Controllable scattering of a single photon inside a one-dimensional coupled resonator waveguide with second-order nonlinearity.

We note that most of the studies of the single photon scattering inside a one-dimensional coupled resonator waveguide are based on the waveguide coupling with the atom systems. In this paper, we will study the single photon scattering enabled by another system, i.e., the second-order nonlinearity, which can act as a single photon switch to control the single photon transmission and reflection inside the one-dimensional coupled resonator waveguide. The transmission rate is calculated to analyze the single-photon scattering properties. In addition, a more complicated second-order nonlinear form, i.e., three-wave mixing, is discussed to control single photon transmission inside the one-dimensional coupled resonator waveguide.

GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner.

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis. METHODS: The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism. RESULTS: GABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression. CONCLUSIONS: Overexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

The spectrum of viral pathogens in children with severe acute lower respiratory tract infection: A 3-year prospective study in the pediatric intensive care unit.

BACKGROUND: No comprehensive analysis is available on the viral etiology and clinical characterization among children with severe acute lower respiratory tract infection (SALRTI) in Southern China. METHODS: Cohort of 659 hospitalized children (2 months to 14 years) with SALRTI admitted to the Pediatric Intensive Care Unit (PICU) in the Guangzhou from May 2015 to April 2018 was enrolled in this study. Nasopharyngeal aspirate specimens or induced sputum were tested for eight categories respiratory viral targets. The viral distribution and its clinical characters were statistically analyzed. RESULTS: Viral pathogen was detected in 326 (49.5%) of children with SALRTI and there were 36 (5.5%) viral coinfections. Overall, the groups of viruses identified were, in descending order of prevalence: Influenza virus (IFV) (n = 94, 14.3%), respiratory syncytial virus (RSV) (n = 75, 11.4%), human rhinovirus (HRV) (n = 56, 8.5%), adenovirus (ADV) (n = 55, 8.3%), parainfluenza (PIV) (n = 47, 7.1%), human coronavirus (HCoV) (n = 15, 2.3%), human metapneumovirus (HMPV) (n = 14, 2.1%) and human bocavirus (HBoV) (n = 11, 1.7%). The positive rate in younger children (< 5 years) was significantly higher than the positive rate detected in elder children (> 5 years) (52.5% vs 35.1%, P = 0.001). There were clear seasonal peaks for IFV, RSV, HRV, ADV, PIV, and HMPV. And the individuals with different viral infection varied significantly in terms of clinical profiles. CONCLUSIONS: Viral infections are present in a consistent proportion of patients admitted to the PICU. IFV, RSV, HRV, and ADV accounted for more than two-thirds of all viral SALRTI. Our findings could help the prediction, prevention and potential therapeutic approaches of SALRTI in children.

The effect of quality of segmental bowel preparation on adenoma detection rate.

BACKGROUND: The effectiveness in surveillance colonoscopy largely depends on the quality of bowel preparation. We aimed to investigate the quality of bowel preparation segmentally and its effect on Adenoma Detection Rate (ADR) and Advanced Adenoma Detection Rate (AADR) at corresponding bowel segments. METHODS: This is a single-centered and cross-sectional study. A consecutive of 5798 patients who underwent colonoscopy examination were included. Bowel preparation was evaluated based on Bowel Bubble Scale (BBS) in general and Boston Bowel Preparation Scale (BBPS) in each segment (right side, transverse and left side of colon) and total BBPS scores. The quality of bowel preparation was correlated with ADR and AADR. RESULTS: Four thousand nine hundred forty colonoscopies (14,820 bowel segments) were included in the final analysis. In which 30.9% scored 3, 57.5% scored 2, 11.2% scored 1 and 0.4% scored 0 on basis of BBPS. For each score, ADR were 10.8, 7.7, 4.9 and 3.2%, respectively; whereas AADR were 4.5, 2.8,1.8 and 1.6% (P < 0.05). 36.9% of the colonoscopies showed presence of minimal bubbles and 34.3% with no bubble. For bowels without bubbles and with a large amount of bubbles, ADR were 28.3 and 20.0% respectively; and AADR were 13.3 and 7.1% respectively. CONCLUSIONS: Segmental bowels' cleanliness and the amount of bubbles in bowels significantly affect ADR and AADR. The better the bowel preparation at each segment is and the less bubbles in the bowel there are, the higher ADR and AADR we got. We suggest repeating colonoscopy if any segment of the bowel preparation is poor, or if there is more bubbles, even if the total score of BBPS indicates good or fair bowel preparation.

Efficacy and safety of using premedication with simethicone/Pronase during upper gastrointestinal endoscopy examination with sedation: A single center, prospective, single blinded, randomized controlled trial.

BACKGROUND AND AIM: To investigate the efficacy and safety of premedication with simethicone/Pronase during esophagogastroduodenoscopy (EGD) with sedation. METHODS: Six hundred and ten patients were randomly allocated to two groups based on type of premedication given. Premedication used in the control group was 10 mL lidocaine hydrochloride mucilage (LHM, N = 314) and premedication used in the intervention group was 80 mL simethicone/Pronase solution plus 10 mL lidocaine hydrochloride mucilage (SP/LHM, N = 296). EGD was done under sedation. Visibility scores, number of mucosal areas that needed cleansing, water consumption for cleansing, time taken for examination, diminutive lesions, pathological diagnosis, patients' gag reflex and oxygenation (pulse oximetry) were recorded. RESULTS: SP/LHM has significantly lower total visibility score than LHM (7.978 ± 1.526 vs 6.348 ± 1.097, P < 0.01). During the procedure, number of intragastric areas that needed cleansing and amount of water consumed were significantly less in the SP/LHM than in the LHM group (P < 0.01). In SP/LHM (P = 0.01), endoscopy procedure duration was significantly longer. Although there was no significant difference in rate of detection of diminutive lesions between LHM and SP/LHM, the endoscopist carried out more biopsies in SP/LHM. This led to a higher rate of diagnosis of atrophic gastritis (P = 0.014) and intestinal metaplasia (P = 0.024). There was no significant difference in gag reflex (P = 0.604) and oxygenation during the endoscopy procedure for either group of patients. CONCLUSION: Routine use of premedication with simethicone/Pronase should be recommended during EGD with sedation.

Allosteric therapies for lung cancer.

Allostery is a regulation at a distance by conveying information from one site to another and an intrinsic property of dynamic proteins. Allostery plays an essential role in receptor trafficking, signal transmission, controlled catalysis, gene turn on/off, or cell apoptosis. Allosteric mutations are considered as one of causes responsible for cancer development, leading to "allosteric diseases" by stabilizing an active or inactive conformation or changing the dynamic distribution of preexisting propagation pathways. The present article mainly focuses on the potential of allosteric therapies for lung cancer. Allosteric drugs may have several advantages over traditional drugs. The epidermal growth factor receptor mutations and signaling pathways downstream (such as PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways) were suggested to play a key role in lung cancer and considered as targets of allosteric therapy. Some allosteric inhibitors for lung cancer-specific targets and a series of preclinical trials of allosteric inhibitors for lung cancer have been developed and reported. We expect that allosteric therapies will gain more attentions to develop combinatorial strategies for lung cancer and metastasis.

Roles of CEACAM1 in cell communication and signaling of lung cancer and other diseases.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a broadly-expressed immunoglobulin-like cell adhesion molecule with a wide range of biological functions to regulate cell signaling. The present article mainly focuses on the role of CEACAM1 as a therapeutic target in lung diseases and discusses the potential of therapeutic strategies targeting CEACAM1. The article overviews the structure and its sub-types, biological function, and potential roles of CEACAM1 in lung diseases. Alterations of CEACAM1 expression and CEACAM1-S/CEACAM1-L ratio promote the growth and metastasis of non-small cell lung carcinoma (NSCLC). Moreover, CEACAM1 mediates bacterial adherence and transcellular transcytosis, resulting in the suppression of immune cell activities and inflammatory responses, which may trigger acute exacerbation of chronic obstructive pulmonary disease (AECOPD). CEACAM1 plays a critical role in the development of NSCLC and AECOPD and can be a diagnostic biomarker and therapeutic target in lung diseases.

IRAK2-NF-κB signaling promotes glycolysis-dependent tumor growth in pancreatic cancer.

BACKGROUND: Metabolic reprogramming has emerged as a core hallmark of cancer, and cancer metabolism has long been equated with aerobic glycolysis. Moreover, hypoxia and the hypovascular tumor microenvironment (TME) are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is imperative for tumor cell survival and proliferation. Here, we explored the impact of interleukin 1 receptor-associated kinase 2 (IRAK2) on the biological behavior of PDAC and investigated the underlying mechanism. METHODS: The expression pattern and clinical relevance of IRAK2 was determined in GEO, TCGA and Ren Ji datasets. Loss-of-function and gain-of-function studies were employed to investigate the cellular functions of IRAK2 in vitro and in vivo. Gene set enrichment analysis, Seahorse metabolic analysis, immunohistochemistry and Western blot were applied to reveal the underlying molecular mechanisms. RESULTS: We found that IRAK2 is highly expressed in PDAC patient samples and is related to a poor prognosis. IRAK2 knockdown led to a significant impairment of PDAC cell proliferation via an aberrant Warburg effect. Opposite results were obtained after exogenous IRAK2 overexpression. Mechanistically, we found that IRAK2 is critical for sustaining the activation of transcription factors such as those of the nuclear factor-κB (NF-κB) family, which have increasingly been recognized as crucial players in many steps of cancer initiation and progression. Treatment with maslinic acid (MA), a NF-κB inhibitor, markedly attenuated the aberrant oncological behavior of PDAC cells caused by IRAK2 overexpression. CONCLUSIONS: Our data reveal a role of IRAK2 in PDAC metabolic reprogramming. In addition, we obtained novel insights into how immune-related pathways affect PDAC progression and suggest that targeting IRAK2 may serve as a novel therapeutic approach for PDAC.

The Analysis of Anxiety and Depression in Different Stages of in vitro Fertilization-Embryo Transfer in Couples in China.

BACKGROUND: This study aimed to examine the differences in anxiety and depression between infertile Chinese couples in diverse stages of in vitro fertilization-embryo transfer (IVF-ET) and their relationship with the IVF-ET outcomes. METHODS: From February 2016 to December 2018, a total of 247 couples that were undergoing IVF-ET were randomly selected for this study. On the day they started their treatment (T1), the day human chorionic gonadotropin was administered (T2), and 4 days after the embryo transfer (T3), self-designed questionnaires, the Self-Rating Anxiety Scale, and the Self-Rating Depression Scale were completed to investigate anxiety and depression in different stages. RESULTS: Age had an effect on the anxiety and depression in women. Male infertility type and the cause of infertility had an effect on the anxiety and depression in men. The incidence of anxiety in women in the T1, T2, and T3 stages was 29.96%, 44.94%, and 17.81%, respectively. The anxiety scores of women were 46.14 ± 8.37, 50.83 ± 8.50, and 44.09 ± 8.17, respectively, which were significantly higher than those of men (p < 0.05). The anxiety score in stage T2 was the highest in women, and the depression score of women in stage T1 was the highest. The incidence of anxiety in men in the T1, T2, and T3 stages was 20.65%, 8.50%, and 6.07%, respectively. The incidence of anxiety was not significantly different in diverse stages (p > 0.05), and the same result was obtained for the incidence of depression. The anxiety and depression scores of the infertile couples in different stages were not related to the outcome of IVF-ET. CONCLUSION: The incidence of anxiety and depression in infertile couples in diverse stages of IVF-ET is different, especially in women, and the anxiety and depression of infertile couples in the process of IVF-ET may not be related to the outcome of assisted pregnancy.

Invasive Blood Pressure Measurement and In-hospital Mortality in Critically Ill Patients With Hypertension.

Background: Invasive blood pressure (IBP) measurement is common in the intensive care unit, although its association with in-hospital mortality in critically ill patients with hypertension is poorly understood. Methods and Results: A total of 11,732 critically ill patients with hypertension from the eICU-Collaborative Research Database (eICU-CRD) were enrolled. Patients were divided into 2 groups according to whether they received IBP. The primary outcome in this study was in-hospital mortality. Propensity score matching (PSM) and inverse probability of treatment weighing (IPTW) models were used to balance the confounding covariates. Multivariable logistic regression was used to evaluate the association between IBP measurement and hospital mortality. The IBP group had a higher in-hospital mortality rate than the no IBP group in the primary cohort [238 (8.7%) vs. 581 (6.5%), p < 0.001]. In the PSM cohort, the IBP group had a lower in-hospital mortality rate than the no IBP group [187 (8.0%) vs. 241 (10.3%), p = 0.006]. IBP measurement was associated with lower in-hospital mortality in the PSM cohort (odds ratio, 0.73, 95% confidence interval, 0.59-0.92) and in the IPTW cohort (odds ratio, 0.81, 95% confidence interval, 0.67-0.99). Sensitivity analyses showed similar results in the subgroups with high body mass index and no sepsis. Conclusions: In conclusion, IBP measurement was associated with lower in-hospital mortality in critically ill patients with hypertension, highlighting the importance of IBP measurement in the intensive care unit.

CD74 promotes perineural invasion of cancer cells and mediates neuroplasticity via the AKT/EGR-1/GDNF axis in pancreatic ductal adenocarcinoma.

Perineural invasion (PNI) is a common feature of pancreatic ductal adenocarcinoma (PDAC) and is one of the important causes of local recurrence in resected pancreatic cancer, but the molecular mechanism remains largely unexplored. Here, we used immunohistochemistry staining to determine the expression of CD74. Then the in vivo PNI model, in vitro neuroplasticity assay, cell proliferation assay, wound healing and Transwell-based invasion assay were performed to examine the function of CD74 in pancreatic cancer cell lines. ChIP assay and Luciferase reporter assay were used to illustrate the mechanism underlying CD74 induced GDNF expression. We confirmed that the expression level of CD74 was an independent predictor of PNI and poor prognosis for PDAC. Moreover, we found that upregulation of CD74 on PDAC enhanced its migration and invasive capabilities and potentiated the secretion of neurotrophic factor GDNF to promote the neuroplasticity. Mechanistically, CD74 promoted GDNF production via the AKT/EGR-1/GDNF axis in PDAC. Taken together, our findings suggest a supportive role of CD74 in the PNI of PDAC, and deepen our understanding of how cancer cells promote neuroplasticity in the microenvironment of PDAC.

SF3B1 mutation in pancreatic cancer contributes to aerobic glycolysis and tumor growth through a PP2A-c-Myc axis.

Hot spot gene mutations in splicing factor 3b subunit 1 (SF3B1) are observed in many types of cancer and create abundant aberrant mRNA splicing, which is profoundly implicated in tumorigenesis. Here, we identified that the SF3B1 K700E (SF3B1K700E ) mutation is strongly associated with tumor growth in pancreatic ductal adenocarcinoma (PDAC). Knockdown of SF3B1 significantly retarded cell proliferation and tumor growth in a cell line (Panc05.04) with the SF3B1K700E mutation. However, SF3B1 knockdown had no notable effect on cell proliferation in two cell lines (BxPC3 and AsPC1) carrying wild-type SF3B1. Ectopic expression of SF3B1K700E but not SF3B1WT in SF3B1-knockout Panc05.04 cells largely restored the inhibitory role induced by SF3B1 knockdown. Introduction of the SF3B1K700E mutation in BxPC3 and AsPC1 cells also boosted cell proliferation. Gene set enrichment analysis demonstrated a close correlation between SF3B1 mutation and aerobic glycolysis. Functional analyses showed that the SF3B1K700E mutation promoted tumor glycolysis, as evidenced by glucose consumption, lactate release, and extracellular acidification rate. Mechanistically, the SF3B1 mutation promoted the aberrant splicing of PPP2R5A and led to the activation of the glycolytic regulator c-Myc via post-translational regulation. Pharmacological activation of PP2A with FTY-720 markedly compromised the growth advantage induced by the SF3B1K700E mutation in vitro and in vivo. Taken together, our data suggest a novel function for SF3B1 mutation in the Warburg effect, and this finding may offer a potential therapeutic strategy against PDAC with the SF3B1K700E mutation.

Longitudinal Analysis of Risk Factors for Clinical Outcomes of Enterobacteriaceae Meningitis/Encephalitis in Post-Neurosurgical Patients: A Comparative Cohort Study During 2014-2019.

PURPOSE: Our study is a retrospective observational study conducted in one of the largest clinical centers of neurosurgery in China. We aimed to investigate the antimicrobial susceptibility patterns of the Enterobacteriaceae isolates responsible for nosocomial meningitis/encephalitis in post-neurosurgical patients. Meanwhile, we tried to evaluate the risk factors for mortality following Enterobacteriaceae meningitis/encephalitis. PATIENTS AND METHODS: Medical data on clinical characteristics, antibiotic susceptibilities, and mortality were reviewed until patients' discharge or death in the hospital. Data for a total of 164 cerebrospinal fluid (CSF) infection cases due to Enterobacteriaceae after neurosurgery were collected between January 2014 and November 2019 in order to identify risk factors affecting the outcome. Kaplan-Meier survival analysis and multivariable Cox proportional hazard models were applied. RESULTS: In this study, a total of 2416 neurosurgical meningitis/encephalitis cases were reported between 2014 and 2019. Enterobacteriaceae accounted for 7.3% (176/2416) of all the bacterial infections. Of them, 164 Enterobacteriaceae isolates were available to divide into two groups according to the final outcome of whether the patient died or survived. In total, 38 patients died (23.2%) and 126 patients survived (76.8%). The most frequent infecting species was Klebsiella pneumoniae (47.0%, 77/164). Fourteen-day and 30-day mortality rates were 7.9% (13/164) and 15.2% (25/164). Kaplan-Meier survival analysis revealed that the risk factors of Enterobacteriaceae meningitis/encephalitis that resulted in poor outcomes included comorbidities, Glasgow Coma Scale (GCS) score, sepsis, intensive care unit (ICU) admission, extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, and ventilation. A GCS score of less than or equal to 8 (P=0.04, HR 2.562) was identified to be a significant risk factor for mortality according to the multivariable Cox proportional hazards model. CONCLUSION: In-hospital mortality caused by Enterobacteriaceae meningitis/encephalitis in neurosurgery was high. A GCS score of ≤8 was an independent risk factor for mortality following Enterobacteriaceae meningitis/encephalitis in post-neurosurgical patients.

Perineural Invasion Reprograms the Immune Microenvironment through Cholinergic Signaling in Pancreatic Ductal Adenocarcinoma.

Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8+ T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8+ T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8+ T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8+ T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion-triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8+ T-cell infiltration and a reduced Th1/Th2 ratio. SIGNIFICANCE: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion.

Substrate elasticity regulates vascular endothelial growth factor A (VEGFA) expression in adipose-derived stromal cells: Implications for potential angiogenesis.

Adipose-derived stromal cells (ASCs) have potential in bioengineering angiogenesis due to their paracrine role in supporting endothelial tubulogenesis and vascular network formation. However, the precise mechanism of the inner angiogenic capacity of ASCs determined by the biophysical properties of the extracellular matrix needs to be further elucidated. In the current study, we fabricated two silicon-based elastomer polydimethylsiloxane (PDMS) substrates with different stiffnesses (stiff substrate, E = 195 kPa and soft substrate, E = 15 kPa) and found there were cytoskeletal changes in ASCs in response to different substrate stiffnesses. We then showed the expression of vinculin in focal adhesion plaques was enhanced and the nuclear translocation of ß-catenin signaling was increased in ASCs on the stiff substrate relative to those on the soft substrate. We next used bioinformatics and found the downstream proteins of ß-catenin signaling had binding sites in the promoter of vascular endothelial growth factor A (VEGFA), which is responsible for angiogenesis; then, we further confirmed the enhanced endogenous VEGFA expression in ASCs on the stiff substrate relative to that on the soft substrate. Finally, by using ectogenic VEGFA, we showed the stiff substrate could promote angiogenesis of ASCs in the form of more ring-like formations in 2D and vessel-like structure formations in 3D under VEGFA induction compared to that of the soft substrate. This study not only indicates the inner angiogenic capacity of ASCs but also elucidates the influence of substrate elasticity on ASC differentiation in bioengineering angiogenesis.

NFATc1 is a Necessary Transcription Factor in Polarisation of T Helper Type 2 Lymphocytes Induced by Thymic Stromal Lymphopoietin.

Thymic stromal lymphopoietin (TSLP) activates lung dendritic cells (DCs) to promote a T helper type 2 lymphocyte (Th2) response in animal models. However, the mechanism behind this process remains unclear. In this study, we investigate the role of a nuclear factor for activated T-cells 1 (NFATc1) in the TSLP-induced polarisation towards a Th2 response. A cluster of differentiated (CD)14+ peripheral blood mononuclear cells (PBMCs) and naïve T cells were isolated from blood collected from healthy human volunteers, and TSLP was used to induce DC maturation. The effects of TSLP-DCs and treatments with FK506, an NFATc1 inhibitor, on naïve T cell differentiation were monitored by measuring the interleukin (IL)-4, IL-13, and interferon-γ (IFN-γ) expression levels. In addition, the mRNA levels of T-box expression in T cells (T-bet), GATA binding protein 3 (GATA-3), TSLP, and NFATc1 were measured for the same purpose. IL-4, IL-13, and mRNA levels of GATA-3 and NFATc1 significantly increased with TSLP-DC induction (P<0.01), indicating polarization towards the Th2 response. These changes were reversed by treatment with FK506 (P<0.01). Our findings suggest that NFATc1 plays a key role in the TSLP-induced differentiation of T cells to Th2, and NFATc1 is a potential therapeutic target for treating allergic diseases.

Mechanisms of brain damage caused by inorganic fluoride using proteomics-based techniques / 环境与职业医学

Background Chronic excessive exposure to fluoride can cause damage to the central nervous system and a certain degree of learning and memory impairment. However, the associated mechanism is not yet clear and further exploration is needed. Objective Using 4D unlabelled quantitative proteomics techniques to explore differentially expressed proteins and their potential mechanisms of action in chronic excessive fluoride exposure induced brain injury. Methods Twenty-four SPF-grade adult SD rats, half male and half male, were selected and divided into a control group and a fluoride group by random number table method, with 12 rats in each group. Among them, the control group drank tap water (fluorine content<1 mg·L−1), the fluoride group drank sodium fluoride solution (fluorine content 10 mg·L−1), and both groups were fed with ordinary mouse feed (fluoride content<0.6 mg·kg−1). After 180 d of feeding, the SD rats were weighed, and then part of the brain tissue was sampled for pathological examination by hematoxylin-eosin (HE) staining and Nissl staining. The rest of the brain tissue was frozen and stored at −80 ℃. Three brain tissue samples from each group were randomly selected for proteomics detection. Differentially expressed proteins were screened and subcellular localization analysis was performed, followed by Gene Ontology (GO) function analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, cluster analysis, and protein-protein interaction analysis. Finally, Western blotting was used to detect the expression levels of key proteins extracted from the brain tissue samples. Results After 180 d of feeding, the average weight of the rats in the fluoride group was significantly lower than that in the control group (P<0.05). The brain tissue stained with HE showed no significant morphological changes in the cerebral cortex of the fluoride treated rats, and neuron loss, irregular arrangement of neurons, eosinophilic changes, and cell body pyknosis were observed in the hippocampus. The Nissl staining results showed that the staining of neurons in the cerebral cortex and hippocampus of rats exposed to fluoride decreased (Nissl bodies decreased). The proteomics results showed that a total of 6927 proteins were identified. After screening, 206 differentially expressed proteins were obtained between the control group and the fluoride group, including 96 up-regulated proteins and 110 down-regulated proteins. The differential proteins were mainly located in cytoplasm (30.6%), nucleus (27.2%), mitochondria (13.6%), plasma membrane (13.6%), and extracellular domain (11.7%). The GO analysis results showed that differentially expressed proteins mainly participated in biological processes such as iron ion transport, regulation of dopamine neuron differentiation, and negative regulation of respiratory burst in inflammatory response, exercised molecular functions such as ferrous binding, iron oxidase activity, and cytokine activity, and were located in the smooth endoplasmic reticulum membrane, fixed components of the membrane, chloride channel complexes, and other cellular components. The KEGG significantly enriched pathways included biosynthesis of secondary metabolites, carbon metabolism, and microbial metabolism in diverse environments. The results of differential protein-protein interaction analysis showed that the highest connectivity was found in glucose-6-phosphate isomerase (Gpi). The expression level of Gpi in the brain tissue of the rats in the fluoride group was lower than that in the control group by Western blotting (P<0.05). Conclusion Multiple differentially expressed proteins are present in the brain tissue of rats with chronic fluorosis, and their functions are related to biosynthesis of secondary metabolites, carbon metabolism, and microbial metabolism in diverse environments; Gpi may be involved in cerebral neurological damage caused by chronic overdose fluoride exposure.

SFRP4 is a prognostic marker and correlated with Treg cell infiltration in pancreatic ductal adenocarcinoma.

Secreted Frizzled-Related Protein 4 (SFRP4), a member of secreted frizzled-related protein family, has been found as a vital modulator in cell proliferation, cell self-renew and apoptosis through Wnt signaling transduction pathway. In the present study, we re-analyzed the expression pattern of SFRPs in Gene Expression Omnibus (GEO) datasets and evaluated the expression of SFRP4 at protein level in both KrasG12D/+; Trp53R172H/+; Pdx1-Cre; (KPC) mice and human pancreatic ductal adenocarcinoma (PDAC) tissue. We found that the expression of SFRP4 increased gradually in PanINs and PDAC lesions in KPC mice and high expression of SFRP4 was much more common in tumor lesions compared to the adjacent non-tumor tissues. Then we performed Kaplan-Meier survival and Cox regression analysis and found that high expression of SFRP4 in the serum and tumor lesions predicted poor prognosis for pancreatic cancer patients. Furthermore, we demonstrated that SFRP4 positively correlated with FOXP3+ Treg cells infiltration while the down-regulation of SFRP4 in tumor cells impaired the production of cytokines and the recruitments of T cells. This study suggested that SFRP4 can be a novel prognostic biomarker and potential therapeutic target for pancreatic cancer.

Targeting Purinergic Receptor P2Y2 Prevents the Growth of Pancreatic Ductal Adenocarcinoma by Inhibiting Cancer Cell Glycolysis.

PURPOSE: Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment. EXPERIMENTAL DESIGN: Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression. RESULTS: P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice. CONCLUSIONS: These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.

Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas.

BACKGROUND: Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas (G-NECs) remains unknown. AIM: To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant. METHODS: We investigated the expression of PD-L1 on tumor cells and PD-1+, CD8+, and FOXP3+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR. RESULTS: Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43 G-NECs, 21 (48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival (OS). The high expression of PD-L1 was correlated with abundant PD-1+ tumor infiltrating lymphocytes (TILs) instead of CD8+ TILs and FOXP3+ regulatory T cells (Tregs). Our analysis also suggested that the infiltration of CD8+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance (P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without. CONCLUSION: Our data demonstrated for the first time that high expression of PD-L1 in G-NECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in G-NECs.