肺外小细胞神经内分泌癌是极为罕见且具有高度恶性的肿瘤,临床诊断时多数已是晚期,预后较差.该病的诊断主要依赖于肿瘤的形态学表现和免疫组织化学特征.本文报告1例舌根转移性小细胞神经内分泌癌,结合临床考虑为宫颈来源,通过回顾国内外文献对其诊断和治疗进行讨论.

Chemodynamic therapy (CDT) is an emerging treatment that usually employs chemical agents to decompose hydrogen peroxide (H2O2) into hydroxyl radical (•OH) via Fenton or Fenton-like reactions, inducing cell apoptosis or necrosis by damaging biomacromolecules such as, lipids, proteins, and DNA. Generally, CDT shows high tumor-specificity and minimal-invasiveness in patients, thus it has attracted extensive research interests. However, the catalytic reaction efficiency of CDT is largely limited by the relatively high pH at the tumor sites. Herein, a 808 nm laser-potentiated peroxidase catalytic/mild-photothermal therapy of molybdenum diphosphide nanorods (MoP2 NRs) is developed to improve CDT performance, and simultaneously achieve effective tumor eradication and anti-infection. In this system, MoP2 NRs exhibit a favorable cytocompatibility due to their inherent excellent elemental biocompatibility. Upon irradiation with an 808 nm laser, MoP2 NRs act as photosensitizers to efficiently capture the photo-excited band electrons and valance band holes, exhibiting enhanced peroxidase-like catalytic activity to sustainedly decompose tumor endogenous H2O2 to •OH, which subsequently destroy the cellular biomacromolecules both in tumor cells and bacteria. As demonstrated both in vitro and in vivo, this system exhibits a superior therapeutic efficiency with inappreciable toxicity. Hence, the work may provide a promising therapeutic technique for further clinical applications.

BACKGROUND: As a novel class of endogenous ncRNAs, Circular RNAs (circRNAs) have been verified to be involved in the carcinogenesis and tumor progression. OBJECTIVE: This study aimed to investigate the potential function of a candidate circRNA hsa_circ_0036988 in oral squamous cell carcinoma (OSCC). METHODS: The altered expression of hsa_circ_0036988 was validated by quantitative real-time polymerase chain reaction (qRT-PCR) in OSCC samples and OSCC cell lines. The associations between the levels of hsa_circ_0036988 and the clinicopathological features were statistically analysed. The function of hsa_circ_0036988 in OSCC were evaluated via a series of in vitro experiments by using constructed plasmids or siRNA. Western blotting assays were conducted to evaluate changes in protein expression levels. RESULTS: Hsa_circ_0036988 was significantly downregulated in OSCC tissues compared with adjacent normal tissues. While low expression of hsa_circ_0036988 was highly correlated with lymph nodes metastasis. Overexpression or knockdown of hsa_circ_0036988 significantly affected the proliferation, migration and invasion of OSCC cells. Furthermore, the altered expression of hsa_circ_0036988 have an impact on the epithelial-to-mesenchymal transition (EMT)-related protein expression levels. CONCLUSIONS: Our findings indicated that hsa_circ_0036988 may affect cell proliferation, migration and invasion by regulating EMT progress, which might provide a therapeutic strategy for the treatment of OSCC.

Previous studies have shown multiple mechanisms and pathophysiological changes after anesthesia, and genome-wide studies have been implemented in the studies of brain aging and neurodegenerative diseases. However, the genome-wide gene expression patterns and modulation networks after general anesthesia remains to be elucidated. Therefore, whole transcriptome microarray analysis was used to explore the coding gene expression patterns in the hippocampus of aged rats after sevoflurane anesthesia. Six hundred and thirty one upregulated and 183 downregulated genes were screened out, then 44 enriched terms of biological process, 16 of molecular function and 18 of the cellular components were identified by Gene Ontology (GO) and KEGG analysis. Among them, oxidative stress, metabolism, aging, and neurodegeneration were the most enriched biological processes and changed functions. Thus, involved genes of these processes were selected for qPCR verification and a good consistency was confirmed. The potential signaling pathways were further constructed including mitochondrion and oxidative stress-related Hifs-Prkcd-Akt-Nfe2l2-Sod1 signaling, multiple metabolism signaling (Scd2, Scap-Hmgcs2, Aldh18a1-Glul and Igf1r), as well as aging and neurodegeneration related signaling (Spidr-Ercc4-Cdkn1a-Pmaip1 and Map1lc3b). These results provide potential therapeutic gene targets for brain function modulation and memory formation process after inhaled anesthesia in the elderly, which could be valuable for preventing postoperative brain disorders and diseases, such as perioperative neurocognitive disorders (PND), from the genetic level in the future.

DNA methylation is an essential epigenetic mechanism involving in gene transcription modulation. An age-related increase in promoter methylation has been observed for neuronal activity and memory genes, and participates in neurological disorders. However, the position and precise mechanism of DNA methylation for memory gene modulation in anesthesia related cognitive impairment remained to be determined. Here, we studied the effects of sevoflurane anesthesia on the transcription of memory genes in the aged rat hippocampus. Then, we investigated changes in DNA methylation of involved genes and verified whether dysregulated DNA methylation would contribute to anesthesia induced cognitive impairment. The results indicated that sevoflurane anesthesia down-regulated the mRNA and protein levels of three memory genes, Arc, Bdnf, and Reln, which were accompanied with promoter hypermethylation and increased Dnmt1, Dnmt3a, and Mecp2 expression, and finally impaired hippocampus dependent memory. Furthermore, inhibition of DNA hypermethylation by 5-Aza rescued sevoflurane induced memory gene expression decrease and cognitive impairment. These findings provide an epigenetic understanding for the pathophysiology of cognitive impairment induced by general anesthesia in aged brain.

Emerging evidence indicates that the intestinal microbiota could interact with the central nervous system and modulate multiple pathophysiological changes, including the integrity of intestinal barrier and blood-brain barrier, as well as neuroinflammatory response. In the present study, we investigated the potential role of intestinal microbiota in the pathophysiological process of postoperative cognitive dysfunction. Six-month-old APP/PS1 mice were subjected to partial hepatectomy to establish surgery model and exhibited cognitive dysfunction. The expressions of inflammatory mediators increased and tight junction proteins (ZO-1 and Occludin) levels decreased in the intestine and hippocampus. The 16S ribosomal RNA gene sequencing showed altered β diversity and intestinal microbiota richness after surgery, including genus Rodentibacter, Bacteroides, Ruminococcaceae_UCG_014 and Faecalibaculum, as well as family Eggerthellaceae and Muribaculaceae. Furthermore, prebiotics (Xylooligosaccharides, XOS) intervention effectively attenuated surgery-induced cognitive dysfunction and intestinal microbiota alteration, reduced inflammatory responses, and improved the integrity of tight junction barrier in the intestine and hippocampus. In summary, the present study indicates that intestinal microbiota alteration, the related intestinal barrier and blood-brain barrier damage, and inflammatory responses participate the pathophysiological process of postoperative cognitive dysfunction. Prebiotics intervention could be a potential preventative approach.

Objective: Increasing evidence suggests that circular RNAs (circRNAs) play a major role in tumorigenesis and cancer progression. This study aimed to identify aberrant expression of hsa_circ_0003829 in oral squamous cell carcinoma (OSCC) and to explore its clinical significance. Methods: We conducted a prospective clinical study to examine the expression pattern of hsa_circ_0003829 in 60 paired OSCC and normal clinical samples and in cell lines using real-time quantitative polymerase chain reaction. We also evaluated the diagnostic value of hsa_circ_0003829 in OSCC based on receiver operating characteristic (ROC) curve analysis, and examined the relationships between hsa_circ_0003829 expression and clinicopathological features in patients with OSCC. We further used bioinformatics software CircInteractome (https: //Circinteractome.nia.nih.gov/) to predict circRNA-microRNA interactions. Results: Hsa_circ_0003829 was significantly downregulated in OSCC compared with adjacent normal tissues. The area under the ROC curve was 0.81. Low expression levels of hsa_circ_0003829 in OSCC tissues were negatively correlated with lymph node metastasis status and TNM stage. Conclusions: Downregulated expression of has_circ_0003829 suggests that this may be a key circRNA in OSCC, and may serve as a prospective biomarker for the diagnosis of OSCC.

Long noncoding RNAs (lncRNAs) play important roles in brain function modulation and neurodegenerative diseases. However, whether lncRNA regulations are involved in the mechanisms of perioperative neurocognitive disorders, especially in anesthesia-related brain dysfunction, remain unknown. Therefore, we explored the expression and regulation pattern profiles of lncRNAs in the hippocampus of aged rats after sevoflurane anesthesia. Three lncRNAs and 772 protein-coding genes were identified by microarray analysis and evidenced by in vitro and in vivo experiments as differentially expressed. Functional annotation and differentially expressed- (DE-) lncRNA-mRNA coexpression networks reveal that DE-lncRNAs are associated with mitochondrial dysfunction and oxidative stress, aging-related metabolism alterations, DNA damage, and apoptosis, as well as neurodegenerative features during sevoflurane anesthesia. These results suggest that lncRNAs play roles in general anesthesia-related brain function modulation during the perioperative context and provide insights into the lncRNA-related modulation mechanisms and targets.

Airway management is an indispensable skill for residents.Integrating the visualization technology of airway management into the standardized residency training program can optimize the management process and strategy of difficult airway,and standardize the application of new airway management techniques.This paper introduced the status quo of airway management and training system,analyzed the characteristics and advantages of visualized airway management technology.Then the feasible schemes,related technologies and evaluation systems for establishing airway management training system based on visualization technology were discussed,with a view to further improve residents' airway management competences and ensure patients' safety.

The quick development of perioperative medicine requires expanded qualifications and capabilities for the physicians participated in perioperative management. It provides a new opportunity and orientation for the reform of residency training. By analyzing the practice of resident training in perioperative management at home and abroad, we elucidate the necessity and feasibility to integrate perioperative management training system into the current residency standardized training framework. Its clinical practice, training objectives and contents, teaching methods, curriculum frameworks and evaluation systems are explored in order to develope a set of scientific and practical training models for perioperative talents. The training system is expected to reserve high level and innovative perioperative medical personnel, and promote the practice and development of the perioperative medicine. Key words: Perioperative medicine; Management; Residency training; Medical education

Melatonin exerts many physiological effects via melatonin receptors, among which the melatonin-2 receptor (MT2) plays a critical role in circadian rhythm disorders, Alzheimer's disease and other neurological disorders. A melatonin replacement strategy has been tested previously, and MT2 was a critical target during the process. cAMP response element binding (CREB) is an essential transcription factor for memory formation and could be involved in MT2 signalling. Therefore, the present study was designed to investigate the effects of prophylactic melatonin on inhaled anaesthetic isoflurane-induced cognitive impairment, and to determine whether the protective effects of melatonin are dependent on MT2 and downstream CREB signalling in the hippocampus of aged rats. The results showed that prophylactic melatonin attenuated isoflurane-induced decreases in plasma/hippocampal melatonin levels and cognitive impairment in aged rats. Furthermore, 4P-PDOT, a selective MT2 antagonist, blocked the protective effects of melatonin on isoflurane-induced decreases in both hippocampal MT2 expression and downstream CREB phosphorylation. And 4P-PDOT blocked the attenuation of melatonin on isoflurane-induced memory impairment. Collectively, the results suggest that the protective effects of prophylactic melatonin are dependent on hippocampal MT2-CREB signalling, which could be a potential therapeutic target for anaesthetic-induced cognitive impairment.

The stochastic Hodgkin-Huxley model is one of the best-known examples of piecewise deterministic Markov processes (PDMPs), in which the electrical potential across a cell membrane, V(t), is coupled with a mesoscopic Markov jump process representing the stochastic opening and closing of ion channels embedded in the membrane. The rates of the channel kinetics, in turn, are voltage-dependent. Due to this interdependence, an accurate and efficient sampling of the time evolution of the hybrid stochastic systems has been challenging. The current exact simulation methods require solving a voltage-dependent hitting time problem for multiple path-dependent intensity functions with random thresholds. This paper proposes a simulation algorithm that approximates an alternative representation of the exact solution by fitting the log-survival function of the inter-jump dwell time, H(t), with a piecewise linear one. The latter uses interpolation points that are chosen according to the time evolution of the H(t), as the numerical solution to the coupled ordinary differential equations of V(t) and H(t). This computational method can be applied to all PDMPs. Pathwise convergence of the approximated sample trajectories to the exact solution is proven, and error estimates are provided. Comparison with a previous algorithm that is based on piecewise constant approximation is also presented.

Objective To evaluate the effect of melatonin on postoperative apoptosis in hippocampal cells of aged rats undergoing surgery under isoflurane anesthesia.Methods Sixty healthy male Sprague-Dawley rats, aged 18 months, weighing 550-610 g, were randomized into 5 groups (n=12 each) using a random number table: control group (group C), 2％ isofiurane anesthesia group (group I), 2％ isoflurane + melatonin group (group IM), surgery group (group S), and surgery + melatonin group (group SM).Group IM inhaled 2％ isoflurane for 4 h.Group S inhaled 2％ isoflurane for 4 h, and then back surgery was performed.In IM and SM groups, melatonin 10 mg/kg was injected intraperitoneally everyday for 7 consecutive days before anesthesia, while the equal volume of normal saline was given in C, I and S groups.The cognitive function was assessed using the Morris water maze test on 2nd after anesthesia.The escape latency, space exploration time spent at the original platform quadrant, and frequency of crossing the original platform were recorded.After the end of the Morris water maze test, the rats were sacrificed on that day, and the hippocampi were isolated for detection of the expression of Bcl-2, Bax and caspase-3 by Western blot.Bcl-2/Bax ratio was calculated.Results Compared with group C, the escape latency was significantly prolonged on days 1-3 after anesthesia in group I, the escape latency was significantly prolonged, the space exploration time spent at the original platform quadrant was shortened,and the frequency of crossing the original platform was decreased on days 1-3 after operation in group S,and the expression of caspase-3 and Bax was significantly up-regulated, the expression of Bcl-2 was downregulated, and Bcl-2/Bax ratio was decreased in I and S groups (P＜0.05).Compared with group I, theescape latency was significantly shortened on days 1-3 after anesthesia (P ＜ 0.05) , and no significant change was found in the expression of caspase-3, Bcl-2 and Bax, and Bcl-2/Bax ratio in group IM (P＞ 0.05).Compared with group S, the escape latency was significantly shortened, the space exploration time spent at the original platform quadrant was prolonged, and the frequency of crossing the original platform was increased on days 3-5 after operation, the expression of caspase-3 and Bax was significantly downregulated, the expression of Bcl-2 was up-regulated, and Bcl-2/Bax ratio was increased in group SM (P＜0.05).Conclusion Melatonin can inhibit apoptosis in hippocampal cells and improve postoperative cognitive dysfunction in aged rats undergoing isoflurane anesthesia.

Multiple dynamic pathways always exist in biological networks, but their robustness against internal fluctuations and relative stability have not been well recognized and carefully analyzed yet. Here we try to address these issues through an illustrative example, namely the Siah-1/beta-catenin/p14/19 ARF loop of protein p53 dynamics. Its deterministic Boolean network model predicts that two parallel pathways with comparable magnitudes of attractive basins should exist after the protein p53 is activated when a cell becomes harmfully disturbed. Once the low but non-neglectable intrinsic fluctuations are incorporated into the model, we show that a phase transition phenomenon is emerged: in one parameter region the probability weights of the normal pathway, reported in experimental literature, are comparable with the other pathway which is seemingly abnormal with the unknown functions, whereas, in some other parameter regions, the probability weight of the abnormal pathway can even dominate and become globally attractive. The theory of exponentially perturbed Markov chains is applied and further generalized in order to quantitatively explain such a phase transition phenomenon, in which the nonequilibrium "activation energy barriers" along each transiting trajectory between the parallel pathways and the number of "optimal transition paths" play a central part. Our theory can also determine how the transition time and the number of optimal transition paths between the parallel pathways depend on each interaction's strength, and help to identify those possibly more crucial interactions in the biological network.

Calcineurin (CaN) over-activation constrains synaptic plasticity and memory formation. Upon CaN activation, NFAT imports into the nucleus and guides its downstream genes, which also affect neuronal and synaptic function. Aberrant CaN/NFAT signaling involves in neurotoxicity and cognitive impairment in neurological disorders such as Alzheimer's disease, but its role in postoperative cognitive dysfunction (POCD) remains uninvestigated. Inhaled anesthetic isoflurane facilitates the development of POCD, and the present study investigated the role of CaN/NFAT signaling in isoflurane induced cognitive impairment of aged rats, and the therapeutic effects of CaN inhibitor cyclosporine A (CsA). The results indicated that hippocampal CaN activity increased and peaked at 6 h after isoflurane exposure, and NFAT, especially NFATc4, imported into the nucleus following CaN activation. Furthermore, phamacological inhibition of CaN by CsA markedly attenuated isoflurane induced aberrant CaN/NFATc4 signaling in the hippocampus, and rescued relevant spatial learning and memory impairment of aged rats. Overall, the study suggests hippocampal CaN/NFAT signaling as the upstream mechanism of isoflurane induced cognitive impairment, and provides potential therapeutic target and possible treatment methods for POCD.

A Brownian-ratchet-like stochastic theory for the electrochemical membrane system of Hodgkin-Huxley (HH) is developed. The system is characterized by a continuous variable Q(m)(t), representing mobile membrane charge density, and a discrete variable K-t representing ion channel conformational dynamics. A Nernst-Planck-Nyquist-Johnson-type equilibrium is obtained when multiple conducting ions have a common reversal potential. Detailed balance yields a previously unknown relation between the channel switching rates and membrane capacitance, bypassing an Eyring-type explicit treatment of gating charge kinetics. From a molecular structural standpoint, the membrane charge Q(m) is a more natural dynamic variable than the potential V-m; our formalism treats Q(m)-dependent conformational transition rates lambda(ij) as intrinsic parameters. Therefore, in principle lambda(ij) vs. V-m is experimental-protocol-dependent, e. g., different from voltage or charge clamping measurements. For constant membrane capacitance per unit area C-m and neglecting the membrane potential induced by gating charges, V-m = Q(m)/C-m, and HH's formalism is recovered. The presence of two types of ions, with different channels and reversal potentials, gives rise to a nonequilibrium steady state with positive entropy production e(p). For rapidly fluctuating channels, an expression for e(p) is obtained. Copyright (C) EPLA, 2014

This paper presents a theoretical analysis on frequency-locking of N coupled oscillators driven by both periodic forces and white noise. The difficulty is that the considered system is time-inhomogeneous and thus no stationary distribution exists. Technically, by considering a set of stationary Markov processes subtracted from the original non-stationary process, we prove that for any given coupling strength K > 0, all the coupled oscillators have the same rotation number in L-2 sense. Furthermore, some interesting numerical results are presented, such as the benefit of noise on accelerating the rotation number, a bell-shaped dependence of the rotation number on the coupling strength, and the robust of the synchronization to noise perturbation. (C) 2014 Elsevier B.V. All rights reserved.

Objective To investigate the effects of isoflurane anesthesia on β-amyloid protein (Aβ) generation and phosphorylation of c-Jun N-terminal kinase (JNK) and cyclic AMP responsive element binding protein (CREB) in the hippocampus of aged rats.Methods Ninety-six male Sprague-Dawley rats,aged 18 months,weighing 450-500 g,were randomly divided into control group (group C,n =24),1％ isoflurane anesthesia group (group S1,n =36) and 2 ％ isoflurane anesthesia group (group S2,n =36).Groups S1 and S2 inhaled 1％ and 2％ isoflurane for 4 h,respectively.Twelve rats were chosen in each group and Morris water maze was performed 1 day after anesthesia.Twelve rats in each group were chosen on day 1 and 7 after anesthesia (T1,T7) and open field test was performed.The rats were sacrificed after open field test and hippocampi were isolated for determination of the expression of Aβ,phosphorylated JNK (p-JNK) and phosphorylated CREB (p-CREB) in hippocampal tissues by Western blot.Results Compared with group C,the escape latency was significantly prolonged and target quadrant dwell time ratio was decreased significantly in groups S1 and S2,the total movement distance,leave border distance and inner toroid distance were prolonged,Aβ expression was up-regulated,and p-CREB expression was down-regulated at T1 and leave border distance and inner toroid distance were prolonged,Aβ expression was up-regulated at T7 in group S1,and the total movement distance,faster movement distance,leave border distance and inner toroid distance were prolonged,the expression of Aβ and p-JNK was up-regulated,and p-CREB expression was down-regulated at T1,and the total movement distance,faster movement distance,leave border distance and inner toroid distance were prolonged,the expression of Aβ was up-regulated at T7 in group S2 (P ＜ 0.05 or 0.01).Conclusion The mechanism by which isoflurane anesthesia induces cognitive dysfunction is related to promotion of Aβ generation and JNK activation and inhibition of CREB activation in the hippocampus of aged rats.

Melatonin is an endogenous hormone with neuroprotective effects. Melatonin levels in elderly patients are reduced after surgeries that require anaesthesia. Whether reduced melatonin levels are important for postoperative cognitive dysfunction ( POCD ) remains unclear. Here, we investigated the effects of melatonin on cognitive dysfunctions induced by isoflurane and mechanisms underlying these effects. Seventy‐two 20‐month‐old Sprague–Dawley rats were randomly divided into six groups (n = 12). These groups included M1 and M10 groups that received intraperitoneal melatonin at 1 mg/kg or 10 mg/kg, respectively, and an ISO group that received 4 hr of inhaled 2% isoflurane. They also included M1+ ISO and M10+ ISO groups that received 1 mg/kg or 10 mg/kg of melatonin plus 4 hr of inhaled 2% isoflurane, respectively, and a control group that received an equal volume of saline. Injections were administered daily for 14 consecutive days. Memory was assessed in the Morris water maze. Plasma and hippocampi were harvested to determine melatonin concentrations and MT 1/ MT 2 receptor expression. Rats treated only with isoflurane showed significantly longer latencies in Morris water maze test trials compared with the control group, with shorter time in the probe trial ( p < 0.05). Although plasma melatonin levels and MT 2 expression in the hippocampus were significantly decreased, MT 1 expression was higher in the isoflurane group than in the control group ( p < 0.001). However, these parameters did not significantly vary in animals administered melatonin compared with controls. Isoflurane may induce cognitive dysfunction by influencing melatonin and MT 1/ MT 2 levels. Melatonin can improve cognitive dysfunction by normalizing plasma melatonin and its receptor levels.

Recent reports from animal studies provide mounting evidence that exposure to anesthetics during the period of rapid synaptogenesis triggers widespread neuronal apoptosis in the developing brains and causes significant long-term neurocognitive impairment.Animal studies have confirmed that both the intrinsic and extrinsic pathways of the apoptotic cascade are involved in anesthetics induced apoptotic neurodegeneration.However,the exact cell signaling mechanisms for activation of the apoptotic cascade and cellular selectivity remains unclear.Recent preliminary data from human clinical studies is still scarce and has not demonstrated causal relationships between long-term developmental and behavioral disorders following surgery and anesthesia early in life.Further animal studies and well-designed clinical studies are needed to examine the mechanisms,clinical relevance and promising protecting strategies.