Role of Complement in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and debilitating side effect of cancer chemotherapy with an unclear pathogenesis. Consequently, the available therapies for this neuropathic pain syndrome are inadequate, leading to a significantly reduced quality of life in many patients. Complement, a key component of the innate immune system, has been associated with neuroinflammation, a potentially important trigger of some types of neuropathic pain. However, the role of complement in CIPN remains unclear. To address this issue, we developed a C3 knockout (KO) rat model and induced CIPN in these KO rats and wild-type littermates via the i.p. administration of paclitaxel, a chemotherapeutic agent associated with CIPN. We then compared the severity of mechanical allodynia, complement activation, and intradermal nerve fiber loss between the groups. We found that 1) i.p. paclitaxel administration activated complement in wild-type rats, 2) paclitaxel-induced mechanical allodynia was significantly reduced in C3 KO rats, and 3) the paclitaxel-induced loss of intradermal nerve fibers was markedly attenuated in C3 KO rats. In in vitro studies, we found that paclitaxel-treated rat neuronal cells activated complement, leading to cellular injury. Our findings demonstrate a previously unknown but pivotal role of complement in CIPN and suggest that complement may be a new target for the development of novel therapeutics to manage this painful disease.

Inhibitory Effect of Sirtuin6 (SIRT6) on Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells.

BACKGROUND The imbalance between bone resorption and formation is the basic mechanism underlying osteoporosis in the elderly. Osteogenesis is the differentiation of human mesenchymal stem cells (hMSCs) into osteoblasts. Sirtuin6 (SIRT6) regulates various biological functions, including differentiation. Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a non-selective cation channel that can be activated by physical and chemical stimulation. However, experimental data supporting the role of SIRT6 in osteogenic differentiation (OD) of hMSCs are lacking. MATERIAL AND METHODS Differentiation of hMSCs was induced. The expressions of SIRT6, TRPV1, and CGRP were detected by Q-PCR, Western blot, and ELISA, respectively. SIRT6 was overexpressed in hMSCs by transfection. ALP activity and Alizarin Red staining were utilized to detect the effect of SIRT6 on hMSC OD. Then, capsaicin and capsazepine, the TRPV1 agonist and antagonist, respectively, were administrated to assess the role of TRPV1. RESULTS SIRT6 expression was downregulated during hMSC differentiation. SIRT6 overexpression was accompanied by reduced expression of specific genes and alkaline phosphatase (ALP) activity in osteoblasts. Furthermore, TRPV1 channel was also reduced by SIRT6 overexpression via ubiquitinating TRPV1. Capsaicin was utilized in SIRT6-overexpressed cells. Capsaicin therapy counteracted the effect of SIRT6 overexpression on OD, and markedly decreased OD. CONCLUSIONS The SIRT6-TRPV1-CGRP signal axis is the key to regulating OD in hMSCs, which could be a potential therapeutic target for osteoporosis and bone loss-related diseases.

Bilateral anterior elevation prosthesis boosts chondrocytes proliferation in mice mandibular condyle.

OBJECTIVE: We aimed to develop a mouse model predominating in a proliferative response in the articular cartilage of the temporomandibular joints. MATERIALS AND METHODS: Bilateral anterior elevation of occlusion was developed by installing metal tubes onto the incisors of mice with edge-to-edge relation to prevent tooth wear, leading to an increase in the vertical height of the dental occlusion with time. Morphological changes and expression changes in Cyclin D1, Aggrecan, and type II and type X collagen in the mandibular condylar cartilage were detected. In addition, cells were isolated from the mandibular condylar cartilage and exposed to cyclic tensile strain (CTS). RESULTS: Compared with age-matched controls, the tooth length was longer at 3 weeks, 7 weeks, and 11 weeks in BAE mice (p < 0.05), with increased condylar cartilage thickness, matrix amount, and cell number (p < 0.05). Compared with the deep zone cells, CTS stimulated the superficial zone cells to express a higher level of proliferating cell nuclear antigen, Cyclin D1, Aggrecan, and type II collagen but a lower level of type X collagen and alkaline phosphatase. CONCLUSION: Bilateral anterior elevation stimulated the proliferative response in the mandibular condylar cartilage, offering a new therapeutic strategy for cartilage degeneration.

Early growth response 1 reduction in peripheral blood involving condylar subchondral bone loss.

OBJECTIVES: To detect whether early growth response 1 (EGR1) in peripheral blood leucocytes (PBLs) indicates temporomandibular joint (TMJ) osteoarthritis (OA) lesions. MATERIALS AND METHODS: Egr1 mRNA expression levels in PBLs were detected in eight malocclusion patients without temporomandibular disorder (TMD) signs and 16 malocclusion patients with clinical TMD signs with (eight) or without (eight) imaging signs of TMJ OA. Twelve 6-week-old rats were randomized to a control group and a unilateral anterior crossbite (UAC) group and were sampled at 4 weeks. The Egr1 mRNA expression levels in PBLs and protein expression levels in different orofacial tissues were measured. RESULTS: Patients with TMD signs with/without TMJ OA diagnosis showed lower Egr1 mRNA expression levels in PBLs than patients without TMD signs. The lower Egr1 mRNA expression was also found in the PBLs of UAC rats, which were induced to exhibit early histo-morphological signs of TMJ OA lesions. In subchondral bone of UAC rats, EGR1 protein expression was decreased, co-localization of EGR1 with osterix or dentin matrix protein-1 was identified, and the number of EGR1 and osterix double-positive cells was reduced (all p < .05). CONCLUSION: Egr1 reduction in PBLs potentially indicates subchondral bone OA lesions at an early stage.

Catabolic changes of rat temporomandibular joint discs induced by unilateral anterior crossbite.

BACKGROUND: The temporomandibular joint (TMJ) disc plays a role in joint movement and in load absorbance and distribution. An experimental unilateral anterior crossbite (UAC) prosthesis induces mandibular condylar cartilage degeneration in rats. However, the changes in the articular disc are still unknown. OBJECTIVE: To describe changes in the TMJ discs of UAC rats. METHODS: The discs of fifty-four Sprague-Dawley rats, equally distributed into a UAC group and an age-matched sham-operated control group at 4, 12 and 20 weeks (n = 9), were evaluated by gross and histomorphological observation and by detection at the mRNA or protein expression levels of the markers related to the matrix elements. RESULTS: No macro- or micro-morphological differences were observed between groups. However, there were catabolic degradative changes at the molecular level in the UAC group, showing a significant reduction in the mRNA and/or protein expression levels of many molecules. The reduction became worse with time (P < 0.05). The reduced molecules included: (a) those related to the extracellular matrix, such as type I collagen, decorin and fibromodulin; (b) those related to chondrogenesis, such as type II collagen and aggrecan; and (c) those related to osteogenesis, such as alkaline phosphatase and runt-related transcription factor 2. The mRNA expression of vascular endothelial growth factor did not change. In contrast, fibronectin, which can promote wound healing, and its N-terminal fragment, which can induce cartilage degradation, were accumulated (P < 0.05). CONCLUSION: TMJ discs were stimulated to catabolic changes by the aberrant dental occlusion and seemed to go to inanimate with time.

Molecular changes in peripheral blood involving osteoarthritic joint remodelling.

Biomarkers of temporomandibular joint (TMJ) osteoarthritis (OA) remain unknown. The objective was to detect whether molecular biomarkers from peripheral blood leucocytes (PBLs) engage in TMJ OA lesions. Thirty-four six-week-old Sprague Dawley rats were used. The top upregulated gene ontology categories and gene-fold changes in PBLs were detected by a microarray analysis comparing rats that received 20-week unilateral anterior crossbite (UAC) treatment with age-matched controls (n = 4). Twenty weeks of UAC treatment had been reported to induce TMJ OA-like lesions. The other twenty-four rats were randomly placed in the UAC and control groups at 12- and 20-week time points (n = 6). The mRNA expression levels of the selected biomarkers derived from the microarray analysis and their protein expression in the alveolar bone and TMJ were detected. The microarray analysis indicated that the three most highly involved genes in PBLs were Egr1, Ephx1 and Il10, which were confirmed by real-time PCR detection. The increased protein expression levels of the three detected molecules were demonstrated in cartilage and subchondral bone (P < 0.05), and increased levels of EPHX1 were reported in discs (P < 0.05); however, increased levels were not present in the alveolar bone. Immunohistochemistry revealed the increased distribution of EGR1-positive, EXPH1-positive and IL10-positive cells predominantly in the osteochondral interface, with EXPH1 also present in TMJ discs. In conclusion, the increased mRNA expression of Egr1, Ephx1 and Il10 in PBLs may serve as potential biomarkers for developed osteoarthritic lesions relating to osteochondral interface hardness changes induced by dental biomechanical stimulation.

Ski regulates Smads and TAZ signaling to suppress lung cancer progression.

Ski, the transforming protein of the avian Sloan-Kettering retrovirus, displays both pro- and anti-oncogenic activities in human cancer. The mechanisms underlying these conflicting observations have not been fully understood. Herein, we investigated the mechanism underlying the tumor suppressor activity of Ski. To investigate the effect of Ski re-activation on TGF-ß and Hippo/TAZ pathway, we measured its effect on the endogenous Smad target genes (PAI-1 and P15INK4B ) and TAZ target gene CTGF. The results revealed that Ski exerted its inhibitory activity in TGF-ß1/Smad signaling pathway. Ski inhibited TAZ by increasing their phosphorylation by Lats2 and did not alter the localization of TAZ. Ski inhibited lung cancer growth and invasion. Ski methylation correlated with decreased mRNA expression in human lung cancer cell lines. Thus, Ski inhibited the function of TGF-ß and TAZ through multiple mechanisms in human lung cancer.

Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post-ischemic pain model of complex regional pain syndrome type I in rats.

Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.

γ Secretase inhibitor BMS-708163 reverses resistance to EGFR inhibitor via the PI3K/Akt pathway in lung cancer.

Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitor (TKI). Acquired resistance to EGFR TKI develops after prolonged treatment. The aim of this study was to investigate the effect of the novel γ secretase inhibitor BMS-708163 on acquired resistance to the EGFR TKI gefitinib. We did not observe known mechanisms of acquired resistance to EGFR TKI, including the EGFR T790M mutation and MET gene amplification in the gefitinib-resistant PC9/AB2 cells. BMS-708163 inhibited PI3K/Akt expression and sensitized PC9/AB2 cells to gefitinib-induced cytotoxicity. In contrast, BMS-708163 had no significant effect on gefitinib sensitivity in PC9 parental cells. Combined treatment with BMS-708163 and gefitinib induced high levels of apoptosis. Our in vivo studies showed that combined treatment of gefitinib and BMS-708163 inhibited the growth of PC9/AB2 xenografts. In conclusion, our data show that combined treatment of gefitinib and γ secretase inhibitors may be useful for treating lung adenocarcinomas harboring EGFR mutations with acquired gefitinib resistance.

Secretory expression of a bispecific antibody targeting tumor necrosis factor and ED-B fibronectin in Pichia pastoris and its functional analysis.

Specific targeting of tumor necrosis factor (TNF)-α antagonist to the inflamed site could increase its efficacy and reduce side-effects. Here, we constructed a bispecific diabody (BsDb) that targets TNF-α and ED-B-containing fibronectin, a fibronectin isoform specifically expressed in the pannus of the inflamed synovium in rheumatoid arthritis. BsDb was secreted from Pichia pastoris as functional protein and was purified to homogeneity. BsDb could simultaneously bind to human TNF-α and B-FN and neutralize TNF-α action. Additionally, BsDb showed a significant gain both in the antigen-binding affinity and in TNF-α-neutralizing ability as compared to its original antibodies, L19 and anti-TNF-α scFv, which were produced in E. coli. BsDb was constructed and was endowed with enhanced bioactivities and improved production processing. Therefore, it holds great potential for in vivo applications.

[Construction and functional analysis of a bispecific antibody that targets TNF-α and ED-B].

In order to enhance the specificity of TNF-α monoclonal antibody to inflamed site, a bispecific antibody BsDb that targets TNF-α and the extra-domain B (ED-B) of fibronectin (FN) was constructed by covalently linking the anti-TNF-α single chain Fv antibody (TNF-scFv) and the anti-ED-B scFv L19 via a flexible peptide linker deriving from human serum albumin (HSA). ED-B is an antigen specifically expressed at the inflamed site. BsDb is expressed in E. coli, identified by immunoblot, and purified with affinity chromatography. This was followed by further examination of its bioactivities and pharmacokinetics. We demonstrated that BsDb retained the immunoreactivity of its original antibodies as it could simultaneously bind to TNF-α and ED-B and neutralize the biological action of TNF-α. In the collagen-induced arthritis mice model, BsDb selectively accumulate in the inflamed joint with a maximal uptake of (12.2 ± 1.50)% ID/g in a single inflamed paw and retain in the inflamed paw for at least 72 h. In contrast, BsDb showed a short serum half-life of (0.50 ± 0.05) h and a rapid clearance from normal tissues. The findings reported herein indicate that BsDb has good specificity to the inflamed site and low toxicity to normal tissues. BsDb is therefore likely to have greater clinical applications in the treatment of rheumatoid arthritis and other autoimmune diseases. This laid a stable basis for its preclinical study.

Atrial arrhythmias after pulmonary resection: the important role of pulmonary vein resection.

BACKGROUND: Atrial arrhythmias (AAs) remain one of the most common complications after pulmonary resection. The association between postoperative AAs and pulmonary vein (PV) resection has not previously been clearly elucidated. A retrospective study on this issue is reported. METHODS: A total of 125 patients were involved in this study and all the performed surgical procedures and all postoperative AAs were carefully reviewed and recorded. A univariate and multivariate analyses were utilized to clarify the effect of PV resection on postoperative AAs. RESULTS: The overall incidence of postoperative AAs was 14.4% (n = 18). A stepwise increase in the incidence of AAs was observed from none, to the inferior of PV resection only, superior PV resection only and up to both inferior and superior PV resection (0, 3.1, 14.3, and 38.5%, respectively; p = 0.000). During multivariate analysis, PV resection was identified as an independent risk factor for postoperative AAs when it was entered either as an ordinal or as a categorical variable. The area under the receiver operating characteristic curve of PV resection revealed 0.786 (95% confidence interval [CI], 0.685-0.887), which was significantly larger than the extent of pulmonary resection (0.724; 95% CI, 0.637-0.800; p = 0.015). CONCLUSION: PV resection plays an important role in the development of postoperative AAs after pulmonary resection and could be used as a good predictor for postoperative AAs.

Activation of Notch-1 enhances epithelial-mesenchymal transition in gefitinib-acquired resistant lung cancer cells.

Despite an initial response to EGFR tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer, most patients eventually become resistant and result in treatment failure. Recent studies have shown that epithelial to mesenchymal transition (EMT) is associated with drug resistance and cancer cell metastasis. Strong multiple gene signature data indicate that EMT acts as a determinant of insensitivity to EGFR-TKI. However, the exact mechanism for the acquisition of the EMT phenotype in EGFR-TKI resistant lung cancer cells remains unclear. In the present study, we showed that the expression of Notch-1 was highly upregulated in gefitinib-resistant PC9/AB2 lung cancer cells. Notch-1 receptor intracellular domain (N1IC), the activated form of the Notch-1 receptor, promoted the EMT phenotype in PC9 cells. Silencing of Notch-1 using siRNA reversed the EMT phenotype and restored sensitivity to gefitinib in PC9/AB2 cells. Moreover, Notch-1 reduction was also involved in inhibition of anoikis as well as colony-formation activity of PC9/AB2 cells. Taken together, these results provide strong molecular evidence that gefitinib-acquired resistance in lung cancer cells undergoing EMT occurs through activation of Notch-1 signaling. Thus, inhibition of Notch-1 can be a novel strategy for the reversal of the EMT phenotype thereby potentially increasing therapeutic drug sensitivity to lung cancer cells.

Facilitation versus depression in cultured hippocampal neurons determined by targeting of Ca2+ channel Cavbeta4 versus Cavbeta2 subunits to synaptic terminals.

Ca(2+) channel beta subunits determine the transport and physiological properties of high voltage-activated Ca(2+) channel complexes. Our analysis of the distribution of the Ca(v)beta subunit family members in hippocampal neurons correlates their synaptic distribution with their involvement in transmitter release. We find that exogenously expressed Ca(v)beta(4b) and Ca(v)beta(2a) subunits distribute in clusters and localize to synapses, whereas Ca(v)beta(1b) and Ca(v)beta(3) are homogenously distributed. According to their localization, Ca(v)beta(2a) and Ca(v)beta(4b) subunits modulate the synaptic plasticity of autaptic hippocampal neurons (i.e., Ca(v)beta(2a) induces depression, whereas Ca(v)beta(4b) induces paired-pulse facilitation [PPF] followed by synaptic depression during longer stimuli trains). The induction of PPF by Ca(v)beta(4b) correlates with a reduction in the release probability and cooperativity of the transmitter release. These results suggest that Ca(v)beta subunits determine the gating properties of the presynaptic Ca(2+) channels within the presynaptic terminal in a subunit-specific manner and may be involved in organization of the Ca(2+) channel relative to the release machinery.

[Preliminary research into the relation between characteristic parameters of transesophageal photoelectric pulse wave in descending aorta and ambulatory artery blood pressure].

The present paper aims to investigate the relation between characteristic parameters of transesophageal photoelectric pulse wave in descending aorta and ambulatory artery blood pressure. The chests of ten adult experimental dogs were performed to take the photoelectric pulse wave of descending aorta transesophageally. The concurrent femoral artery invasive blood pressure was recorded simultaneously. Stepwise regression analysis method was used to study the correlation efficient between characteristic parameters of descending aorta pulse wave (H, h, h/H, g/H, At, s, H(1 + ts/td), k)and invasive artery blood pressure. The characteristic parameters, k and h/H (ratio: 90% and 80%) was proved that they had good correlation with systolic pressure; and k, H and s (ratio: 90%, 80% and 70%), had good correlation with diastolic pressure; while k and H (ratio: 90% for both) had good correlation with mean pressure. The mean values of multiple correlation coefficients of the selected characteristic parameters of descending aorta pulse wave with systolic pressure, diastolic pressure and mean pressure of femoral artery were 0.871, 0.900 and 0.856, respectively. The characteristic parameters of descending aorta pulse wave had specific correlation with systolic pressure, diastolic pressure and mean pressure.

Changes in NMDA Receptor Function in Rapid Ischemic Tolerance: A Potential Role for Tri-Heteromeric NMDA Receptors.

In this study, we characterize biophysical changes in NMDA receptor function in response to brief non-injurious ischemic stress (ischemic preconditioning). Electrophysiological studies show NMDA receptor function is reduced following preconditioning in cultured rat cortical neurons. This functional change is not due to changes in the reversal potential of the receptor, but an increase in desensitization. We performed concentration-response analysis of NMDA-evoked currents, and demonstrate that preconditioned neurons show a reduced potency of NMDA to evoke currents, an increase in Mg2+ sensitivity, but no change in glycine sensitivity. Antagonists studies show a reduced inhibition of GluN2B antagonists that have an allosteric mode of action (ifenprodil and R-25-6981), but competitive antagonists at the GluR2A and 2B receptor (NVP-AMM077 and conantokin-G) appear to have similar potency to block currents. Biochemical studies show a reduction in membrane surface GluN2B subunits, and an increased co-immunoprecipitation of GluN2A with GluN2B subunits, suggestive of tri-heteromeric receptor formation. Finally, we show that blocking actin remodeling with jasplakinolide, a mechanism of rapid ischemic tolerance, prevents NMDA receptor functional changes and co-immunoprecipitation of GluN2A and 2B subunits. Together, this study shows that alterations in NMDA receptor function following preconditioning ischemia are associated with neuroprotection in rapid ischemic tolerance.

Tracheal Extubation Under Deep Anesthesia Using Transnasal Humidified Rapid Insufflation Ventilatory Exchange vs. Awake Extubation: An Open-Labeled Randomized Controlled Trial.

Background: Tracheal extubation can be associated with several complications, including desaturation, agitation, hypertension, and tachycardia. We hypothesize that the use of transnasal humidified rapid insufflation ventilator exchange (THRIVE) immediately after extubation under deep anesthesia reduces the incidence of these adverse events. Methods: One hundred patients who underwent elective abdominal surgery under general anesthesia were randomly assigned to undergo tracheal extubation under deep anesthesia employing THRIVE (THRIVE group) or awake extubation (CONTROL group). The primary outcome was the incidence of experiencing desaturation (SpO2 < 90%) at any time during emergence from anesthesia. Secondary outcomes included variations in heart rate and blood pressure, comfort level, bucking, and agitation. Results: The THRIVE group showed a lower incidence of desaturation than the CONTROL group (12 vs. 54%, OR = 0.22 [95% CI, 0.10-0.49], P < 0.001). Less patients in the THRIVE group experienced a 20% (or more) increase in mean arterial pressure (4 vs. 26%, OR = 0.15 [95% CI, 0.04-0.65], P = 0.002). THRIVE patients did not suffer from agitation or bucking, while in the CONTROL group agitation and bucking occurred in 22 and 58% of the patients, respectively. Additionally, the THRIVE group showed a lower incidence of uncomfortable experience than the CONTROL group (8 vs. 36%, OR = 0.22 [95% CI, 0.08-0.61], P = 0.001). Conclusion: Tracheal extubation under deep anesthesia using THRIVE decreases the incidence of desaturation and adverse haemodynamic events and increases patient satisfaction. Extubation under deep anesthesia using THRIVE might be an alternative strategy in selected patient populations.

Influence of ketamine versus fentanyl on pain relief for pediatric orthopedic emergencies: A meta-analysis of randomized controlled studies.

INTRODUCTION: The comparison of ketamine with fentanyl for pain control of pediatric orthopedic emergencies remains controversial. We conduct a systematic review and meta-analysis to explore the influence of ketamine versus fentanyl on pain management among pediatric orthopedic emergencies. METHODS: We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through September 2020 for randomized controlled trials assessing the effect of ketamine versus fentanyl on pain management for pediatric orthopedic emergencies. RESULTS: Five randomized controlled trials are included in the meta-analysis. Overall, compared with fentanyl for pediatric orthopedic emergencies, ketamine led to similar change in pain scores at 15 to 20 minutes (standard mean difference = -0.05; 95% confidence interval [CI] = -0.38 to 0.28; P = .77) and 30 minutes (standard mean difference = 0.11; 95% CI = -0.20 to 0.42; P = .49), as well as rescue analgesia (RR = 0.90; 95% CI = 0.54 to 1.51; P = .69), but revealed the increase in nausea/vomiting (RR = 2.65; 95% CI = 1.13 to 6.18; P = .02) and dizziness (RR = 3.83; 95% CI = 1.38 to 10.60; P = .01). CONCLUSIONS: Ketamine may be similar to fentanyl in terms of the analgesic efficacy for pediatric orthopedic emergencies.

Clinicopathological and molecular characterizations of pulmonary NUT midline carcinoma.

INTRODUCTION: Pulmonary nuclear protein of the testis (NUT) midline carcinoma (NMC) is a aggressive cancer with t (15, 19) translocation. Here we present the clinicopathological characteristics and molecular genetics alterations of primary pulmonary NMC. METHODS: Fluorescence in situ hybridization (FISH) assay was performed to evaluate NUT translocation. Next generation sequencing (NGS) was performed to investigate genomic landscape. A panel of 289 lung cancer tissues with undifferentiation was retrospectively screened for NUT expression by immunohistochemical (IHC) assay. RESULTS: Overall, 2136 lung cancer samples were reviewed. We consecutively identified 12 cases of primary pulmonary NMC. Computed tomography revealed centrally located bulky lung mass with ipsilateral mediastinal lymph node and pleural involvements. Tumor cells presented diffuse poor differentiation and focal squamous differentiation with positive NUT expression. NUT rearrangement was confirmed by FISH assay. Ten NMC samples were investigated by NGS. The most common alterations identified were P53, PIK3CA, AUTS2, ITIH2, and CDKL5 genes. Pulmonary NMC exhibited increased activity of PI3K/AKT pathway. In the screening study, BRD4-NUT rearrangement was identified in two cases. CONCLUSION: NUT rearrangement remains the gold standard in the diagnosis of pulmonary NMC. PI3K inhibition is a potential targeted therapy for pulmonary NMC.

Notch1/TAZ axis promotes aerobic glycolysis and immune escape in lung cancer.

Oncogenic signaling pathway reprograms cancer cell metabolism to promote aerobic glycolysis in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. Notch1 signaling, dysregulated in lung cancer, is correlated with increased glycolysis. Herein, we demonstrate in lung cancer that Notch1 promotes glycolytic gene expression through functional interaction with histone acetyltransferases p300 and pCAF. Notch1 signaling forms a positive feedback loop with TAZ. Notch1 transcriptional activity was increased in the presence of TAZ and the activation was TEAD1 independent. Notably, aerobic glycolysis was critical for Notch1/TAZ axis modulation of lung cancer growth in vitro and in vivo. Increased level of extracellular lactate via Notch1/TAZ axis inhibited cytotoxic T-cell activity, leading to the invasive characteristic of lung cancer cells. Interaction between Notch1 and TAZ promoted aerobic glycolysis and immune escape in lung cancer. Our findings provide potential therapeutic targets against Notch1 and TAZ and would be important for clinical translation in lung cancer.