index (11% ± 11% versus 20% ± 12%; p = 0.01) in the previous surgery group, all other preoperative radiographic parameters were consistent between the two groups. Additionally, the previous surgery group had a higher frequency of arthritis progression (28% versus 8%; p = 0.02), while the frequencies of other complications were similar between the two groups. Specifically, the frequencies of pubic ramus nonunion (22% versus 21%; p = 0.89), intraoperative posterior column fracture (19% versus 10%; p = 0.50), and insufficient acetabular coverage (25% versus 15%; p = 0.31) were high in both groups. CONCLUSION: We found no clinically important difference in the magnitude of improvement between patients who had childhood treatment and those who did not, but patients who had prior childhood treatment were more likely to experience serious complications, and radiographic correction in those patients was less complete. As in the case of patients who have had prior operative treatments, it is crucial not to overlook the unexpectedly severe deformity of residual DDH after previous nonoperative treatment and complications following PAO. Surgeons and patients alike should be aware of the potential for worse radiographic outcomes or an increased risk of complications when prior operative or nonoperative treatment has preceded PAO. Future studies might investigate optimal management strategies for this specific group of patients to improve outcomes and reduce complications. LEVEL OF EVIDENCE: Level III, therapeutic study.

Can we determine anterior hip coverage from pelvic anteroposterior radiographs? A study of patients with hip dysplasia.

PURPOSE: Insufficient coverage causes hip joint instability and results in hip pain. Anterior hip coverage can be determined on both pelvic anteroposterior (AP) radiographs and false profile (FP) radiographs. Four parameters are commonly used to determine the anterior coverage on pelvic AP radiographs: the crossover index, crossover sign, anterior wall index (AWI), and rule of thirds. This study aims to clarify the relationship between these 4 parameters on AP radiographs and the anterior center edge angle (ACEA) on FP radiographs. METHODS: In this study, 53 patients who underwent periacetabular osteotomy for hip dysplasia at our center between July 2020 and October 2020 were retrospectively reviewed. Four parameters on AP radiographs and the ACEA on FP radiographs before surgery and 6 months after surgery were measured and compared for each hip. RESULTS: Upon examining the 53 hips in this study, there was no correlation between either the crossover index and the ACEA (P = 0.66) or the crossover sign before surgery. The postoperative correlation between the crossover index and the ACEA was weak (r = 0.36, P = 0.007), and that between the crossover sign and the ACEA was moderate (r = 0.41, P = 0.003). There was a weak correlation between the AWI and ACEA both before (r = 0.288, P = 0.036) and after (r = 0.349, P = 0.011) the operation. Evaluation of the anterior coverage by the rule of thirds was also not consistent when determining the anterior coverage with the ACEA. CONCLUSION: Anterior coverage on AP radiographs is largely inconsistent with ACEA on FP radiographs, especially before the surgery. It is recommended to take FP radiographs routinely for determining anterior hip coverage.

Periacetabular osteotomy for Tönnis grade 2 osteoarthritis secondary to hip dysplasia.

PURPOSE: To investigate the clinical outcomes of periacetabular osteotomy (PAO) for Tönnis grade 2 osteoarthritis secondary to hip dysplasia. METHODS: Forty-nine patients (51 hips) with Tönnis grade 2 osteoarthritis secondary to hip dysplasia, followed by a mean of 52.3 months (range: 24.1 to 95.2 months), were reviewed. As a control group, 51 patients (51 hips) with Tönnis grade 1 osteoarthritis were matched for age, surgery date, and follow-up period. All patients were evaluated clinically with the use of modified Harris hip score (mHHS) questionnaire, WOMAC score, and the 12-item International Hip Outcome Tool (iHot-12). Radiographic measurements included the lateral centre-edge angle (LCEA), Tönnis angle, and anterior centre-edge angle (ACEA). Kaplan-Meier survivorship analysis was performed to predict a five year survival rate of no osteoarthritis progression. RESULTS: All functional scores and radiographic measurements of the two groups significantly improved at the final follow-up. There were no significant differences between the two groups either in functional scores or radiographic measurements. The five year survival rate of no osteoarthritis progression was 86.2% in Tönnis grade 2 group and 93.1% in Tönnis grade 1 group, respectively. In the Tönnis grade 2 group, the osteoarthritis progressed in six hips. Of which, four hips had an ACEA of < 25°. No osteoarthritis progression was found in hips with an ACEA > 40°. CONCLUSIONS: PAO yielded similar results for patients with Tönnis grade 2 and grade 1 osteoarthritis secondary to hip dysplasia. The majority of hips can be preserved without progression of osteoarthritis at five years postoperatively. The slight overcorrection anteriorly may be helpful in preventing osteoarthritis progression.

The lateral center-edge angle as radiographic selection criteria for periacetabular osteotomy for developmental dysplasia of the hip in patients aged above 13 years.

BACKGROUND: This retrospective study sought to delineate the radiographic characteristics of DDH patients over 13 years of age and investigate whether the lateral center-edge angle (LCEA) could serve as radiographic selection criteria for periacetabular osteotomy. METHODS: We enrolled patients with Hartofilakidis type I DDH without dislocation who underwent periacetabular osteotomy between August 2009 and August 2012. LCEA, anterior central edge angle (ACEA), femoral neck-shaft angle (FNSA), Shenton line and Tönnis acetabular index (AI) were evaluated by anteroposterior and 65° false⁃profile pelvic X-ray radiographs in the standing position. Femoral neck anteversion angle (FNA), labral lesion, labral inversion and cartilage lesion were evaluated by direct magnetic resonance arthrography. DDH was categorized by LCEA into four grades (grade I: 10° ≤ LCEA< 20°, grade II: 0° ≤ LCEA< 10°, grade III: -10° ≤ LCEA< 0°, grade IV: LCEA<-10) and osteoarthritis (OA) severity was assessed using Tönnis OA classification. Pearson correlation analysis was done between LCEA and other variables. RESULTS: Totally patients (274 hips) with a mean age of 27.3 years (range 13-47 years) were included. The mean LCEA was 3.5° (range: - 30° to 20°). Based on LCEA grades, grade I DDH was present in 104 hips, grade II in 40 hips, grade III in 76 hips, and grade IV in 54 hips. Based on Tönnis OA classification, 54.5% hips (150/274) were grade 0, 33.1% hips (91/274) grade 1, 8.4% hips (23/274) grade 2 and 4% hips (11/274) grade 3. Pearson correlation analysis showed a negative correlation between LCEA grade and Tönnis OA grades (r = 0.3987; P < 0.001). Cochran-Armitage trend test further showed a positive correlation between LCEA grades and labral lesion (P < 0.001) and interrupted Shenton line (P < 0.001). CONCLUSION: The LCEA classification scheme offers a simple and practical approach to categorize the level of acetabulum coverage on the femoral head, hip deformity and characteristics of DDH. Our findings could provide clinically useful guidance for orthopedic surgeons in preparation for periacetabular osteotomy in DDH patients aged above 13 years.

Protective potential of miR-146a-5p and its underlying molecular mechanism in diverse cancers: a comprehensive meta-analysis and bioinformatics analysis.

BACKGROUND/AIMS: Studies have shown that miR-146a-5p was differentially expressed in diverse cancers, but the associations between miR-146a-5p expression and prognosis across multiple types of cancer as well its potential targets and downstream pathways have not been comprehensively analyzed. In this study, we performed the first meta-analysis of the prognostic value of miR-146a-5p expression in diverse malignancies and explored prospective targets of miR-146a-5p and related signaling pathways. METHODS: A thorough search for articles related to miR-146a-5p was performed, and RNA-seq data from The Cancer Genome Atlas (TCGA) and microarray data from gene expression omnibus profiles were used to collect information about the prognostic value of miR-146a-5p. A comprehensive meta-analysis was conducted. Twelve platforms in miRWalk 2.0 were applied to predict targets of miR-146a-5p. TCGA RNA-seq data were used to validate the inverse relationships between miR-146a-5p and its likely targets. Subsequently, gene ontology and pathway analyses were conducted using Funrich version 3.1.3. Potential protein-protein interaction (PPI) networks were constructed. Potential target genes of miR-146a-5p in lung cancer were validated by RT-qPCR. RESULTS: We included 10 articles in the meta-analysis. In a pooled analysis, the high miR-146a-5p expression group showed a better overall survival in solid cancers, particularly in reproductive system cancers and digestive system cancers. A total of 120 predicted target genes were included in a bioinformatics analysis. Five pathways involving phospholipase C (PLC) and aquaporins (AQPs) were the most significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways. Moreover, the PPI network displayed the related signaling pathways and interactions among proteins. AQP1 and FYN were validated by RT-qPCR to be potential targets of miR-146a-5p in lung cancer. CONCLUSION: There is a close link between high miR-146a-5p expression and better overall survival in 21 types of solid cancer, especially in reproductive system and digestive system cancers. Furthermore, miR-146a-5p could inhibit diverse malignancies by modulating pathways linked to PLC or AQPs. In summary, miR-146a-5p is a potential prognostic biomarker and therapeutic target for various cancers.

Sciatic and femoral nerve injury among patients who received Bernese peri-acetabular osteotomy.

AIM: To investigate the incidence, risk factors, and the last follow-up recovery status of sciatic and femoral nerve injury among patients who received Bernese peri-acetabular osteotomy (PAO). PATIENTS AND METHODS: The clinical file of 643 consecutive patients who received PAO from June 2012 to June 2016 was retrospectively reviewed. The number of nerve injury patients was calculated and the causes of injury were recorded. RESULTS: The sciatic or femoral nerve injury occurred in eight patients (1.24%), including four sciatic nerve injuries and four femoral nerve injuries. The reasons for sciatic nerve injury included one direct sciatic nerve injury happened at the time when deep osteotomy penetrated the posterior column to cut the nerve trunk at the area where the nerve runs through out of the greater sciatic foramen during quadrilateral bone osteotomy. The other two direct sciatic nerve injuries occurred at the inside pelvis by long drill bit or Kirschner wire drilling before the transverse screw fixation. No direct injury reasons could be found for the remaining five patients with one partial sciatic nerve injury and four femoral nerve palsies. The three patients with direct sciatic nerve injuries were partly recovered at the last follow-up. Full recovery was found in one sciatic nerve injury and four femoral nerve injury patients. CONCLUSION: The sciatic nerve can be injured directly or indirectly during PAO. It is of great importance to understand the risk factors and the precautionary measures of nerve injuries during PAO.

Distinguishable Prognostic Signatures of Left- and Right-Sided Colon Cancer: a Study Based on Sequencing Data.

BACKGROUND/AIMS: Left- and right-sided colon cancers are considered to be two different diseases and have altered outcomes. However, specific molecules to predict the prognosis of left- and right-sided colon cancers are currently lacking. METHODS: Expression profiling of colon cancer were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) of left- and right-sided colon cancers were compared by DESeq analysis. The prognostic values of DEGs were assessed by univariate and multivariate Cox regression. Prognostic index models of two side colon cancers were conducted with prognostic values genes, respectively. Interaction of DEGs was then analyzed by the protein-protein interaction (PPI). Different biology function of two sides of colon cancer was assessed by Gene Set Enrichment Analysis (GSEA). RESULTS: A total of 167 DEGs were identified between left- and right-sided colon cancers based on TCGA data. Using univariate COX regression analysis, five genes (PHACTR3, CKMT2, CYP2W1, ERFE, HOXC4) were related to overall survival in left-sided, and eight distinguishable genes (EREG, ERFE, HOXC6, SLC22A31, TFF1, GFI1, ZG16, RASL10B) in right-sided. Further, left-sided prognostic model was established with PHACTR3 and CKMT2 (HR=2.040; 95%CI=1.004-4.145; P=0.049). Distinguishable prognostic signature for right-sided colon cancer was established based on EREG, ERFE, GFI1, and RASL10B (HR=3.530; 95%CI: 1.934-6.444; P< 0.001) in multivariate analysis. PPI analysis of 167 DEGs showed that CCL5, GNG4, GNLY, GZMH, DRD2, and FASLG genes were at the core of interaction network. In GSEA function analysis, four pathways, including antigen processing and presentation, natural killer cell mediated cytotoxicity, intestinal immune network for Iga production, and type I diabetes mellitus, were significantly enriched in the DEGs of the right-sided colon cancer. CONCLUSIONS: This study constructs a panel of potential prognostic model of left- and right-sided colon cancers, respectively. We also provide molecular biological alterations between left- and right-sided colon cancers.

Biological Effect and Mechanism of the miR-23b-3p/ANXA2 Axis in Pancreatic Ductal Adenocarcinoma.

BACKGROUND/AIMS: Accumulating evidence strongly suggests that microRNAs (miRNAs) modulate the expression of known tumor suppressor genes and oncogenes. In the present study, we found that the proliferation and invasion ability of pancreatic ductal adenocarcinoma (PDAC) cells were significantly suppressed by the overexpression of miR-23b-3p. In addition, there are miR-23b-3p binding sites in annexin A2 (ANXA2). Here, we investigated whether miR-23b-3p had an impact on the progression and metastasis of PDAC by targeting ANXA2. METHODS: Cell proliferation, migration, and invasion, and cell cycle assays were performed to explore the effect of miR-23b-3p on various malignant phenotypes of pancreatic cancer cells. The size of tumors was observed following miR-23b-3p overexpression in an in vivo chick chorioallantoic membrane assay. Dual-luciferase reporter, quantitative real-time PCR, western blot, and immunohistochemical analyses were used to validate the relationship between miR-23b-3p and ANXA2 in vitro. RESULTS: We observed that miR-23b-3p could bind specifically to the 3' untranslated region of ANXA2 and inhibit its expression. MiR-23b-3p overexpression downregulated the expression of ANXA2 mRNA in PDAC cells and limited the size of tumors or even prevented tumor formation. In addition, there was a negative correlation between miR-23b-3p expression and ANXA2 protein expression in clinical specimens. CONCLUSION: MiR-23b-3p inhibits the development and progression of PDAC by regulating ANXA2 directly.

The LncRNA NEAT1 Accelerates Lung Adenocarcinoma Deterioration and Binds to Mir-193a-3p as a Competitive Endogenous RNA.

BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) contribute to the development of multiple malignant tumors. Here, we focused on the biological function and underlying molecular mechanism of an lncRNA, nuclear-enriched abundant transcript 1 (NEAT1), in lung adenocarcinoma (LUAD). METHODS: In vitro experiments were conducted to determine the biological effects of NEAT1 in LUAD cells. A luciferase activity reporter assay was performed to corroborate the interaction between NEAT1 and miR-193a-3p. Data from Gene Expression Omnibus (GEO), Oncomine, The Cancer Genome Atlas (TCGA), and our in-house reverse transcription quantitative PCR (RT-qPCR) were combined to examine the expression of NEAT1 and miR-193a-3p in LUAD. To further explore the regulatory mechanism of NEAT1, we searched for putative target genes of miR-193a-3p from 12 online prediction databases and determined genes positively correlated with NEAT1 as candidate targets. Furthermore, we analyzed the expression of these selected genes using data from TCGA. RESULTS: In vitro experiments showed that knockdown of NEAT1 in LUAD cells markedly restrained cell proliferation, invasion, and migration and stimulated cell apoptosis. The dual-luciferase reporter assay demonstrated that miR-193a-3p directly targeted NEAT1 at its 3'-UTR. We then detected NEAT1 and miR-193a-3p in LUAD cells and normal lung epithelial cells and discovered high expression of NEAT1 and low expression of miR-193a-3p in LUAD cell lines. Simultaneously, the pooled results from the GEO, Oncomine, TCGA, and in-house RT-qPCR showed that the NEAT1 expression increased while the miR-193a-3p expression decreased in LUAD tissues versus normal lung tissues. Furthermore, the USF1 gene was not only upregulated in LUAD, but also positively correlated with NEAT1, suggesting that NEAT1 may function as a ceRNA to sponge miR-193a-3p and abrogate the inhibitory effect of miR-193a-3p on USF1. CONCLUSIONS: Our findings indicate that NEAT1 plays important roles in the occurrence and progression of LUAD. It may exert its role by acting as a ceRNA to regulate miR-193a-3p.

A Preliminary Investigation of PVT1 on the Effect and Mechanisms of Hepatocellular Carcinoma: Evidence from Clinical Data, a Meta-Analysis of 840 Cases, and In Vivo Validation.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) remains a difficult problem that significantly affects the survival of the afflicted patients. Accumulating evidence has demonstrated the functions of long non-coding RNA (lncRNA) in HCC. In the present study, we aimed to explore the potential roles of PVT1 in the tumorigenesis and progression of HCC. METHODS: In this study, quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was applied to detect the differences between PVT1 expression in HCC tissues and cell lines. Then, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were searched to confirm the relationship between PVT1 expression and HCC. Moreover, a meta-analysis comprising TCGA, GEO, and RT-qPCR was applied to estimate the expression of PVT1 in HCC. Then, cell proliferation was evaluated in vitro. A chicken chorioallantoic membrane (CAM) model of HCC was constructed to measure the effect on tumorigenicity in vivo. To further explore the sponge microRNA (miRNA) of PVT1 in HCC, we used TCGA, GEO, a gene microarray, and target prediction algorithms. TCGA and GEO and the gene microarray were used to select the differentially expressed miRNAs, and the different target prediction algorithms were applied to predict the target miRNAs of PVT1. RESULTS: We found that PVT1 was markedly overexpressed in HCC tissue than in normal liver tissues based on both RT-qPCR and data from TCGA, and the overexpression of PVT1 was closely related to the gender and race of the patient as well as to higher HCC tumor grades. Also, a meta-analysis of 840 cases from multiple sources (TCGA, GEO and the results of our in-house RT-qPCR) showed that PVT1 gained moderate value in discriminating HCC patients from normal controls, confirming the results of RT-qPCR. Additionally, the upregulation of PVT1 could promote HCC cell proliferation in vitro and vivo. Based on the competing endogenous RNA (ceRNA) theory, the PVT1/miR-424-5p/INCENP axis was finally selected for further research. The in silico prediction revealed that there were complementary sequences between PVT1 and miR-424-5p as well as between miR-424-5p and INCENP. Furthermore, a negative correlation trend was found between miR-424-5p and PVT1 based on RT-qPCR, whereas a positive correlation trend was found between PVT1 and INCENP based on data from TCGA. Also, INCENP small interfering RNA (siRNA) could significantly inhibit cell proliferation and viability. CONCLUSIONS: We hypothesized that PVT1 could affect the biological function of HCC cells via targeting miR-424-5p and regulating INCENP. Focusing on the new insight of the PVT1/miR-424-5p/INCENP axis, this study provides a novel perspective for HCC therapeutic strategies.

A circRNA-miRNA-mRNA network identification for exploring underlying pathogenesis and therapy strategy of hepatocellular carcinoma.

BACKGROUND: Circular RNAs (circRNAs) have received increasing attention in human tumor research. However, there are still a large number of unknown circRNAs that need to be deciphered. The aim of this study is to unearth novel circRNAs as well as their action mechanisms in hepatocellular carcinoma (HCC). METHODS: A combinative strategy of big data mining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and computational biology was employed to dig HCC-related circRNAs and to explore their potential action mechanisms. A connectivity map (CMap) analysis was conducted to identify potential therapeutic agents for HCC. RESULTS: Six differently expressed circRNAs were obtained from three Gene Expression Omnibus microarray datasets (GSE78520, GSE94508 and GSE97332) using the RobustRankAggreg method. Following the RT-qPCR corroboration, three circRNAs (hsa_circRNA_102166, hsa_circRNA_100291 and hsa_circRNA_104515) were selected for further analysis. miRNA response elements of the three circRNAs were predicted. Five circRNA-miRNA interactions including two circRNAs (hsa_circRNA_104515 and hsa_circRNA_100291) and five miRNAs (hsa-miR-1303, hsa-miR-142-5p, hsa-miR-877-5p, hsa-miR-583 and hsa-miR-1276) were identified. Then, 1424 target genes of the above five miRNAs and 3278 differently expressed genes (DEGs) on HCC were collected. By intersecting the miRNA target genes and the DEGs, we acquired 172 overlapped genes. A protein-protein interaction network based on the 172 genes was established, with seven hubgenes (JUN, MYCN, AR, ESR1, FOXO1, IGF1 and CD34) determined from the network. The Gene Oncology, Kyoto Encyclopedia of Genes and Genomes and Reactome enrichment analyses revealed that the seven hubgenes were linked with some cancer-related biological functions and pathways. Additionally, three bioactive chemicals (decitabine, BW-B70C and gefitinib) based on the seven hubgenes were identified as therapeutic options for HCC by the CMap analysis. CONCLUSIONS: Our study provides a novel insight into the pathogenesis and therapy of HCC from the circRNA-miRNA-mRNA network view.

Analysis of microarrays of miR-34a and its identification of prospective target gene signature in hepatocellular carcinoma.

BACKGROUND: Currently, some studies have demonstrated that miR-34a could serve as a suppressor of several cancers including hepatocellular carcinoma (HCC). Previously, we discovered that miR-34a was downregulated in HCC and involved in the tumorigenesis and progression of HCC; however, the mechanism remains unclear. The purpose of this study was to estimate the expression of miR-34a in HCC by applying the microarray profiles and analyzing the predicted targets of miR-34a and their related biological pathways of HCC. METHODS: Gene expression omnibus (GEO) datasets were conducted to identify the difference of miR-34a expression between HCC and corresponding normal tissues and to explore its relationship with HCC clinicopathologic features. The natural language processing (NLP), gene ontology (GO), pathway and network analyses were performed to analyze the genes associated with the carcinogenesis and progression of HCC and the targets of miR-34a predicted in silico. In addition, the integrative analysis was performed to explore the targets of miR-34a which were also relevant to HCC. RESULTS: The analysis of GEO datasets demonstrated that miR-34a was downregulated in HCC tissues, and no heterogeneity was observed (Std. Mean Difference(SMD) = 0.63, 95% confidence intervals(95%CI):[0.38, 0.88], P < 0.00001; Pheterogeneity = 0.08 I2 = 41%). However, no association was found between the expression value of miR-34a and any clinicopathologic characteristics. In the NLP analysis of HCC, we obtained 25 significant HCC-associated signaling pathways. Besides, we explored 1000 miR-34a-related genes and 5 significant signaling pathways in which CCND1 and Bcl-2 served as necessary hub genes. In the integrative analysis, we found 61 hub genes and 5 significant pathways, including cell cycle, cytokine-cytokine receptor interaction, notching pathway, p53 pathway and focal adhesion, which proposed the relevant functions of miR-34a in HCC. CONCLUSION: Our results may lead researchers to understand the molecular mechanism of miR-34a in the diagnosis, prognosis and therapy of HCC. Therefore, the interaction between miR-34a and its targets may promise better prediction and treatment for HCC. And the experiments in vivo and vitro will be conducted by our group to identify the specific mechanism of miR-34a in the progress and deterioration of HCC.

Coronal plane alignment of the lower limbs in patients with unilateral developmental hip dislocation.

PURPOSE: We aimed to identify the coronal plane alignment of lower limbs in patients with unilateral developmental hip dislocation (UDHD) and observe the difference between Hartofilakidis type II and III. PATIENTS AND METHODS: The radiographic data of 76 patients who met the inclusion criteria were retrospectively reviewed, including the hip-knee-ankle angle (HKA), mechanical lateral distal femoral angle (mLDFA), anatomical lateral distal femoral angle (aLDFA), mechanical proximal tibial angle (MPTA), and lateral distal tibial angle (LDTA). RESULTS: The valgus alignment on ipsilateral side was most frequently seen in both Hartofilakidis type II (51.3%) and type III groups (67.6%), whereas for the contralateral side, the neutral alignment in type II group (69.2%) and varus alignment in type III group (51.4%) were most commonly observed. Both the mLDFA and aLDFA of the ipsilateral side were significantly smaller than the contralateral side. CONCLUSIONS: UDHD patients may present with lower limb malalignment on both sides. The ipsilateral valgus alignment is the most common deformity. On the contralateral side, Hartofilakidis type III patients may be more prone to be varus than type II patients. The lower limb malalignment and deformity of the ipsilateral distal femur should be considered during surgery involving hip, knee, or femur.

The suppressive role of miR-542-5p in NSCLC: the evidence from clinical data and in vivo validation using a chick chorioallantoic membrane model.

BACKGROUND: Non-small cell lung cancer (NSCLC) has led to the highest cancer-related mortality for decades. To enhance the efficiency of early diagnosis and therapy, more efforts are urgently needed to reveal the origins of NSCLC. In this study, we explored the effect of miR-542-5p in NSCLC with clinical samples and in vivo models and further explored the prospective function of miR-542-5p though bioinformatics methods. METHODS: A total of 125 NSCLC tissue samples were collected, and the expression of miR-542-5p was detected by qRT-PCR. The relationship between miR-542-5p level and clinicopathological features was analyzed. The effect of miR-542-5p on survival time was also explored with K-M survival curves and Cox's regression. The effect of miR-542-5p on the tumorigenesis of NSCLC was verified with a chick chorioallantoic membrane (CAM) model. The potential target genes were predicted by bioinformatics tools, and relevant pathways were analyzed by GO and KEGG. Several hub genes were validated by Proteinatlas. RESULTS: The expression of miR-542-5p was down-regulated in NSCLC tissues, and consistent results were also found in the subgroups of adenocarcinoma and squamous cell carcinoma. Down-regulation of miR-542-5p was found to be connected with advanced TNM stage, vascular invasion, lymphatic metastasis and EGFR. Survival analyses showed that patients with lower miR-542-5p levels had markedly poorer prognosis. Both tumor growth and angiogenesis were significantly suppressed by miR-542-5p mimic in the CAM model. The potential 457 target genes of miR-542-5p were enriched in several key cancer-related pathways, such as morphine addiction and the cAMP signaling pathway from KEGG. Interestingly, six genes (GABBR1, PDE4B, PDE4C, ADCY6, ADCY1 and GIPR) from the cAMP signaling pathway were confirmed to be overexpressed in NSCLCs tissues. CONCLUSIONS: This evidence suggests that miR-542-5p is a potential tumor-suppressed miRNA in NSCLC, which has the potential to act as a diagnostic and therapeutic target of NSCLC.

Comprehensive analysis of the long noncoding RNA HOXA11-AS gene interaction regulatory network in NSCLC cells.

BACKGROUND: Long noncoding RNAs (lncRNAs) are related to different biological processes in non-small cell lung cancer (NSCLC). However, the possible molecular mechanisms underlying the effects of the long noncoding RNA HOXA11-AS (HOXA11 antisense RNA) in NSCLC are unknown. METHODS: HOXA11-AS was knocked down in the NSCLC A549 cell line and a high throughput microarray assay was applied to detect changes in the gene profiles of the A549 cells. Bioinformatics analyses (gene ontology (GO), pathway, Kyoto Encyclopedia of Genes and Genomes (KEGG), and network analyses) were performed to investigate the potential pathways and networks of the differentially expressed genes. The molecular signatures database (MSigDB) was used to display the expression profiles of these differentially expressed genes. Furthermore, the relationships between the HOXA11-AS, de-regulated genes and clinical NSCLC parameters were verified by using NSCLC patient information from The Cancer Genome Atlas (TCGA) database. In addition, the relationship between HOXA11-AS expression and clinical diagnostic value was analyzed by receiver operating characteristic (ROC) curve. RESULTS: Among the differentially expressed genes, 277 and 80 genes were upregulated and downregulated in NSCLC, respectively (fold change ≥2.0, P < 0.05 and false discovery rate (FDR) < 0.05). According to the degree of the fold change, six upregulated and three downregulated genes were selected for further investigation. Only four genes (RSPO3, ADAMTS8, DMBT1, and DOCK8) were reported to be related with the development or progression of NSCLC based on a PubMed search. Among all possible pathways, three pathways (the PI3K-Akt, TGF-beta and Hippo signaling pathways) were the most likely to be involved in NSCLC development and progression. Furthermore, we found that HOXA11-AS was highly expressed in both lung adenocarcinoma and squamous cell carcinoma based on TCGA database. The ROC curve showed that the area under curve (AUC) of HOXA11-AS was 0.727 (95% CI 0.663-0.790) for lung adenocarcinoma and 0.933 (95% CI 0.906-0.960) for squamous cell carcinoma patients. Additionally, the original data from TCGA verified that ADAMTS8, DMBT1 and DOCK8 were downregulated in both lung adenocarcinoma and squamous cell carcinoma, whereas RSPO3 expression was upregulated in lung adenocarcinoma and downregulated in lung squamous cell carcinoma. For the other five genes (STMN2, SPINK6, TUSC3, LOC100128054, and C8orf22), we found that STMN2, TUSC3 and C8orf22 were upregulated in squamous cell carcinoma and that STMN2 and USC3 were upregulated in lung adenocarcinoma. Furthermore, we compared the correlation between HOXA11-AS and de-regulated genes in NSCLC based on TCGA. The results showed that the HOXA11-AS expression was negatively correlated with DOCK8 in squamous cell carcinoma (r = -0.124, P = 0.048) and lung adenocarcinoma (r = -0.176, P = 0.005). In addition, RSPO3, ADAMTS8 and DOCK8 were related to overall survival and disease-free survival (all P < 0.05) of lung adenocarcinoma patients in TCGA. CONCLUSIONS: Our results showed that the gene profiles were significantly changed after HOXA11-AS knock-down in NSCLC cells. We speculated that HOXA11-AS may play an important role in NSCLC development and progression by regulating the expression of various pathways and genes, especially DOCK8 and TGF-beta pathway. However, the exact mechanism should be verified by functional experiments.

Expression and clinicopathological significance of miR-193a-3p and its potential target astrocyte elevated gene-1 in non-small lung cancer tissues.

BACKGROUND: Aberrant expression of miR-193a-3p and astrocyte elevated gene-1 (AEG-1) have been revealed to be related to the tumorigenesis of various cancers, including non-small cell lung cancer (NSCLC). However, the significance of miR-193a-3p and its correlation with AEG-1 in NSCLC has not been explored. The purpose of this study was to evaluate the association between miR-193a-3p and AEG-1 and their relationship with the clinicopathological features in NSCLC patients. METHODS: Via online in silico prediction, complementary sequences were found between miR-193a-3p and the 3'-untranslated region of AEG-1. Three independent cohorts were applied in the current study. Firstly, miR-193a-3p level was detected in 125 cases of NSCLC with quantitative real-time PCR (qRT-PCR). Secondly, AEG-1 protein level was evaluated in 339 cases of lung cancers with immunohistochemistry. Finally, the relationship between miR-193a-3p and AEG-1 protein expression was verified in another group with 65 cases of NSCLC. RESULTS: The results showed that miR-193a-3p level was decreased in NSCLC tissues and significantly negatively related to tumor size (r = -0.277, P = 0.002), clinical TNM stage (r = -0.226, P = 0.011), lymph node metastasis (r = -0.186, P = 0.038), epidermal growth factor receptor (EGFR) protein level (r = -0.272, P = 0.041). On the contrary, AEG-1 protein expression was up-regulated in NSCLC and positively relative to tumor size (r = 0.240, P < 0.001), TNM stages (r = 0.164, P = 0.002) and lymph node metastasis (r = 0.232, P < 0.001) in NSCLC patients. In addition, miR-193a-3p was found to be inversely associated with AEG-1 protein expression in the third cohort (r = -0.564, P < 0.001). CONCLUSION: In conclusion, miR-193a-3p and AEG-1 might be responsible for the carcinogenesis and aggressiveness of NSCLC. AEG-1 has the potential to be one of the targeted genes of miR-193a-3p. However, future in vitro and in vivo experiments are needed to verify this hypothesis.

Downregulation of MiR-30a is Associated with Poor Prognosis in Lung Cancer.

BACKGROUND: Recent reports have suggested that miR-30a plays a tumor-suppressive role in various cancers. However, miR-30a has not been completely studied in non-small lung cancer (NSCLC). Thus, the aim of the present study was to clarify the association between the expression of miR-30a and the clinicopathological features in NSCLC patients. MATERIAL AND METHODS: Total RNA of miR-30a was extracted from 125 pairs of NSCLC patients (male 75, female 50) and their matching normal tissues. The miR-30a level was detected by using quantitative real-time polymerase chain reaction (qRT-PCR). Simultaneously, the 2-ΔCq method was used to calculate the correlation between miR-30a expression and the clinicopathological parameters and prognosis of NSCLC patients. RESULTS: MiR-30a expression was significantly down-regulated in NSCLC tissues (4.0696±2.4178) compared to their non-tumor lung tissues (7.4530±3.0561, P<0.001). Level of miR-30a was negatively correlated to tumor size (r=-0.197, P=0.028), lymphatic metastasis (r=-0.312, P<0.001), clinical TNM stage (r=-0.299, P=0.001), pathological grading (I/II vs. III, r=-0.224, P=0.001), and histological classification (r=-0.299, P=0.001). Survival time was 3.23±2.18 months in the low miR-30a expression group, remarkably shorter than that of the high expression group (20.72±11.63 months, P<0.001). CONCLUSIONS: MiR-30a may be regarded as a tumor suppressor in NSCLC, and it could become a prognostic marker and potential therapeutic target for NSCLC.

[Imaging observation of the femoral neck anteversion in patients with developmental dysplasia of the hip].

OBJECTIVE: To observe the distribution law and study the factors related to the femoral neck anteversion angle among the patients with developmental dysplasia of the hip of Hartofilakidis type I. METHODS: Among the patients with hip dysplasia of Hartofilakidis type I who was admitted to Department of Orthopaedic Surgery, the First Affiliated Hospital of People's Liberation Army General Hospital from June 2010 to June 2013, a total of 340 hips (25 male and 161 female) were included in the study. The average age was 28.3 years, ranging from 13.5 to 49.9 years. The observation index included: femoral neck anteversion angle, lateral center-edge angle, acetabular index angle, lateral displacement of the femoral head, superior displacement of the femoral head, continuity of Shenton's line and Calve's line. The correlation between different factors was analyzed, and the factor closest to femoral neck anteversion angle was analyzed further by regression analysis. RESULTS: Among the patients of developmental dysplasia of the hip of Hartofilakidis type I, the femoral neck anteversion angle increased, with an average of 28°±13°. Correlation and regression analysis showed significant negative correlation with treatment age (r=-0.158, P=0.003; t=-6.892, P=0.000); positive correlation with gender (r=0.332, P=0.000; t=-4.376, P=0.000); significant positive correlation with lateral displacement of the femoral head (r=0.092, P=0.000; t=3.766, P=0.000); significant negative correlation with central-edge angle (r=-0.122, P=0.024; t=2.031, P=0.043). The femoral neck anteversion angle showed correlation with acetabular index angle, continuity of Calve's line and superior displacement of the femoral head in correlation analysis, not in regression analysis, however, it did not show correlation with side and continuity of Shenton's line. CONCLUSION: Among the patients of developmental dysplasia of the hip of Hartofilakidis type I, the increasing of the femoral neck anteversion angle may not only lead to early onset and therefore early treatment of pain in the hip joint but also the lateral displacement of the femoral head that requires immediate medical attention.

Mesenchymal stem cells suppress CD8+ T cell-mediated activation by suppressing natural killer group 2, member D protein receptor expression and secretion of prostaglandin E2, indoleamine 2, 3-dioxygenase and transforming growth factor-ß.

Bone marrow mesenchymal stem cells (BMSCs) inhibit immune cell responsiveness, and especially of T lymphocytes. We showed that BMSCs markedly inhibited the proliferation and cytokine production by CD8(+) T cells by a cell-to-cell contact phenomenon and secretion of soluble factors. BMSCs down-regulate the expression of natural killer group 2, member D protein (NKG2D) receptors on CD8(+) T cells when co-cultured with them. Moreover, CD8(+) T cells that express low levels of NKG2D had impaired proliferation after triggering by a mitogen. The major histocompatibility complex (MHC) class I chain-related (MIC) A/B molecule, which is a typical ligand for NKG2D, was expressed on BMSCs, and caused dampening of cell proliferation. Monoclonal antibody blocking experiments targeted to MIC A/B impaired CD8(+) T cell function, as evaluated by proliferation and cytokine production. In addition, the production of prostaglandin E2 (PGE2 ), indoleamine 2, 3-dioxygenase (IDO) and transforming growth factor (TGF)-ß1 were increased when BMSCs were co-cultured with CD8(+) T cells. The addition of specific inhibitors against PGE2 , IDO and TGF-ß partially restored the proliferation of CD8(+) T cells. Our results suggest that BMSCs suppress CD8(+) T cell-mediated activation by suppressing NKG2D expression and secretion of PGE2, IDO and TGF-ß. Our observations further confirm the feasibility of BMSCs as a potential adoptive cellular therapy in immune-mediated diseases such as graft-versus-host disease (GVHD).

[Early results of modified Colonna capsular arthroplasty for young patients with unilateral hip dislocation].

OBJECTIVE: To discuss the early clinical results and risk factors of modified Colonna capsular arthroplasty for young patients with unilateral hip dislocation. METHODS: From July 2011 to February 2013, 25 cases (25 hips) of modified Colonna capsular arthroplasty for unilateral hip dislocation in the 1st affiliated hospital of People's Liberation Army General hospital was collected, including 7 males, 18 females; aged 9.7-25.8 years, averaging 17.8 years; left 12 cases, right 13 cases; Body mass index ranged 15.6-29.6 kg/m², averaging 20.9 kg/m². Clinical indexes were collected, including: range of motion (ROM) of the hip, the Harris Hip Score (HHS), West Ontario and McMaster University Osteoarthritis Index (WOMAC), visual analogue scale (VAS) score before and after surgery, along with the satisfaction score of the surgery, Severin grades, and Tönnis osteoarthritis grades at last follow-up. Paired t-test was applied for the indexes before and after surgery, variances components analysis was applied for the satisfaction score and the function scores at last follow-up compared in 2 groups, aging at surgery <16 years (15 cases) and ≥ 16 years (10 cases). RESULTS: All cases were followed up for 12-18 months, mean 13.4 months. The average hip ROM decreased from 380° in average pre-surgery to 200° in average at last follow-up. Indexes decreased comparing 9 months follow-up to pre-surgery, HHS(78 ± 9 vs. 84 ± 15, t = 2.107, P = 0.046), WOMAC function score(14.8 ± 8.4 vs. 8.6 ± 9.6, t = -2.657, P = 0.014) appeared statistically difference. Indexes increased at the last follow-up, showing no statistically difference. VAS and the satisfaction score were much better in patients <16 years group compared with ≥ 16 years group at last follow-up. VAS was 1.1 ± 0.8 compared with 2.8 ± 1.4 (F = 12.810, P = 0.002), whereas the satisfaction score was 89 ± 17 compared with 66 ± 22 (F = 7.535, P = 0.012). The last radiological follow-up resulted that, Severin grade I 21 cases, grade II 1 case, grade III 2 cases, grade IV 2 cases, and the Tönnis osteoarthritis grade 0 with 5 cases, grade 1 with 12 cases, grade 2 with 7 cases, grade 3 with 1 case. CONCLUSIONS: In this early follow up, the majority of patients who underwent modified Colonna capsular arthroplasty for their unilateral hip dislocation would obtained satisfactory results, but with long term recovery, and the younger group (<16 years) with better clinical results than the elder group ( ≥ 16 years).With strict indications, exacted surgical techniques and optimized rehabilitation, the modified Colonna arthroplasty would have better clinical results.