Quantification of the Engraftment Status of Mesenchymal Stem Cells in Glioma Using Dual-Modality Magnetic Resonance Imaging and Bioluminescence Imaging.

RATIONALE AND OBJECTIVES: The tumor-tropic properties of mesenchymal stem cells (MSCs) enable them to serve as appealing cellular vehicles for delivering therapeutic agents to treat malignant glioma. However, the exact engraftment status of MSCs in glioma via different administration routes remains unclear due to the lack of quantitative analysis. This study aimed to quantify the engraftment of MSCs in glioma after administration via different routes using non-invasive dual-modality magnetic resonance imaging (MRI) and bioluminescence imaging (BLI). MATERIALS AND METHODS: MSCs were transduced with a lentivirus overexpressing ferritin heavy chain (FTH) and firefly luciferase (FLUC) reporter genes to yield FTH- and FLUC-overexpressed MSCs (FTH-FLUC-MSCs). Wistar rats bearing intracranial C6 glioma received peritumoral, intratumoral, intra-arterial, and intravenous injection of FTH-FLUC-MSCs, respectively. MRI and BLI were performed to monitor FTH-FLUC-MSCs in vivo. RESULTS: FTH-FLUC-MSCs administered via peritumoral, intratumoral and intra-arterial routes migrated specially toward the intracranial glioma in vivo, as detected by MRI and BLI. As quantified by the BLI signal intensity, the percentages of FTH-FLUC-MSCs in the glioma were significantly higher with peritumoral injection (61%) and intratumoral injection (71%) compared to intra-arterial injection (30%) and intravenous injection (0%). Peritumorally injected FTH-FLUC-MSCs showed a gradual decline, with approximately 6% of FTH-FLUC-MSCs still retained within the tumor up to 11 days after injection. Meanwhile, the number of FTH-FLUC-MSCs injected via other routes dropped quickly, and none were detectable by day 11 post-injection. CONCLUSION: Peritumoral delivery of FTH-FLUC-MSCs offers robust engraftment and could be used as the optimal delivery route for treating malignant glioma.

Predictive Factors for Delayed Recovery From Anesthesia in Patients Receiving Free Vascularized Flap Reconstruction for Head and Neck Defects: A Retrospective Cohort Study.

OBJECTIVE: Free flap reconstruction for head and neck defects is currently a common procedure. This study aimed to create and validate a predictive model for identifying patients at risk of delayed recovery from anesthesia after free flap reconstruction for head and neck defect. METHODS: Electronic medical records from all patients were retrospectively collected. The primary outcome variable was delayed recovery from anesthesia. The least absolute shrinkage and selection operator regression model was employed to identify the most relevant features, followed by the construction of a nomogram model using multivariable logistic regression analysis. The discriminatory power, calibration, and clinical utility of the nomogram model were assessed using receiver operating characteristic curve analysis, calibration curve analysis, and decision curve analysis, respectively. RESULTS: This novel nomogram model incorporated 4 predictors for delayed recovery from anesthesia: preoperative albumin, intraoperative fresh frozen plasma infusion, preoperative platelet-to-lymphocyte ratio, and duration of intraoperative hypotension. The area under the receiver operating characteristic curve (area under the curve) for the nomogram model was determined to be 0.821 (95% CI: 0.803-0.836). After internal validation, the corrected area under the curve was found to be 0.768 (95% CI: 0.639-0.812). In addition, the model exhibited well-fitted calibration curves and demonstrated favorable clinical usability as indicated by the calibration curve and decision curve analysis curve. CONCLUSION: The authors created and validated a novel predictive model utilizing a limited number of 4 predictors, yet exhibiting commendable predictive performance. This innovative tool holds the potential to mitigate delayed recovery from anesthesia and enhance the efficient allocation of medical resources.

Surgery induces neurocognitive disorder via neuroinflammation and glymphatic dysfunction in middle-aged mice with brain lymphatic drainage impairment.

Background: Brain lymphatic drainage impairment is a prevalent characteristic in both aging and neurodegeneration. Surgery is more likely to induce excessive neuroinflammation and postoperative neurocognitive disorder (PND) among patients with aging and neurodegeneration. We hypothesized that surgical trauma may aggravate PND through preexisting cerebral lymphatic drainage impairment. However, there remains limited understanding about the role of surgery in changes of neurocognitive function in the populations with preoperative brain lymphatic drainage impairment. This study aims to expand our insight into surgery-induced glymphatic dysfunction, neuroinflammation and PND in middle-aged mice with preoperative brain lymphatic drainage impairment. Materials and methods: Deep cervical lymph nodes ligation (LdcLNs) was performed on middle-aged mice to establish preoperative brain lymphatic drainage impairment. A month later, laparotomy was performed on these mice with or without LdcLNs followed by analysis of brain neuroinflammation, glymphatic function, neuronal damage, and behavioral test. Results: LdcLNs disrupted meningeal lymphatic drainage. In middle-aged mice with LdcLNs, surgery exacerbated more serious glymphatic dysfunction accompanied by aggravation of A1 astrocytes activation and AQP4 depolarization. Furthermore, surgery caused neuronal damage via reducing expression of neuronal nuclei (NeuN), post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), as well as impairment in exploratory behavior and spatial working memory in middle-aged mice with LdcLNs. Additionally, surgery induced neuroinflammation with elevated microglia activation and increased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6, as well as activated more expression of HMGB1/TLR-4/NF-κB pathway in middle-aged mice with LdcLNs. Conclusion: Surgery exacerbates neuroinflammation and glymphatic dysfunction, ultimately resulting in neuronal damage and neurocognitive disorder in middle-aged mice with preoperative brain lymphatic drainage impairment. These results suggest that brain lymphatic drainage impairment may be a deteriorating factor in the progression of PND, and restoring its function may serve as a potential strategy against PND.

Engineering Internal and External Low-Coordination Atoms in Nickel-Organic Framework Nanoarrays to Promote the Electrochemical Oxygen Evolution Reaction.

Monometallic nickel-organic frameworks based on a carboxylated ligand [2,6-naphthalenedicarboxylic acid (Ni-NDC)] have abundant and uniformly distributed single-atom Ni sites, enabling superior oxygen evolution reaction (OER) activity. In theory, most of the Ni atoms inside Ni-NDC microcrystals are coordinatively saturated except for the surface. Therefore, there are no accessible low-coordination atoms (LCAs) as electrocatalytic sites for the OER. One effective way is to expose more LCAs by preparing self-supporting Ni-NDC nanoarrays (Ni-NDC NAs) with hierarchical secondary structural units. Another effective method is to create more internal LCAs by removing partial ligands or coordination atoms attached to the Ni atoms. Herein, by combining the two strategies, we engineered LCAs in the interior and exterior of Ni-NDC to synergistically accelerate the OER. In brief, ultrathick "brick-like" Ni-NDC NAs were first prepared with dissolution and coordination effects of NDC on self-sacrificial templates of "agaric-like" nickel hydroxide nanoarrays [Ni(OH)2 NAs]. Subsequently, dual-coordinated NDC was partially replaced by monocoordinated 2-naphthoic acid (NA). The Ni-NDC NAs were further tailed into ultrathin "liner leaf-like" nanoneedle arrays (LCAs-Ni-NDC NAs). As a consequence, the LCAs-Ni-NDC NAs have more internal and external LCAs, which can deliver an OER performance that is superior to that of Ni-NDC NAs.

TET1-Lipid Nanoparticle Encapsulating Morphine for Specific Targeting of Peripheral Nerve for Pain Alleviation.

Background: Opioids are irreplaceable analgesics owing to the lack of alternative analgesics that offer opioid-like pain relief. However, opioids have many undesirable central side effects. Restricting opioids to peripheral opioid receptors could reduce those effects while maintaining analgesia. Methods: To achieve this goal, we developed Tet1-LNP (morphine), a neural-targeting lipid nanoparticle encapsulating morphine that could specifically activate the peripheral opioid receptor in the dorsal root ganglion (DRG) and significantly reduce the side effects caused by the activation of opioid receptors in the brain. Tet1-LNP (morphine) were successfully prepared using the thin-film hydration method. In vitro, Tet1-LNP (morphine) uptake was assessed in differentiated neuron-like PC-12 cells and dorsal root ganglion (DRG) primary cells. The uptake of Tet1-LNP (morphine) in the DRGs and the brain was assessed in vivo. Von Frey filament and Hargreaves tests were used to assess the antinociception of Tet1-LNP (morphine) in the chronic constriction injury (CCI) neuropathic pain model. Morphine concentration in blood and brain were evaluated using ELISA. Results: Tet1-LNP (morphine) had an average size of 131 nm. Tet1-LNP (morphine) showed high cellular uptake and targeted DRG in vitro. CCI mice treated with Tet1-LNP (morphine) experienced prolonged analgesia for nearly 32 h compared with 3 h with free morphine (p < 0.0001). Notably, the brain morphine concentration in the Tet1-LNP (morphine) group was eight-fold lower than that in the morphine group (p < 0.0001). Conclusion: Our study presents a targeted lipid nanoparticle system for peripheral neural delivery of morphine. We anticipate Tet1-LNP (morphine) will offer a safe formulation for chronic neuropathic pain treatment, and promise further development for clinical applications.

Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis.

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate. Here we show that extracellular vesicles from breast cancer cells with a high potential to develop brain metastases carry high levels of miR-199b-5p, which shows higher levels in the blood of breast cancer patients with brain metastases comparing to those with metastatic cancer in other organs. miR-199b-5p targets solute carrier transporters (SLC1A2/EAAT2 in astrocytes and SLC38A2/SNAT2 and SLC16A7/MCT2 in neurons) to hijack the neuron-astrocyte metabolic coupling, leading to extracellular retention of these metabolites and promoting cancer cell growth. Our findings reveal a mechanism through which cancer cells of a non-brain origin reprogram neural metabolism to fuel brain metastases.

Development and validation of a novel nomogram model for identifying risk of prolonged length of stay among patients receiving free vascularized flap reconstruction of head and neck cancer.

Background: The aim of the present study was to build and internally validate a nomogram model for predicting prolonged length of stay (PLOS) among patients receiving free vascularized flap reconstruction of head and neck cancer (HNC). Methods: A retrospective clinical study was performed at a single center, examining patients receiving free vascularized flap reconstruction of HNC from January 2011 to January 2019. The variables were obtained from the electronic information system. The primary outcome measure was PLOS. Univariate and multivariate analyses were used to find risk factors for predicting PLOS. A model was then built according to multivariate results. Internal validation was implemented via 1000 bootstrap samples. Results: The study included 1047 patients, and the median length of stay (LOS) was 13.00 (11.00, 16.00) days. Multivariate analysis showed that flap types ((radial forearm free flap (odds ratio [OR] = 2.238; 95% CI, 1.403-3.569; P = 0.001), free fibula flap (OR = 3.319; 95% CI, 2.019-4.882; P < 0.001)), duration of surgery (OR = 1.002; 95% CI, 1.001-1.003; P = 0.004), postoperative complications (OR = 0.205; 95% CI, 0.129-0.325; P = P < 0.001) and unplanned reoperation (OR = 0.303; 95% CI, 0.140-0.653; P = 0.002) were associated with PLOS. In addition to these variables, blood transfusion was comprised in the model. The AUC of the model was 0.78 (95% CI, 0.711-0.849) and 0.725 (95% CI, 0.605-0.845) in the primary and internal validation cohorts, respectively. The DCA revealed the clinical utility of the current model when making intervention decisions within the PLOS possibility threshold range of 0.2-0.8. Conclusions: Our study developed a nomogram that exhibits a commendable level of accuracy, thereby aiding clinicians in assessing the risk of PLOS among patients receiving free vascularized flap reconstruction for HNC.

Colocalization of protein and microRNA markers reveals unique extracellular vesicle subpopulations for early cancer detection.

Extracellular vesicles (EVs) play important roles in cell-cell communication but are highly heterogeneous, and each vesicle has dimensions smaller than 200 nm with very limited amounts of cargos encapsulated. The technique of NanOstirBar (NOB)-EnabLed Single Particle Analysis (NOBEL-SPA) reported in the present work permits rapid inspection of single EV with high confidence by confocal fluorescence microscopy, thus enables colocalization assessment for selected protein and microRNA (miRNA) markers in the EVs produced by various cell lines, or present in clinical sera samples. EV subpopulations marked by the colocalization of unique protein and miRNA combinations were discovered to be able to detect early-stage (stage I or II) breast cancer (BC). NOBEL-SPA can be adapted to analyze other types of cargo molecules or other small submicron biological particles. Study of the sorting of specific cargos to heterogeneous vesicles under different physiological conditions can help discover distinct vesicle subpopulations valuable in clinical examination and therapeutics development and gain better understanding of their biogenesis.

Lung Fibroblasts Take up Breast Cancer Cell-derived Extracellular Vesicles Partially Through MEK2-dependent Macropinocytosis.

Extracellular vesicles (EV) have emerged as critical effectors in the cross-talk between cancer and normal cells by transferring intracellular materials between adjacent or distant cells. Previous studies have begun to elucidate how cancer cells, by secreting EVs, adapt normal cells at a metastatic site to facilitate cancer cell metastasis. In this study, we utilized a high-content microscopic screening platform to investigate the mechanisms of EV uptake by primary lung fibroblasts. A selected library containing 90 FDA-approved anticancer drugs was screened for the effect on fibroblast uptake of EVs from MDA-MB-231 breast cancer cells. Among the drugs identified to inhibit EV uptake without exerting significant cytotoxicity, we validated the dose-dependent effect of Trametinib (a MEK1/2 inhibitor) and Copanlisib (a PI3K inhibitor). Trametinib suppressed macropinocytosis in lung fibroblasts and inhibited EV uptake with a higher potency comparing with Copanlisib. Gene knockdown and overexpression studies demonstrated that uptake of MDA-MB-231 EVs by lung fibroblasts required MEK2. These findings provide important insights into the mechanisms underlying lung fibroblast uptake of breast cancer cell-derived EVs, which could play a role in breast cancer metastasis to the lungs and suggest potential therapeutic targets for preventing or treating this deadly disease. SIGNIFICANCE: Through a phenotypic screen, we found that MEK inhibitor Trametinib suppressed EV uptake and macropinocytosis in lung fibroblasts, and that EV uptake is mediated by MEK2 in these cells. Our results suggest that MEK2 inhibition could serve as a strategy to block cancer EV uptake by lung fibroblasts.

Characterization of hypoxia-responsive states in ovarian cancer to identify hot tumors and aid adjuvant therapy.

BACKGROUNDS: The hypoxia-responsive state of cancer is a complex pathophysiological process involving numerous genes playing different roles. Due to the rapid proliferation of cancer cells and chaotic angiogenesis, the clinical features of hypoxia-responsive states are not yet clear in patients with ovarian cancer. METHODS: Based on the RNA expression levels of 14 hypoxic markers, our study screened out hypoxia-related genes and construct a hypoxic score pattern to quantify the hypoxia-responsive states of a single tumor. Combining clinical prognosis, tumor mutation burden, microsatellite instability, the expression level of the immune checkpoint, IC50, and other indicators to evaluate the impact of different hypoxia-responsive states on clinical prognosis and therapeutic sensitivity. RESULTS: Our study identified a subgroup with an active hypoxia-responsive state and they have a worse clinical prognosis but exhibit higher immunogenicity and higher sensitivity to immunotherapy. CONCLUSIONS: This work revealed that hypoxia-responsive states played an important role in formation of tumor immunogenicity. Evaluating the hypoxia-responsive state will contribute to guiding more effective immunotherapy strategies.

CXCL10 and Nrf2-upregulated mesenchymal stem cells reinvigorate T lymphocytes for combating glioblastoma.

BACKGROUND: Lack of tumor-infiltrating T lymphocytes and concurrent T-cell dysfunction have been identified as major contributors to glioblastoma (GBM) immunotherapy resistance. Upregulating CXCL10 in the tumor microenvironment (TME) is a promising immunotherapeutic approach that potentially increases tumor-infiltrating T cells and boosts T-cell activity but is lacking effective delivery methods. METHODS: In this study, mesenchymal stem cells (MSCs) were transduced with a recombinant lentivirus encoding Cxcl10, Nrf2 (an anti-apoptosis gene), and a ferritin heavy chain (Fth) reporter gene in order to increase their CXCL10 secretion, TME survival, and MRI visibility. Using FTH-MRI guidance, these cells were injected into the tumor periphery of orthotopic GL261 and CT2A GBMs in mice. Combination therapy consisting of CXCL10-Nrf2-FTH-MSC transplantation together with immune checkpoint blockade (ICB) was also performed for CT2A GBMs. Thereafter, in vivo and serial MRI, survival analysis, and histology examinations were conducted to assess the treatments' efficacy and mechanism. RESULTS: CXCL10-Nrf2-FTH-MSCs exhibit enhanced T lymphocyte recruitment, oxidative stress tolerance, and iron accumulation. Under in vivo FTH-MRI guidance and monitoring, peritumoral transplantation of CXCL10-Nrf2-FTH-MSCs remarkably inhibited orthotopic GL261 and CT2A tumor growth in C57BL6 mice and prolonged animal survival. While ICB alone demonstrated no therapeutic impact, CXCL10-Nrf2-FTH-MSC transplantation combined with ICB demonstrated an enhanced anticancer effect for CT2A GBMs compared with transplanting it alone. Histology revealed that peritumorally injected CXCL10-Nrf2-FTH-MSCs survived longer in the TME, increased CXCL10 production, and ultimately remodeled the TME by increasing CD8+ T cells, interferon-γ+ cytotoxic T lymphocytes (CTLs), GzmB+ CTLs, and Th1 cells while reducing regulatory T cells (Tregs), exhausted CD8+ and exhausted CD4+ T cells. CONCLUSIONS: MRI-guided peritumoral administration of CXCL10 and Nrf2-overexpressed MSCs can significantly limit GBM growth by revitalizing T lymphocytes within TME. The combination application of CXCL10-Nrf2-FTH-MSC transplantation and ICB therapy presents a potentially effective approach to treating GBM.

Modified intraoperative temperature management prevents prolonged length of stay after head and neck surgery with free flap reconstruction.

The present study aimed to investigate the association between intraoperative body temperature and prolonged length of stay (PLOS) after free flap reconstruction. A total of 753 patients who underwent head and neck surgery with free flap reconstruction were collected and randomly assigned into primary and validation cohorts. In the primary cohort, univariable and multivariable analyses were conducted to evaluate associations between intraoperative time-weighted (TW) temperature (TW average [TWA] temperature, TW hypothermia and TW hyperthermia) and PLOS. Nomograms were developed with and without intraoperative TW temperature, and validated in the validation cohort. Severe intraoperative TW hypothermia (OR = 1.004; 95% CI: 1.000, 1.007; p = 0.032) was identified as an independent risk factor for PLOS. Intraoperative TWA temperature and TW hypothermia showed linear related predictive effect for PLOS. The nomogram incorporating intraoperative TW temperature showed higher C-index (0.652, 95% CI: 0.591, 0.713) and improved net reclassification improvement for non-event (0.277, 95% CI: 0.118, 0.435; p < 0.001). Lower TWA temperature with mild TW hypothermia had a preventive effect on PLOS with a linear association, which may provide a modified range for intraoperative temperature management. The proposed nomogram incorporating intraoperative TW temperature could be used to develop personalized preventive strategies for PLOS after free flap reconstruction. IRB NUMBER: SYSEC-KY-KS-2022-037. CLINICAL TRIAL REGISTRATION NUMBER: Not applicable.

Preoperative flurbiprofen diminishes the rate of reoperation after free flap reconstruction: A retrospective study.

This study aimed to evaluate the association between preoperative flurbiprofen, a non-selective COX inhibitor, and reoperation for flap crisis after free flap reconstruction. In this retrospective study, patients who underwent head and neck surgery with free flap reconstructions were collected. To identify risk factors for reoperation from demographic features and perioperative variables, univariate and multivariate logistic analyses were conducted. After propensity score matching (PSM), univariate and adjusted multivariate analyses were employed to explore the impact of preoperative flurbiprofen on reoperation after free flap reconstruction. This study comprised 437 patients, 33 of whom underwent reoperations for flap crisis. After multivariate analysis, radiotherapy history (P = 0.005; odds ratio [OR] = 0.225; 95% CI, 0.080-0.636) and preoperative flurbiprofen (P = 0.038; OR = 5.059; 95% CI, 1.094-23.386) were identified as independent factors for reoperation. PSM was achieved, and preoperative flurbiprofen was found to diminish the reoperation rate (P = 0.046; OR = 4.765; 95% CI, 1.029-22.202) without increasing bleeding complications. Within the limitations of the study, flurbiprofen should be administered preoperatively to reduce the rate of reoperations for flap crisis whenever appropriate.

Nomogram incorporating potent inflammatory indicators for overall survival estimation of patients with primary oral squamous cell carcinoma.

Background: Inflammation has been recognized to be a factor that substantially influences tumorigenesis and tumor prognosis. Hence, this study was aimed to investigate an inflammatory marker with the most potent prognostic ability and to evaluate the survival estimation capability of dynamic change in this marker for patients suffered from oral squamous cell carcinoma (OSCC). Methods: 469 patients' inflammatory indicators including lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic inflammatory response index (SIRI), were calculated. Their predictive abilities for overall survival (OS) were evaluated by Kaplan-Meier curves to screen for the one with the most potent prognostic value. The predictive ability of dynamic changes in this marker was verified and a predictive nomogram incorporating inflammatory indicators was developed. Results: A high LMR was identified to be an indicator of a satisfactory survival rate. Compared with that of other inflammatory markers, area under the receiver operating characteristics (ROC) curve (AUC) of LMR for 1-year and 3-year OS was significantly larger (P<0.001). Dynamic LMR change remained an significant parameter for predicting OS (OR: 2.492, 95% CI: 1.246-4.981, p = 0.010). The nomogram incorporating LMR exhibited a superior prognostic significance than the TNM system, as suggested by the C-index (0.776 vs 0.651 in primary cohort; 0.800 vs 0.707 in validation cohort, P<0.001) and AUC. Conclusions: LMR was demonstrated to possess a more potent survival estimation capability than the other three inflammatory parameters. Dynamic changes in LMR serves as a significant parameter for overall survival estimation of primary OSCC patients. The established nomogram incorporating inflammatory markers showed more accuracy and sensitivity for survival estimation of primary OSCC patients.

Cancer-cell-secreted extracellular vesicles target p53 to impair mitochondrial function in muscle.

Skeletal muscle loss and weakness are associated with bad prognosis and poorer quality of life in cancer patients. Tumor-derived factors have been implicated in muscle dysregulation by inducing cachexia and apoptosis. Here, we show that extracellular vesicles secreted by breast cancer cells impair mitochondrial homeostasis and function in skeletal muscle, leading to decreased mitochondrial content and energy production and increased oxidative stress. Mechanistically, miR-122-5p in cancer-cell-secreted EVs is transferred to myocytes, where it targets the tumor suppressor TP53 to decrease the expression of TP53 target genes involved in mitochondrial regulation, including Tfam, Pgc-1α, Sco2, and 16S rRNA. Restoration of Tp53 in muscle abolishes mitochondrial myopathology in mice carrying breast tumors and partially rescues their impaired running capacity without significantly affecting muscle mass. We conclude that extracellular vesicles from breast cancer cells mediate skeletal muscle mitochondrial dysfunction in cancer and may contribute to muscle weakness in some cancer patients.

Genetic liability to multi-site chronic pain increases the risk of cardiovascular disease.

BACKGROUND: Observational studies have shown associations between multi-site chronic pain (MCP) and cardiovascular disease. However, it remains unclear whether these associations are causal. Therefore, this study aimed to assess the causal associations between MCP and cardiovascular disease and identify possible mediators between them. METHODS: A two-sample Mendelian randomisation analysis was applied in this study. The summary data for MCP were obtained from a genome-wide association study that included 387 649 individuals from the UK Biobank, whereas summary-level data for cardiovascular disease and its subtypes were obtained from relevant genome-wide association studies. Finally, summary-level data for common cardiovascular risk factors and inflammatory biomarkers were leveraged to identify possible mediators. RESULTS: Genetic liability to multi-site chronic pain is associated with higher risks for coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), and stroke, with a combined odds ratio (OR) of 1.537 (per site increment in MCP; 95% confidence interval [CI]: 1.271-1.858; P=0.0001) for CAD, 1.604 (95% CI: 1.277-2.014; P=0.0005) for MI, 1.722 (95% CI: 1.423-2.083; P<0.00001) for HF, and 1.332 (95% CI: 1.093-1.623; P=0.00001) for stroke. Genetic liability to MCP was found to be associated with mental disorders, smoking initiation, physical activity, BMI, and lipid metabolites. Multivariable Mendelian randomisation suggested a mediating role for mental disorders, smoking initiation, physical activity, and BMI in the relationship between multi-site chronic pain and cardiovascular disease. CONCLUSIONS: Our findings provide new insights into the role of multi-site chronic pain in cardiovascular disease. Additionally, we identified several modifiable risk factors for reducing cardiovascular disease.

The value of quantitative plaque analysis based on coronary computed tomography angiography in predicting the percutaneous coronary intervention outcome of chronic total occlusion lesions.

Background: Due to the uncertainty of the success of percutaneous coronary intervention (PCI) and the complexity of selecting suitable treatment cases, the interventional outcome of coronary chronic total occlusion (CTO) remains challenging. The purpose of this study was to evaluate the role of quantitative plaque analysis based on coronary computed tomography angiography (CCTA) in predicting the CTO-PCI outcome. Methods: We retrospectively included 78 patients with CTO (80 lesions) confirmed by invasive coronary angiography from July 2016 to December 2018. All patients underwent PCI treatment according to standard practice. A total of 47 lesions in 47 patients were successfully treated with PCI. PCI failed in the remaining 33 lesions in 31 patients. The following conventional CCTA morphologic parameters were evaluated and compared between the PCI-success and PCI-failure groups: stump morphology; occlusion length, tortuous course; CTO lesion calcium; bridging collateral vessel; retrograde collateral vessel; the appearance of the occluded distal segment; and quantitative CTO plaque characteristics, including total plaque volume, calcified plaque (CP) volume, noncalcified plaque (NCP) volume, low-density noncalcified plaque (LDNCP) volume, and plaque length. Univariate and multivariate logistic regression analyses were performed to determine independent parameters predictive of CTO-PCI outcomes. The predictive performances were assessed using receiver operating characteristic curve analysis. Results: The blunt stump was the only independent CCTA morphologic parameter to predict the outcome of CTO-PCI [odds ratio (OR): 10.807; P<0.001]. NCP volume (OR: 1.018; P<0.001), CP volume (OR: 1.026; P=0.049), and plaque length (OR: 1.058; P=0.037) were independent quantitative CTO plaque characteristics predictive of CTO-PCI outcomes. The plaque-based model combining NCP volume with CP volume and plaque length had a higher area under the curve (AUC =0.96) than did the morphology-based model that included blunt stump (AUC 0.68) in predicting the outcomes of CTO-PCI (P<0.001). Conclusions: The CCTA-based plaque characteristics, including NCP volume, CP volume, and plaque length, outperformed morphologic parameters in predicting the CTO-PCI outcomes.

Microglial IL-1RA ameliorates brain injury after ischemic stroke by inhibiting astrocytic CXCL1-mediated neutrophil recruitment and microvessel occlusion.

Acute ischemic stroke (AIS), one of the leading causes of mortality worldwide, is characterized by a rapid inflammatory cascade resulting in exacerbation of ischemic brain injury. Microglia are the first immune responders. However, the role of postischemic microglial activity in ischemic brain injury remains far from being fully understood. Here, using the transgenic mouse line CX3 CR1creER :R26iDTR to genetically ablate microglia, we showed that microglial deletion exaggerated ischemic brain injury. Associated with this worse outcome, there were increased neutrophil recruitment, microvessel blockade and blood flow stagnation in the acute phase, accompanied by transcriptional upregulation of chemokine (C-X-C motif) ligand 1 (CXCL1). Our study showed that microglial interleukin-1 receptor antagonist (IL-1RA) suppressed astrocytic CXCL1 expression induced by oxygen and glucose deprivation and inhibited neutrophil migration. Furthermore, neutralizing antibody therapy against CXCL1 or the administration of recombinant IL-1RA protein reduced brain infarct volume and improved motor coordination performance of mice after ischemic stroke. Our study suggests that microglia protect against acute ischemic brain injury by secreting IL-1RA to inhibit astrocytic CXCL1 expression, which reduces neutrophil recruitment and neutrophil-derived microvessel occlusion.

Perioperative Risk Factors Associated With Unplanned Reoperation Following Vascularized Free Flaps Reconstruction of the Oral Squamous Cell Carcinoma.

OBJECTIVES: To find out the occurrence rate and risk factors of unplanned reoperation (any unscheduled surgery within 30 d after the initial surgery) in patients who have received oral squamous cell carcinoma (OSCC) surgery and vascularized free flap reconstruction. PATIENTS AND METHODS: We organized a retrospective study of 1058 patients who underwent OSCC resection and reconstruction with vascularized free flaps from 2011 to 2019. Clinical characteristics, reasons for unplanned reoperation, flap types, and previous treatment were compared between the unplanned reoperation group and the control group. Univariate and multivariate analyses were performed to identify perioperative risk factors for unplanned reoperation. The related perioperative factors that may influence perioperative infusion were included in propensity score matching to investigate the independent contribution of intraoperative colloid infusion on unplanned reoperation. RESULTS: The overall rate of unplanned reoperation in OSCC patients was 11% (n=115). Flap necrosis and bleeding were the most common causes. Higher American Society of Anesthesiologists (ASA) grade [odds ratio (OR)=1.709, P=0.009], postoperative anemia (OR=0.983, P=0.011) and excessive intraoperative colloid input (OR=1.55, P=0.037) were identified as risk factors for unplanned reoperation. Propensity score matching was applied, and the difference of unplanned reoperation incidence between the matched groups was statistically significant (14.59% versus 8.54%; P=0.025). The multivariate analyses after propensity score matching confirmed that the intraoperative rate of colloid infusion of more than 2.3 mL/kg/h (OR=1.756, P=0.042) and prior radiotherapy (OR=2.78, P=0.001) are independent risk factors for unplanned reoperation. CONCLUSION: High intraoperative colloid infusion rate and prior radiotherapy may increase the risk of unplanned reoperation in patients who underwent OSCC surgery and vascularized free flap reconstruction.

Cancer-cell-secreted extracellular vesicles suppress insulin secretion through miR-122 to impair systemic glucose homeostasis and contribute to tumour growth.

Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. We show that BC-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. EV-encapsulated miR-122 targets PKM in ß-cells to suppress glycolysis and ATP-dependent insulin exocytosis. Mice receiving high-miR-122 EVs or bearing BC tumours exhibit suppressed insulin secretion, enhanced endogenous glucose production, impaired glucose tolerance and fasting hyperglycaemia. These effects contribute to tumour growth and are abolished by inhibiting EV secretion or miR-122, restoring PKM in ß-cells or supplementing insulin. Compared with non-cancer controls, patients with BC have higher levels of circulating EV-encapsulated miR-122 and fasting glucose concentrations but lower fasting insulin; miR-122 levels are positively associated with glucose and negatively associated with insulin. Therefore, EV-mediated impairment of whole-body glycaemic control may contribute to tumour progression and incidence of type 2 diabetes in some patients with BC.