This study aimed to investigate the minimum number of operations required for itinerant nurses in the operating room to master the skills needed to operate the Ti-robot-assisted spinal surgery equipment. Additionally, we aimed to provide a corresponding basis for the development of qualification admission criteria and skill training for nurses who cooperate with this type of surgery. Nine operating room itinerant nurses independently performed Ti-robot equipment simulations using a spine model as a tool, with 16 operations per trainee. Four evaluation indices were recorded: time spent on equipment preparation and line connections, time spent on image acquisition and transmission, time spent on surgical spine screw placement planning, and time spent on robot arm operation. Individual and general learning curves were plotted using cumulative sum analysis. The number of cases in which the slope of the individual learning curves began to decrease was 3–11 cases, and the number of cases in which the slope of the general learning curve began to decrease was 8 cases. The numbers of cases in which the learning curves began to decrease in the four phases were the 5th, 8th, 11th, and 3rd cases. Itinerant nurses required at least eight cases to master the equipment operation skills of Ti-robot-assisted spinal surgery. Among the four phases, the image acquisition and transmission phases and the surgical spine screw placement planning phase were the most difficult and must be emphasized in future training.
Abstract Background: Neuromyelitis optica (NMO), multiple sclerosis (MS) and autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy are idiopathic inflammatory demyelinating diseases (IIDDs) that mainly present as encephalomyelitis. Heparan sulfate (HS) and hyaluronic acid (HA) are two components of glycocalyx, a carbohydrate-rich layer on the surface of blood vessels that mediates interaction with blood. Degradation of glycocalyx in IIDDs is poorly understood. Purpose: To detect the serum and cerebrospinal fluid (CSF) levels of shed HS and HA and to correlate these levels with disease severity to determine their diagnostic value. Methods: We obtained serum and CSF samples from 24 NMO patients, 15 MS patients, 10 autoimmune GFAP astrocytopathy patients, and 18 controls without non-inflammatory neurological diseases. Soluble HS and HA, and IFNγ, IL17A, and matrix metalloproteinase (MMP) 1 were detected via ELISA. Results: Serum and CSF levels of HS, HA and related cytokines but not of plasma MMP1 were significantly elevated in these diseases. Notably, HS and HA levels were positively correlated with Expanded Disability Status Scale scores. Conclusions: Our results indicate glycocalyx degradation and inflammation in NMO, MS and autoimmune GFAP astrocytopathy. Moreover, increased shedding of HS or HA may indicate a worse clinical situation. Furthermore, therapeutic strategies that protect glycocalyx may be effective in these diseases.
Our recent investigation on the insecticidal activities of several doramectin derivatives preliminarily revealed that the presence of hydrogen bonds at the C4″ position of the molecule with target protein γ-aminobutyric acid (GABA) receptor was crucial for retaining high insecticidal activity. As a continuation of our research work on the development of new insecticides, two series of novel acylurea and acylthiourea doramectin derivatives were designed and synthesized. The bioassay results indicated that the newly synthesized compounds (5o, 5t, and 6t) exhibited higher insecticidal activity against diamondback moth, oriental armyworm, and corn borer than the control compounds doramectin, commercial avermectins, chlorbenzuron, and lead compound 3g in our laboratory. Specifically, compound 5t was identified as the most promising insecticide against diamondback moth, with a final mortality rate of 80.00% at the low concentration of 12.50 mg/L, showing approximately 7.75-fold higher potency than the parent doramectin (LC50 value of 48.1547 mg/L), 6.52-fold higher potency than commercial avermectins (LC50 value of 40.5507 mg/L), and 3.98-fold higher potency than compound 3g (LC50 value of 24.7742 mg/L). Additionally, molecular docking simulations revealed that compound 5t (2.17, 2.20, 2.56, and 2.83 Å) displayed stronger hydrogen-bond action in binding with the GABA receptor, better than that of compound 5o (1.64 and 2.15 Å) and compound 6t (2.20 and 2.31 Å) at the C4″ position. This work demonstrated that these compounds containing hydrogen-bond groups might contribute to the improvement of insecticidal activity and supply certain hints toward structure optimization design for the development of new insecticides.
Clinical need for treating allergic conjunctivitis (AC) is rapidly increasing. However, AC-relevant anti-inflammatory compounds are generally difficult to solubilize in water, thus limiting their therapeutic potential. Solubility-improved eye drop formulations of these compounds have poor bioavailability and a short retention time in ophthalmic tissues. Herein, we report a DNA/poly(lactic-co-glycolicacid) (PLGA) hybrid hydrogel (HDNA) for water-insoluble ophthalmic therapeutic delivery. PLGA pre-encapsulation enables loading of water-insoluble therapeutics. HDNA's porous structure is capable of sustained delivery of therapeutics. Dexamethasone (DEX), with demonstrated activities in attenuating inflammatory symptom in AC, was used as a model system. The designed HDNA hybrid hydrogels significantly improved the DEX accumulation and mediated the gradual DEX release in ophthalmic cells and tissues. Using the HDNA–DEX complexes, potent efficacy in two animal models of AC was acquired. Given this performance, demonstrable biocompatibility, and biodegradability of DNA hydrogel, the HDNA-based ophthalmic therapeutic delivery system enables novel treatment paradigms, which will have widespread applications in the treatment of various eye diseases.
Abstract The 5-year relative survival rate for triple-negative breast cancer (TNBC) is 77%, which is notably lower than 90%, the overall survival rate for breast cancer. The primary systemic treatment for TNBC remains to be chemotherapy. However, patients frequently develop resistance to conventional chemotherapy, greatly compromising the anti-tumor effects of chemodrugs. Therefore, this study is aimed to enhance the effects of chemotherapy. The RNA-binding protein Hu antigen R (HuR) plays an important role in chemotherapy resistance. HuR post-transcriptionally regulates the stability of the target mRNA by binding to the U- or AU-rich elements (ARE) mainly in the 3’ untranslated region (UTR) of mRNA. In most cases, the binding stabilizes mRNA, thereby enhancing the translation of the encoded protein, many of which are implicated in multiple cancer hallmarks, including chemoresistance. The overexpression of HuR, and accumulated cytoplasmic expression, are reported to be related to chemoresistance in many types of cancer cells. We hypothesized that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of mRNA and thus reduce the translation of proteins contributing to chemoresistance. Previously, our lab reported a small molecule HuR inhibitor, KH-3, which potently inhibits HuR function by disrupting the HuR-mRNA interactions. To test our hypothesis, we utilized KH-3 as a tool compound to assess whether HuR inhibition enhances the efficacy of chemotherapy for TNBC cells. We generated a cell sub-line (231-TR) derived from the human TNBC cell line MDA-MB-231 with acquired resistance against docetaxel (TXT). Compared with the parental cell line, 231-TR exhibited similar sensitivity to KH-3 in the MTT-based cytotoxicity assay and the colony formation assay. The in vitro and in vivo combination of KH-3 and TXT synergized in inhibiting cell proliferation and tumor growth of multiple TNBC cell lines. Regarding mechanisms of action, the apoptosis pathway was downregulated and the Wnt signaling pathway was upregulated in 231-TR cells. KH-3 treatment downregulated β-Catenin, involved in promoting cell proliferation, in a time and dose-dependent manner. KH-3 was also identified to induce apoptosis cell death via inhibiting the anti-apoptotic protein BCL2. The cell cycle analysis revealed that KH-3 treatment caused the S phase accumulation. Therefore, the cell proliferation inhibition by KH-3 results from a combination of apoptosis and cell cycle arrest. Furtherly, KH-3 restored the effects of docetaxel in inducing apoptotic cell death in 231-TR cells. Together, this study provides a new strategy to overcome chemotherapy resistance in TNBC cells by functional inhibiting HuR. Citation Format: Lanjing Wei, Qi Zhang, Cuncong Zhong, Jeffrey Aubé, Danny R. Welch, Xiaoqing Wu, Liang Xu. Inhibition of RNA binding protein HuR function sensitizes the TNBC to chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-08.
Abstract The 5-year relative survival rate for triple-negative breast cancer (TNBC) is 77%, which is notably lower than 90%, the overall survival rate for breast cancer. The primary systemic treatment for TNBC remains to be chemotherapy. However, patients frequently develop resistance to conventional chemotherapy, greatly compromising the anti-tumor effects of chemodrugs. Therefore, this study is aimed to enhance the effects of chemotherapy. The RNA-binding protein Hu antigen R (HuR) plays an important role in chemotherapy resistance. HuR post-transcriptionally regulates the stability of the target mRNA by binding to the U- or AU-rich elements (ARE) mainly in the 3’ untranslated region (UTR) of mRNA. In most cases, the binding stabilizes mRNA, thereby enhancing the translation of the encoded protein, many of which are implicated in multiple cancer hallmarks, including chemoresistance. The overexpression of HuR, and accumulated cytoplasmic expression, are reported to be related to chemoresistance in many types of cancer cells. We hypothesized that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of mRNA and thus reduce the translation of proteins contributing to chemoresistance.Previously, our lab reported a small molecule HuR inhibitor, KH-3, which potently inhibits HuR function by disrupting the HuR-mRNA interactions. To test our hypothesis, we utilized KH-3 as a tool compound to assess whether HuR inhibition enhances the efficacy of chemotherapy for TNBC cells. We generated a cell sub-line (231-TR) derived from the human TNBC cell line MDA-MB-231 with acquired resistance against docetaxel (TXT). Compared with the parental cell line, 231-TR exhibited similar sensitivity to KH-3 in the MTT-based cytotoxicity assay and the colony formation assay. The in vitro and in vivo combination of KH-3 and TXT synergized in inhibiting cell proliferation and tumor growth of multiple TNBC cell lines. Regarding mechanisms of action, the apoptosis pathway was downregulated and the Wnt signaling pathway was upregulated in 231-TR cells. KH-3 treatment downregulated β-Catenin, involved in promoting cell proliferation, in a time and dose-dependent manner. KH-3 was also identified to induce apoptosis cell death via inhibiting the anti-apoptotic protein BCL2. The cell cycle analysis revealed that KH-3 treatment caused the S phase accumulation. Therefore, the cell proliferation inhibition by KH-3 results from a combination of apoptosis and cell cycle arrest. Furtherly, KH-3 restored the effects of docetaxel in inducing apoptotic cell death in 231-TR cells. Together, this study provides a new strategy to overcome chemotherapy resistance in TNBC cells by functional inhibiting HuR. Citation Format: Lanjing Wei, Qi Zhang, Cuncong Zhong, Jeffrey Aubé, Danny Welch, Xiaoqing Wu, Liang Xu. Functional inhibition of the RNA-binding protein HuR sensitizes triple-negative breast cancer to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1753.
Chemotherapy remains the primary option for the systemic treatment of triple-negative breast cancer (TNBC). However, chemoresistance frequently occurs with the conventional use of chemotherapeutic drugs, resulting in a poorer prognosis and a higher recurrence rate of TNBC than other subtypes of breast cancer. Therefore, overcoming chemoresistance is a critical challenge to conquer for the successful treatment of TNBC. The RNA-binding protein Hu antigen R (HuR) is a posttranscriptional regulator. It can stabilize mRNA by binding to U- or AU-rich elements (ARE) mainly in 3' untranslated region (UTR) of mRNA and therefore upregulate the translation most of the time. The encoded proteins of HuR target mRNAs are implicated in multiple cancer hallmarks, including therapeutic resistance. The cytoplasmic accumulation of HuR is reported to contribute to chemoresistance in several types of cancer cells, and HuR inhibition sensitizes cells to chemodrugs. We hypothesize that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of target mRNA and thus reduce the translation level of proteins responsible for chemoresistance. Recently, our lab reported a small molecule HuR inhibitor, KH-3, which potently inhibits HuR function by disrupting HuR-mRNA interactions. In this study, we investigate the roles HuR played in the chemoresistance of TNBC and evaluate whether HuR inhibition by KH-3 can enhances the chemotherapy efficacy. To determine whether HuR inhibition overcomes acquired chemoresistance of TNBC, two MDA-MB-231 cell sub-lines resistant to docetaxel (231-TR) or doxorubicin (231-DR) were generated. Compared to the parental cell line, two sub-lines exhibit similar sensitivity to KH-3, and KH-3 re-sensitizes chemoresistant cells to docetaxel or doxorubicin in the MTT-based cytotoxicity assay and the colony formation assay, indicating that HuR inhibition can overcome the acquired chemoresistance. The combination index suggests that the combination of KH-3 with docetaxel or doxorubicin has a synergistic effect. The in vivo efficacy studies in both MDA-MB-231 and 231-TR orthotopic xenograft mouse models confirm that KH-3 synergizes docetaxel treatment. Mechanistically, several HuR direct target mRNAs implicated in chemoresistance were found upregulated in the resistant cells, which were reversed by KH-3 treatment. The detailed molecular mechanisms of how KH-3 sensitized TNBC cells to chemodrugs are being investigated. This research suggests that HuR inhibition is a promising strategy for overcoming chemoresistance in TNBC.
Deficiency in the TGF-β-induced regulatory T (iTreg) cell differentiation is associated with compromised immune homeostasis and plays a key role in many autoimmune diseases. Therapeutic intervention to enhance in situ iTreg differentiation has become a promising treatment modality for autoimmune diseases. Here we describe that the development of autoimmune inflammation in experimental autoimmune encephalomyelitis (EAE) is associated with selective impairment of iTreg differentiation largely due to the increased production of TNF-α. The neutralization of TNF-α markedly increases iTreg differentiation, leading to the amelioration of EAE, whereas the depletion of iTreg cells abolishes the therapeutic effect of an anti-TNF-α antibody. The inhibition of iTreg differentiation by TNF-α is mediated through a signaling cascade involving the induction of TNF receptor II (TNFR2) expression and the activation of Akt. The activated Akt in turn interacts with Smad3, resulting in the inhibition of TGF-β-induced Smad3 phosphorylation and consequently the reduction of p-Smad3 results in the decreased binding to the specific binding site of the foxp3 promoter, and finally foxp3 transcription itself. Interestingly, this regulatory pathway is iTreg cell specific as TNF-α does not activate Akt in naturally occurring regulatory T cells, therefore conferring a selective effect of TNF-α and its antagonism on iTreg cells. The study sheds new light on the critical role and underlying mechanism of TNF-α in the regulation of iTreg differentiation and provides a novel rationale for TNF-α antagonistic therapy for autoimmune diseases.
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