CIP2A deficiency promotes depression-like behaviors in mice through inhibition of dendritic arborization.

Major depressive disorder (MDD) is a severe mental illness. Decreased brain plasticity and dendritic fields have been consistently found in MDD patients and animal models; however, the underlying molecular mechanisms remain to be clarified. Here, we demonstrate that the deletion of cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor of protein phosphatase 2A (PP2A), leads to depression-like behaviors in mice. Hippocampal RNA sequencing analysis of CIP2A knockout mice shows alterations in the PI3K-AKT pathway and central nervous system development. In primary neurons, CIP2A stimulates AKT activity and promotes dendritic development. Further analysis reveals that the effect of CIP2A in promoting dendritic development is dependent on PP2A-AKT signaling. In vivo, CIP2A deficiency-induced depression-like behaviors and impaired dendritic arborization are rescued by AKT activation. Decreased CIP2A expression and impaired dendrite branching are observed in a mouse model of chronic unpredictable mild stress (CUMS). Indicative of clinical relevance to humans, CIP2A expression is found decreased in transcriptomes from MDD patients. In conclusion, we discover a novel mechanism that CIP2A deficiency promotes depression through the regulation of PP2A-AKT signaling and dendritic arborization.

Remote monitoring of patient recovery following lung cancer surgery: a messenger application approach.

BACKGROUND: Repeated assessment of patient recovery after discharge is challenging. This study used a popular messenger application to remotely collect patient self-reported symptoms and their severity so as to monitor patient recovery and identify the factors affecting the recovery of symptoms following lung cancer surgery. METHODS: This prospective observational study was conducted at a single tertiary lung cancer center in China between November 2018 and June 2019. Participants received demonstration videos and repeated symptom surveys regarding pain and cough severity (assessed using numeric rating scores of 0-10 for pain and 0-6 for cough) at 2, 4, 6, 8, and 12 weeks after discharge via a smartphone program bound to the WeChat application. Patients who responded to at least 3 of the 5 post-discharge surveys were included in this study. The data were analyzed to investigate the symptom recovery and its related factors. RESULTS: Of the 826 patients enrolled, 589 (71.3%) responded to at least three surveys. The average pain score reduced from 4.1±2.5 at 2 weeks to 2.2±2.0 at 12 weeks (P<0.001). Factors associated with higher pain severity included the female gender, age over 60 years, thoracotomy, longer operation time (>90 minutes), and prolonged chest tube drainage (>7 days). The average cough score decreased from 2.34±1.30 at 2 weeks to 1.93±1.26 at 12 weeks (P<0.001). Being female and a prolonged operation time (>90 min) were related to increased cough severity. Sublobar resection and limited lymphadenectomy may contribute to lower cough severity post-surgery. CONCLUSIONS: The messenger application-based remote monitoring successfully collected post-discharge symptom information and identified factors associated with recovery following lung surgery.

Application of artificial neural networks in detection and diagnosis of gastrointestinal and liver tumors.

As a form of artificial intelligence, artificial neural networks (ANNs) have the advantages of adaptability, parallel processing capabilities, and non-linear processing. They have been widely used in the early detection and diagnosis of tumors. In this article, we introduce the development, working principle, and characteristics of ANNs and review the research progress on the application of ANNs in the detection and diagnosis of gastrointestinal and liver tumors.

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease.

In Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetylation, resulting in higher AMPAR stability and protein accumulation. Here we report that AMPAR acetylation was significantly reduced in AD and neurons with Aß incubation. We identified p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Aß-induced reductions in total and cell-surface AMPARs. Importantly, expression of acetylation mimetic GluA1 (GluA1-4KQ) in APP/PS1 mice rescued impairments in synaptic plasticity and memory. These findings indicate that Aß-induced reduction in AMPAR acetylation and stability contributes to synaptopathy and memory deficiency in AD, suggesting that AMPAR acetylation may be an effective molecular target for AD therapeutics.

Inhibition of Tumor Lymphangiogenesis is an Important Part that EGFR-TKIs Play in the Treatment of NSCLC.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used to treat non-small cell lung cancer (NSCLC) because they inhibit tumour growth and metastasis. However, the underlying mechanisms are not fully understood. Here, we investigate whether anti-lymphangiogenesis mechanisms contribute to the anti-tumour effects of EGFR-TKIs. Three different EGFR-TKIs (Gefitinib, Afatinib, and AZD9291) were used to determine the possible biological effects of EGFR-TKIs on lymphangiogenesis in vitro and in vivo. EGFR-TKIs inhibited human lymphatic endothelial cells (HLEC) proliferation, migration and tube formation at the indicated concentrations. Conditioned medium from human lung adenocarcinoma HCC827 cells treated with EGFR-TKIs also inhibited HLEC migration and tube formation. EGFR-TKIs inhibited VEGFC secretion, which further influenced HLEC behaviour in vitro. Afatinib inhibited tumour growth and lymphangiogenesis in the HCC827 xenograft mouse model. The densities and tube diameters of the lymphatic vessels were decreased in a dose-dependent manner, as shown by lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) staining. EGFR-TKIs also inhibited the expression of important lymphangiogenesis regulatory factors vascular endothelial growth factor 2/3 (VEGF2/3), VEGFC, and chemokine receptor 7 (CCR7) as shown by immunocytochemistry (IHC) staining. Additional assays confirmed that the JAK/STAT3 signalling pathways play important roles in the anti-lymphangiogenesis process induced by EGFR-TKIs. Inhibition of lymphangiogenesis is another important role that the three EGFR-TKIs play in the treatment of lung cancer and the Janus kinase/signal transducers and activators of transcription 3 (JAK/STAT3) maybe an important signalling pathway regulating lymphangiogenesis, which provides a new idea for clinical therapy of lung cancer.

Genistein Decreases APP/tau Phosphorylation and Ameliorates Aß Overproduction Through Inhibiting CIP2A.

BACKGROUND: Upregulation of Cancerous Inhibitor of PP2A (CIP2A) plays an important role in disease-related phosphorylation of tau/APP and tau pathology/Aß overproduction through inhibiting PP2A in AD brain. Genistein has been shown to potently reduce CIP2A in experimental cancer treatment research. Whether Genistein can ameliorate AD pathology through targeting CIP2A needs further investigation. METHODS: The inhibitory effects of Genistein on tau/APP phosphorylation and Aß overproduction in AD cell models have been explored. HEK293-T cells were co-transfected with CIP2A and APP plasmids, or CIP2A and tau plasmids, with Genistein incubation at 0, 30, 60 or 120 µM for 48 h, cell viability and PP2A activities were measured. HEK293-T cells with CIP2A/APP overexpression treated with Genistein at 30 µM for 48 h were collected and lyzed for Western blotting detection of CIP2A, PP2Ac, APP-T668, total APP, PS1, BACE1, sAPPα and sAPPß. Aß40 and Aß42 levels in cell supernatant, soluble fraction (RIPA) and insoluble fraction (formic acid soluble) of cell lysates were measured by ELISA. HEK293-T cells with CIP2A/tau overexpression treated with Genistein at 30 µM for 48 h were collected for Western blotting detection of CIP2A, PP2Ac, tau-S396, tau-S404 and total tau. RESULTS: Genistein effectively reduced CIP2A expression, and restored PP2A activities both in CIP2A/APP, CIP2A/tau co-expressed cells. Genistein reduced APP phosphorylation at T668 site and inhibited Aß production. Meantime, Genistein ameliorated tau hyperphosphorylation through repressing the inhibitory effect of CIP2A on PP2A. CONCLUSION: CIP2A is a target of Genistein in AD therapy. Genistein reduces APP/tau hyperphosphorylation and Aß production through inhibiting the effect of CIP2A on PP2A.

CIP2A-promoted astrogliosis induces AD-like synaptic degeneration and cognitive deficits.

Reactive astrogliosis and early synaptic degeneration are 2 characteristic hallmarks in Alzheimer's disease (AD) brains, but a direct link between the 2 events has not been established. Here, we show that cancerous inhibitor of PP2A (CIP2A), a cancerous protein with high expression level in astrocytes, is upregulated in patients with AD and 3xTg-AD transgenic mice. Overexpression of CIP2A in astrocytes through adeno-associated virus infection both in cultured cells and in mice brains results in activation of astrocytes, increased production of cytokines and Aß, and synaptic degeneration indicated by decreased levels of synaptic proteins, spine loss, and impairment in long-term potentiation. As a result of synaptic degeneration, CIP2A overexpression in astrocytes in vivo induces significant deficits in visual episodic memory detected by novel objective recognition test and spatial memory detected by Morris water maze. We conclude that CIP2A-promoted astrogliosis induces synaptic degeneration and cognitive deficits in AD.

Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke.

CDK5 activation promotes ischemic neuronal death in stroke, with the recognized activation mechanism being calpain-dependent p35 cleavage to p25. Here we reported that CDK5-Tyr15 phosphorylation by zinc induced CDK5 activation in brain ischemic injury. CDK5 activation and CDK5-Tyr15 phosphorylation were observed in the hippocampus of the rats that had been subjected to middle cerebral artery occlusion, both of which were reversed by pretreatment with zinc chelator; while p35 cleavage and calpain activation in ischemia were not reversed. Zinc incubation resulted in CDK5-Tyr15 phosphorylation and CDK5 activation, without increasing p35 cleavage in cultured cells. Site mutation experiment confirmed that zinc-induced CDK5 activation was dependent on Tyr15 phosphorylation. Further exploration showed that Src kinase contributed to zinc-induced Tyr15 phosphorylation and CDK5 activation. Src kinase inhibition or expression of an unphosphorylable mutant Y15F-CDK5 abolished Tyr15 phosphorylation, prevented CDK5 activation and protected hippocampal neurons from ischemic insult in rats. We conclude that zinc-induced CDK5-Tyr15 phosphorylation underlies CDK5 activation and promotes ischemic neuronal death in stroke.

CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer's Disease.

Protein phosphatase 2A (PP2A) inhibition causes hyperphosphorylation of tau and APP in Alzheimer's disease (AD). However, the mechanisms underlying the downregulation of PP2A activity in AD brain remain unclear. We demonstrate that Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is overexpressed in AD brain. CIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APP ß-cleavage and Aß production. Increase in CIP2A expression also leads to tau mislocalization to dendrites and spines and synaptic degeneration. In mice, injection of AAV-CIP2A to hippocampus induced AD-like cognitive deficits and impairments in long-term potentiation (LTP) and exacerbated AD pathologies in neurons. Indicative of disease exacerbating the feedback loop, we found that increased CIP2A expression and PP2A inhibition in AD brains result from increased Aß production. In summary, we show that CIP2A overexpression causes PP2A inhibition and AD-related cellular pathology and cognitive deficits, pointing to CIP2A as a potential target for AD therapy.

Bexarotene inhibits the viability of non-small cell lung cancer cells via slc10a2/PPARγ/PTEN/mTOR signaling pathway.

BACKGROUND: Thirty to 40 % of non-small cell lung cancer (NSCLC) patients developed higher hypertriglyceridemia in the process of treatment with bexarotene. And bioinformatics studies discovered that the expression of slc10a2 was increased in high-grade hypertriglyceridemia patients. So, we will explore the mechanism which may involve in this process. METHODS: We constructed slc10a2 overexpressed A549 cells and H1299 cells as cell models, normal A549 cells and H1299 cells as control. Then we explored the effects of slc10a2 on A549 cells and H1299 cells behaviors, including proliferation, invasion and apoptosis. The expression of apoptotic related genes and anti-cancer genes also been detected. RESULTS: We found that the proliferation and migration were inhibited and the apoptosis of NSCLC cells was accelerated by bexarotene. In addition, overexpressed slc10a2 in NSCLC cells can further suppress the proliferation and migration, and promote apoptosis under the treatment of bexarotene. On the contrary, the opposite results were obtained after slc10a2 gene was silenced in NSCLC cells treated with bexarotene. Moreover, the expression of caspase 3, caspase 7, PTEN, P21, P53, LKB1, TSC2 were increased and the expression of Bcl-2, cyclin D1, c-FLIP were declined in NSCLC cells and slc10a2 overexpressed NSCLC cells with the treatment of bexarotene, and the opposite situations were seen after slc10a2 gene was silenced in NSCLC cells. The further studies revealed the increased expression of slc10a2 activated the expression of peroxisome proliferator-activated receptor γ (PPARγ), then up-regulated PTEN expression and down-regulated mTOR expression. CONCLUSION: These results suggest that bexarotene inhibits the viability of lung cancer cells via slc10a2/PPARγ/PTEN/mTOR signaling pathway.

Long-term Helicobacter pylori infection does not induce tauopathy and memory impairment in SD rats.

Helicobacter pylori (H.pylori) infection is a recognized risk factor of dementia, while its role and mechanism in Alzheimer disease (AD) remained unclarified. Our previous study has identified that injection of soluble H.pylori filtrate could induce AD-like pathologic changes and cognitive impairment in SD rats. In the present study, we further explored the effect of long-term stomach colonization of H.pylori bacteria on the brains of SD rats. The results showed that H.pylori bacteria gavage induced an efficient colonization of H.pylori in the stomach after four weeks. However, there was no significant change of tau phosphorylation at Thr205 (pT205), Thr231 (pT231), Ser396 (pS396) and Ser404 (pS404) sites in the hippocampus and cerebral cortex. The H.pylori-infected rats also showed no cognitive impairment. These observations may result from inefficient release of bacterial pathogenic factors or the overall lack of host inflammatory responses. We conclude that SD rat with long-term H.pylori colonization in the stomach is not a suitable animal model for exploring the effects of H.pylori infection on brain function in human beings; administration of bacterial filtrates may better reveal the systemic pathologic changes induced by bacterial infection in animals which show a negative host response to bacterial colonization.

Zinc mediates the neuronal activity-dependent anti-apoptotic effect.

Synaptic activity increases the resistance of neurons to diverse apoptotic insults; however, the underlying mechanisms remain less well understood. Zinc promotes cell survival under varied conditions, but the role of synaptically released zinc in the activity-dependent anti-apoptotic effect is unknown. Using cultured hippocampal slices and primary neurons we show that a typical apoptosis inducer-staurosporine (STP) was able to cause concentration-dependent apoptotic cell death in brain slices; Enhanced synaptic activity by bicuculline (Bic)/4-Aminopyridine (AP) treatment effectively prevented neurons from STP-induced cell apoptosis, as indicated by increased cell survival and suppressed caspase-3 activity. Application of Ca-EDTA, a cell membrane-impermeable zinc chelator which can efficiently capture the synaptically released zinc, completely blocked the neuronal activity-dependent anti-apoptotic effect. Same results were also observed in cultured primary hippocampal neurons. Therefore, our results indicate that synaptic activity improves neuronal resistance to apoptosis via synaptically released zinc.

Long-term Helicobacter pylori Infection Does Not Induce Tauopathy and Memory Impairment in SD Rats / 华中科技大学学报（医学）（英德文版）

Helicobacter pylori (H.pylori) infection is a recognized risk factor of dementia,while its role and mechanism in Alzheimer disease (AD) remained unclarified.Our previous study has identified that injection of soluble H.pylori filtrate could induce AD-like pathologic changes and cognitive impairment in SD rats.In the present study,we further explored the effect of long-term stomach colonization of H.pylori bacteria on the brains of SD rats.The results showed that H.pylori bacteria gavage induced an efficient colonization of H.pylori in the stomach after four weeks.However,there was no significant change of tau phosphorylation at Thr205 (pT205),Thr231 (pT231),Ser396 (pS396) and Ser404 (pS404) sites in the hippocampus and cerebral cortex.The H.pylori-infected rats also showed no cognitive impairment.These observations may result from inefficient release of bacterial pathogenic factors or the overall lack of host inflammatory responses.We conclude that SD rat with long-term H.pylori colonization in the stomach is not a suitable animal model for exploring the effects of H.pylori infection on brain function in human beings;administration of bacterial filtrates may better reveal the systemic pathologic changes induced by bacterial infection in animals which show a negative host response to bacterial colonization.

[Effect of autophagy inhibitor chloroquine on the proliferation of PASMCs induced by hypoxia].

OBJECTIVE: To investigate the role of autophagy inhibitor chloroquine (CQ) in the proliferation of pulmonary arterial smooth muscle cells (PASMCs) in hypoxia conditions. METHODS: The following groups in this study were set up: control group, hypoxia group, 50 micromol/L CQ + hypoxia group, 50 micromol/L CQ group. The viability of PASMCs in every group was detected by MTT assay. Autophagic vacuoles in the cells were observed by MDC staining. Protein expression of microtubule associated protein light chain 3 (LC3) was measured by Western blot. Migration of PASMCs was detected by wound healing assay. RESULTS: Compared with control group, no effect on the viability of PASMCs was observed treated by CQ alone. In 1% hypoxia group, cell viability increased significantly compared with that in control group. The number of autophagic vacuoles and the rate of cell migration and also protein expression of LC3-II were also markedly increased. Compared with hypoxia group, addition of CQ increased the number of autophagic vacuoles and the levels of LC3-II protein, but decreased the proliferation and migration of PASMCs. CONCLUSION: Hypoxia could activates autophagy and contributes to proliferation and migration of PASMCs, and autophagy inhibitor CQ could decrease the effect of hypoxia on PASMCs through inhibiting autophagy process.

A new technique combining virtual simulation and methylene blue staining for the localization of small peripheral pulmonary lesions.

BACKGROUND: Quickly and accurately localizing small peripheral pulmonary lesions can avoid prolonged operative time and unplanned open thoracotomy. In this study, we aimed to introduce and evaluate a new technique combining virtual simulation and methylene blue staining for the localization of small peripheral pulmonary lesions. METHODS: Seventy four (74) patients with 80 peripheral pulmonary lesions <20 mm in size on computer tomography (CT) were virtually punctured using a radiotherapy planning simulator on the day before operation. Under general anaesthesia, methylene blue dye was injected to the virtually identified point according to the surface point, angle and depth previously determined by the simulator. The wedge resection of the marked lesion was performed under video-assisted thoracoscopic surgery (VATS) and the specimens were sent for immediate pathologic examination. According to pathology results, appropriate surgical procedures were decided and undertaken. RESULTS: The average lesion size was 10.4±3.5 mm (range: 4-17 mm) and the average distance to the pleural surface was 9.4±4.9 mm. Our preoperative localization procedure was successful in 75 of 80 (94%) lesions. Histological examination showed 28 benign lesions and 52 lung cancers. The shortest distance between the edges of the stain and lesion was 5.1±3.1 mm. Localization time was 17.4±2.3 min. All patients with malignant lesions subsequently underwent lobectomy and systematic lymph node dissection. No complications were observed in all participants. CONCLUSIONS: The novel technique combining the preoperative virtual simulation and methylene blue staining techniques has a high success rate for localizing small peripheral pulmonary lesions, particularly for those tiny lesions which are difficult to visualise and palpate during VATS.

[Prevention of refractory cough with mediastinal fat to fill the residual cavity after radical systematic mediastinal lymphadenectomy in patients with right lung cancer].

BACKGROUND AND OBJECTIVE: The aim of this study is to analyze the impact on the cough after radical systematic mediastinal lymphadenectomy and prevention of refractory cough with mediastinal fat to fill the residual cavity after radical systematic mediastinal lymphadenectomy. METHODS: Sixty patients clinically diagnosed of lung cancer were selected according to the adopt standardization, from January 2008 to December 2008. All of the patients were divided into two groups randomly: the filling-fat group and the non-filling-fat group. The surgical information such as operation duration time bleeding volume during operation, post-operation bleeding volume were recorded. After one month, FACT-L and LCQ were completed. RESULTS: There are no remarkably differences between the operation duration time, bleeding volume in operation and 1st postoperation day's drainage volume of the two groups. There's significant difference in the scores of cough at night after taking off the chest tube, as well as in the scores of LCQ after one month and in the scores of last items of FACT-L. CONCLUSIONS: Filling the fat of the mediastinal to cover the residual cavity left by completely systematic mediastinal lymphadenectomy can reduce the refractory cough after surgery, and can also improve the quality of the life. It has no effect on the the operation duration time, bleeding volume in operation and 1st post-operation day's drainage volume of the patients.

[The clinical value of routine preoperative surgical staging to mediastinal lymph nodes on lung cancer].

BACKGROUND AND OBJECTIVE: The aim of this study is the clinical value of preoperative routine surgical staging to mediastinal lymph nodes on lung cancer. METHODS: Seventy-six cases underwent lymph nodes biopsy with mediastinoscopy. The diagnostic efficacy of thoracic CT scan and mediastinoscopy on mediastinal lymph nodes metastasis were compared. RESULTS: The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of thoracic CT scan and mediastinoscopy on diagnosing mediastinal lymph nodes metastasis were 68.5%, 66.7%, 68.4%, 84.6%, 16.7% and 87.5%, 100%, 84.2%, 100%, 60%, respectively. CONCLUSION: Routine preoperative mediastinoscopy had obvious advantage compared with thoracic CT scan on mediastinal lymph nodes staging. The routine preoperative surgical staging of mediastinal lymph nodes on lung cancer had high clinical value.

[Progress of lymphadenectomy on lung cancer surgery].

Lymphatic metastasis is the main metastatic route for lung cancer, and is also one of the most important prognostic factors. Therefore, lymph node dissection has been an important procedure in standard lung cancer surgery. But so far, the mode and the extent of lymph node dissection during surgery are controversial for lung cancer in different pathological types, stages, or in different lobes. In this review, we summarize advances on the clinical significance, modes and extents of lymph node dissection during lung cancer surgery.

[Effects of MVP regimen on operation and cancer tisswes of Lung Cancer patients.].

BACKGROUND: Preoperative chemotherapy increases the difficulty and risk of patients' operation. The aim of this study is to analyze the change of thoracic tissue, study the influence of chemotherapy to operation, discuss the special aspects of surgical management and observe the pathological change of focus after chemotherapy. METHODS: 100 patients were chosen and randomly divided into two groups(operation first group, 50 cases; chemotherapy first group, 50 cases) . Some patient's pathological sections were observed to investigate focus morphological influence of preoperative chemotherapy and the clinical response rate were compared with pathological response rate. RESULTS: It was showed that preoperative chemotherapy conduced different degree thoracic tissue fibrosis. Data statistics demonstrated that there were no significance difference of the operation time, blood loss during operation and drainage volume in first day after operation between two groups. The preoperative chemotherapy increased the difficulty of operation because of tissue fibrosis and scarification, but the risk could be avoided by skillful operation. In first operation group, there were various pathological changes in tumor tissue and the pathological response rate was not completely accordance with the clinical response rate. The focus pathological response rate of two cycles chemotherapy was more higher than that of one cycle chemotherapy. CONCLUSIONS: IDO Chemotherapy increases the risks of operation. Surgeons carefulness and better skills during operation are the key points to avoid the hazards of surgery. Two preoperative chemotherapy cycles are more suitable for the patients.