Rutin attenuates ensartinib-induced hepatotoxicity by non-transcriptional regulation of TXNIP.

Ensartinib, an approved ALK inhibitor, is used as a first-line therapy for advanced ALK-positive non-small cell lung cancer in China. However, the hepatotoxicity of ensartinib seriously limits its clinical application and the regulatory mechanism is still elusive. Here, through transcriptome analysis we found that transcriptional activation of TXNIP was the main cause of ensartinib-induced liver dysfunction. A high TXNIP level and abnormal TXNIP translocation severely impaired hepatic function via mitochondrial dysfunction and hepatocyte apoptosis, and TXNIP deficiency attenuated hepatocyte apoptosis under ensartinib treatment. The increase in TXNIP induced by ensartinib is related to AKT inhibition and is mediated by MondoA. Through screening potential TXNIP inhibitors, we found that the natural polyphenolic flavonoid rutin, unlike most reported TXNIP inhibitors can inhibit TXNIP by binding to TXNIP and partially promoting its proteasomal degradation. Further studies showed rutin can attenuate the hepatotoxicity of ensartinib without antagonizing its antitumor effects. Accordingly, we suggest that TXNIP is the key cause of ensartinib-induced hepatotoxicity and rutin is a potential clinically safe and feasible therapeutic strategy for TXNIP intervention.

Insights from the 2nd China intelligent sleep staging competition.

STUDY OBJECTIVES: Artificial intelligence (AI) is quickly advancing in the field of sleep medicine, which bodes well for the potential of actual clinical use. In this study, an analysis of the 2nd China Intelligent Sleep Staging Competition was conducted to gain insights into the general level and constraints of AI-assisted sleep staging in China. METHODS: The outcomes of 10 teams from the children's track and 13 teams from the adult track were investigated in this study. The analysis included overall performance, differences between five different sleep stages, variations across subjects, and performance during stage transitions. RESULTS: The adult track's accuracy peaked at 80.46%, while the children's track's accuracy peaked at 88.96%. On average, accuracy rates stood at 71.43% for children and 68.40% for adults. All results were produced within a mere 5-min timeframe. The N1 stage was prone to misclassification as W, N2, and R stages. In the adult track, significant differences were apparent among subjects (p < 0.05), whereas in the children's track, such differences were not observed. Nonetheless, both tracks experienced a performance decline during stage transitions. CONCLUSIONS: The computational speed of AI is remarkably fast, simultaneously holding the potential to surpass the accuracy of physicians. Improving the machine learning model's classification of the N1 stage and transitional periods between stages, along with bolstering its robustness to individual subject variations, is imperative for maximizing its ability in assisting clinical scoring.

Detection of pediatric obstructive sleep apnea using a multilayer perceptron model based on single-channel oxygen saturation or clinical features.

PURPOSE: This study was performed to develop and evaluate a method of detecting pediatric obstructive sleep apnea (OSA) using a multilayer perceptron (MLP) model based on single-channel nocturnal oxygen saturation (SpO2) with or without clinical data. METHODS: Polysomnography data for 888 children with OSA and 417 unaffected children were included. An MLP model was proposed based on the features obtained from SpO2 and combined features of SpO2 and clinical data to screen symptomatic children for OSA. The performance of the overall classification was evaluated with the receiver operating characteristics curve and the metrics of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), negative likelihood ratio (LR-), and accuracy. RESULTS: The sensitivity, specificity, PPV, NPV, LR+, LR-, and accuracy of the MLP model for SpO2 of an obstructive apnea-hypopnea index (OAHI) cutoff value of 1, 5, and 10 were 0.62-0.96, 0.11-0.97, 0.70-0.81, 0.55-0.93, 1.08-21.0, 0.39-0.39, and 0.69-0.91, respectively. The area under the receiver operating characteristics curve of an OAHI cutoff value of 1, 5, and 10 was 0.720, 0.842, and 0.922, respectively. After adding the clinical data of age, sex, body mass index, weight category, adenoid grade, or tonsil scale, the performance of the MLP model was basically at the same level as only single-channel SpO2. CONCLUSIONS: Application of this MLP model using single-channel SpO2 in children with snoring has high accuracy in the diagnosis of moderate to severe OSA but a poor effect in the diagnosis of mild OSA. The combination of clinical data did not significantly improve the diagnostic performance of the MLP model.

Aberrant Topological Properties of Brain Functional Network in Children with Obstructive Sleep Apnea Derived from Resting-State fMRI.

To examine the difference in the topological properties of brain functional network between the children with obstructive sleep apnea (OSA) and healthy controls, and to explore the relationships between these properties and cognitive scores of OSA children. Twenty-four OSA children (6.5 ± 2.8 years, 15 males) and 26 healthy controls (8.0 ± 2.9 years, 11 males) underwent resting-state fMRI (rs-fMRI), based on which brain functional networks were constructed. We compared the global and regional topological properties of the network between OSA children and healthy controls. Partial correlation analysis was performed between topological properties and cognitive scores across OSA children. When comparing the OSA children with the healthy controls, lower full-scale intelligent quotient (FIQ) and verbal intelligent quotient (VIQ) were observed. Additionally, nodal degree centrality decreased in the bilateral anterior cingulate and paracingulate gyrus, but increased in the right middle frontal gyrus, the left fusiform gyrus, and the left supramarginal gyrus. Nodal efficiency decreased in the right precentral gyrus, and the bilateral anterior cingulate and paracingulate gyrus, but increased in the left fusiform gyrus. Nodal betweenness centrality increased in the dorsolateral part of the right superior frontal gyrus, the left fusiform gyrus, and the left supramarginal gyrus. Further, the nodal degree centrality in the left supramarginal gyrus was positively correlated with FIQ. In contrast, none of global topological properties showed difference between those two groups. The outcomes of OSA may impaired the regional topological properties of the brain functional network of OSA children, which may be potential neural mechanism underlying the cognitive declines of these patients.

Development and safety of PI3K inhibitors in cancer.

The phosphatidylinositol 3-kinase (PI3K) signalling pathway regulates cell survival, proliferation, migration, metabolism and other vital cellular life processes. In addition, activation of the PI3K signalling pathway is important for cancer development. As a result, a variety of PI3K inhibitors have been clinically developed to treat malignancies. Although several PI3K inhibitors have received approval from the Food and Drug Administration (FDA) for significant antitumour activity, frequent and severe adverse effects have greatly limited their clinical application. These toxicities are mostly on-target and immune-mediated; nevertheless, the underlying mechanisms are still unclear. Current management usually involves intervention through symptomatic treatment, with discontinuation if toxicity persists. Therefore, it is necessary to comprehensively understand these adverse events and ensure the clinical safety application of PI3K inhibitors by establishing the most effective management guidelines, appropriate intermittent dosing regimens and new combination administration. Here, the focus is on the development of PI3K inhibitors in cancer therapy, with particular emphasis on isoform-specific PI3K inhibitors. The most common adverse effects of PI3K inhibitors are also covered, as well as potential mechanisms and management approaches.

Selective and Nongenetic Peroxidase Tag of Membrane Protein: a Nucleic Acid Tool for Proximity Labeling.

The protein nanoenvironment on the plasma membrane is intimately linked to cellular biological functions. Elucidation of the protein nanoenvironment contributes to understanding the pathological mechanism and discovery of disease biomarkers. However, methods enabling characterization of the protein nanoenvironment in the endogenous biological environment have been rarely developed. Toward this end, we created a nucleic acid tool called Apt-Gq/h for proximity labeling to decipher the endogenous protein nanoenvironment. Here, the aptamer acts as an anchor for binding the protein of interest (POI). The G-quadruplex/hemin complex induces proximity labeling of POI via catalyzing the conversion of inert small-molecule substrates into short-lived reactive species. The labeled proteins enable the subsequent affinity-based enrichment and proteomic analysis. We first characterized Apt-Gq/h-mediated POI labeling in vitro and tested its utility by interrogating the protein nanoenvironment of POI in living cells. Taking advantage of the nongenetic, multiple reaction sites, and rapid proximity labeling, Apt-Gq/h was further utilized to imaging the cell-cell connection and amplification detection of biomarkers in living cells and tissue sections. We believe that Apt-Gq/h will be a potential tool for basic science and clinical applications.

Autonomic nervous function and low-grade inflammation in children with sleep-disordered breathing.

BACKGROUND: The objective of the study was to assess the relationship between autonomic nervous function and low-grade inflammation in children with sleep-disordered breathing. METHODS: We enrolled habitually snoring children aged 3-14 years for overnight polysomnography (PSG) and high-sensitivity C-reactive protein (hsCRP) measurement. Low-grade inflammation was defined as hsCRP >1.0 mg/L to <10.0 mg/L. An electrocardiogram recording was extracted from PSG. Heart rate variability was analyzed using time and frequency domain methods. RESULTS: In total, 190 children were included, with 61 having primary snoring (PS), 39 mild obstructive sleep apnea (OSA), and 90 moderate-to-severe OSA. The average RR interval displayed a significant decline, whereas the low frequency/high frequency (LF/HF) ratio showed an increasing tendency in children with PS, mild OSA, and moderate-to-severe OSA. Mean RR was mainly influenced by age and the apnea hypopnea index (AHI) (all P < 0.01). AHI was an independent risk factor for the altered LF/HF ratio at all sleep stages except N3 stage (all P < 0.05). In the wake stage, low-grade inflammation was an independent risk factor of altered LF/HF ratio (P = 0.014). CONCLUSIONS: Autonomic nervous function was impaired in children with OSA. The sympathetic-vagal balance was influenced by low-grade inflammation in the wake stage, whereas it was only affected by AHI when falling asleep. IMPACT: We found that autonomic nervous function was impaired in children with OSA. We found that there was a negative correlation between systemic inflammation and autonomic nervous function in children with SDB only at wake stage. A negative association between systemic inflammation and autonomic nervous function was demonstrated in children in this study. Furthermore, altered LF/HF ratio maybe a good indicator of autonomic nervous dysfunction in children as it only correlated with the SDB severity, not with age.

Transcervical inflatable mediastinoscopic esophagectomy versus thoracoscopic esophagectomy for local early- and intermediate-stage esophageal squamous cell carcinoma: A propensity score-matched analysis.

BACKGROUND AND OBJECTIVE: Transcervical inflatable mediastinoscopic esophagectomy (TIME) is a novel method of minimally invasive esophagectomy (MIE) for esophageal cancer. However, whether TIME is effective and feasible as conventional MIE remains unclear. This study aimed to evaluate the efficacy of TIME by comparing it with thoracoscopic esophagectomy (TE). METHODS: Surgical outcomes and relapse-free survival (RFS) rates of patients with local early- or intermediate-stage thoracic esophageal squamous cell carcinoma that underwent TIME or TE from January 2017 to December 2019 were analyzed in this retrospective study. Propensity score matching was used to control the confounding factors. RESULTS: The mean operation time in TIME was shorter than that in TE (p < 0.05). Patients in the TIME group achieved postoperative ambulation earlier than those in the TE group (p < 0.05). The rate of pulmonary complications was lower in TIME than in TE (p < 0.05). The number of lymph nodes harvested during surgery and the RFS rates of two groups did not have significant differences. CONCLUSION: TIME may be a feasible and safe method to treat local early- and intermediate-stage thoracic esophageal squamous cell carcinoma effectively and it could be a supplementary surgical method of TE for patients with poor pulmonary function or cannot undergo TE.

Comparison of low-dose morphine intrathecal analgesia and sufentanil PCIA in elderly patients with hip fracture undergoing single spinal anesthesia - a randomized clinical trial.

BACKGROUND: The complications of postoperative pain, such as hypertension, hypermetabolism, irritability, and postoperative cognitive dysfunction, significantly affect the postoperative rehabilitation of elderly patients. Intrathecal morphine prolongs analgesia after surgery, but has been implicated in nausea and vomiting, pruritus, postoperative respiratory depression, or apneic episodes. The present study explored the effect and safety of low-dose morphine used adjunctively with bupivacaine during single spinal anesthesia or sufentanil patient-controlled intravenous analgesia (PCIA) in elderly patients with hip fracture surgery. Since elderly patients often need anticoagulant therapy in the early postoperative period, single spinal anesthesia was involved in completing the operation in this study. METHODS: Eighty elderly patients aged 70-85 years who underwent elective hip fracture surgery with single spinal anesthesia were divided into two groups, 12.5 mg of 0.5% hyperbaric bupivacaine with 100 µg of morphine (morphine group, group M) and 12.5 mg of 0.5% hyperbaric bupivacaine with 100 µg of sufentanil PCIA (sufentanil group, group S). The analgesia scores using the visual analogue scale (VAS), the Brinell comfort scale (BCS) were evaluated at 6, 12, 24, and 48 h after operation, and adverse reactions were recorded such as nausea and vomiting, pruritus, sedation, respiratory depression, and POD (postoperative delirium) with Delirium Rating Scale-r 98. RESULTS: Within 24 h after operation, the analgesic and BCS scores of group M were better than those of group S (P < 0.05). Group M had higher frequency of skin pruritus than group S within 24 h, and the difference was statistically significant. The incidence of POD in group M (2 cases) was lower than that in group S (6 cases) (5.71% vs 18.18%) (P < 0.05) with the DRS-r 98 scores. No significant difference was observed in nausea and vomiting between the two groups, and the difference of severe respiratory depression was not found in both groups. CONCLUSION: Compared with sufentanil PCIA, low-dose intrathecal morphine has a satisfactory analgesic effect, and little effect on the patient's cognitive function with low medical cost. Under effective respiratory monitoring, it can be used safely and effectively in elderly patients with hip fracture. TRIAL REGISTRATION: Registered with the Chinese Clinical Trial Registry under ChiCTR2100042706 . 26/01/2021.

[Characteristics of slow wave activity of sleep electroencephalogram and the changes of slow wave activity after adenotonsillectomy in children with severe obstructive sleep apnea].

Objective: To investigate the characteristics of slow wave activity (SWA) during sleep and the changes of SWA after adenotonsillectomy in children with severe obstructive sleep apnea (OSA). Methods: A total of 24 children with severe OSA, who completed adenotonsillectomy in Sleep Center of Beijing Children's Hospital and 26 control children category matched for age and sex and excluded from OSA were included as subjects from May 2018 to December 2019. The subjects underwent overnight PSG, as well as SWA analysis of sleep electroencephalogram. The differences of PSG indexes and SWA intensity between children with severe OSA and control children, before and after operation in severe OSA children were compared and the correlations between SWA intensity and PSG indexes were analyzed. Results: The age of the children with severe OSA before surgery was (6.1±1.7) years, including 20 males (83.3%), and the interval M(Q1,Q3) between surgery and follow-up was 6.3 (5.8, 7.1) months. The age of the control children was (6.2±1.1) years, including 20 males (76.9%). In severe OSA group, the M (Q1,Q3) of non-rem sleep stage 1 to total sleep time, obstructive apnea hypopnea index, oxygen desaturation index (ODI) and proportion of oxygen saturation (SpO2)<90% during night sleep to total sleep time were 6.8% (5.6%, 8.9%), 1.2 (0.4, 2.4) events/h, 2.1 (0.7, 4.3) events/h and 0(0, 0) after surgery, respectively, which were lower than those before surgery [9.1% (7.5%, 16.8%), 21.6 (14.1, 39.5) events/h, 23.1 (10.2, 36.0) events/h and 0.8% (0, 3.9%), respectively], while non-rem sleep stage 3 to total sleep time%, rem sleep stage to total sleep time% and lowest SpO2 were (24.3±5.7)%, (19.1±3.7)% and 91%(86%, 94%) after surgery, which were higher than those before operation [(19.0±5.3)%, (15.4±3.9)% and 83%(70%, 88%) respectively] (all P values<0.05). The repeated measure ANOVA of SWA intensity in phase N1 showed no interaction between OSA and sleep time course (F=0.02, P=0.997), the main effect of OSA was statistically significant (F=5.12, P=0.040), SWA intensity in children with severe OSA at stage N1 was higher than that of the control group [SWA(severe OSA group before surgery-control group)(95%CI): 0.379,(0.020, 0.739)], while the main effect of sleep time course was not statistically significant (F=1.66, P=0.191). There was no interaction between adenotonsillectomy and sleep time course (F=0.88,P=0.461), the main effect of surgery was statistically significant (F=8.95, P=0.010), SWA intensity of children with severe OSA at N1 stage after surgery was lower than before [SWA(after surgery-before surgery)(95%CI):-0.572(-0.982, -0.162)] and the main effect of sleep time course was statistically significant (F=6.33, P=0.001). The intensity of SWA in the fourth sleep cycle of N1 stage was positively correlated with ODI (r=0.299, P=0.048). Conclusion: The intensity of slow-wave activity at N1 stage is affected by OSA which might be caused by intermittent hypoxia, and adenotonsillectomy significantly reduces SWA intensity at stage N1.

Systematic Interrogation of Cellular Signaling in Live Cells Using a Membrane-Anchored DNA Multitasking Processor.

Systematic interrogation of correlative signaling components in their native environment is of great interest for dissecting sophisticated cellular signaling. However, it remains a challenge because of the lack of versatile and effective approaches. Herein, we propose a cell membrane-anchored DNA multitasking processor acting as a "traffic light" for integrated analyses of cellular signal transduction. Enhanced and controllable inhibition of c-Met signaling was achieved by membrane-anchoring of DNA processors. Moreover, the multitasking capability of the DNA processor allowed the monitoring of correlative VEGF secretion induced by c-Met activity regulation directly. By exploiting versatile aptameric nucleic acids, this modular designed DNA multitasking processor dissected how cell surface receptors coordinated with related components in live cells systematically. Therefore, it provides a powerful chemical tool for both fundamental cell biology research and precision medicine applications.

Tim-3 is a potential regulator that inhibits monocyte inflammation in response to intermittent hypoxia in children with obstructive sleep apnea syndrome.

The mechanism of the characteristic intermittent hypoxia (IH) of obstructive sleep apnea syndrome (OSAS) on monocyte remain unclear. Our study found that OSAS children had a significantly upregulated expression in circulating proinflammatory cytokines IL-6 and IL-12, and endothelial injury markers VEGF and ICAM1. Association analysis revealed that the plasma TNFα, IL-1ß, IL-6, IL-10 and IL-12 concentration were negatively associated with the minimal SpO2, a negative index for disease severity. OSAS monocytes presented an inflammatory phenotype with higher mRNA levels of inflammatory cytokines. Importantly, we noted a significant decrease in T-cell immunoglobulin and mucin domain (Tim)-3 expression in OSAS monocytes with the increase of the plasma proinflammatory cytokines. In vitro assay demonstrated that IH induced THP-1 cell overactivation via NF-κB dependent pathway was inhibited by the Tim-3 signal. Our results indicated that activation of monocyte inflammatory responses is closely related to OSAS-induced IH, and negatively mediated by a Tim-3 signaling pathway.

DNA-Templated Glycan Labeling for Monitoring Receptor Spatial Distribution in Living Cells.

Tracking the spatial distribution of receptor tyrosine kinases in their native environment contributes to understanding the homeostatic or pathological states at a molecular level. Conjugation of DNA tags to a specific receptor is a powerful tool for monitoring receptor spatial distribution. However, long-term stable trafficking in live cells without interfering with the intrinsic receptor function remains a challenge. Here, we report a general DNA-templated glycan labeling strategy to track spatial distribution of a specific receptor in living cells. Different from existing target-selective covalent methods, the DNA tags were incorporated in glycan of a specific receptor via aptamer-assisted metabolic glycan labeling, thus resulting in minimal perturbation to the receptor's biological function. As proof of concept, covalent tagging of MET, HER2, and EGFR was achieved, and then the spatial distribution was successfully monitored, including homo-/heterodimerization and internalization. Overall, the proposed strategy will greatly aid in investigating receptor dynamics and is conducive to understanding their biological function in the native environment.

Long non-coding RNA HEIH suppresses the expression of TP53 through enhancer of zeste homolog 2 in oesophageal squamous cell carcinoma.

It is increasingly evident that the molecular and biological functions of long non-coding RNAs (lncRNA) are vital for understanding the molecular biology and progression of cancer. The lncRNA-HEIH, a newly identified lncRNA, has been demonstrated to be up-regulated in hepatocellular cancer. However, little is known about its role in oesophageal squamous cell carcinoma (ESCC). In the present study, an obvious up-regulation of lncRNA-HEIH was observed in ESCC compared to the adjacent normal tissues. Meanwhile, patients with high expression of lncRNA-HEIH have significantly poorer prognosis than those with low expression. We further found that lncRNA-HEIH was associated with enhancer of zeste homolog 2 (EZH2) and that this association led to the repression of TP53. These findings indicate that lncRNA-HEIH may serve as a prognostic marker and a potential therapeutic target for ESCC.

Cloud algorithm-driven oximetry-based diagnosis of obstructive sleep apnoea in symptomatic habitually snoring children.

The ability of a cloud-driven Bluetooth oximetry-based algorithm to diagnose obstructive sleep apnoea syndrome (OSAS) was examined in habitually snoring children concurrently undergoing overnight polysomnography.Children clinically referred for overnight in-laboratory polysomnographic evaluation for suspected OSAS were simultaneously hooked to a Bluetooth oximeter linked to a smartphone. Polysomnography findings were scored and the apnoea/hypopnoea index (AHIPSG) was tabulated, while oximetry data yielded an estimated AHIOXI using a validated algorithm.The accuracy of the oximeter in identifying correctly patients with OSAS in general, or with mild (AHI 1-5 events·h-1), moderate (5-10 events·h-1) or severe (>10 events·h-1) OSAS was examined in 432 subjects (6.5±3.2 years), with 343 having AHIPSG >1 event·h-1 The accuracies of AHIOXI were consistently >79% for all levels of OSAS severity, and specificity was particularly favourable for AHI >10 events·h-1 (92.7%). Using the criterion of AHIPSG >1 event·h-1, only 4.7% of false-negative cases emerged, from which only 0.6% of cases showed moderate or severe OSAS.Overnight oximetry processed via Bluetooth technology by a cloud-based machine learning-derived algorithm can reliably diagnose OSAS in children with clinical symptoms suggestive of the disease. This approach provides virtually limitless scalability and should alleviate the substantial difficulties in accessing paediatric sleep laboratories while markedly reducing the costs of OSAS diagnosis.

Logic-Gate-Actuated DNA-Controlled Receptor Assembly for the Programmable Modulation of Cellular Signal Transduction.

Programming cells to sense multiple inputs and activate cellular signal transduction cascades is of great interest. Although this goal has been achieved through the engineering of genetic circuits using synthetic biology tools, a nongenetic and generic approach remains highly demanded. Herein, we present an aptamer-controlled logic receptor assembly for modulating cellular signal transduction. Aptamers were engineered as "robotic arms" to capture target receptors (c-Met and CD71) and a DNA logic assembly functioned as a computer processor to handle multiple inputs. As a result, the DNA assembly brings c-Met and CD71 into close proximity, thus interfering with the ligand-receptor interactions of c-Met and inhibiting its functions. Using this principle, a set of logic gates was created that respond to DNA strands or light irradiation, modulating the c-Met/HGF signal pathways. This simple modular design provides a robust chemical tool for modulating cellular signal transduction.

Nocturnal Oximetry-based Evaluation of Habitually Snoring Children.

RATIONALE: The vast majority of children around the world undergoing adenotonsillectomy for obstructive sleep apnea-hypopnea syndrome (OSA) are not objectively diagnosed by nocturnal polysomnography because of access availability and cost issues. Automated analysis of nocturnal oximetry (nSpO2), which is readily and globally available, could potentially provide a reliable and convenient diagnostic approach for pediatric OSA. METHODS: Deidentified nSpO2 recordings from a total of 4,191 children originating from 13 pediatric sleep laboratories around the world were prospectively evaluated after developing and validating an automated neural network algorithm using an initial set of single-channel nSpO2 recordings from 589 patients referred for suspected OSA. MEASUREMENTS AND MAIN RESULTS: The automatically estimated apnea-hypopnea index (AHI) showed high agreement with AHI from conventional polysomnography (intraclass correlation coefficient, 0.785) when tested in 3,602 additional subjects. Further assessment on the widely used AHI cutoff points of 1, 5, and 10 events/h revealed an incremental diagnostic ability (75.2, 81.7, and 90.2% accuracy; 0.788, 0.854, and 0.913 area under the receiver operating characteristic curve, respectively). CONCLUSIONS: Neural network-based automated analyses of nSpO2 recordings provide accurate identification of OSA severity among habitually snoring children with a high pretest probability of OSA. Thus, nocturnal oximetry may enable a simple and effective diagnostic alternative to nocturnal polysomnography, leading to more timely interventions and potentially improved outcomes.

Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumour and has poor prognosis. Currently, systematic chemotherapy is the only approach to prolong survival. Thus the development of new treatment regimens is urgently needed to improve the therapeutic efficacy. Our study intended to assess the combination of dasatinib and irinotecan against HCC and made an effort to develop a potential medical choice for advanced HCC patients. METHODS: We used SRB colorimetric assay and clonogenic assay to assess antitumour effect in vitro and HCC xenograft model to assess antitumour effect in vivo. We applied flow cytometry and western blotting to explore the mechanism of the combined therapy. Knockdown and overexpression of PLK1 are also applied for validation. RESULTS: We confirmed that dasatinib has synergistic effect with irinotecan (or SN38) on HCC both in vitro and in vivo. The effect is due to arisen apoptosis rate of HCC cells that is accompanied by mitochondria dysfunction. The enhanced antitumour efficacy of SN38 could be explained by additional inhibition of PLK1, which is triggered by dasatinib. Unlike existed PLK1 inhibitors, dasatinib does not inhibit PLK1 activity in a direct way. Instead, we found that dasatinib reduces PLK1 level by interfering with its protein synthesis progress. We validated that this kind of downregulation of PLK1 level has a key role in the synergistic effect of the two agents. CONCLUSIONS: Dasatinib is able to reinforce the anti-HCC efficacy of irinotecan/SN38 by downregulation of PLK1 synthesis. The combination of the two agents might be a potential medical choice for HCC therapy.

Shp2 Inhibits Proliferation of Esophageal Squamous Cell Cancer via Dephosphorylation of Stat3.

Shp2 (Src-homology 2 domain-containing phosphatase 2) was originally reported as an oncogene in kinds of solid tumors and hematologic malignancies. However, recent studies indicated that Shp2 may act as tumor suppressors in several tumor types. We investigated the function of Shp2 in esophageal squamous cell cancer (ESCC). The expression level of Shp2 was analyzed in tumor tissues in comparison with adjacent normal tissues of ESCC patients by immunohistochemistry and Western blot. Shp2 was knocked down by Short hairpin RNA to evaluate its function in ESCC cell lines. The relationship between Shp2 and p-Stat3 (signal transducer and activator of transcription 3) in human ESCC tissues was statistically examined. A significant low expression of Shp2 was found in ESCC tissues. Low expression of Shp2 was related to poorer overall survival in patients from The Cancer Genome Atlas (TCGA) dataset. Knockdown of Shp2 increased the growth of ESCC cell lines both in vivo and vitro. Activation of Stat3 (p-Stat3) was induced by Shp2 depletion. Expression of p-Stat3 was negatively correlated with Shp2 expression in ESCC tissues. Furthermore, knockdown of Shp2 attenuated cisplatin-sensitivity of ESCC cells. Shp2 might suppress the proliferation of ESCC by dephosphorylation of p-Stat3 and represents a novel research field for targeted therapy.