Role of Wnt canonical pathway in hematological malignancies

Wnt canonical signaling pathway plays a diverse role in embryonic development and maintenance of organs and tissues in adults. It has been observed that Wnt/β-catenin signaling pathway is involved in the pathogenesis of many carcinomas. Moreover, Wnt/β-catenin pathway has been revealed to be associated with angiogenesis. Wnt canonical pathway signaling has great potential as a therapeutic target. It has been disclosed that some hematological malignancies, such as chronic lymphocytic leukemia, mantle cell lymphoma, may occur partly due to the constitutive activation of Wnt canonical signaling pathway. This review will summarize the latest development in Wnt canonical signaling pathway and its roles in tumorigenesis and angiogenesis

An Animal Model of Emotional Blunting in Schizophrenia

Schizophrenia is often associated with emotional blunting—the diminished ability to respond to emotionally salient stimuli—particularly those stimuli representative of negative emotional states, such as fear. This disturbance may stem from dysfunction of the amygdala, a brain region involved in fear processing. The present article describes a novel animal model of emotional blunting in schizophrenia. This model involves interfering with normal fear processing (classical conditioning) in rats by means of acute ketamine administration. We confirm, in a series of experiments comprised of cFos staining, behavioral analysis and neurochemical determinations, that ketamine interferes with the behavioral expression of fear and with normal fear processing in the amygdala and related brain regions. We further show that the atypical antipsychotic drug clozapine, but not the typical antipsychotic haloperidol nor an experimental glutamate receptor 2/3 agonist, inhibits ketamine's effects and retains normal fear processing in the amygdala at a neurochemical level, despite the observation that fear-related behavior is still inhibited due to ketamine administration. Our results suggest that the relative resistance of emotional blunting to drug treatment may be partially due to an inability of conventional therapies to target the multiple anatomical and functional brain systems involved in emotional processing. A conceptual model reconciling our findings in terms of neurochemistry and behavior is postulated and discussed

Völkisch und sozial? : Neonazistische Agitation gegen die neue EU-Freizügigkeit für Arbeitnehmerinnen

Wnt/β-catenin signalling pathway is crucial for the formation of many tissues and organs during development. In recent years, this pathway has also been found to regulate the biology of stem cells in the intestine and probably in other organs in adult life. Abnormal activation of Wnt/β-catenin signalling, which controls the expression of a high number of genes, is critical for the initiation and progression of most colorectal cancers. In line with this, the gene expression signature induced by activation of the Wnt/β-catenin pathway defines the intestinal stem cells present at the bottom of the crypts and also colon cancer stem cells. This supports the importance of inhibitors of the Wnt/β-catenin pathway as potential agents in colorectal cancer therapy. However, the complexity, wide activity in the organism modulating the biology of several cell types, and characteristics of this pathway have delayed the identification of suitable targets and so, the development of such inhibitors that are only now reaching the clinic.Peer reviewe

Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

SIRT1 Influences the Sensitivity of A549 Non-small Cell Lung Cancer Cell Line to Cisplatin via Modulating the Noxa Expression

Background and objective The resistance of non-small cell lung cancer cells to cisplant is a common clinical phenomenon which could induce a poor therapeutic effect and should be difficult problem to be solved. SIRT1 and Noxa expression are associated with the chemotherapy for tumors. The present study focused on how SIRT1 expression influence the senstivity of non-small cell lung cancer cells and dissected the potential mechanism involved with Noxa. Methods The difference of SIRT1 and Noxa expression between A549 cells and A549/DDP cells was detected by real-time quantitative PCR (qRT-PCR) and Western blot. SIRT1 targeted siRNA was uesed to inhibit the SIRT1 expression in A549/DDP, after transfection, Cell Titer Blue assay, flow cytometry were performed to analyze the cell viability, cell cycle and cell apoptosis in order to reveal the effect of inhibition of SIRT1 on sensitivity of A549/DDP cells to cisplant. Moreover, the expression changes of Noxa in A549/DDP cells after siRNA treatment were detected by qRT-PCR and Western blot. Results There was a significant difference in senstivity to cisplant between A549 and A549/DDP cells. Compared with A549 cells, the A549/DDP cells showed a higher SIRT1 expression and lower Noxa expression. After transfected with SIRT1 targeted siRNA, the cell viability decreased accompanied with a increasing apoptosis rate, meanwhile, higher percent of G2/M phase was detected after the 4 μg/mL cisplant treatment. Further more, inhibition of SIRT1 could induce the Noxa expression in A549/DDP cells. Conclusion Higher SIRT1 expression may induce resistance to cisplant in A549 cells. SIRT1 inhibition may improve the sensitivity of A549/DDP cells to cisplantin though modulating the Noxa expression

Ultrasound-guided serratus anterior plane block versus paravertebral block on postoperation analgesia and safety following the video-assisted thoracic surgery: A prospective, randomized, double-blinded non-inferiority clinical trial

Summary: Background: Both the anesthetic efficacy of ultrasound-guided serrate anterior plane block (SAPB) and the ultrasound-guided paravertebral block (PVB) in alleviating postoperative pain have been well concerned. This study primarily aims to evaluate whether the ultrasound-guided SAPB and ultrasound-guided PVB can provide comparable analgesia for video-assisted thoracic surgery. Secondarily, the safety and clinical satisfaction of the two blocks are evaluated. Methods: It was a prospective, randomized, double-blinded non-inferiority clinical trial involving 99 patients with lung nodules receiving video-assisted thoracic surgery with ultrasound-guided SAPB or PVB on T4 and T7 vertebra using 0.375% ropivacaine at 3 mg/kg. The Visual Analogue Scale (VAS) scores at rest and cough at 24 h/48 h postoperatively and the incidence and severity of chronic pain at 3 and 6 months postoperatively were the primary outcome. Secondary outcomes included the complications and block application time of two kinds of blocks, and consumption of sufentanil as an analgesic rescue. Results: A total of 92 eligible patients were recruited, including 46 in the SAPB group and 46 in the PVB group. No significant differences in VAS scores at rest and cough at first 48 h, 3 months, and 6 months postoperatively between the SAPB group and PVB group were detected (all P > 0.05). The SAPB group had fewer complications and higher patient satisfaction(P＜0.05). Conclusion: The ultrasound-guided SAPB was not inferior to PVB in alleviating postoperative pain following the VATS with fewer complications and higher patient satisfaction

Risk Management of Fuel Hedging Strategy Based on CVaR and Markov Switching GARCH in Airline Company

Using a hedging strategy to stabilize fuel price is very important for airline companies in order to reduce the cost of their main business. In this paper, we construct models for managing the risk of the hedging strategy. First, we use conditional value at risk (CVaR) to measure the risk of an airline company’s hedging strategy. Compared with the value at risk (VaR), CVaR satisfies subadditivity, positive homogeneity, monotonicity, and transfer invariance. Therefore, CVaR is a consistent method of risk measurement. Second, time-varying state transition probability is introduced into our model in order to build a Markov Switching-GARCH (MS-GARCH). MS-GARCH takes dynamic changes of market state into account, a feature which has obvious advantages over the traditional constant state model. Additionally, we use a Markov chain Monte Carlo (MCMC) algorithm to estimate the parameters of MS-GARCH based on Gibbs sampling. We use fuel oil futures data from the Shanghai Futures Stock Exchange to implement and evaluate our model. In this paper, we empirically estimate the risk of airlines’ hedging strategy and draw the conclusion that our model is obviously effective in terms of the risk management of hedging, a use which has a certain guiding significance for reality

Risk Management of Fuel Hedging Strategy Based on CVaR and Markov Switching GARCH in Airline Company

Using a hedging strategy to stabilize fuel price is very important for airline companies in order to reduce the cost of their main business. In this paper, we construct models for managing the risk of the hedging strategy. First, we use conditional value at risk (CVaR) to measure the risk of an airline company’s hedging strategy. Compared with the value at risk (VaR), CVaR satisfies subadditivity, positive homogeneity, monotonicity, and transfer invariance. Therefore, CVaR is a consistent method of risk measurement. Second, time-varying state transition probability is introduced into our model in order to build a Markov Switching-GARCH (MS-GARCH). MS-GARCH takes dynamic changes of market state into account, a feature which has obvious advantages over the traditional constant state model. Additionally, we use a Markov chain Monte Carlo (MCMC) algorithm to estimate the parameters of MS-GARCH based on Gibbs sampling. We use fuel oil futures data from the Shanghai Futures Stock Exchange to implement and evaluate our model. In this paper, we empirically estimate the risk of airlines’ hedging strategy and draw the conclusion that our model is obviously effective in terms of the risk management of hedging, a use which has a certain guiding significance for reality

Metabolic heterogeneity in clear cell renal cell carcinoma revealed by single-cell RNA sequencing and spatial transcriptomics

Abstract Background Clear cell renal cell carcinoma is a prototypical tumor characterized by metabolic reprogramming, which extends beyond tumor cells to encompass diverse cell types within the tumor microenvironment. Nonetheless, current research on metabolic reprogramming in renal cell carcinoma mostly focuses on either tumor cells alone or conducts analyses of all cells within the tumor microenvironment as a mixture, thereby failing to precisely identify metabolic changes in different cell types within the tumor microenvironment. Methods Gathering 9 major single-cell RNA sequencing databases of clear cell renal cell carcinoma, encompassing 195 samples. Spatial transcriptomics data were selected to conduct metabolic activity analysis with spatial localization. Developing scMet program to convert RNA-seq data into scRNA-seq data for downstream analysis. Results Diverse cellular entities within the tumor microenvironment exhibit distinct infiltration preferences across varying histological grades and tissue origins. Higher-grade tumors manifest pronounced immunosuppressive traits. The identification of tumor cells in the RNA splicing state reveals an association between the enrichment of this particular cellular population and an unfavorable prognostic outcome. The energy metabolism of CD8+ T cells is pivotal not only for their cytotoxic effector functions but also as a marker of impending cellular exhaustion. Sphingolipid metabolism evinces a correlation with diverse macrophage-specific traits, particularly M2 polarization. The tumor epicenter is characterized by heightened metabolic activity, prominently marked by elevated tricarboxylic acid cycle and glycolysis while the pericapsular milieu showcases a conspicuous enrichment of attributes associated with vasculogenesis, inflammatory responses, and epithelial–mesenchymal transition. The scMet facilitates the transformation of RNA sequencing datasets sourced from TCGA into scRNA sequencing data, maintaining a substantial degree of correlation. Conclusions The tumor microenvironment of clear cell renal cell carcinoma demonstrates significant metabolic heterogeneity across various cell types and spatial dimensions. scMet exhibits a notable capability to transform RNA sequencing data into scRNA sequencing data with a high degree of correlation