Identifying Novel Proteins for Chronic Pain: Integration of Human Brain Proteomes and Genome-Wide Association Data.

Numerous genome-wide association studies have identified risk genes for chronic pain, yet the mechanisms by which genetic variants modify susceptibility have remained elusive. We sought to identify key genes modulating chronic pain risk by regulating brain protein expression. We integrated brain proteomic data with the largest genome-wide dataset for multisite chronic pain (N=387,649) in a proteome-wide association study (PWAS) using discovery and confirmatory proteomic datasets (N=376 and 152) from the dorsolateral prefrontal cortex (dPFC). Leveraging summary data-based Mendelian randomization (SMR) and Bayesian colocalization analysis (COLOC), we pinpointed potential causal genes, while a transcriptome-wide association study (TWAS) integrating 452 human brain transcriptomes investigated whether cis-effects on protein abundance extended to the transcriptome. Single-cell RNA sequencing data and single-nucleus transcriptomic data revealed cell-type specific expression patterns for identified causal genes in the dPFC and dorsal root ganglia (DRG), complemented by RNA microarray analysis of expression profiles in other pain-related brain regions. Of the 22 genes cis-regulating protein abundance identified by the discovery PWAS, 18 (82%) were deemed causal by SMR or COLOC analyses, with 7 of these 18 genes (39%) replicating in the confirmatory PWAS, including GMPPB, which also associated at the transcriptome level. Several causal genes exhibited selective expression in excitatory neurons, inhibitory neurons, oligodendrocytes, and astrocytes, while most identified genes were expressed across additional pain-related brain regions. This integrative proteogenomic approach identified 18 high-confidence causal genes for chronic pain, regulated by cis-effects on brain protein levels, suggesting promising avenues for treatment research and indicating a contributory role for the DRG. PERSPECTIVE: The current post-GWAS analyses identified 18 high-confidence causal genes regulating chronic pain risk via cis-modulation of brain protein abundance, suggesting promising avenues for future chronic pain therapies. Additionally, the significant expression of these genes in the DRG indicated a potential contributory role, warranting further investigation.

A multi-center study to predict the risk of intraoperative hypothermia in gynecological surgery patients using preoperative variables.

OBJECTIVES: Hypothermia is highly common in patients undergoing gynecological surgeries under general anesthesia, so the length of hospitalization and even the risk of mortality are substantially increased. Our aim was to develop a simple and practical model to preoperatively identify gynecological surgery patients at risk of intraoperative hypothermia. METHODS: In this retrospective study, we collected data from 802 patients who underwent gynecological surgery at three medical centers from June 2022 to August 2023. We further allocated the patients to a training group, an internal validation group, or an external validation group. The preliminary predictive factors for intraoperative hypothermia in gynecological patients were determined using the least absolute shrinkage and selection operator (LASSO) method. The final predictive factors were subsequently identified through multivariate logistic regression analysis, and a nomogram for predicting the occurrence of hypothermia was established. RESULTS: A total of 802 patients were included, with 314 patients in the training cohort (mean age 48.5 ± 12.6 years), 130 patients in the internal validation cohort (mean age 49.9 ± 12.5 years), and 358 patients in the external validation cohort (mean age 47.6 ± 14.0 years). LASSO regression and multivariate logistic regression analyses indicated that body mass index, minimally invasive surgery, baseline heart rate, baseline body temperature, history of previous surgery, and aspartate aminotransferase level were associated with intraoperative hypothermia in gynecological surgery patients. This nomogram was constructed based on these six variables, with a C-index of 0.712 for the training cohort. CONCLUSIONS: We established a practical predictive model that can be used to preoperatively predict the occurrence of hypothermia in gynecological surgery patients. CLINICAL TRIAL REGISTRATION: chictr.org.cn, identifier ChiCTR2300071859.

Value of Evoked Potential Changes Associated with Neck Extension Prior to Cervical Spine Surgery.

Background: Multimodal intraoperative monitoring (MIOM) is a useful tool to warn surgeons to intervene for intraoperative spinal cord injury in cervical spine surgery. However, the value of MIOM remains controversial before cervical spine surgery. Objective: To explore the value of MIOM in early detecting spinal cord injury associated with neck extension before cervical spine surgery. Methods and Materials: Data of 191 patients receiving cervical spine surgery with the MIOM were enrolled from June 2014 to June 2020. The subjects were divided into a group of evoked potentials (EP) changes and a group of no EP changes for analysis according to the monitoring alerts or not. Results: Five (2.62%) patients showed EP changes associated with neck extension during intubation or positioning. After early different interventions, such as repositioning and timely surgical decompression, none or transient postoperative neurological deficits were observed in four cases, and only one case was with permanent neurological deficits. The average preoperative Japanese Orthopaedic Association (JOA) scores of the group with EP changes were lower than those of the group with no EP changes (P = 0.037 < 0.05). There was no statistical significance in gender, average age, mean Pavlov ratio, and the minimum Palov ratio between the two groups (P > 0.05). Conclusions: The MIOM could identify spinal cord injury associated with neck extension before cervical spine surgery. Active and effective interventions could prevent or reduce permanent postoperative neurological deficits. Severe spinal cord compression might be a risk factor for EP changes.

Infusion management associated with prolonged length of stay following free flap reconstruction of head and neck defects: A propensity score matching study.

BACKGROUND: Surgical resection of the primary lesion and reconstruction of the defects with free flaps are common treatments for head and neck cancer (HNC). However, various variables can lead to prolonged length of stay (LOS). The aim of this study is to investigate risk factors correlated with prolonged LOS following free flap reconstruction of head and neck defects. METHODS: A retrospective study of patients with all types of free flaps reconstruction of HNC between January 2011 and January 2019 at Sun Yat-sen Memorial Hospital was performed. We recorded predictive variables and divided them into: personal and clinical, hemodynamic, anesthetic and surgical. The primary endpoint was prolonged length of stay. Univariate and multivariate analyses were applied to identify risk factors that associated with prolonged LOS. Propensity score matching was performed with the identified risk variables and other perioperative factors that may impact transfusion decision to explore the independent influence of intraoperative blood transfusion on prolonged LOS. RESULTS: A total of 1047 patients were included in this study. The median LOS was 13.00 (11.00, 16.00) days. Multivariate analysis suggested that blood transfusion, duration of surgery, postoperative complications and unplanned reoperation were associated with prolonged LOS. After propensity score matching, unnecessary blood transfusion and inadequate fluid rate over 24 h, postoperative complications and unplanned reoperation were identified risk factors that led to prolonged LOS. CONCLUSION: Unnecessary blood transfusion and inadequate fluid infusion rate over 24 h were independent risk factors associated with prolonged LOS in HNC patients who underwent free flap reconstruction. Our results indicated consideration of restrictive blood transfusion and adequate fluid infusion over postoperative 24 h in these patients.

Risk factors associated with postoperative complications following free flap reconstruction of head and neck defects.

BACKGROUND: Free flap reconstruction of head and neck defects is routinely performed with a high success rate nowadays. However, postoperative complications are still commonly observed. The aim of this study is to investigate risk factors correlated with postoperative complications following free flap reconstruction of head and neck defects. METHODS: A retrospective study of all patients undergoing free flap reconstruction of head and neck defects between January 2018 and January 2020 at Sun Yat-sen Memorial Hospita, Guangzhou, China was performed. Preoperative, intraoperative, and postoperative data were collected retrospectively. The primary outcome variables were postoperative complications, which were divided into medical and surgical complications. All patients were grouped by either complications or no complications. Univariate and multivariate logistic regression models were used to identify risk factors predicting complications. RESULTS: 850 patients underwent free flap reconstruction of head and neck defects during the study period (Male: 65.29%; Mean [SD] age: 54.90 [13.78] years). Postoperative complications developed in 125 (14.71%) patients, among which, 101 (11.88%) patients developed surgical complications, 29 (3.41%) patients developed medical complications and 5 (0.59%) patients developed both surgical and medical complications. Total flap necrosis was observed in 11 (1.29%) patients. After multivariate analysis, several risk factors incluing postoperative ICU admission, coronary heart disease, post radiotherapy surgery and flap types were identified correlated with postoperative complications. CONCLUSIONS: Our study identified related variables for a higher risk of postoperative complications development following free flap reconstruction of head and neck defects. Early detection of these risk factors will improve prognosis.

Can anesthetic effects and pain treatment influence the long-term prognosis of early-stage lymph node-negative breast cancer after breast-conserving surgery?

BACKGROUND: Breast cancer is currently the leading cause of women's death. It is crucial to further improve the approach to treatment and the long-term survival rate of breast cancer patients, and to reduce the rates of recurrence and metastasis. It has been reported that the possibility of tumor metastasis depends on the metastatic potential of the tumor and the host defense against tumor metastasis, in which cellular immunity and the function of natural killer (NK) cells are critical to maintaining this balance. Surgical stress response and postoperative pain inhibit perioperative immune function in patients and increase the likelihood of dissemination and metastasis of cancer cells after cancer surgery. The study aims to investigate the effect of anesthetic factors and pain treatment on the long-term prognosis of patients with early stage lymph node negative breast preservation surgery. METHODS: A total of 337 patients with early-stage lymph node negative breast cancer (ASA I-II) who had undergone successful breast-conserving surgery in our hospital were included in this retrospective analysis. Cases were divided into general anesthesia with postoperative analgesia group (GA + PCA), general anesthesia without postoperative analgesia group (GA), epidural anesthesia with postoperative analgesia group (EA + PCA), and epidural anesthesia without postoperative analgesia group (EA). The 5-year survival rate and 5-year disease-free survival were recorded in the 4 groups. RESULTS: The general condition and length of hospital stay of the patients were not statistically different between the 4 groups. However, the 5-year survival rate and 5-year disease-free survival rate of the 4 groups were statistically different. The 5-year survival rate and 5-year disease-free survival rate were the lowest in the GA group, while the EA + PCA group had the highest 5-year disease-free survival rate. The 5-year survival rate and 5-year disease-free survival rate in the GA + PCA group were significantly higher than those in the GA group. The 5-year disease-free survival rate in EA group was significantly higher than GA group. CONCLUSIONS: Epidural anesthesia and postoperative pain treatment maybe beneficial to the long-term prognosis of patients with early-stage lymph node-negative breast cancer.

The use of bronchial blockers in patients with aberrant tracheobronchial anatomy: a case report.

Abnormal tracheal bronchus originates from the sidewall of the trachea, and most frequently occurs on the right side, involves subsegmental bronchi and the segmental. The anatomical structure of the airway is of great significance for general anesthesia and lung isolation. Abnormal tracheal bronchus makes lung isolation more complicated. This study presents four rare cases of aberrant tracheobronchial anatomy in the right main bronchus. We review the literature and discuss our solution and propose possible solutions for lung isolation in patients with tracheobronchial abnormalities. Of these, three patients were scheduled for radical resection of lung cancer, and one patient was scheduled for radical resection of middle esophageal cancer. After anesthesia induction, we intubated the right-side double-lumen tube (DLT) using a fiberoptic bronchoscope to guide the intubation. During DLT repositioning, we discovered the tracheobronchial abnormality of the patients. We could not place the DLT appropriately, however we made an effort to achieve lung isolation. We used a bronchus blocker [(BB) Univent tube] to achieve lung isolation for case 1, and the patient had good ventilation and no dyspnea and carbon dioxide retention during the operation. We completed lung isolation for the other three patients with abnormal airways by adjusting the position and replacing the DLT.

Early-Phase Urine Output and Severe-Stage Progression of Oliguric Acute Kidney Injury in Critical Care.

Background: The relationship between urine output (UO) and severe-stage progression in the early phase of acute kidney injury (AKI) remains unclear. This study aimed to investigate the relationship between early-phase UO6-12h [UO within 6 h after diagnosis of stage 1 AKI by Kidney Disease: Improving Global Outcomes (KDIGO) UO criteria] and severe-stage progression of AKI and to identify a reference value of early-phase UO6-12h for guiding initial therapy in critical care. Methods: Adult patients with UO < 0.5 ml/kg/h for the first 6 h after intensive care unit (ICU) admission (meeting stage 1 AKI by UO) and UO6-12h ≥ 0.5 ml/kg/h were identified from the Medical Information Mart for Intensive Care (MIMIC) III database. The primary outcome was progression to stage 2/3 AKI by UO. After other variables were adjusted through multivariate analysis, generalized additive model (GAM) was used to visualize the relationship between early-phase UO6-12h and progression to stage 2/3 AKI by UO. A two-piecewise linear regression model was employed to identify the inflection point of early-phase UO6-12h above which progression risk significantly leveled off. Sensitivity and subgroup analyses were performed to assess the robustness of our findings. Results: Of 2,984 individuals, 1,870 (62.7%) with KDIGO stage 1 UO criteria progressed to stage 2/3 AKI. In the multivariate analysis, early-phase UO6-12h showed a significant association with progression to stage 2/3 AKI by UO (odds ratio, 0.40; 95% confidence interval, 0.34-0.46; p < 0.001). There was a non-linear relationship between early-phase UO6-12h and progression of AKI. Early-phase UO6-12h of 1.1 ml/kg/h was identified as the inflection point, above which progression risk significantly leveled off (p = 0.780). Patients with early-phase UO6-12h ≥ 1.1 ml/kg/h had significantly shorter length of ICU stay (3.82 vs. 4.17 days, p < 0.001) and hospital stay (9.28 vs. 10.43 days, p < 0.001) and lower 30-day mortality (11.05 vs. 18.42%, p < 0.001). The robustness of our findings was confirmed by sensitivity and subgroup analyses. Conclusions: Among early-stage AKI patients in critical care, there was a non-linear relationship between early-phase UO6-12h and progression of AKI. Early-phase UO6-12h of 1.1 ml/kg/h was the inflection point above which progression risk significantly leveled off.

Nomogram based on albumin and neutrophil-to-lymphocyte ratio for predicting postoperative complications after pancreaticoduodenectomy.

BACKGROUND: The aim of this study was to identify a preoperative inflammatory marker with the most predictive value for postoperative complications after pancreaticoduodenectomy (PD). We then combined it with other perioperative variables to construct and validate a nomogram for complications after PD. METHODS: A total of 223 patients who received PD from January 2014 to July 2019 at a high-volume (>60 PDs/year) pancreatic centers in China were included in this retrospective study. All of the PDs were performed by the same surgeon who is beyond the learning curve with more than 100 PDs over the previous 3 years before 2014. 15 preoperative inflammatory markers were collected, including neutrophils, lymphocytes, high-sensitivity C-reactive protein and lactic dehydrogenase. The inflammatory markers' predicting abilities for complications were analyzed by calculating the values of an area under the curve (AUC). The complications included surgical complications (such as pancreatic fistula, delayed gastric emptying and bile leakage) and medical complications (such as sepsis, pneumonia, urinary tract infection, acute heart failure and acute liver failure) in this study. Univariable and multivariable logistic regression analyses were performed to investigate the perioperative features for independent risk factors for complications after PD. Nomograms with or without the most predictive inflammatory for complications were subsequently developed based on multivariable logistic regression using Akaike information criterion. Nomograms' performance was quantified and compared in terms of calibration and discrimination. We studied the utility of the nomograms using decision curve analysis. RESULTS: The albumin/ NLR score (ANS) exhibited the highest AUC value (0.616) for predicting postoperative complications. ANS and approach method were identified as independent risk factors for complications. The nomogram with ANS had higher C-index (0.725) and better calibration. The NRI compared between nomograms was 0.160 (95% CI: 0.023-0.296; P=0.022). By decision curve analysis, the model with ANS had higher clinical value. CONCLUSIONS: The ANS is a useful predictor and an independent risk factor for postoperative complications after PD. The nomogram with ANS was constructed with better performance and more clinical benefit for predicting postoperative complications.

Injectable PLGA-Coated Ropivacaine Produces A Long-Lasting Analgesic Effect on Incisional Pain and Neuropathic Pain.

The management of persistent postsurgical pain and neuropathic pain remains a challenge in the clinic. Local anesthetics have been widely used as simple and effective treatment for these 2 disorders, but the duration of their analgesic effect is short. We here reported a new poly lactic-co-glycolic acid (PLGA)-coated ropivacaine that was continuously released in vitro for at least 6 days. Perisciatic nerve injection of the PLGA-coated ropivacaine attenuated paw incision-induced mechanical allodynia and heat hyperalgesia during the incisional pain period, and spared nerve injury-induced mechanical and cold allodynia for at least 7 days postinjection. This effect was dose-dependent. Perisciatic nerve injection of the PLGA-coated ropivacaine did not produce detectable inflammation, tissue irritation, or damage in the sciatic nerve and surrounding muscles at the injected site, dorsal root ganglion, spinal cord, or brain cortex, although the scores for grasping reflex were mildly and transiently reduced in the higher dosage-treated groups. PERSPECTIVE: Given that PLGA is an FDA-approved medical material, and that ropivacaine is used currently in clinical practice, the injectable PLGA-coated ropivacaine represents a new and highly promising avenue in the management of postsurgical pain and neuropathic pain.

MG53 Protects against Sepsis-Induced Myocardial Dysfunction by Upregulating Peroxisome Proliferator-Activated Receptor-α.

BACKGROUND: The heart is one of the most commonly affected organs during sepsis. Mitsugumin-53 (MG53) has attracted attention in research due to its cardioprotective function. However, the role of MG53 in sepsis-induced myocardial dysfunction (SIMD) remains unknown. The purpose of this study was to explore the underlying mechanism of MG53 in SIMD and investigate its potential relationship with peroxisome proliferator-activated receptor-α (PPARα). METHODS: The cecal ligation and puncture (CLP) model was created to induce SIMD in rats. Protein levels of MG53 and PPARα, cardiac function, cardiomyocyte injury, myocardial oxidative stress and inflammatory indicators, and cardiomyocyte apoptosis were measured at 18 h after CLP. The effects of MG53 on PPARα in SIMD were investigated via preconditioning recombinant human MG53 (rhMG53) and PPARα antagonist GW6471. RESULTS: The expression of MG53 and PPARα sharply decreased in the myocardium at 18 h after CLP. Compared with the sham group, cardiac function was significantly depressed, which was associated with the destructed myocardium, upregulated oxidative stress indicators and proinflammatory cytokines, and excessive cardiomyocyte apoptosis in the CLP group. Supplementation with rhMG53 enhanced myocardial MG53, increased the survival rate with improved cardiac function, and reduced oxidative stress, inflammation, and myocardial apoptosis, which were associated with PPARα upregulation. Pretreatment with GW6471 abolished the abovementioned protective effects induced by MG53. CONCLUSIONS: Both MG53 and PPARα were downregulated after sepsis shock. MG53 supplement protects the heart against SIMD by upregulating PPARα expression. Our results provide a new treatment strategy for SIMD.

Elevated vitreous Lipocalin-2 levels of patients with proliferative diabetic retinopathy.

BACKGROUND: Lipocalin-2 (LCN2) is a novel adipokine with potential roles in obesity, insulin resistance, and inflammation. This study aims to assess the concentrations of LCN2 and vascular endothelial growth factor (VEGF) expressed in the vitreous humors of patients with proliferative diabetic retinopathy (PDR). METHODS: The concentrations of LCN2 and VEGF were measured from the vitreous of 67 patients undergoing vitrectomy (20 controls and 47 PDR) via enzyme-linked immunosorbent assay (ELISA). Patients with non-ocular pathology that could elevate the LCN2 level in the vitreous were excluded. PDR activity and a history of panretinal photocoagulation were used for further grouping analysis. RESULTS: The vitreous concentration of LCN2 was statistically significantly higher in the PDR group compared to the control group (63,522 (30,009) pg/ml versus 1663 (1191) pg/ml, respectively; P < 0.001). VEGF level was also significantly higher in the PDR group than in the control group (1038 (1326) pg/ml versus 9 pg/ml, respectively; P < 0.001). The mean vitreous LCN2 and VEGF levels in active PDR patients were significantly higher than that of the inactive PDR patients. The mean LCN2 concentration in vitreous humor was significantly lower in the 28 PDR patients with a history of complete PRP (37,304 (16,651) pg/mL) in comparison with 19 PDR patients without preperformed panretinal photocoagulation or with preperformed incomplete panretinal photocoagulation (79,796 (24,391) pg/mL). A significant correlation between the vitreous LCN2 level and VEGF level was found in patients with PDR (R = 0.34; P = 0.019). CONCLUSIONS: This report shows a significant increase of LCN2 in the vitreous fluid of patients with PDR and present a significant correlation between LCN2 and VEGF, suggesting LCN2 might be involved in the pathogenesis of PDR.

Postoperative administration of ketorolac averts morphine-induced angiogenesis and metastasis in triple-negative breast cancer.

AIMS: Opioids (i.e. morphine) were found to induce triple negative breast cancer (TNBC) metastasis while nonsteroidal anti-inflammatory drugs (i.e. ketolorac) were associated with decreased metastasis in TNBC. These contradictory findings demand clarification on the effect of postoperative morphine and ketorolac on TNBC metastasis. MATERIALS AND METHODS: TNBC xenograft mice were established using MDA-MB-231 cells. When tumors reached ~100 mm3, the primary tumor was resected. Mice were then randomly assigned to four groups (n = 14): (i) saline, (ii) morphine (10 mg kg-1) (iii) morphine + ketorolac (10 mg kg-1 of morphine and 20 mg kg-1 of ketorolac) (iv) ketorolac (20 mg kg-1); administrated for three consecutive days after resection. Three weeks after resection, the number of lung metastases was measured. Microvessel density, thrombospondin-1 (TSP-1) and c-Myc expression in recurrent tumors were determined. To elucidate the above phenomenon in vitro, MDA-MB-231 cells were treated according to the regiment above; with or without supplementation of an AKT inhibitor to determine the activation of PI3K/AKT/c-Myc pathway. KEY FINDINGS: In mice, morphine promoted TNBC metastasis and angiogenesis, decreased TSP-1 expression and increased c-Myc expression, while co-administration of ketorolac significantly reversed the phenotypes above (p < .05). Mechanistically, morphine inhibited TSP-1 secretion by activating PI3K/AKT/c-Myc pathway (p < .05), while ketorolac promoted TSP-1 secretion (p < .05) by suppressing PI3K/AKT/c-Myc pathway. SIGNIFICANCE: Our study indicated that morphine enhanced TNBC metastasis and angiogenesis while ketorolac suppressed this effect. Mechanistically, this may be related to the enhancement of TSP-1 synthesis after ketorolac administration which further de-activated PI3K/AKT/c-Myc pathway.

Perioperative Risk Factors for Radial Forearm-Free Flap Complications.

PURPOSE: To determine perioperative risk factors predicted complications in elderly Chinese patients undergoing oral and maxillofacial reconstruction with radial forearm free flaps (RFFF). PATIENTS AND METHODS: The authors implemented a retrospective study and enrolled a sample of patients at least 65-year old who underwent resection of oral and maxillofacial tumors and RFFF reconstruction from January 2011 to June 2018. Predictor variables were divided into: demographic variables (gender, age, weight, comorbidities, history of smoking, radiotherapy history, primary lesions); hemodynamic (preoperative and postoperative hemoglobin and albumin level, blood loss, blood transfusion, urine output (mL), and rate (mL/kg/h), and infusion rates for crystalloids and colloids (mL/kg/h, and volumes given intraoperatively and postoperatively for 24 hours); anesthetic and surgical (American Society of Anesthesiologists classification, visual analogue score, duration of tourniquet, and operation). The primary outcome was the presence of postoperative complications (yes/no), and secondary outcome was types of complications (medical and surgical). All the variables were analyzed by univariate and multivariable analysis and statistical significance was set at a P < 0.05 RESULTS:: The study sample was composed of 118 patients with a mean age of 72 years. There were 15 complications, of which 9 were surgical and 6 medical. Risk factors were: postoperative hypoproteinemia, crystal in 24 hours, and hypertension combined with diabetes. CONCLUSIONS: Although reconstruction with a RFFF is a common and safe treatment for elderly patients with oral and maxillofacial tumors, postoperative hypoproteinemia, crystal in 24 hours, and hypertension combined with diabetes are potential predictors of postoperative complications.

LncRNA THOR promotes tongue squamous cell carcinomas by stabilizing IGF2BP1 downstream targets.

THOR, a highly conserved lncRNA, is potentially involved in various cancer development. However, its involvement in tongue squamous cell carcinoma (TSCC) remains unclear. The present study aims to explore the biological function and molecular mechanism of THOR in TSCC progression. The expressions of THOR and IGF2BP1 in TSCC tissues and adjacent non-cancerous tongue tissues (ANT) were examined through qRT-PCR. THOR levels were manipulated in TSCC cells to explore its function in cancer progression in vitro and in vivo, which were subsequently evaluated by CCK8, colony formation assay, flow cytometry, xenograft tumor assays. In situ hybridization, RIP and Western blot assay were performed to explore the underlying molecular mechanisms. We discovered that THOR and IGF2BP1 were dramatically upregulated in TSCC tissues. The expression of THOR is positively correlated with IGF2BP1 mRNA level. THOR mediated IGF2 expression via interacting with IGF2BP1, and affected the downstream MEK-ERK signaling pathway to regulate TSCC cells proliferation. THOR/IGF2BP1/IGF2-MEK-ERK axis regulated the proliferation of TSCC cells, implying that THOR would be a promising therapeutic target for TSCC patients.

TET1 Overexpression Mitigates Neuropathic Pain Through Rescuing the Expression of µ-Opioid Receptor and Kv1.2 in the Primary Sensory Neurons.

Peripheral nerve injury downregulates the expression of the µ-opioid receptor (MOR) and voltage-gated potassium channel subunit Kv1.2 by increasing their DNA methylation in the dorsal root ganglion (DRG). Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) causes DNA demethylation. Given that DRG MOR and Kv1.2 downregulation contribute to neuropathic pain genesis, this study investigated the effect of DRG TET1 overexpression on neuropathic pain. Overexpression of TET1 in the DRG through microinjection of herpes simplex virus expressing full-length TET1 mRNA into the injured rat DRG significantly alleviated the fifth lumbar spinal nerve ligation (SNL)-induced pain hypersensitivities during the development and maintenance periods, without altering acute pain or locomotor function. This microinjection also restored morphine analgesia and attenuated morphine analgesic tolerance development after SNL. Mechanistically, TET1 microinjection rescued the expression of MOR and Kv1.2 by reducing the level of 5-methylcytosine and increasing the level of 5-hydroxymethylcytosine in the promoter and 5' untranslated regions of the Oprml1 gene (encoding MOR) and in the promoter region of the Kcna2 gene (encoding Kv1.2) in the DRG ipsilateral to SNL. These findings suggest that DRG TET1 overexpression mitigated neuropathic pain likely through rescue of MOR and Kv1.2 expression in the ipsilateral DRG. Virus-mediated DRG delivery of TET1 may open a new avenue for neuropathic pain management.

Identification of Independent Risk Factors for Complications: A Retrospective Analysis of 163 Fibular Free Flaps for Mandibulofacial Reconstruction.

PURPOSE: Fibular free flap transfer is a powerful tool available to the reconstructive surgeon when treating oral and maxillofacial defects, but complications still occasionally occur and predictive analysis focusing on this specific flap is limited in terms of risk factors for complication. The purpose of this study was to identify key variables associated with complications in patients undergoing fibular free flap transfer. PATIENTS AND METHODS: The data of 163 consecutive patients who underwent fibular free flap surgery at the Department of Oral and Maxillofacial Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, between 2012 and 2015 were reviewed retrospectively. Patient demographic data, laboratory data, surgical data, and fluid infusion-related data that may have an influence on free flap outcomes were recorded. Univariate and multivariate logistic regression analyses were used to identify relevant risk factors. RESULTS: A total of 163 fibular free flaps were transferred for mandibulofacial reconstruction in 163 patients with a mean age of 50.9 years. Postoperative complications developed in 33 (20.2%). Multivariate analysis showed that free flap complications were significantly associated with radiotherapy history (odds ratio [OR], 5.12; P = .001), postoperative anemia (OR, 1.048; P = .041), postoperative hypoalbuminemia (OR, 0.844; P = .002), and prolonged operative time (OR, 1.005; P = .004). CONCLUSIONS: Radiotherapy history, decreased postoperative hemoglobin and albumin levels, and prolonged operative time are potential predictors of postoperative complications after fibular free flap reconstruction for mandibulofacial defects.

The Postoperative Immunosuppressive Phenotypes of Peripheral T Helper Cells Are Associated with Poor Prognosis of Breast Cancer Patients.

PURPOSE: T helper cells play essential roles in anti-tumor immune response. However, the postoperative changes of peripheral T cell subsets and their clinical significance in breast cancer patients remain largely unknown. METHODS: We evaluated the perioperative changes of T lymphocyte subsets in invasive breast cancer (IBC) patients and breast fibroadenoma (BF) patients preoperatively (preop) and 6, 24, 72 hours postoperatively (POH6, POH24, and POH72). Proportions of CD3, CD4, CD8, T helper (Th) 1, Th2, Th17 cells, regulatory T cells (Treg), and CD4+/CD8+, Th1/Th2 ratio were detected by flow cytometry. Changes in T helper cell quantity were correlated to clinicopathological parameters. Furthermore, we explored the association between the perioperative variations of T cell subsets and disease-free survival (DFS) of IBC patients. RESULTS: In IBC patients, Th1 cells diminished while Tregs elevated in postoperative 72 hours in the peripheral blood. In contrast, no significant perioperative changes of T cell subsets were observed in BF patients. Postoperative lower Th1 cells at POH 72 of IBC patients were correlated with greater tumor burden, HER2 positive and Ki67 positive. The increased Tregs at POH 72 of IBC patients were correlated with larger tumor size and HER2 positive. Th1 cell decline and Treg increment were both associated with shorter DFS in IBC patients. CONCLUSIONS: The variations of peripheral T helper cell subsets showed postoperative immunosuppression and were associated with poor prognosis in IBC patients.

Propofol post-conditioning protects the blood brain barrier by decreasing matrix metalloproteinase-9 and aquaporin-4 expression and improves the neurobehavioral outcome in a rat model of focal cerebral ischemia-reperfusion injury.

Propofol, an intravenous anesthetic, inhibits neuronal apoptosis induced by ischemic stroke, protects the brain from ischemia/reperfusion injury and improves neuronal function. However, whether propofol is able to protect the blood brain barrier (BBB) and the underlying mechanisms have remained to be elucidated. In the present study, a rat model of cerebral ischemia/reperfusion was established, using a thread embolism to achieve middle cerebral artery occlusion. Rats were treated with propofol (propofol post-conditioning) or physiological saline (control) administered by intravenous injection 30 min following reperfusion. Twenty-four hours following reperfusion, neurobehavioral manifestations were assessed. The levels of cephaloedema, damage to the BBB and expression levels of matrix metalloproteinase-9 (MMP-9), aquaporin-4 (AQP-4) and phosphorylated c-Jun N-terminal kinase (pJNK) were determined in order to evaluate the effects of propofol on the BBB. In comparison to the cerebral ischemia/reperfusion group, the levels of brain water content and Evans blue content, as well as the expression levels of MMP-9, AQP-4 and pJNK were significantly reduced in the propofol post-conditioning group. These results indicated that propofol post-conditioning improved the neurobehavioral manifestations and attenuated the BBB damage and cephaloedema induced following cerebral ischemia/reperfusion. This effect may be due to the inhibition of MMP-9 and AQP-4 expression, and the concurrent decrease in JNK phosphorylation.

Curcumin exerts antinociceptive effects by inhibiting the activation of astrocytes in spinal dorsal horn and the intracellular extracellular signal-regulated kinase signaling pathway in rat model of chronic constriction injury.

BACKGROUND: Activation of glial cells and the extracellular signal-regulated kinase (ERK) signaling pathway play an important role in the development and maintenance of neuropathic pain. Curcumin can alleviate the symptom of inflammatory pain by inhibiting the production and release of interleukin and tumor necrosis factor. However, whether curcumin affects neuropathic pain induced by nerve injury and the possible mechanism involved are still unknown. This study investigated the effects of tolerable doses of curcumin on the activation of astrocytes and ERK signaling in the spinal dorsal horn in rat model of neuropathic pain. METHODS: Adult male Sprague-Dawley rats were randomly divided into three groups: a control (sham operated) group, and chronic constriction injury groups (to induce neuropathic pain) that were either untreated or treated with curcumin. Thermal and mechanical hyperalgesia thresholds were measured. The distribution and morphological changes of astrocytes were observed by immunofluorescence. Western blotting was used to detect changes in the expression of glial fibrillary acid protein (GFAP) and phosphorylated ERK. RESULTS: Injured rats showed obvious mechanical allodynia and thermal hyperalgesia. The number of GFAP-positive astrocytes, and the fluorescence intensity of GFAP were significantly increased in the spinal dorsal horn of injured compared with control rats. The soma of astrocytes also appeared hypertrophied in injured animals. Expression of GFAP and phosphorylated ERK was also significantly increased in the spinal dorsal horn of injured compared with control rats. Curcumin reduced the injury-induced thermal and mechanical hyperalgesia, the increase in the fluorescence intensity of GFAP and the hypertrophy of astrocytic soma, activation of GFAP and phosphorylation of ERK in the spinal dorsal horn. CONCLUSIONS: Curcumin can markedly alleviate nerve injury-induced neuropathic pain in rats. The analgesic effect of curcumin may be attributed to its inhibition of astrocyte hypertrophy in the spinal dorsal horn and phosphorylation of the ERK signaling pathway.