AI-enhanced diagnostic model for pulmonary nodule classification.

Background: The identification of benign and malignant pulmonary nodules (BPN and MPN) can significantly reduce mortality. However, a reliable and validated diagnostic model for clinical decision-making is still lacking. Methods: Enzyme-linked immunosorbent assay and electro chemiluminescent immunoassay were utilized to determine the serum concentrations of 7AABs (p53, GAGE7, PGP9.5, CAGE, MAGEA1, SOX2, GBU4-5), and 4TTMs (CYFR21, CEA, NSE and SCC) in 260 participants (72 BPNs and 188 early-stage MPNs), respectively. The malignancy probability was calculated using Artificial intelligence pulmonary nodule auxiliary diagnosis system, or Mayo model. Along with age, sex, smoking history and nodule size, 18 variables were enrolled for model development. Baseline comparison, univariate ROC analysis, variable correlation analysis, lasso regression, univariate and stepwise logistic regression, and decision curve analysis (DCA) was used to reduce and screen variables. A nomogram and DCA were built for model construction and clinical use. Training (60%) and validation (40%) cohorts were used to for model validation. Results: Age, CYFRA21_1, AI, PGP9.5, GAGE7, and GBU4_5 was screened out from 18 variables and utilized to establish the regression model for identifying BPN and early-stage MPN, as well as nomogram and DCA for clinical practical use. The AUC of the nomogram in the training and validation cohorts were 0.884 and 0.820, respectively. Moreover, the calibration curve showed high coherence between the predicted and actual probability. Conclusion: This diagnostic model and DCA could provide evidence for upgrading or maintaining the current clinical decision based on malignancy probability stratification. It enables low and moderate risk or ambiguous patients to benefit from more precise clinical decision stratification, more timely detection of malignant nodules, and early treatment.

The Severity of CVB3-Induced Myocarditis Can Be Improved by Blocking the Orchestration of NLRP3 and Th17 in Balb/c Mice.

BACKGROUND: The functional characteristics of NLRP3 in the pathogenesis of coxsackievirus B3- (CVB3-) induced viral myocarditis (VMC) have not been fully elucidated, and the targeted therapeutic effect of NLRP3 or its related pathway in VMC has not been reported. METHOD: In this work, the change patterns of NLRP3- and Th17-related factors were detected during the pathological process of CVB3-induced VMC in Balb/c mice. The correlation between NLRP3 and Th17 cells during the VMC process was analyzed by Spearman test. The coculture system of spleen CD4+ T and bone marrow CD11c+ DC cells was set to explore the orchestration of NLRP3 and Th17 in the pathological development of VMC in vitro. Anti-IL-1ß antibody or NLRP3-/- Balb/c were used to block the NLRP3 pathway indirectly and directly to analyze the NLRP3-targeting therapeutic value. RESULTS: The change patterns of NLRP3- and Th17-related molecules in the whole pathological process of mouse CVB3-induced VMC were described. Through Spearman correlation analysis, it was confirmed that there was a close correlation between NLRP3 and Th17 cells in the whole pathological process of VMC. And the interaction mode between NLRP3 and Th17 was preliminarily explored in the cell experiment in vitro. Under the intervention of an anti-IL-1ß antibody or NLRP3 knockout, the survival rate of the intervention group was significantly improved, the degree of myocardial inflammation and fibrosis was significantly alleviated, and the content of myocardial IL-17 and spleen Th17 was also significantly decreased. CONCLUSION: Our findings demonstrated a key role of the NLRP3 inflammasome and its close relationship with Th17 in the pathological progression of CVB3-induced VMC and suggested a possible positive feedback-like mutual regulation mechanism between the NLRP3 inflammasome and Th17 in vitro and in the early stage of CVB3 infection. Taking NLRP3 as a new starting point, it provides a new target and idea for the prevention and treatment of CVB3-induced VMC.

The Value of a Seven-Autoantibody Panel Combined with the Mayo Model in the Differential Diagnosis of Pulmonary Nodules.

BACKGROUND: Identifying malignant pulmonary nodules and detecting early-stage lung cancer (LC) could reduce mortality. This study investigated the clinical value of a seven-autoantibody (7-AAB) panel in combination with the Mayo model for the early detection of LC and distinguishing benign from malignant pulmonary nodules (MPNs). METHODS: The concentrations of the elements of a 7-AAB panel were quantitated by enzyme-linked immunosorbent assay (ELISA) in 806 participants. The probability of MPNs was calculated using the Mayo predictive model. The performances of the 7-AAB panel and the Mayo model were analyzed by receiver operating characteristic (ROC) analyses, and the difference between groups was evaluated by chi-square tests (χ 2). RESULTS: The combined area under the ROC curve (AUC) for all 7 AABs was higher than that of a single one. The sensitivities of the 7-AAB panel were 67.5% in the stage I-II LC patients and 60.3% in the stage III-IV patients, with a specificity of 89.6% for the healthy controls and 83.1% for benign lung disease patients. The detection rate of the 7-AAB panel in the early-stage LC patients was higher than that of traditional tumor markers. The AUC of the 7-AAB panel in combination with the Mayo model was higher than that of the 7-AAB panel alone or the Mayo model alone in distinguishing MPN from benign nodules. For early-stage MPN, the sensitivity and specificity of the combination were 93.5% and 58.0%, respectively. For advanced-stage MPN, the sensitivity and specificity of the combination were 91.4% and 72.8%, respectively. The combination of the 7-AAB panel with the Mayo model significantly improved the detection rate of MPN, but the positive predictive value (PPV) and the specificity were not improved when compared with either the 7-AAB panel alone or the Mayo model alone. CONCLUSION: Our study confirmed the clinical value of the 7-AAB panel for the early detection of lung cancer and in combination with the Mayo model could be used to distinguish benign from malignant pulmonary nodules.

High-Dose Vitamin C Tends to Kill Colorectal Cancer with High MALAT1 Expression.

BACKGROUND: Vitamin C (Vc) deficiency is frequently observed in cancer sites and has been proposed to have an antitumor effect. However, the mechanism of Vc's killing effect is not clear. Besides, epigenetic alterations exhibit significant effects on colorectal cancer (CRC). This study aimed to explore the mechanism of Vc's killing effect and its association to epigenetic alterations in CRC. METHODS: Cell morphology, apoptosis, proliferation, and cycle were assayed to test Vc's suppressive function in CRC cell lines. Xenograft and peritoneal implantation metastasis models were performed to evaluate the high-dose Vc's inhibitory effect on tumor growth and metastasis. Immunohistochemistry was used to measure CD31 expression in solid tumors. A literature summary was applied for screening differently expressed long noncoding RNAs (lncRNAs) in CRC tissues and was closely associated with CRC progression. The qPCR was used to detect the expression of these lncRNAs. The association between Vc and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was evaluated in MALAT1-transfected CRC cells and a xenograft model. RESULTS: Vc was confirmed to function in proliferation suppression, apoptosis induction, and S phase arresting in CRC cell lines. High-dose Vc, but not physiologically low-dose Vc, was identified as a suppressive function on tumor growth in xenograft models and an inhibitory effect on implantation metastasis in peritoneal implantation metastasis mice. Furthermore, a consistent downregulation of MALAT1 induced by Vc was verified among CRC cell lines and tumor tissues from both mouse models. Finally, experiments on MALAT1-knockdown CRC cells and its xenograft model suggested that Vc had a tendency in killing CRC with high MALAT1 expression. CONCLUSIONS: Our findings demonstrate that high-dose Vc has more efficiency in suppressing CRC with higher MALAT1 expression. It gives high-dose Vc the possibility of a better curative effect on CRC with overexpressed MALAT1. Further clinical studies are still needed.

LncRNA TGFB2-AS1 regulates lung adenocarcinoma progression via act as a sponge for miR-340-5p to target EDNRB expression.

Long non-coding RNA TGFB2-antisense RNA1 (TGFB2-AS1) has been reported could regulate tumorigenesis. However, the roles of TGFB2-AS1 in lung adenocarcinoma (LUAD) remain largely unknown. In this work, we aimed to explore the expression levels of TGFB2-AS1 and mechanisms in regulating LUAD progression. Expression level of TGFB2-AS1 in LUAD tissues and normal tissues was analyzed at StarBase. Moreover, its expression in LUAD cells and normal cell was analyzed with quantitative real-time polymerase chain reaction method. Gain- and loss-of-function studies were conducted to analyze the biological roles of TGFB2-AS1 in LUAD. Results indicated TGFB2-AS1 was evidently downregulated in LUAD tissues and cells. Moreover, as analyzed by cell counting kit-8 assay, wound-healing and transwell invasion assays, results revealed TGFB2-AS1 overexpression could suppress proliferation, migration and invasion abilities of LUAD cells in vitro and tumor growth in vivo. In addition, LncBase V2.0 and TargetScan prediction tools showed TGFB2-AS1 and endothelin receptor type B (EDNRB) shares binding site in microRNA-340-5p (miR-340-5p). Furthermore, luciferase activity reporter assay and RT-qPCR assay validated these prediction results. Furthermore, we showed TGFB2-AS1 functions as sponge for miR-340-5p to regulate EDNRB expression. Collectively, our results indicated TGFB2-AS1/miR-340-5p/EDNRB axis plays crucial roles in regulating LUAD progression, indicating TGFB2-AS1 may be a novel therapeutic target for LUAD.

Anti-TGF-ß attenuates tumor growth via polarization of tumor associated neutrophils towards an anti-tumor phenotype in colorectal cancer.

Tumor associated neutrophils (TANs) play important roles in the progress of CRC. Since tumor microenvironments could influence the phenotypes of TANs, altering the tumor microenvironment to polarize the phenotype of TANs may be a new strategy for tumor treatment. This study aims to investigate the effect of anti-TGF-ß on the polarization of TANs from a pro-tumor phenotype towards an anti-tumor phenotype in CRC. In this work, CRC patients had more infiltration of TANs and higher expression of TGF-ß in CRC tissue when compared with the controls. In vitro, SW480 cells were co-cultured with primed neutrophils, which simulated the TANs in the tumor microenvironment, and TGF-ß was blocked by anti-TGF-ß (1D11) in order to polarize TANs. Anti-TGF-ß treatment increased the cytotoxicity of TANs and decreased the metastatic chemoattractants secreted by TANs, and ultimately increased the apoptosis of CRC cells significantly while remarkably suppressing the migration of tumor cells. The changes of signaling pathways in the TANs and tumor cells were explored. The results showed that anti-TGF-ß attenuated CRC may be partly mediated by suppression of PI3K/AKT signaling pathways in TANs and partly mediated by suppression of TGF-ß/Smad signaling pathways in tumor cells. Furthermore, the tumor in the mice treated with 1D11 was obviously smaller and had reverse tumorigenesis compared with the controls, while neutrophil depletion reduced the anti-tumor effect of 1D11. Our data suggest that anti-TGF-ß attenuates tumor growth via the polarization of TANs to an anti-tumor phenotype in CRC, which provides new strategies for CRC treatment.

Injectable double-crosslinked hydrogels with kartogenin-conjugated polyurethane nano-particles and transforming growth factor ß3 for in-situ cartilage regeneration.

Articular cartilage has a limited ability for self-repair after injury. Implantation of scaffolds functionalized with bioactive molecules that could induce the migration and chondrogenesis of endogenous mesenchymal stem cells (MSCs) provides a convenient alternative for in-situ cartilage regeneration. In this study, we found the synergistic effects of kartogenin (KGN) and transforming growth factor ß3 (TGF-ß3) on chondrogenesis of MSCs in vitro, indicating that KGN and TGF-ß3 are a good match for cartilage regeneration. Furthermore, we confirmed that KGN promoted the chondrogenesis of MSCs through attenuating the degradation of Runx1, which physically interacted with p-Smad3 in nuclei of MSCs. Meanwhile, we designed an injectable double-crosslinked hydrogel with superior mechanical property and longer support for cartilage regeneration by modifying sodium alginate and gelatin. When loaded with KGN conjugated polyurethane nanoparticles (PN-KGN) and TGF-ß3, this hydrogel showed biological functions by the release of KGN and TGF-ß3, which promoted the MSC migration and cartilage regeneration in one system. In conclusion, the cell-free hydrogel, along with PN-KGN and TGF-ß3, provides a promising strategy for cartilage repair by attracting endogenous MSCs and inducing chondrogenesis of recruited cells in a single-step procedure.

Lack of Efficacy of Combined Carbohydrate Antigen Markers for Lung Cancer Diagnosis.

BACKGROUND: Lung cancer (LC) is top-ranked in cancer incidence and is the leading cause of cancer death globally. Combining serum biomarkers can improve the accuracy of LC diagnosis. The identification of the best potential combination of traditional tumor markers is essential for LC diagnosis. Patients and Methods. Blood samples were collected from 132 LC cases and 118 benign lung disease (BLD) controls. The expression levels of ten serum tumor markers (CYFR21, CEA, NSE, SCC, CA15-3, CA 19-9, CA 125, CA50, CA242, and CA724) were assayed, and that the expression in the levels of tumor markers were evaluated, isolated, and combined in different patients. The performance of the biomarkers was analyzed by receiver operating characteristic (ROC) analyses, and the difference between combinations of biomarkers was compared by Chi-square (χ 2) tests. RESULTS: As single markers, CYFR21 and CEA showed good diagnostic efficacy for nonsmall cell lung cancer (NSCLC) patients, while NSE and CEA were the most sensitive in the diagnosis of small cell lung cancer (SCLC). The area under the curve (AUC) value was 0.854 for the panel of four biomarkers (CYFR21, CEA, NSE, and SCC), 0.875 for the panel of six biomarkers (CYFR21, CEA, NSE, SCC, CA125, and CA15-3), and 0.884 for the panel of ten markers (CYFR21, CEA, NSE, SCC, CA125, CA15-3, CA19-9, CA50, CA242, and CA724). With a higher sensitivity and negative predictive value (NPV), the diagnostic accuracy of the three panels was better than that of any single biomarker, but there were no statistically significant differences among them (all P values > 0.05). However, the panel of six carbohydrate antigen (CA) biomarkers (CA125, CA15-3, CA19-9, CA50, CA242, and CA724) showed a lower diagnostic value (AUC: 0.776, sensitivity: 59.8%, specificity: 73.0%, and NPV: 60.4%) than the three panels (P value < 0.05). The performance was similar even when analyzed individually by LC subtypes. CONCLUSION: The biomarkers isolated are elevated for different types of lung cancer, and the panel of CYFR21, CEA, NSE, and SCC seems to be a promising serum biomarker for the diagnosis of lung cancer, while the combination with carbohydrate antigen markers does not improve the diagnostic efficacy.

Soy Foods Might Weaken the Sensitivity of Tamoxifen in Premenopausal Patients With Lumina A Subtype of Breast Cancer.

BACKGROUND: Based on estrogen active substances, many women consume soy foods in the belief that it could prevent breast cancer (BC). Women with different molecular subtypes would be likely to have diverse reactions to soy foods, especially those with the estrogen-receptor-positive (ER+) subtype. The aim of the current study is to identify the differentially expressed genes (DEGs) on soy foods in premenopausal patients with Lumina A subtype of BC (LABC) after soy food treatment, and to further investigate the critical molecule change. MATERIALS AND METHODS: GSE58792 retrieved from Gene Expression Omnibus was analyzed to obtain DEGs using GEO2R. Gene Ontology and pathway enrichment analysis were performed using FunRich and GeneMINIA. Overall survival of critical genes was performed by the Kaplan-Meier plotter online tool. RESULTS: A total of 108 DEGs were obtained from the dataset, among which 35 were up-regulated and 73 down-regulated. Soy foods significantly reduced the expression of TFF3, TFF1, GATA3, and ESR1, which were related to the activity of the ER-related pathway and the sensitivity of tamoxifen. Furthermore, the lower expressions of TOX3, FSIP1, ESR1, and CLGN were related to prolonged survival time of patients with BC. The most significant signaling pathways were epithelial-to-mesenchymal transition in up-regulated DEGs, mesenchymal-to-epithelial transition, and mammary gland alveolus development in down-regulated DEGs, which were all related to the development and prognosis of BC. CONCLUSIONS: Soy foods could dramatically alter the ER-related gene profile in LABC. Particularly, down-regulated DEGs of TFF3, TFF1, GATA3, and ESR1 might weaken the sensitivity of tamoxifen and increase the efficacy of neoadjuvant chemotherapy in premenopausal patients with LABC.

Molecular mechanism and role of microRNA-93 in human cancers: A study based on bioinformatics analysis, meta-analysis, and quantitative polymerase chain reaction validation.

INTRODUCTION: Currently, studies have shown that microRNA-93 (miR-93) can be an oncogene or a tumor suppressor in different kinds of cancers. The role of miR-93 in human cancers is inconsistent and the underlying mechanism on the aberrant expression of miR-93 is complicated. METHODS: We first conducted gene enrichment analysis to give insight into the prospective mechanism of miR-93. Second, we performed a meta-analysis to evaluate the clinical value of miR-93. Finally, a validation test based on quantitative polymerase chain reaction (qPCR) was performed to further investigate the role of miR-93 in pan-cancer. RESULTS: Gene Ontology (GO) enrichment analysis results showed that the target genes of miR-93 were closely related to transcription, and MAPK1, RBBP7 and Smad7 became the hub genes. In the diagnostic meta-analysis, the overall sensitivity, specificity, and area under the curve were 0.76 (0.64-0.85), 0.82 (0.64-0.92), and 0.85 (0.82-0.88), respectively, which suggested that miR-93 had excellent performance on the diagnosis for human cancers. In the prognostic meta-analysis, dysregulated miR-93 was found to be associated with poor OS in cancer patients. In the qPCR validation test, the serum levels of miR-93 were upregulated in breast cancer, breast hyperplasia, lung cancer, chronic obstructive pulmonary disease, nasopharyngeal cancer, hepatocellular cancer, gastric ulcer, endometrial cancer, esophageal cancer, laryngeal cancer, and prostate cancer compared with healthy controls. CONCLUSIONS: miR-93 could act as an effective diagnostic and prognostic factor for cancer patients. Its clinical value for cancer early diagnosis and survival prediction is promising.

sTLR4/sMD-2 complex alleviates LPS-induced acute lung injury by inhibiting pro-inflammatory cytokines and chemokine CXCL1 expression.

Activation of Toll-like receptor 4 (TLR4) and its accessory proteins myeloid differentiation protein 2 (MD-2) can trigger immune and inflammatory activities, and contribute to developing chronic inflammatory diseases. The formation of the TLR4/MD-2 complex after binding to lipopolysaccharide (LPS) leads to the activation of downstream signaling pathway. The present study was designed to reveal the effect of the soluble form of the extracellular TLR4 domain and MD-2 (sTLR4/sMD-2) complex lacking the intracellular and transmembrane domains on various aspects of LPS-induced inflammation in vivo and in vitro. It was demonstrated that the sTLR4/sMD-2 complex inhibited the LPS-induced production of tumor necrosis factor-α, interleukin-8 and C-X-C motif chemokine ligand 1 (CXCL1) in THP-1 cells. In addition, it was revealed that the sTLR4/sMD-2 complex significantly reduced LPS-induced acute lung injury (ALI) with a reduction of total cells and neutrophil count, pro-inflammatory cytokines and chemokine CXCL1 in bronchoalveolar lavage fluid. Moreover, the sTLR4/sMD-2 complex inhibited the number of inflammatory cells in the lung of treated animals. These novel mechanisms emphasized the important role of sTLR4/sMD-2 complex in ALI and suggested sTLR4/sMD-2 complex could provide an anti-inflammatory strategy for treating inflammatory diseases.

Regulatory effect of microRNA-34a on osteogenesis and angiogenesis in glucocorticoid-induced osteonecrosis of the femoral head.

Glucocorticoid-induced osteonecrosis of the femoral head (GIOFH) is a common and devastating orthopedic disease, and its underlying mechanism remains unclear. The aim of this study was to determine the role of microRNA-34a (mir-34a) in GIOFH. C57 mouse mesenchymal stem cells (mMSCs) and human umbilical vein endothelial cells (HUVECs) were cultured with dexamethasone (Dex). A total of 48 adult rats were treated with glucocorticoids, and after the onset of GIOFH, each femoral head was removed. Mir-34a mimics, an inhibitor and over-expressing lentivirus were used in vitro and in vivo, respectively. Real-time PCR, immunohistochemistry, ELISA, cell proliferation assays, osteoblastic differentiation, and endothelial activity assays were employed to evaluate the effect of mir-34a on mMSCs, osteoblasts, and vascular endothelial cells in glucocorticoid-treated mice. We found that Dex inhibited mMSC proliferation and osteoblastic differentiation, as well as the viability and activity of endothelial cells. Dex also caused osteonecrosis and decreased new vessel formation in vivo. Mir-34a alleviated the inhibitory effects of Dex on mMSCs and osteoblasts, while facilitating its inhibitory effects on endothelial cells. Mir-34a is an important regulator in osteogenesis and angiogenesis, and it might be useful as a therapeutic target for GIOFH. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:417-424, 2018.

sTLR4/MD-2 complex inhibits colorectal cancer migration and invasiveness in vitro and in vivo by lncRNA H19 down-regulation.

Long non-coding RNAs (lncRNAs) have multiple functions in gene regulation and during cellular processes. However, the functional roles of lncRNAs in colorectal cancer (CRC) have not yet been well understood. In our previous study, we demonstrated that sTLR4/MD-2 complex can inhibit CRC in vitro and in vivo by targeting LPS. Therefore, the aim of the present study is to investigate the expression of lncRNA H19 in CRC and to evaluate its effect on the inhibition of sTLR4/MD-2 complex. The expression of H19 is measured in 63 CRC tumor tissues and adjacent normal tissues by quantitative real-time PCR (qRT-PCR). The effects of H19 on migration and invasiveness are evaluated by wound healing assay, migration and invasion assays. Results showed that H19 is significantly overexpressed in cancerous tissues and CRC cell lines compared with adjacent normal tissues and a normal human intestinal epithelial cell line. Moreover, H19 overexpression is closely associated with CRC patients. Our in vitro data indicated that knockdown of H19 inhibits the migration and invasiveness of CRC cells. And in vivo sTLR4/MD-2 complex inhibits tumor growth in mice and the expression of H19 is down-regulated. These results suggest that sTLR4/MD-2 complex inhibits CRC migration and invasiveness in vitro and in vivo by lncRNA H19 down-regulation.

Effectiveness of acupuncture for breast cancer related lymphedema: protocol for a single-blind, sham-controlled, randomized, multicenter trial.

BACKGROUND: Although various treatments for breast cancer related lymphedema exist, there is still a need for a more effective and convenient approach. Pilot studies and our clinical observations suggested that acupuncture may be a potential option. This study aims to verify the effectiveness of acupuncture on BCRL and evaluate its safety using a rigorously designed trial. METHODS/DESIGN: Women who are clinically diagnosed as unilateral BCRL, with a 10% to 40% increase in volume compared to the unaffected arm, will be recruited. Following baseline assessment, participants will be randomized to either the real acupuncture group or sham-acupuncture group at a ratio of 1:1, and given a standard real acupuncture or sham-acupuncture treatment accordingly on both arms followed by the same usual care of decongestive therapy. Volume measurements of both arms will be performed for every participant after each treatment. Data collected at baseline and the last session will be used to calculate the primary outcome and secondary outcomes. Other data will be exploited for interim analyses and trial monitoring. The primary outcome is the absolute reduced limb volume ratio. Secondary outcomes are incidence of adverse events and change in quality of life. A t test or non-parameter test will be used to compare the difference between two groups, and assess the overall effectiveness of acupuncture using the SPSS software (version 12). DISCUSSION: This study will help expand our knowledge about the effectiveness of acupuncture on BCRL, and how acupuncture might be used in the management of this condition. Acupuncture may be a promising complement or alternative to conventional lymphedema treatment methods, if its effectiveness is confirmed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02803736 (Registered on October 31, 2016).

Free Vascularized Fibular Grafting Improves Vascularity Compared With Core Decompression in Femoral Head Osteonecrosis: A Randomized Clinical Trial.

BACKGROUND: Management of osteonecrosis of the femoral head remains challenging. Core decompression and free vascularized fibular grafting are commonly used surgical procedures for treatment of osteonecrosis of the femoral head. Few studies, however, have compared these two procedures in a randomized controlled study, in terms of improved vascularity of the femoral head, progression of disease, or hip scores. QUESTION/PURPOSES: (1) What is the effect of core decompression and fibular grafting on vascularity of the femoral head as measured by single-photon emission CT (SPECT)/CT? (2) Does one of these two methods lead to greater progression of Association Research Circulation Osseous (ARCO) stage as determined by serial MRI? (3) What is the relationship between the change in vascularity of the femoral head and hip function as measured by the Harris hip score (HHS) and progression to THA as an endpoint? METHODS: A randomized controlled trial was performed between June 2010 and October 2012 at Zhongshan Hospital, Fudan University. During the study period, 51 patients who presented with ARCO Stages I to IIIB bilateral osteonecrosis were potentially eligible for inclusion, and 33 patients were identified as meeting the inclusion criteria and offered enrollment and randomization. Six patients declined to participate at the time of randomization, leaving a final sample of 27 participants (54 hips). Bilateral hips of each patient were randomly assigned to surgical options: one side was treated with core decompression and the contralateral side was concurrently treated with fibular grafting. SPECT/CT examinations were performed to quantify radionuclide uptake to evaluate vascularity of the femoral head before treatment and at 6 and 36 months after surgery. With the numbers available, we found no differences between the groups regarding vascularity at baseline (64% ± 8% core decompression-treated hips versus 64% ± 7% in the fibular-grafted hips; 95% CI, -5% to 5%; p = 0.90). MR images of the hips were obtained before surgery and at 6, 12, 24, and 36 months postoperatively and staged based on the ARCO classification. All patients were assessed clinically before treatment and followed up at 6, 12, 18, 24, 30, and 36 months after treatment using the HHS. We considered a difference in the HHS of 10 as the minimal clinically important difference (MCID). Patient progression to THA was defined as the endpoint for followup. Six patients (22%) were lost to followup. RESULTS: By SPECT/CT analysis, decompression-treated hips had lower vascularity than fibular-grafted hips at 6 months (68 % ± 6% versus 95% ± 5%; mean difference, -27%; 95% CI, -32% to -23%; p < 0.001) and 36 months (57% ± 4% versus 91% ± 3%; mean difference, -34%; 95% CI, -37% to -32%; p < 0.001). MRI analysis showed no differences between decompression-treated hips and fibular-grafted hips regarding ARCO stage at 12 months (p = 0.306) and 24 months (p = 0.06). Progression of ARCO staging was more severe in the decompression group than the fibular grafting group at 36 months (p = 0.027). The mean HHS was lower in the decompression group than in the fibular grafting group throughout the followup period, although these differences were at or below the MCID of 10 points early on. However, by 18 months, the scores favored fibular grafting (72 ± 4 versus 84 ± 4; mean difference, -13; 95% CI, -15 to -7; p < 0.001), a finding that was maintained at 24, 30, and 36 months. We found no differences between decompression-treated hips and fibular-grafted hips regarding progression to THA at 36 months (two of 21; p = 0.893). CONCLUSIONS: Hips that underwent a vascularized fibular grafting procedure fared better than hips receiving core decompression as measured by improved vascularity and less progression of osteonecrosis as measured by ARCO staging. The mean HHS of the fibular-grafted hips was better than that of the decompression-treated hips during the entire postoperative period, but the differences were modest early on, and for the early postoperative period the differences were unlikely to have been clinically important; by 18 months after surgery, the differences probably were clinically important. The mid-term outcomes associated with vascularized fibular grafting seen in our patients are associated with improvements in femoral head vascularity and the potential for bone revitalization. LEVEL OF EVIDENCE: Level I, therapeutic study.

Efficacy and safety of Wuling San for treatment of breast-cancer-related upper extremity lymphoedema: study protocol for a pilot trial.

INTRODUCTION: Breast-cancer-related upper extremity lymphoedema (BCUL), a common complication of mastectomy, can cause physical discomfort, psychological distress, cosmetic defects, functional disability and chronic recurrent erysipelas in the affected arm(s). It is a challenge to physicians involved in the management of these patients. Wuling San, a classic prescription in Traditional Chinese Medicine used in treating oedema for thousands of years, is reported by many Chinese journals to perform well in BCUL. Therefore, the aim of this study is to verify its efficacy and evaluate its safety using rigorous methodological designs in patients with BCUL. METHODS AND ANALYSIS: To verify the efficacy and assess the safety of Wuling San over a placebo, this double-blind, randomised, placebo-controlled, multicentre trial will be carried out in three hospitals. A total of 200 eligible patients with BCUL will be randomly allocated, in a ratio of 1:1, to either the experimental medicine group or the placebo group. The primary outcome measure will be the proportion of absolute reduced limb volume, as measured by perometry. The second outcome measure will be the number of participants with adverse events. The assessment will be carried out at the following time points: before enrolment (baseline) and 2, 4, 6 and 8 weeks after treatment. ETHICS AND DISSEMINATION: This trial will be conducted in accordance with the Declaration of Helsinki and supervised by the institutional review board of the Fourth Affiliated Hospital of Guangxi Medical University (approval number PJK2016088). All patients will receive information about the trial in verbal and written forms and will give informed consent before enrolment. This trial will help to demonstrate whether Wuling San is effective in the treatment of patients with BCUL. The results will be published in peer-reviewed journals or disseminated through conference presentations. TRIAL REGISTRATION NUMBER: NCT02726477; Pre-results.

sTLR4/MD-2 complex inhibits colorectal cancer in vitro and in vivo by targeting LPS.

Colorectal cancer (CRC) is aggressive and associated with TLR4-MD-2 signaling. Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2) were highly expressed in human CRC. The soluble form of extracellular TLR4 domain (sTLR4) and MD-2 may have important roles in binding lipopolysaccharide (LPS). In this study, sTLR4 and MD-2 protein and prepared sTLR4/MD-2 complex were synthesized successfully to restrain LPS-TLR4/MD-2 activation by competing with cellular membrane TLR4 for binding LPS. The sTLR4/MD-2 complex can significantly attenuate LPS induced pro-inflammatory and migration cytokine production in vitro and in vivo, and inhibit the effect of LPS on the cell cycle, migration and invasion of human CRC cells in vitro. Administration of sTLR4/MD-2 complex protected mice from tumor both in xenograft and implantation metastasis model. The sTLR4/MD-2 complex treated mice had smaller tumor, less body weight loss and lower expression of inflammatory cytokines. Here, the azoxymethane/dextran sulfate sodium salt (AOM/DSS) murine model was used as an experimental platform to simulate the physiological and pathological processes of cancers associated with chronic intestinal inflammation. AOM/DSS-induced tumors were inhibited in mice treated by sTLR4/MD-2 complex. It is demonstrated in our study that sTLR4/MD-2 complex could inhibit CRC by competing with binding LPS, raising the complex's possibility of a new prevention agent against CRC.

ELR-CXC chemokine antagonism and cisplatin co-treatment additively reduce H22 hepatoma tumor progression and ameliorate cisplatin-induced nephrotoxicity.

Cisplatin (cis-diamminedichloroplatinum) is one of the most commonly used agents for the chemotherapy of various types of cancers, but its use is limited by its dose-dependent side-effects (e.g., nephrotoxicity). The ELR-CXC chemokines are potent tumor growth, metastatic and angiogenic factors and can foster tumor resistance to chemotherapeutic agents. They are also potent proinflammatory agents. The aim of the present study was to evaluate the added effects of combining cisplatin chemotherapy with ELR-CXC chemokine antagonism in a mouse H22 hepatoma cancer cell model. The mice were injected with tumor cells and were then treated with cisplatin (12.5 or 2 mg/kg doses), either alone or together with the chemokine antagonist CXCL8(3-72)K11R/G31P (G31P) (50 µg/kg). At varying time-points renal function was examined using blood urea nitrogen (BUN) and serum creatinine (SCr) as read-outs for the toxic effects of cisplatin, while tumor growth and metastasis were assessed as endpoints. High-dose cisplatin therapy reduced the tumor burden by 52%, while co-delivery of G31P further augmented the tumor growth-suppressive effects of this dose of cisplatin to 71%; G31P by itself and low-dose cisplatin reduced the tumor burden by 19 and 39%, respectively. G31P also reduced the nephrotoxic effects of high-dose cisplatin to the effects observed in the low-dose cisplatin-treated animals. These data confirm the beneficial effects of combined cisplatin chemotherapy and ELR-CXC chemokine anatagonism in the context of both tumor progression and adverse side-effects.

[Total hip arthroplasty combined with femoral head autograft for Crowe type II and type III developmental dysplasia of hip].

OBJECTIVE: To evaluate the efficacy of total hip arthroplasty (THA) combined with femoral head autograft for Crowe type II and type III developmental dysplasia of the hip (DDH). METHODS: From January 2001 to January 2004, THA was performed for 23 patients (29 hips) with osteoarthritis secondary to DDH. There were 20 females (26 hips) and 3 males (3 hips) with an average age of 52 years (range 43-65 years). Unilateral DDH occurred in 17 patients and bilateral DDH occurred in 6 patients. Based on radiographic classification of Crowe, there were 17 cases (20 hips) of type II and 6 cases (9 hips) of type III. The length difference was (2.9 +/- 0.8) cm between two lower limbs of the unilateral DDH patients. The Harris scores were 43.6 +/- 13.8 preoperatively. The standard procedure of THA was performed in 3 patients (4 hips), the structural femoral head autograft for restoring normal level of rotating center of the acetabulum in other patients. RESULTS: The incision healed by first intention in all patients. No patient suffered complications after operation. The duration of follow-up ranged from 4 to 7 years (average 5.6 years). The X-ray films showed bony healing between the grafted bone and the ilium in all patients. At last follow-up, the length difference was (0.9 +/- 0.2) cm between two lower limbs and the Harris score was 86.3 +/- 6.4; showing statistically differences (P < 0.05) when compared with preoperation. The X-ray films showed no dislocation of acetabulum, and femoral prosthesis, and no signs of dislocation, absorption and collapse of the grafted bone. CONCLUSION: THA combined with structural femoral head autograft for patients with osteoarthritis secondary to DDH can obtain favorable results. This method can restore normal level of rotating center of the acetabulum, provide reliable acetabular fixation, and restore acetabular bone stock in patients with Crowe type II and type III DDH.