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Graft availability from donation after circulatory death (DCD) is significantly limited by ischaemia reperfusion (IR) injury. Effective strategies to mitigate IR injury in DCD grafts are essential to improve graft quality and expand the donor pool. In this study, liver grafts from DCD pigs were preserved in the University of Wisconsin (UW) solution saturated with 0.1 nM dexmedetomidine (Dex) and various concentrations of noble gases Argon (Ar) and/or Xenon (Xe) at 4 °C for 24 or 72 h. The combined 50% Ar and Dex provided maximum protection to liver grafts by reducing morphological damage, apoptosis, necroptosis, ferroptosis, hepatocyte glycogen depletion, reticulin framework collapse, iron deposition, and oxidative stress. In vitro, human liver Hep G2 cells were preserved in the UW solution saturated with 0.1 nM Dex and 50% Ar in combination at 4 °C for 24 h, followed by recovery in medium at 37 °C for up to 48 h to mimic clinical IR injury. This treatment significantly increased the expression of anti-oxidative stress proteins by promoting the translocation of thioredoxin-interacting protein (TXNIP) to mitochondria, thereby inhibiting ferroptosis, increasing plasma membrane integrity, and maintaining cell viability.In summary, The combination of 0.1 nM Dex and 50% Ar may be a promising strategy to reduce ferroptosis and other form cell death, and preserve liver grafts.
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Hypoxic-ischaemic encephalopathy (HIE) in termed infants remains a significant cause of morbidity and mortality worldwide despite the introduction of therapeutic hypothermia. Depending on the cell type, cellular context, metabolic predisposition and insult severity, cell death in the injured immature brain can be highly heterogenous. A continuum of cell death exists in the H/I-injured immature brain. Aside from apoptosis, emerging evidence supports the pathological activation of necroptosis, pyroptosis and ferroptosis as alternative regulated cell death (RCD) in HIE to trigger neuroinflammation and metabolic disturbances in addition to cell loss. Upregulation of autophagy and mitophagy in HIE represents an intrinsic neuroprotective strategy. Molecular crosstalk between RCD pathways implies one RCD mechanism may compensate for the loss of function of another. Moreover, mitochondrion was identified as the signalling "hub" where different RCD pathways converge. The highly-orchestrated nature of RCD makes them promising therapeutic targets. Better understanding of RCD mechanisms and crosstalk between RCD subtypes likely shed light on novel therapy development for HIE. The identification of a potential RCD converging node may open up the opportunity for simultaneous and synergistic inhibition of cell death in the immature brain.
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BACKGROUND: Acute kidney injury (AKI) was reported to be one of the initiators of chronic kidney disease (CKD) development. Necroinflammation may contribute to the progression from AKI to CKD. Dexmedetomidine (Dex), a highly selective α2-adrenoreceptor (AR) agonist, has cytoprotective and "anti-" inflammation effects. This study was designed to investigate the anti-fibrotic properties of Dex in sepsis models. METHODS: C57BL/6 mice were randomly treated with an i.p. injection of lipopolysaccharides (LPS) (10â¯mg/kg) alone, LPS with Dex (25⯵g/kg), or LPS, Dex and Atipamezole (Atip, an α2-adrenoreceptor antagonist) (500⯵g/kg) (n=5/group). Human proximal tubular epithelial cells (HK2) were also cultured and then exposed to LPS (1⯵g/ml) alone, LPS and Dex (1⯵M), transforming growth factor-beta 1 (TGF-ß1) (5â¯ng/ml) alone, TGF-ß1 and Dex, with or without Atip (100⯵M) in culture media. Epithelial-mesenchymal transition (EMT), cell necrosis, necroptosis and pyroptosis, and c-Jun N-terminal kinase (JNK) phosphorylation were then determined. RESULTS: Dex treatment significantly alleviated LPS-induced AKI, myofibroblast activation, NLRP3 inflammasome activation, and necroptosis in mice. Atip counteracted its protective effects. Dex attenuated LPS or TGF-ß1 induced EMT and also prevented necrosis, necroptosis, and pyroptosis in response to LPS stimulation in the HK2 cells. The anti-EMT effects of Dex were associated with JNK phosphorylation. CONCLUSIONS: Dex reduced EMT following LPS stimulation whilst simultaneously inhibiting pyroptosis and necroptosis via α2-AR activation in the renal tubular cells. The "anti-fibrotic" and cytoprotective properties and its clinical use of Dex need to be further studied.
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Agonistas de Receptores Adrenérgicos alfa 2 , Dexmedetomidina , Fibrosis , Ratones Endogámicos C57BL , Receptores Adrenérgicos alfa 2 , Animales , Humanos , Ratones , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Línea Celular , Dexmedetomidina/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Lipopolisacáridos/farmacología , Necroptosis/efectos de los fármacos , Fenotipo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismoRESUMEN
BACKGROUND: Sideroflexin 1 (SFXN1), a mitochondrial serine transporter implicated in one-carbon metabolism, is a prognostic biomarker in lung adenocarcinoma (LUAD). However, its role in LUAD progression remains elusive. This study aimed to investigate the functional significance of SFXN1 in LUAD and evaluate its potential as a therapeutic target. METHODS: We analyzed SFXN1 expression and its diagnostic and prognostic value in LUAD using the Pan-cancer TCGA dataset. In vitro assays (CCK-8, cell cycle, EDU, wound-healing, and transwell) were employed to assess the role of SFXN1, complemented by in vivo experiments. RNA sequencing elucidated SFXN1-mediated cellular functions and potential mechanisms. Bulk RNA-seq and scRNA-seq data from TCGA and GEO were used to investigate the correlation between SFXN1 and the tumor immune microenvironment. RT-qPCR, Western blot, and IHC assays validated SFXN1 expression and its impact on the immune microenvironment in LUAD. RESULTS: SFXN1 was upregulated in LUAD tissues and associated with poor prognosis. RNA-seq and scRNA-seq analyses revealed increased SFXN1 expression in tumor cells, accompanied by decreased infiltration of NK and cytotoxic T cells. SFXN1 knockdown significantly reduced cell proliferation and migration, and the inhibition of ERK phosphorylation and CCL20 expression may be the molecular mechanism involved. In vivo, targeting SFXN1 decreased Tregs infiltration and inhibited tumor growth. CONCLUSIONS: Our findings suggest that SFXN1 may be a potential therapeutic target for LUAD treatment.
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Adenocarcinoma del Pulmón , Sistemas de Transporte de Aminoácidos Neutros , Neoplasias Pulmonares , Linfocitos Infiltrantes de Tumor , Microambiente Tumoral , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinogénesis/genética , Carcinogénesis/inmunología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Linfocitos Infiltrantes de Tumor/inmunología , Pronóstico , Microambiente Tumoral/inmunología , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismoRESUMEN
Postoperative multi-organ dysfunction (MOD) is associated with significant mortality and morbidity. Necroptosis has been implicated in different types of solid organ injury; however, the mechanisms linking necroptosis to inflammation require further elucidation. The present study examines the involvement of necroptosis and NLR family pyrin domain containing 3 (NLRP3) inflammasome in small intestine injury following traumatic surgery. Kidney transplantation in rats and renal ischaemia-reperfusion (I/R) in mice were used as traumatic and laparotomic surgery models to study necroptosis and inflammasome activation in the small intestinal post-surgery; additional groups also received receptor-interacting protein kinase 1 (RIPK1) inhibitor necrostatin-1s (Nec-1s). To investigate whether necroptosis regulates inflammasome activity in vitro, necroptosis was induced in human colonic epithelial cancer cells (Caco-2) by a combination of tumour necrosis factor-alpha (TNFα), SMAC mimetic LCL-161 and pan-caspase inhibitor Q-VD-Oph (together, TLQ), and necroptosis was blocked by Nec-1s or mixed lineage kinase-domain like (MLKL) inhibitor necrosulfonamide (NSA). Renal transplantation and renal ischaemia-reperfusion (I/R) upregulated the expression of necroptosis mediators (RIPK1; RIPK3; phosphorylated-MLKL) and inflammasome components (P2X purinoceptor subfamily 7, P2X7R; NLRP3; caspase-1) in the small intestines at 24 h, and Nec-1s suppressed the expression of inflammasome components. TLQ treatment induced NLRP3 inflammasome, promoted cleavage of caspase-1 and interleukin-1 beta (IL-1ß), and stimulated extracellular ATP release from Caco-2 cells, and MLKL inhibitor NSA prevented TLQ-induced inflammasome activity and ATP release from Caco-2 cells. Our work suggested that necroptosis and inflammasome interactively promote remote postoperative small intestinal injury, at least in part, through ATP purinergic signalling. Necroptosis-inflammasome axis may be considered as novel therapeutic target for tackling postoperative MOD in the critical care settings.
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Background: Effective preservation strategies to ameliorate lung graft ischaemia injury are needed to rescue 'extended criteria' or 'marginal' lung grafts, and to improve recipient outcomes after transplantation. Methods: Lung grafts from male Lewis rats were extracted after 40 min of cardiocirculatory death, and healthy human lung tissues were collected from patients undergoing a lobectomy. Lung samples were then preserved in a 4°C preservation solution supplemented with 0.1 nM Dexmedetomidine (Dex, α2-adrenoceptor agonist) for 16 h. In vitro, human lung epithelial A549 cells were preserved in the 4°C preservation solution with 0.1 nM Dex for 24 h, then re-cultured in the cell culture medium at 37°C to mimic the clinical scenario of cold ischaemia and warm reperfusion. Lung tissues and cells were then analysed with various techniques including western blot, immunostaining and electron microscope, to determine injuries and the protection of Dex. Results: Prolonged warm ischaemia after cardiocirculatory death initiated Rip kinase-mediated necroptosis, which was exacerbated by cold storage insult and enhanced lung graft injury. Dex supplementation significantly reduced necroptosis through upregulating Nrf2 activation and reducing oxidative stress, thereby significantly improving lung graft morphology. Dex treatment also attenuated endoplasmic reticulum stress, stabilised lysosomes and promoted cell membrane resealing function, consequently reducing cell death and inflammatory activation after hypothermic hypoxia-reoxygenation in A549 cells. Conclusions: Inhibition of regulated cell death through Dex supplementation to the graft preservation solution improves allograft quality which may aid to expand the donor lung pool and enhance lung transplant outcomes per se.
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Trasplante de Pulmón , Muerte Celular Regulada , Ratas , Animales , Humanos , Masculino , Ratas Endogámicas Lew , Necroptosis , PulmónRESUMEN
The cellular and molecular actions of general anesthetics to induce anesthesia state and also cellular signaling changes for subsequent potential "long term" effects remain largely elusive. General anesthetics were reported to act on voltage-gated ion channels and ligand-gated ion channels. Here we used single-cell RNA-sequencing complemented with whole-cell patch clamp and calcium transient techniques to examine the gene transcriptome and ion channels profiling of sevoflurane and propofol, both commonly used clinically, on the human fetal prefrontal cortex (PFC) mixed cell cultures. Both propofol and sevoflurane at clinically relevant dose/concentration promoted "microgliosis" but only sevoflurane decreased microglia transcriptional similarity. Propofol and sevoflurane each extensively but transiently (<2 h) altered transcriptome profiling across microglia, excitatory neurons, interneurons, astrocytes and oligodendrocyte progenitor cells. Utilizing scRNA-seq as a robust and high-through put tool, our work may provide a comprehensive blueprint for future mechanistic studies of general anesthetics in clinically relevant settings.
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Colorectal cancer (CRC) is the third most predominant malignancy in the world. Although the importance of immune system in cancer development has been well established, the underlying mechanisms remain to be investigated further. Here we studied a novel protein prokineticin 2 (Prok2, also known as Bv8) as a key pro-tumoral factor in CRC progression in in vitro and ex vivo settings. Human colorectal tumor tissues, myeloid cell lines (U937 cells and HL60 cells) and colorectal cancer cell line (Caco-2 cells) were used for various studies. Myeloid cell infiltration (especially neutrophils) and Bv8 accumulation were detected in human colorectal tumor tissue with immunostaining. The chemotactic effects of Bv8 on myeloid cells were presented in the transwell assay and chemotaxis assy. Cultured CRC cells treated with myeloid cells or Bv8 produced reactive oxygen species (ROS) and vascular endothelial growth factor (VEGF). Furthermore, ROS and VEGF acted as pro-angiogenesis buffer in myeloid cell-infiltrated CRC microenvironment. Moreover, myeloid cells or Bv8 enhanced energy consumption of glycolysis ATP and mitochondria ATP of CRC cells. Interestingly, myeloid cells increased CRC cell viability, but CRC cells decreased the viability of myeloid cells. ERK signalling pathway in CRC cells was activated in the presence of Bv8 or co-cultured myeloid cells. In conclusion, our data indicated the vital roles of Bv8 in myeloid cell infiltration and CRC development, suggesting that Bv8 may be a potential therapeutic target for colorectal cancer-related immunotherapy.
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Neoplasias Colorrectales , Neuropéptidos , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Células CACO-2 , Especies Reactivas de Oxígeno/metabolismo , Neuropéptidos/metabolismo , Células Mieloides/metabolismo , Movimiento Celular , Neoplasias Colorrectales/patología , Factores de Crecimiento Endotelial Vascular/metabolismo , Adenosina Trifosfato/metabolismo , Microambiente TumoralRESUMEN
Early diagnosis of cancer is crucial to initiate prompt treatment for better patient outcomes. The host immune function and its associated modulators are considered to be potential biomarkers for early cancer diagnosis. Immune and immune-checkpoint biomarkers have been reported to contribute to cancer development, while a high neutrophil-to-lymphocyte ratio has been shown to be associated with poor survival outcomes in a variety of cancers. One hundred sixty-one cancer patients were recruited to take a cost-effective novel Leukocyte ImmuneTest (LIT). LIT was measured to objectively determine the pre-treatment immune status of patients. The correlation between LIT and other conventional diagnostic markers or tumor-related variables was then investigated. Significant correlations between LIT and white blood cell count, smoking status, and tumor stage 4 were found. In addition, the LIT score significantly differentiated between malignant and benign tumors in this study population. Our work raises the possibility to use LIT for general screening surveillance before further costly specialized equipment is applied for cancer diagnosis.
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Purpose: This study aims to investigate the cytoprotective and anti-inflammatory effects of an α2-adrenoreceptor (α2-AR) agonist, dexmedetomidine (Dex), on lipopolysaccharides (LPS)-induced acute lung injury and underlying mechanisms with focus on alveolar macrophage polarization modulation. Methods: C57BL/6 mice were intraperitoneally injected LPS (10 mg/kg) with or without Dex (25 µg/kg) and/or α2-AR antagonist atipamezole (Atip, 500 µg/kg). Lung tissues were then analysed to determine injuries. In vitro, human pulmonary epithelial cells (A549) and mice alveolar macrophages (MH-S) were exposed to LPS (10 ng/mL) with or without different concentrations of Dex (0.1-100 nM). Alveolar macrophage polarization, NLRP3 inflammasome activation and inflammatory responses were determined. PTEN/Akt signaling and its downstream transcriptional factors as targets for macrophage polarization were assessed. Results: Dex treatment significantly reduced pro-inflammatory M1 macrophage polarization and NLRP3 inflammasome activation in the lungs relative to the mice treated with LPS. The similar pattern reduction of NLRP3 inflammasome activation by Dex was also found in A549 cells. Atip partly reversed the anti-inflammatory effects of Dex. In cultured alveolar macrophages, Dex reduced LPS-mediated expression of IL-1, -6 and TNF-α receptors while promoting alveolar macrophages differentiation towards a M2 anti-inflammatory phenotype. Additionally, LPS increased Akt signaling activation in a time-dependent manner, which was further activated by Dex via inhibiting phosphatase and tensin homolog (PTEN). The action of Dex on Akt signaling shifted alveolar macrophages from M1 to M2 phenotype through increasing STAT6 and IRF4 transcriptional factors. Conclusion: Dex protected against LPS-induced lung injury and suppressed LPS-induced pulmonary inflammatory responses by attenuating the NLRP3 inflammasome activation and promoting anti-inflammatory M2 macrophage polarization.
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BACKGROUND: The number of patients receiving anaesthesia is increasing, but the impact of general anaesthesia on the patient's immune system remains unclear. The aim of the present study is to investigate dynamics of systemic immune cell responses to anaesthesia during perioperative period at a single-cell solution. METHODS: The peripheral blood mononuclear cells (PBMCs) and clinical phenomes were harvested and recorded 1 day before anaesthesia and operation, just after anaesthesia (0 h), and 24 and 48 h after anaesthesia. Single-cell sequencing of PBMCs was performed with 10× genomics. Subsequently, data analysis was performed with R packages: Seurat, clusterProfiler and CellPhoneDB. RESULTS: We found that the cluster of CD56+ NK cells changed at 0 h and the cluster of monocytes increased at 24 and 48 h after anaesthesia. The characteristic genes of CD56+ NK cells were mainly enriched in the Jak-STAT signalling pathway and in cell adhesion molecules (24 h) and carbon metabolism (48 h). The communication between CD14+ monocytes and other cells decreased substantially 0 and 48 h after operation. The number of plasma cells enriched in protein export in men was substantially higher than that in women, although the total number in patients decreased 24 h after operation. CD14+ monocytes dominated that cell-cell communications appeared in females, while CD8+ NKT cells dominated that cell-cell communications appeared in male. The number of plasma cells increased substantially in patients with major surgical trauma, with enrichments of pentose phosphate pathway. The communications between plasma cells with other cells varied between surgical severities and anaesthetic forms. The intravenous anaesthesia caused major alterations of cell types, including CD14+ monocytes, plasmas cells and MAIT cells, as compared with inhalation anaesthesia. CONCLUSION: We initially reported the roles of perioperative anaesthesia/surgery in temporal phenomes of circulating immune cells at a single-cell solution. Thus, the protection against immune cell changes would benefit the recovery from anaesthesia/surgery.
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Anestesia/normas , Leucocitos Mononucleares/citología , Atención Perioperativa/estadística & datos numéricos , Adulto , Anestesia/efectos adversos , Anestesia/estadística & datos numéricos , Antígeno CD56/efectos de los fármacos , Femenino , Humanos , Leucocitos Mononucleares/clasificación , Masculino , Persona de Mediana Edad , Atención Perioperativa/métodosRESUMEN
The epidemic of chronic inflammatory lung diseases such as asthma, bronchitis, and chronic obstructive pulmonary disease (COPD) has become a global public health problem. Oxidative stress, inflammation, and overproduction of airway mucus play critical roles in the progression of these diseases. Omarigliptin, an oral dipeptidyl peptidase 4 (DPP-4) inhibitor, has been demonstrated to have anti-inflammatory effects in patients with type II diabetes. However, its role in chronic inflammatory lung diseases remains enigmatic. This study is to investigate whether Omarigliptin possesses a beneficial effect against Lipopolysaccharide (LPS)-induced injuries in human BEAS-2B bronchial epithelial cells. Our results show that Omarigliptin suppressed LPS-induced oxidative stress by attenuating the generation of mitochondrial reactive oxygen species (ROS) and decrease in reduced glutathione (GSH) in BEAS-2B cells. Additionally, Omarigliptin mitigated inflammatory response by inhibiting the expression of pro-inflammatory mediators, including interleukin-1ß (IL-1ß), interleukin-12 (IL-12), and macrophage chemoattractant protein-1 (MCP-1) in LPS-challenged BEAS-2B cells. Moreover, Omarigliptin mitigated the LPS-induced overproduction of MUC5AC by rescuing the expression of the suppressor of cytokine signaling 1(SOCS1). Importantly, we found that this process is mediated by the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. Based on these findings, we conclude that Omarigliptin might be a promising agent for the treatment of chronic inflammatory lung diseases.
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Bronquios/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Compuestos Heterocíclicos con 2 Anillos/farmacología , Inflamación/tratamiento farmacológico , Mucina 5AC/metabolismo , Sustancias Protectoras/farmacología , Piranos/farmacología , Bronquios/metabolismo , Línea Celular , Diabetes Mellitus Tipo 2/metabolismo , Células Epiteliales/metabolismo , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
To analyze the effects of different anaesthetic methods on perioperative cellular immunity and long-term outcome in patients who undergo esophageal cancer surgery. PARTICIPANTS: A total of 120 patients with esophageal cancer admitted to Zhengzhou University People's Hospital from January 2016 to January 2017 were recruited and randomly divided into a GA group (general anaesthesia, n = 40), a PG group (paravertebral nerve block with general anaesthesia, n = 40) and an EG group (epidural anaesthesia with general anaesthesia, n = 40). METHODS: Self-rating anxiety scale and visual analogue scale scores were adopted to compare postoperative anxiety and the degree of pain of patients in the three groups. In addition, the adverse reactions of patients in the three groups were compared. The levels of interleukin-6 (IL-6), IL-4, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and the survival of T-cell subsets (CD3+, CD4+, CD8+, CD4+/CD8+) before operation, at the end of operation, and on postoperative day (POD) 1 and POD 2 were measured by either ELISA or flow cytometry. RESULTS: In the PG and EG group, the VAS scores were lower, and fewer opioids and vasoactive agents were used than in the GA group. In both the EG and PG groups, higher CD3+ and CD4+ cell survival and lower levels of Cor, IL-4, and IL-6 were identified at the end of or after the surgery than in the GA group. Moreover, the postoperative survival curves of the PG and EG groups were better than that of the GA group. CONCLUSIONS: The combination of paravertebral nerve block or epidural anaesthesia and general anaesthesia may improve perioperative immune function and long-term outcome in patients who undergo esophageal cancer surgery.
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To determine easy-to-use predictors of overall survival (OS), locoregional recurrence (LRR), and distant metastasis (DM) in breast invasive ductal carcinoma (IDC) patients receiving neoadjuvant chemotherapy (NACT) and total mastectomy (TM), we used the pathologic response (PR) of primary breast diseases (T stages), nodal diseases (N stages), and combined primary and nodal diseases (American Joint Committee on Cancer [AJCC] stages) based on existing clinical and pathologic reports as predictors. We enrolled patients with IDC who received NACT followed by TM. Cox regression analysis was used to calculate hazard ratios (HRs) and confidence intervals (CIs) of PR; other independent predictors were controlled for or stratified in the analysis. We analyzed 3654 IDC patients (1031, 1215, 1003, and 405 patients with clinical stages IIB, IIIA, IIIB, and IIIC, respectively) receiving NACT and TM. After multivariate Cox regression analyses, the adjusted HRs (aHRs) (95% CI) for all-cause mortality, LRR, and DM were noted to be 0.21 (0.13-0.34), 0.19 (0.08-0.48), and 0.33 (0.23-0.47), respectively, for pCR; 0.56 (0.48-0.65), 0.67 (0.51-0.89), and 0.61 (0.52-0.70), respectively, for AJCC downstaging; and 1.85 (1.56-2.18), 1.17 (0.84-1.62), and 1.61 (1.36-1.90), respectively, for AJCC upstaging. The PR parameters used in the study are easily applied because they are based on existing staging records, and they can strongly predict OS, LRR, and DM in IDC patients receiving NACT and TM, regardless of clinical stage. The results can be used to guide adjuvant treatment.
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The single-cell RNA sequencing (scRNA-seq) is a powerful tool for exploring the complexity, clusters, and specific functions of the brain cells. Using scRNA-seq, the heterogeneity and changes in transcriptomic profiles of a single neuron were defined during dynamic development and differentiation of cells in cerebral cortex regions, and in the pathogenesis of neurological diseases. One of the great challenges is that the brain sample is susceptible to interference and confounding. More advanced methodologies of computational systems biology need to be developed to overcome the inherent interference and technical differences in the detection of single-cell signals. It is expected that scRNA-seq will be extended to metabolic profiles of the single neuron cell on basis of transcriptional profiles and regulatory networks. It is also expected if the transcriptional profiles can be integrated with molecular and functional phenomes in a single neuron and with disease-specific phenomes to understand molecular mechanisms of brain development and disease occurrence. scRNA-seq will provide the new emerging neurological disciple of the artificial intelligent single neuron for deep understanding of brain diseases.
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Corteza Cerebral/embriología , Corteza Cerebral/metabolismo , RNA-Seq , Análisis de la Célula Individual , Encefalopatías/genética , Encefalopatías/metabolismo , Encefalopatías/patología , Corteza Cerebral/citología , Humanos , TranscriptomaAsunto(s)
Máscaras Laríngeas , Bronquios , Broncoscopía , Tecnología de Fibra Óptica , Humanos , Estudios Prospectivos , UltrasonografíaRESUMEN
STUDY OBJECTIVE: To evaluate the efficacy and safety of pre- and perioperative intravenous administration of dexmedetomidine for enhancing quality of recovery (as measured by 40-item quality of recovery questionnaire (QoR-40), ranged from 40 to 200) after surgery. DESIGN: Meta-analysis. SETTING: Adult patients undergoing elective surgery. INTERVENTION: Intravenous administration of dexmedetomidine during pre- and perioperative period. MEASUREMENTS: The primary outcome was quality of recovery after surgery. The secondary outcome was the incidence of dexmedetomidine-related adverse events. MAIN RESULTS: Moderate to low quality evidence suggested that dexmedetomidine (DEX) increased the quality of recovery after surgery (WMD, weighted mean difference 15.71, 95% CI, confidence interval 0.43 to 31.00; 428 participants; 5 RCTs; low quality evidence), decreased the incidence of postoperative nauseas or vomiting (RR, risk ratio 0.60, 95% CI 0.44 to 0.83; 404 participants; 6 RCTs; moderate quality evidence; RR 0.32, 95% CI 0.19 to 0.55; 356 participants; 5 RCTs; moderate quality evidence) without increased risk of bradycardia (RR: 1.78, 95% CI 0.78 to 4.02; 275 participants; 4 RCTs; moderate quality evidence), dizziness (RR 0.78, 95% CI 0.31 to 2.00; 183 participants; 3 RCTs; moderate quality evidence), pruritus (RR 1.32, 95% CI 0.39 to 4.44; 186 participants; 3 RCTs; moderate quality evidence), hypotension requiring an intervention (RR: 1.48, 95% CI, 0.68 to 3.23; 254 participants; 3 RCTs; moderate quality evidence) and longer length of hospital stay (WMD: -0.75 days, 95% CI -1.95 to 0.44; 246 participants; 3 RCTs; low quality evidence) in early postoperative period. CONCLUSIONS: Dexmedetomidine as an anesthetic adjuvant to general anesthesia was associated with an enhanced quality of recovery (15.71; far more than a clinically significant improvement of 6.3) without increased risk of adverse events in the early postoperative period (moderate to low quality evidence). Further large sample and high quality RCTs are needed to confirm the current findings.
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Dexmedetomidina , Hipotensión , Administración Intravenosa , Adulto , Anestesia General , Dexmedetomidina/efectos adversos , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: The objective of this meta-analysis is to assess the analgesic effect of flurbiprofen on postoperative pain in Chinese surgical patients. METHODS: The primary outcome was acute postoperative pain scores; the secondary outcomes included total opiate consumption during surgery and adverse effects, such as nausea, vomiting, and dizziness. Results were expressed as weighted mean difference (WMD) or odds ratio with 95% confidence intervals (95% CIs). We evaluated heterogeneity by visually examining the forest plots and quantified it by using the I2 statistic. We used random-effects models to pool the data. RESULTS: Of 573 abstracts reviewed, 19 studies involving 1628 participants met the inclusion criteria. Pooled results showed that the intravenous administration of flurbiprofen had a beneficial effect in reducing pain scores at 2 (WMD, -0.78; 95% CI, -1.22 to -0.34; P = 0.001), 6 (WMD, -0.93; 95% CI, -1.40 to -0.46; P = 0.000), 12 (WMD, -1.09; 95% CI, -1.93 to -0.24; P = 0.011), 24 (WMD, -1.08; 95% CI, -1.48 to -0.68; P = 0.000), and 48 (WMD, -0.62; 95% CI, -1.19 to -0.05; P = 0.032) h after surgery. In addition, flurbiprofen administration significantly decreased the incidence of postoperative nausea and vomiting (odds ratio, 0.39; 95% CI, 0.26-0.58; P = 0.000) but had no effects on opiate consumption and dizziness. CONCLUSIONS: The perioperative administration of flurbiprofen is effective in reducing postoperative pain, nausea, and vomiting in Chinese surgical patients. Future studies with adequate power should evaluate the ideal flurbiprofen regimen for postoperative pain.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Antiinflamatorios no Esteroideos/administración & dosificación , Flurbiprofeno/administración & dosificación , Dolor Postoperatorio/tratamiento farmacológico , Náusea y Vómito Posoperatorios/epidemiología , Procedimientos Quirúrgicos Operativos/efectos adversos , Dolor Agudo/diagnóstico , Dolor Agudo/etiología , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Antiinflamatorios no Esteroideos/efectos adversos , China/epidemiología , Flurbiprofeno/efectos adversos , Humanos , Dimensión del Dolor/estadística & datos numéricos , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/etiología , Atención Perioperativa/efectos adversos , Atención Perioperativa/métodos , Náusea y Vómito Posoperatorios/etiología , Náusea y Vómito Posoperatorios/prevención & control , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Perioperative neurocognitive disorders (PND) are common in elderly patients after surgery. It has been reported that BIS-guided anesthesia potentially influenced the occurrence of PND. Therefore, we conducted this systematic review and meta-analysis to explore the associations between bispectral index (BIS) monitoring and PND. METHODS: Two researchers independently searched for relevant randomized controlled trials (RCTs) in PubMed, EMBASE, and the Cochrane Library (CENTRAL) using keywords related to the BIS and PND from inception to April 22, 2019. Odds ratios (OR) with 95% CI were calculated using a random effects model. RESULTS: Nine RCTs involving 4023 participants aged 60 years or older were included into this meta-analysis. BIS-guided anesthesia was not associated with lower incidence of POD (random effects; OR: 0.69; 95% CI 0.48, 1.01), delayed neurocognitive recovery (DNR) at 1 day, 7 days (random effects; OR: 0.14; 95% CI 0.02, 1.23; random effects; OR: 0.97; 95% CI 0.57, 1.63), and postoperative neurocognitive disorder (NCD) at 90 days and 1 year after surgery in older adults (random effects; OR:0.72; 95% CI 0.52, 1.00; random effects; OR: 0.26; 95% CI 0.03, 2.47). CONCLUSIONS: No definite evidence demonstrated that BIS-guided anesthesia decreased the incidence of POD, DNR and postoperative NCD in older patients. More homogeneous RCTs assessing the efficacy of BIS monitoring on reducing the occurrence of these perioperative cognitive disorders are needed.