Analysis of prognostic value of lactate metabolism-related genes in ovarian cancer based on bioinformatics.

BACKGROUND: Recent studies have provided evidence supporting the functional role and mechanism of lactate in suppressing anticancer immunity. However, there is no systematic analysis of lactate metabolism-related genes (LMRGs) and ovarian cancer (OV) prognosis. RESULTS: Six genes (CCL18, CCND1, MXRA5, NRBP2, OLFML2B and THY1) were selected as prognostic genes and a prognostic model was utilized. Kaplan-Meier (K-M) and Receiver Operating Characteristic (ROC) analyses were further performed and indicated that the prognostic model was effective. Subsequently, the neoplasm_cancer_status and RiskScore were determined as independent prognostic factors, and a nomogram was established with relatively accurate forecasting ability. Additionally, 2 types of immune cells (Central memory CD8 T cell and Immature B cell), 4 types of immune functions (APC co inhibition, DCs, Tfh and Th1 cells), 9 immune checkpoints (BTLA, CTLA4, IDO1, LAG3, VTCN1, CXCL10, CXCL9, IFNG, CD27) and tumor immune dysfunction and exclusion (TIDE) scores were significantly different between risk groups. The expression of 6 genes were verified by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and the expression of 6 genes were higher in the high-grade serous carcinoma (HGSC) samples. CONCLUSION: A prognostic model related to lactate metabolism was established for OV based on six genes (CCL18, CCND1, MXRA5, NRBP2, OLFML2B and THY1) that could provide new insights into therapy.

TGFß1-induced hedgehog signaling suppresses the immune response of brain microvascular endothelial cells elicited by meningitic Escherichia coli.

BACKGROUND: Meningitic Escherichia coli (E. coli) is the major etiological agent of bacterial meningitis, a life-threatening infectious disease with severe neurological sequelae and high mortality. The major cause of central nervous system (CNS) damage and sequelae is the bacterial-induced inflammatory storm, where the immune response of the blood-brain barrier (BBB) is crucial. METHODS: Western blot, real-time PCR, enzyme-linked immunosorbent assay, immunofluorescence, and dual-luciferase reporter assay were used to investigate the suppressor role of transforming growth factor beta 1 (TGFß1) in the immune response of brain microvascular endothelial cells elicited by meningitic E. coli. RESULT: In this work, we showed that exogenous TGFß1 and induced noncanonical Hedgehog (HH) signaling suppressed the endothelial immune response to meningitic E. coli infection via upregulation of intracellular miR-155. Consequently, the increased miR-155 suppressed ERK1/2 activation by negatively regulating KRAS, thereby decreasing IL-6, MIP-2, and E-selectin expression. In addition, the exogenous HH signaling agonist SAG demonstrated promising protection against meningitic E. coli-induced neuroinflammation. CONCLUSION: Our work revealed the effect of TGFß1 antagonism on E. coli-induced BBB immune response and suggested that activation of HH signaling may be a potential protective strategy for future bacterial meningitis therapy. Video Abstract.

BRD9-mediated chromatin remodeling suppresses osteoclastogenesis through negative feedback mechanism.

Bromodomain-containing protein 9 (BRD9), a component of non-canonical BAF chromatin remodeling complex, has been identified as a critical therapeutic target in hematological diseases. Despite the hematopoietic origin of osteoclasts, the role of BRD9 in osteoclastogenesis and bone diseases remains unresolved. Here, we show Brd9 deficiency in myeloid lineage enhances osteoclast lineage commitment and bone resorption through downregulating interferon-beta (IFN-ß) signaling with released constraint on osteoclastogenesis. Notably, we show that BRD9 interacts with transcription factor FOXP1 activating Stat1 transcription and IFN-ß signaling thereafter. Besides, function specificity of BRD9 distinguished from BRD4 during osteoclastogenesis has been evaluated. Leveraging advantages of pharmacological modulation of BRD9 and flexible injectable silk fibroin hydrogel, we design a local deliver system for effectively mitigating zoledronate related osteonecrosis of the jaw and alleviating acute bone loss in lipopolysaccharide-induced localized aggressive periodontitis. Overall, these results demonstrate the function of BRD9 in osteoclastogenesis and its therapeutic potential for bone diseases.

Evolutionary Analysis and Functional Identification of Clock-Associated PSEUDO-RESPONSE REGULATOR (PRRs) Genes in the Flowering Regulation of Roses.

Pseudo-response regulators (PRRs) are the important genes for flowering in roses. In this work, clock PRRs were genome-wide identified using Arabidopsis protein sequences as queries, and their evolutionary analyses were deliberated intensively in Rosaceae in correspondence with angiosperms species. To draw a comparative network and flow of clock PRRs in roses, a co-expression network of flowering pathway genes was drawn using a string database, and their functional analysis was studied by silencing using VIGS and protein-to-protein interaction. We revealed that the clock PRRs were significantly expanded in Rosaceae and were divided into three major clades, i.e., PRR5/9 (clade 1), PRR3/7 (clade 2), and TOC1/PRR1 (clade 3), based on their phylogeny. Within the clades, five clock PRRs were identified in Rosa chinensis. Clock PRRs had conserved RR domain and shared similar features, suggesting the duplication occurred during evolution. Divergence analysis indicated the role of duplication events in the expansion of clock PRRs. The diverse cis elements and interaction of clock PRRs with miRNAs suggested their role in plant development. Co-expression network analysis showed that the clock PRRs from Rosa chinensis had a strong association with flowering controlling genes. Further silencing of RcPRR1b and RcPRR5 in Rosa chinensis using VIGS led to earlier flowering, confirming them as negative flowering regulators. The protein-to-protein interactions between RcPRR1a/RcPRR5 and RcCO suggested that RcPRR1a/RcPRR5 may suppress flowering by interfering with the binding of RcCO to the promoter of RcFT. Collectively, these results provided an understanding of the evolutionary profiles as well as the functional role of clock PRRs in controlling flowering in roses.

The relative difficulty of negations of conjunctions and disjunctions-a mental model perspective.

A current issue in propositional reasoning is which of negated disjunctions and conjunctions are more difficult to understand. Using the possibility generation and evaluation tasks, we investigated how people make possibility inferences from negated compound assertions such as not (A and B) and not (A or B). We derive 4 different strategies of negation from the mental model theory (the enumerative negation, the eliminative negation, the element negation, and the clause negation) to predict the relative difficulty of possibility inference from not (A and B) and not (A or B). The results of three experiments convergently demonstrate that possibility inference from not (A or B) is harder than that from not (A and B). Moreover, an interpretation of negation as the complement of the set of possibilities allowed by a compound assertion is in line with the results of not (A and B) rather than not (A or B). The overall results favor the clause negation strategy over the other strategies.

MiR-139-5p-ZEB1 is a Molecular Regulator of Growth, Invasion, and Epithelial-to-Mesenchymal Transition of Cervical Cancer.

OBJECTIVE: To verify that miR-139-5p-zinc finger E-box-binding homeobox 1 (ZEB1) is a molecular regulator of the biological function and epithelial-mesenchymal transition (EMT) of cervical cancer (CC) cells. METHODS: Cancerous tissues, corresponding paracancerous tissues, and serum were sampled from patients with CC. MiR-139-5p and ZEB1 in tissue specimens, serum specimens, and purchased CC cell lines were quantified, and Pearson correlation coefficient was adopted for correlation analysis of miR-139-5p in clinical specimens. Receiver operating characteristic (ROC) curves were adopted to analyze the diagnostic value of miR-139-5p and ZEB1 for CC. The expression of genes in CC cells was changed by transfection. The proliferation, colony formation, invasion, and apoptosis of cells were determined, and the protein level of EMT markers (N-cadherin, vimentin, and E-cadherin) was also quantified. Moreover, the targeting relationship between miR-139-5p and ZEB1 was determined. RESULTS: Our data showed that the expression of miR-139-5p decreased greatly in CC tissues, and it also significantly decreased in the serum, while the expression of serum ZEB1 was opposite. In addition, the miR-139-5p expression in CC tissues was positively correlated with that in serum, while serum miR-139-5p was negatively correlated with serum ZEB1. The areas under the curves (AUCs) of the two for identifying CC were 0.923 and 0.890, respectively. Both up-regulation of miR-139-5p and down-regulation of ZEB1 suppressed the colony formation, proliferation, invasion, and EMT of CC cells, and intensified their apoptosis. Moreover, miR-139-5p negatively regulated the transcription of ZEB1, and down-regulation of the former could reverse the molecular regulatory effects of down-regulating ZEB1 on the above biological behaviors of CC cells. CONCLUSION: The above data imply that miR-139-5p-ZEB1 axis may be the key to curbing the progression of CC.

Reactive oxygen species mediate anlotinib-induced apoptosis via activation of endoplasmic reticulum stress in pancreatic cancer.

Anlotinib (AL3818), a novel multi-targeted receptor tyrosine kinase inhibitor, has recently been proven to be an antitumour drug. This study aimed to explore the antitumour effect of anlotinib and its underlying molecular mechanisms in human pancreatic cancer (PC) cells. The anti-proliferative effect of anlotinib for three PC cell lines was validated using CCK-8, colony formation and EdU detection assays. Cell cycle, cell apoptosis, and reactive oxygen species (ROS) detection assays, a PC xenograft model and immunohistochemistry were performed to elucidate the mechanisms by which anlotinib induced tumour lethality in vitro and in vivo. These results demonstrated that anlotinib inhibited proliferation, induced G2/M phase arrest and triggered apoptosis in PC cell lines. Anlotinib induced PC's apoptosis through the accumulation of ROS which activated the endoplasmic reticulum (ER) stress via PERK/p-eIF2α/ATF4 pathway. Furthermore, we demonstrated that the expression level of Nrf2, an antioxidant protein, increased with anlotinib treatment. Nrf2 knockdown enhanced the pro-apoptotic effect of anlotinib and the expression of the PERK/p-eIF2α/ATF4 pathway. The in vivo results suggested that suppressing Nrf2 improved the antitumour effect of anlotinib on PC cells. These data indicated that the apoptotic effect of anlotinib on PC cells was induced by ER stress via the accumulation of ROS. In the future, anlotinib combined with an Nrf2 inhibitor may provide a new therapeutic strategy for the treatment of human PC.

A situation-modulated minimal change account for causal inferences about causal networks.

Although causal Bayes networks are applicable to examining causal inferences about different static objects and about a changing object with different states, previous studies investigated the former, but not the latter. We propose a situation-modulated minimal change account for causal inferences. It predicts that dynamic situations are more likely to elicit minimal revisions on causal networks and adherence to the Markov assumption than static situations. Two experiments were conducted to investigate qualitative causal inferences about causal networks with binary and numerical variables, respectively. It was found that qualitative causal inferences were more likely to adhere to the Markov assumption in dynamic situations than in static situations. This finding supports the situation-modulated minimal change account rather than the other alternative accounts. We conclude that dynamic situations are more likely to elicit minimal revisions on causal networks and adherence to the Markov assumption than static situations. This conclusion is beyond the previous predominant view that causal inferences are apt to violate the Markov assumption.

The patterns of exercise-induced ß-endorphin expression in the central nervous system of rats.

Exercise at different intensities is able to induce different physical and psychological statuses of the subjects. The ß-endorphin (ß-EP) in central nervous system is thought to play an important role in physical exercise. However, its expression patterns and physiological effects in the central nuclei under different exercise states are not well understood. Five-week old male Sprague-Dawley rats were randomly divided into two groups of 21 each: Control and Exercise. Control rats were sedentary while Exercise rats were arranged to run on a treadmill (5-week adapting or moderate exercise and 2-week high-intensity exercise). Seven rats were taken from each group at day33, day42 and day49 for examination of blood biochemical parameters (lactate, Lac; blood urea nitrogen, BUN; glucose) and for detection of nuclei ß-EP level with immunohistochemistry. The results showed that Lac and BUN levels were significant increased after the high intensity exercise. The five-week exercise caused a significantly increased ß-EP in caudate putamen (CPu), amygdala, paraventricular thalamic nucleus (PVT), ventromedial hypothalamus nucleus (VMH) and gigantocellular reticular nucleus (Gi). The high intensity exercise induced an elevated ß-EP in CPu and nucleus of the solitary tract (Sol), but a decreased ß-EP in globus pallidus (GP). Compared with Control, exercise rats showed an elevated ß-EP in CPu, PVT, VMH, accumbens nucleus, Gi and Sol, and a decreased ß-EP in GP at day49. The ß-EP levels in acurate nucleus, periadueductal gray and parabrachial nucleus were not changed at day33, 42 and 49. In conclusion, ß-EP levels in different nuclei changed under the moderate and high intensity exercises, which may contribute to modifying exercise-produced psychological and physiological effects.

Withdrawn: The radiosynthesis of novel PI3K inhibitor, 8-ethoxy-2-(4-[18 F] fluorophenyl)-3-nitro-2H-chromene (18 F-EFPNC).

Withdrawal: Jianfeng Liu et al. 'The radiosynthesis of novel PI3K inhibitor, 8-ethoxy-2-(4-[18 F]fluorophenyl)-3-nitro-2H-chromene (18 F-EFPNC)', Journal of Labelled Compounds and Radiopharmaceuticals (https://doi.org/10.1002/jlcr.3524). The above article, published online on 30 May 2017 on Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the journal's Editor-in-Chief Committee, and John Wiley & Sons Ltd. The withdrawal has been agreed as it was not possible to complete corrections and finalise the article.

Down-regulation of long non-coding RNA MEG3 suppresses osteogenic differentiation of periodontal ligament stem cells (PDLSCs) through miR-27a-3p/IGF1 axis in periodontitis.

OBJECTIVE: This study aimed to investigate the roles of long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) in osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in periodontitis. METHODS: Differentially expressed lncRNAs and mRNAs between periodontitis periodontal ligament tissues and healthy periodontal ligament tissues were selected out using R project. PDLSCs were identified using flow cytometry. Western blot was employed to detect pathway relative proteins. Besides, targeted relationships between lncRNA and miRNA, as well as miRNA and mRNA were verified by dual luciferase reporter gene assay. Osteogenic differentiation of PDLSCs was assessed by alkaline phosphatase (ALP) staining and Alizarin Red Staining (ARS). Markers for osteoblast (Runx2, Osterix, Osteocalcin, Colla1) were detected using western blot. RESULTS: LncRNA MEG3 and IGF1 were both down-regulated, while miR-27a-3p was up-regulated in periodontitis samples compared with healthy samples. Overexpression of MEG3 promoted osteogenic differentiation by enhancing expression of IGF1 yet suppressing expression of miRNA-27a-3p. Meanwhile, the results of ALP and ARS staining indicated that up-regulation of lncRNA MEG3 or IGF1 promoted osteogenic differentiation in PDLSCs, which could be reversed with up-regulation of miRNA-27a-3p. CONCLUSION: Down-regulation of MEG3 suppressed osteogenic differentiation of PDLSCs through miR-27a-3p/IGF1 axis in periodontitis.

Thymosin Beta 4 Is Involved in the Development of Electroacupuncture Tolerance.

Background: Electroacupuncture (EA) tolerance, a negative therapeutic effect, is a gradual decline in antinociception because of its repeated or prolonged use. This study aims to explore the role of thymosin beta 4 (Tß4), having neuro-protection properties, in EA tolerance (EAT). Methods: Rats were treated with EA once daily for eight consecutive days to establish EAT, effect of Tß4 on the development of EAT was determined through microinjection of Tß4 antibody and siRNA into the cerebroventricle. The mRNA and protein expression profiles of Tß4, opioid peptides (enkephalin, dynorphin and endorphin), and anti-opioid peptides (cholecystokinin octapeptide, CCK-8 and orphanin FQ, OFQ), and mu opioid receptor (MOR) and CCK B receptor (CCKBR) in the brain areas (hypothalamus, thalamus, cortex, midbrain and medulla) were characterized after Tß4 siRNA was administered. Results: Tß4 levels were increased at day 1, 4, and 8 and negatively correlated with the changes of tail flick latency in all areas. Tß4 antibody and siRNA postponed EAT. Tß4 siRNA caused decreased Tß4 levels in all areas, which resulted in increased enkephalin, dynorphin, endorphin and MOR levels in most measured areas during repeated EA, but unchanged OFQ, CCK-8, and CCKBR levels in most measured areas. Tß4 levels were negatively correlated with enkephalin, dynorphin, endorphin, or MOR levels in all areas except medulla, while positively correlated with OFQ and CCK-8 levels in some areas. Conclusion: These results confirmed Tß4 facilitates EAT probably through negatively changing endogenous opioid peptides and their receptors and positively influencing anti-opioid peptides in the central nervous system.

Effect of temperature on the occurrence and distribution of colorado potato beetle (Coleoptera: Chrysomelidae) in China.

Colorado potato beetle, Leptinotarsa decemlineata (Say), is the most destructive pest of potato in many countries of the world. It first invaded China from Kazakhstan in 1990s and now is a major pest of potato in many areas of Xinjiang Uygur Autonomous Region (Xinjiang). The objective of this study was to determine the effect of temperature on the spread of Colorado potato beetle in China after its invasion. Cold temperature in winter (December) and high temperature in summer (July) were analyzed in accordance with the absence and presence of Colorado potato beetle in Xinjiang. The boundary between the absence and presence of Colorado potato beetle in Xinjiang nearly coincided with the -8°C isotherm of monthly mean minimum temperature in winter. The stress of the low temperature in winter for Colorado potato beetle basically disappeared in the southeastern Hexi Corridor in Gansu Province of China, suggesting that the Hexi Corridor is the best channel to prevent any long-distance invasions of Colorado potato beetle into the Central Plains region. However, in Turpan City in northeastern Xinjiang, the extremely hot weather in the summer prevents the local colonization of Colorado potato beetle. Furthermore, according to our monitoring, high temperature in summer also limited Colorado potato beetle to diffuse eastward through Turpan. Results of this study suggest that it is essential to strengthen inspection and quarantine measures to prevent any artificial transmissions of Colorado potato beetle spreading eastward and thus to ensure the sustainable production of potato and other Solanaceae crops in northwest regions of China.

Significant effects of lymph and blood vascular invasion on the prognosis of early-stage cervical squamous cell carcinoma.

AIM: In the past 10 years, therapeutic advances have led to improved short-term efficacy for cervical carcinoma; however, the 5-year survival rate was not significantly enhanced. To investigate the effects of blood vessel invasion (BVI) and lymph vessel invasion (LVI) on the prognosis of early-stage cervical squamous carcinoma, we carried out immunohistochemical staining to distinguish blood and lymph vessels. METHODS: Specimens from 111 IB-stage or IIA-stage cervical squamous carcinoma cases were examined for BVI and LVI by streptavidin-peroxidase immunohistochemistry using CD-34 and D2-40 monoclonal antibodies. Data were analyzed with SPSS version 13.0 (SPSS, Chicago, IL, USA) statistical software. The survival rate and survival curve were derived by using the life table method and the Kaplan-Meier method, respectively. Multivariate prognosis analysis was conducted with Cox regression model, and prognosis was evaluated by measuring overall survival (OS) and progression-free survival (PFS). RESULTS: BVI/LVI double positivity was an independent prognostic factor for both OS and PFS, whereas lymph node metastasis and surgical margin positivity affected only PFS. Patients inflicted with either BVI or LVI displayed no significant difference in survival time. Lymph-vascular space invasion (LVSI), referring to blood and/or lymph vessel invasion correlated with lymph node metastasis, surgical margin positivity, depth of cervical interstitial invasion, squamous cell carcinoma antigen (SccAg) and age. LVSI was a risk factor for both recurrence (P = 0.013, relative risk 3.060) and death (P = 0.005, relative risk 4.512). Post-operation auxiliary external radiation did not improve survival for LVSI-positive cases. CONCLUSION: BVI/LVI double positivity constitutes an independent prognostic factor for early-stage cervical squamous carcinoma.

Influence of lymph vascular space invasion on prognosis of patients with early-stage cervical squamous cell carcinoma.

BACKGROUND AND OBJECTIVE: In the past decade, no remarkable improvement has been made in the 5-year survival of cervical cancer patients. This study was to explore the influence of lymph vascular space invasion (LVSI) on the prognosis of patients with early-stage cervical squamous cell carcinoma. METHODS: A total of 111 eligible patients with FIGO stage IB and IIA cervical squamous cell carcinoma underwent radical hysterectomy and pelvic lymphadenectomy at Sun Yat-sen University Cancer Center between January 1995 and December 2002. The histopathological slides of the 111 patients were reviewed by a senior gynecological pathologist. LVSI, invasion depth, tumor differentiation and lymph node metastasis were evaluated. RESULTS: LVSI was present in 62 patients. The univariate analysis showed that the risk factors of overall survival (OS) included positive LVSI (P = 0.019) and lymph node metastasis (P = 0.002), while the risk factors of progression-free survival (PFS) included LVSI (P = 0.029), lymph node metastasis (P = 0.002), SccAg value (P = 0.018), invasion depth (P = 0.022) and positive surgical margin (P = 0.002). The multivariate analysis showed that lymph node metastasis was the independent prognostic factor of OS (P = 0.015), while lymph node metastasis and positive surgical margin were the independent factors of PFS (P = 0.006, P = 0.006). LVSI was correlated with lymph node metastasis (P = 0.011). CONCLUSION: Whether LVSI is an independent prognostic factor of early-stage cervical squamous cell carcinoma cannot be determined currently while LVSI is a risk factor of metastasis and relapse.