Opposite Outcomes Research Articles

Different mechanisms of CD200-CD200R induce diverse outcomes in cancer treatment

The CD200 is a cell membrane protein expressed by tumor cells, and its receptor CD200 receptor (CD200R) is expressed by immune cells including macrophages and dendritic cells. The formation of CD200-CD200R inhibits the cellular functions of the targeted immune cells, so CD200 is one type of the immune checkpoint and blockade CD200-CD200R formation is a potential cancer treatment. However, the CD200 blockade has opposite treatment outcomes in different types of cancers. For instance, the CD200R deficient mice have a higher tumor load than the wild type (WT) mice in melanoma suggesting that CD200-CD200R inhibits melanoma. On the other hand, the antibody anti-CD200 treatment in pancreatic ductal adenocarcinoma (PDAC) and head and neck squamous cell carcinoma (HNSCC) significantly reduces the tumor load indicating that CD200-CD200R promotes PDAC and HNSCC. In this work, we hypothesize that different mechanisms of CD200-CD200R in tumor microenvironment could be one of the reasons for the diverse treatment outcomes of CD200 blockade in different types of cancers. We create one Ordinary Differential Equations (ODEs) model for melanoma including the inhibition of CCL8 and regulatory T cells and the switching from M2 to M1 macrophages by CD200-CD200R to capture the tumor inhibition by CD200-CD200R. We also create another ODEs model for PDAC and HNSCC including the promotion of the polarization and suppressive activities of M2 macrophages by CD200-CD200R to generate the tumor promotion by CD200-CD200R. Furthermore, we use these two models to investigate the treatment efficacy of the combination treatment between the CD200-CD200R blockade and the other immune checkpoint inhibitor, anti-PD-1. Our result shows that different mechanisms of CD200-CD200R can induce different treatment outcomes in combination treatments, namely, only the CD200-CD200R blockade reduces tumor load in melanoma and only the anti-PD-1 and CD200 knockout decrease tumor load in PDAC and HNSCC. Moreover, in melanoma, the CD200-CD200R mainly utilizes the inhibitions on M1 macrophages and dendritic cells to inhibit tumor growth, instead of M2 macrophages.

Corporate Characteristics and Occupational Injuries by Industry

BackgroundRecent research on occupational injuries in companies has faced difficulties in obtaining representative data, leading to studies relying on surveys or case studies. Moreover, it is difficult to find studies on how a company's industry characteristics affect occupational injuries. This study aims to address these limitations. MethodsWe collected 11 years of disclosure data from 1,247 listed companies in the Korean stock market and combined it with their occupational injury histories collected by the Republic of Korea Occupational Safety and Health Agency (KOSHA) to build a dataset. We attempted to analyze a linear panel model by dividing the dataset into manufacturing, construction, and other industries. ResultsThe higher proportion of full-time employees and better job skills correlate with lower occupational injuries in other industries. The wage increase reduces occupational injuries in manufacturing and other industries, but the substitution effect produces the opposite outcome in construction. Also, foreign ownership and credit ratings increase effectively reduce occupational injuries mainly in the manufacturing industry. ConclusionOur results suggest that in explaining the relationship between corporate characteristics and occupational injuries, it is necessary to consider the nature of the industry more closely, and in particular, employment and labor policies for preventing occupational injuries need to be selectively applied according to industry. In addition, to improve the limitations and increase the usability of the research results, further detailed studies are needed in the future.

Helping and Being Helped: Exploring the Motivations and Barriers to Upstream Reciprocity in Open-World Games

In a game world, if you are having trouble, you may ask experienced players for help; after leveling up, you may help novice players avoid difficulties in turn. This phenomenon is called in-game “upstream reciprocity (UR)”. In this article, we studied the motivations for novice players seeking help and experienced players helping others through focus groups and tested the theoretical models of potential recipients (N = 232) and donors (N = 258), respectively. Our analyses showed that for both potential recipients and donors, higher degrees of extraversion and perceived value (utilitarian and hedonic values) increased in-game UR intention. Loneliness showed the opposite outcome in models that recipients with high loneliness degrees and donors with low loneliness degrees increased in-game UR intention. Besides, self-determination theory (autonomy, competence, and relatedness) was positively associated with UR intention in the donor model. Furthermore, we tested the discouraging factor hindering players from UR. Combining all the results, we suggested the keys for designers are to improve the function and gameplay of the multiplayer mode, encourage the sharing of in-game capital, and lower the rewards of social cooperation to increase autonomy.

Laser Ablated Citrate-Stabilized Silver Nanoparticles Display Size and Concentration Dependant Biological Effects

Silver nanoparticles (AgNPs) have been recognized for widespread biological applications due to their antimicrobial and anti-inflammatory effect, especially in dentistry and for wound healing. Many features determine their beneficial or toxic potential, such as their synthesis type, size, morphology, coating, and concentration. Most synthesis types rely on the use of synthetic chemicals, which contributes to their toxicity. We present an environmentally friendly method for “green” synthesis of AgNPs from the silver target by pulsed laser ablation in liquid (PLAL) using citrate as the stabilizing agent. Since AgNPs already have many dental applications, we examined their antibacterial effect against supragingival biofilm-forming bacteria and bacterial strains known to cause resistant dental infections. Their impact on human fibroblast cells’ cytotoxicity, proliferation (measured by XTT and Ki-67 immunofluorescence), pro/antioxidant balance, and lipid peroxidation (measured by PAB and LPP) was evaluated. AgNPs1 (21 nm) and AgNPs2 (15 nm) spherical nanoparticles with good overall stability were obtained. The highest tested dose of smaller nanoparticles (AgNPs2) displays not only an effective antibacterial effect against the tested oral bacteria strains but also a pro-oxidant and cytotoxic effect on fibroblast cells. Lower doses do not affect bacterial survival but increase the cell proliferation and metabolic activity and show an antioxidative effect, suggesting that different concentrations display a substantially opposite effect. Compared to larger AgNPs1, smaller AgNPs2 possess more potent biological effects, indicating that size plays a pivotal role in their activity. Such opposite outcomes could be important for their medical application, and high concentrations could be used for the inhibition of dental biofilm formation and resistant dental infections as well as proliferative conditions, while low doses could be beneficial in the treatment of atrophic and inflammatory disorders. Finally, we showed that silver-targeted PLAL, using citrate as a stabilizing agent, produces biologically potent nanoparticles that could have many applications depending on their size and concentration.

Current account imbalance and the inequality ratio of income to consumption: evidence from China and other Asian countries

This paper deals with global imbalances as an increasingly important issue in our age. While the literature establishes that current accounts are inversely related to the ratio of income to consumption inequality in OECD, our study finds that this relationship is reversed in Asia. That ratio has much to do with various schemes of consumption smoothing, which are affected by policy interventions to alleviate the effects of rising income inequality. Different policies may generate opposite outcomes. In OECD, policy encourages consumer credit and deficit spending among low-income people so that consumption inequality is kept artificially low, leading up to a current account deficit. In Asia, policy promotes output growth via high savings with no well-developed smoothing schemes designed to help poor households, so that consumption inequality moves in line with income inequality, with excess savings recycled into a current account surplus. Hence, any reduction in global imbalances requires both regions to adjust their policies for mitigating income inequality and optimizing smoothing schemes.

Investigating the flow characteristics and thermodynamic performance of curved detonation waves

Oblique detonation waves (ODWs) are induced by oblique shock waves (OSWs) and hold significant research value for air-breathing ramjet engines due to their high thermodynamic efficiency and specific impulse. In this research, detonation is induced using a curved shock wave (CSW) that provides greater flexibility compared to an OSW. Curved detonation waves (CDWs) are classified into two categories based on the curvature of the CSW: positive-curvature curved detonation waves (PC-CDWs) and negative-curvature curved detonation waves (NC-CDWs). We conduct a numerical investigation of the flow characteristics and potential thermodynamic performance in curved detonation waves (CDWs) by solving the two-dimensional multi-species Euler equations with a detailed hydrogen combustion mechanism. In contrast to ODWs, we observe continuous compression and expansion effects in the flow fields of PC-CDWs and NC-CDWs, respectively. Continuous compression shortens the initiation length of the detonation wave and intensifies the compression wave preceding the combustion front, whereas continuous expansion produces the opposite outcome. Changes in the curvature of the CSW result in alterations to the flow characteristics of the CDW. These flow characteristic changes are manifested in their thermodynamic and propulsion-related performance. More specifically, a lower overdrive of the detonation wave corresponds to a reduced loss in total pressure.

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment.

The pharmacokinetic alteration of an antimicrobial medication leading to sub-therapeutic plasma level can aid in the emergence of resistance, a global threat nowadays. In this context, molnupiravir (prodrug of EIDD-1931) is the most efficacious orally against corona virus disease (COVID-19). In addition to drug-drug interaction, the pharmacokinetics of a drug can significantly vary during any disease state, leading to disease-drug interaction. However, no information is available for such a recently approved drug. Therefore, we aimed to explore the oral pharmacokinetics of EIDD-1931 in seven chemically induced disease states individually compared to the normal state using various rat models. Induction of any disease situation was confirmed by the disease specific study(s) prior to pharmacokinetic investigations. Compared to the normal state, substantially lowered plasma exposure (0.47- and 0.63-fold) with notably enhanced clearance (2.00- and 1.56-fold) of EIDD-1931 was observed in rats of ethanol-induced gastric injury and carbon tetrachloride-induced liver injury states. Conversely, paclitaxel-induced neuropathic pain and cisplatin-induced kidney injury states exhibited opposite outcomes on oral exposure (1.43- and 1.50-fold) and clearance (0.69- and 0.65-fold) of EIDD-1931. Although the highest plasma concentration (2.26-fold) markedly augmented in the doxorubicin-induced cardiac injury state, streptozocin-induced diabetes and lipopolysaccharide-induced lung injury state did not substantially influence the pharmacokinetics of EIDD-1931. Exploring the possible phenomenon behind the reduced or boosted plasma exposure of EIDD-1931, results suggest the need for dose adjustment in respective diseased conditions in order to achieve desired efficacy during oral therapy of EIDD-1931.

Prostaglandin E2 activates melanin-concentrating hormone neurons to drive diet-induced obesity

Hypothalamic inflammation reduces appetite and body weight during inflammatory diseases, while promoting weight gain when induced by high-fat diet (HFD). How hypothalamic inflammation can induce opposite energy balance outcomes remains unclear. We found that prostaglandin E2 (PGE2), a key hypothalamic inflammatory mediator of sickness, also mediates diet-induced obesity (DIO) by activating appetite-promoting melanin-concentrating hormone (MCH) neurons in the hypothalamus in rats and mice. The effect of PGE2 on MCH neurons is excitatory at low concentrations while inhibitory at high concentrations, indicating that these neurons can bidirectionally respond to varying levels of inflammation. During prolonged HFD, endogenous PGE2 depolarizes MCH neurons through an EP2 receptor-mediated inhibition of the electrogenic Na+/K+-ATPase. Disrupting this mechanism by genetic deletion of EP2 receptors on MCH neurons is protective against DIO and liver steatosis in male and female mice. Thus, an inflammatory mediator can directly stimulate appetite-promoting neurons to exacerbate DIO and fatty liver.

Political Conversion Opposites: Two Writers and their 1920sSoviet Union Experience

This study reopens the question of the nature of political commitment and its causes during a time that drastically altered the history of the 20th century, the 1920s and 1930s. Focused largely on a body of texts produced by Japanese female writer Miyamoto Yuriko (1899-1951) who returned from a three-year long trip to the Soviet Union in late 1920s as a convinced communist, the study offers a comparison with communism renunciation writings produced by leftist Romanian French writer Panait Istrati (1894-1935), as well as other communist and fellow travelers who experienced the same Soviet realities as Miyamoto but with opposite outcomes, such as French writer André Gide (1869-1951). What made those members of the intelligentsia so passionately embrace or renounce certain political ideologies that ultimately changed the face of modern history?

The Role of Economics Factors in Driving Economic Growth: An Empirical Study in Iraq

This study examined the implications of inequality, human capital, innovation and entrepreneurship, social and political instability, and other factors on sustainable economic growth in Erbil-Kurdistan. Quantitative methods were applied, and information from 2006–2022 was analyzed. Data analysis included a correlation and regression test. It was observed that inequality, social discontent, and political instability were significantly connected to the opposite outcome (low economic growth), while human capital, innovation, and entrepreneurship were significantly related to high economic growth that could be sustained over time. The findings revealed that all developed research hypotheses are supported. The study highlights the importance of supporting innovation and entrepreneurship, as well as investing in people, for long-term economic growth in Erbil and Kurdistan. Inequality, as well as social and political instability, are addressed, and suggestions for policy change are offered. Further interdisciplinary study is required to properly understand the elements that contribute to Erbil and Kurdistan's sustained economic success.

Material demand and material efficiency for sustainable development in the European Union countries: A stochastic frontier analysis

AbstractMaterials are of great importance as they are fundamentally integrated into many different critical topics, including green transition, technological progress, industrial emissions, and supply chains. Therefore, the amount of materials we demand and employ in the production process or how efficiently we use them become highly crucial. In this paper, we study the emerging role of materials with a special focus on the key role of material efficiency (ME) in climate mitigation. To this end, we empirically investigate the main determinant of material demand and evaluate the ME performance in the European Union (EU) countries over the period of 1995–2019 based on a four‐component Stochastic Frontier Analysis (SFA) panel data approach that separates unobserved country effects from persistent and transient inefficiency. We obtain the following outcomes. First, material demand function estimates reveal that economic growth and energy consumption are the main drivers of domestic material consumption, highlighting the need for promoting sustainable energy and economic growth. Second, although the SFA‐based ME scores significantly vary across countries, transient inefficiency is the main source of overall inefficiency for most countries, suggesting that there is considerable potential for improvement in ME. While Finland, Sweden, Denmark, Bulgaria, Cyprus, France, and Slovenia improve their ME performance over time, the ME score of some other countries, such as Ireland, Portugal, Italy, Spain, and the Slovak Republic reveal an opposite outcome. Third, the results show that material intensity is not always a good proxy for ME.

When the Generational Overlap Is the Challenge Rather Than the Solution. On Some Problematic Versions of Transgenerational Justice

Abstract While in the realm of scholarly debate on intergenerational justice the mechanism of a transgenerational intertwinement has been often adopted as a chief conceptual device in view of overcoming ethical short-termism and legitimizing duties towards future generations, this paper aims at showing that there are good reasons for considering the opposite outcome. Drawing on three paradigmatic examples taken from three mainstream approaches in the debate—Rawls’s contractualism, Gauthier’s contractarianism, and indirect reciprocity—I will show how the grammar of presentism is still largely operative under the surface of theories explicitly recurring to such a device and thereby advocating a chain of duties capable to reach the remote future. A short closing section will be devoted to endorsing a radical reorientation in ethics, such that a direct link to future invocations will be considered as a promising strategy for genuinely justifying intergenerational obligations.

The Drosophila chemokine–like Orion bridges phosphatidylserine and Draper in phagocytosis of neurons

Phagocytic clearance of degenerating neurons is triggered by "eat-me" signals exposed on the neuronal surface. The conserved neuronal eat-me signal phosphatidylserine (PS) and the engulfment receptor Draper (Drpr) mediate phagocytosis of degenerating neurons in Drosophila. However, how PS is recognized by Drpr-expressing phagocytes invivo remains poorly understood. Using multiple models of dendrite degeneration, we show that the Drosophila chemokine-like protein Orion can bind to PS and is responsible for detecting PS exposure on neurons; it is supplied cell-non-autonomously to coat PS-exposing dendrites and to mediate interactions between PS and Drpr, thus enabling phagocytosis. As a result, the accumulation of Orion on neurons and on phagocytes produces opposite outcomes by potentiating and suppressing phagocytosis, respectively. Moreover, the Orion dosage is a key determinant of the sensitivity of phagocytes to PS exposed on neurons. Lastly, mutagenesis analyses show that the sequence motifs shared between Orion and human immunomodulatory proteins are important for Orion function. Thus, our results uncover a missing link in PS-mediated phagocytosis in Drosophila and imply conserved mechanisms of phagocytosis of neurons.

Impact of Unexpected Death in a Simulation Scenario on Skill Retention, Stress, and Emotions: A Simulation-Based Randomized Controlled Trial.

Introduction The simulation of patient death remains controversial in simulation-based education. We investigated the effect of simulated patient death on learners' skill retention, stress levels, and emotions. Methods After ethics approval, we recruited residents at two Canadian universities. Participants were randomized to manage a simulated cardiac arrest ending with either the unexpected death (intervention group) or survival (control group) of the simulated patient (i.e., manikin). Three months later, all participants performed the same scenario but with the opposite outcome. Blinded video raters assessed participants' non-technical and technical crisis resource management (CRM) skills at both time points. Stress levels (represented by anxiety level, salivary cortisol concentration, and cognitive appraisal) and emotional valence were measured. Outcomes were analyzed using analysis of covariance (ANCOVA) or generalized estimating equations as appropriate. Results The analysis included 46 participants (intervention: n=24; control: n=22). Simulated death neither affected retention of non-technical CRM skills (mean retention Ottawa Global Rating Scale score in the death group [29.4, 95% CI: 27.0, 31.8] versus control group [29.4, 95% CI: 26.8, 32.0; p=0.87])nor technical CRM skills (mean retention task-specific checklist score in the manikin death group [11.8, 95% CI: 10.5, 13.0]versus the control group [12.5, 95% CI: 11.3, 13.7; p=0.69]). The simulated death had negative effects on participants' anxiety levels, cognitive appraisal, and emotions. Conclusion Simulated patient death did not affect the retention of non-technical or technical CRM skillsbut led to greater levels of short-term anxiety, stress, and negative emotions among learners.

Oncogenic role of an uncharacterized cold-induced zinc finger protein 726 in breast cancer.

The unobtrusive cold environmental temperature can be linked to the development of cancer. This study, for the first time, envisaged cold stress-mediated induction of a zinc finger protein 726 (ZNF726) in breast cancer. However, the role of ZNF726 in tumorigenesis has not been defined. This study investigated the putative role of ZNF726 in breast cancer tumorigenic potency. Gene expression analysis using multifactorial cancer databases predicted overexpression of ZNF726 in various cancers, including breast cancer. Experimental observations found that malignant breast tissues and highly aggressive MDA-MB-231 cells showed an elevated ZNF726 expression as compared to benign and luminal A type (MCF-7), respectively. Furthermore, ZNF726 silencing decreased breast cancer cell proliferation, epithelial-mesenchymal transition, and invasion accompanied by the inhibition of colony-forming ability. Concordantly, ZNF726 overexpression significantly demonstrated opposite outcomes than ZNF726 knockdown. Taken together, our findings propose cold-inducible ZNF726 as a functional oncogene demonstrating its prominent role in facilitating breast tumorigenesis. An inverse correlation between environmental temperature and total serum cholesterol was observed in the previous study. Furthermore, experimental outcomes illustrate that cold stress elevated cholesterol content hinting at the involvement of the cholesterol regulatory pathway in cold-induced ZNF726 gene regulation. This observation was bolstered by a positive correlation between the expression of cholesterol-regulatory genes and ZNF726. Exogenous cholesterol treatment elevated ZNF726 transcript levels while knockdown of ZNF726 decreased the cholesterol content via downregulating various cholesterol regulatory gene expressions (e.g., SREBF1/2, HMGCoR, LDLR). Moreover, an underlying mechanism supporting cold-driven tumorigenesis is proposed through interdependent regulation of cholesterol regulatory pathway and cold-inducible ZNF726 expression.

Risk factors of focal maculopathy in patients with type 2 diabetes mellitus with hard exudates: A hospital-based case–control study

Abstract Background: Dyslipidemia and hard exudates of the retina have an intricate association. Increased lipid levels cause increased hard exudates. Many studies found dyslipidemia as an independent risk factor for the development of hard exudates in maculopathy. Objectives: The objective of this study was the association between dyslipidemia and the presence of hard exudates among focal maculopathy patients with and without hard exudates. Materials and Methods: This was a hospital-based case–control study. This study included 60 patients with focal maculopathy in type 2 diabetes mellitus (DM) with hard exudates. Sixty patients with Focal maculopathy in type 2 DM without hard exudates were taken as control. Results: Dyslipidemia was significantly seen (P < 0.05) in cases compared to participants. Total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and very LDL-C were significantly higher in cases compared to controls. High-density lipoprotein cholesterol (HDL-C) had the opposite outcome. HDL-C was significantly lower in cases compared to controls. Conclusion: Dyslipidemia was a strong risk factor for the formation of hard exudates in the macula. An increase in lipid levels increased the hard exudates concentration in the macula and retina.

Distinct Signaling Pathways for Autophagy-Driven Cell Death and Survival in Adult Hippocampal Neural Stem Cells.

Autophagy is a cellular catabolic process that degrades and recycles cellular materials. Autophagy is considered to be beneficial to the cell and organism by preventing the accumulation of toxic protein aggregates, removing damaged organelles, and providing bioenergetic substrates that are necessary for survival. However, autophagy can also cause cell death depending on cellular contexts. Yet, little is known about the signaling pathways that differentially regulate the opposite outcomes of autophagy. We have previously reported that insulin withdrawal (IW) or corticosterone (CORT) induces autophagic cell death (ACD) in adult hippocampal neural stem (HCN) cells. On the other hand, metabolic stresses caused by 2-deoxy-D-glucose (2DG) and glucose-low (GL) induce autophagy without death in HCN cells. Rather, we found that 2DG-induced autophagy was cytoprotective. By comparing IW and CORT conditions with 2DG treatment, we revealed that ERK and JNK are involved with 2DG-induced protective autophagy, whereas GSK-3β regulates death-inducing autophagy. These data suggest that cell death and survival-promoting autophagy undergo differential regulation with distinct signaling pathways in HCN cells.

Orexin receptors in paraventricular nucleus influence sexual behavior via regulating the sympathetic outflow in males.

Orexins are hypothalamic neuropeptides associated with various neurophysiological activities such as sleep, arousal, and reward. However, there are few studies investigating the relationships between orexin receptors in the paraventricular nucleus and sexual behaviors. To explore the roles of orexin receptors in the paraventricular nucleus on sexual behaviors and uncover its potential mechanisms in males. Orexin A, orexin 1 receptor antagonist SB334867, and orexin 2 receptor antagonist TCS-OX2-29 were microinjected into the paraventricular nucleus to investigate the effects of orexin receptors on copulatory behavior testing of C57BL/6 mice. To explore if ejaculation could activate orexin 1 receptor-expressing neurons in the paraventricular nucleus, fluorescence immunohistochemical double staining was utilized. The levels of serum norepinephrine were measured and the lumbar sympathetic nerve activity was recorded to reflect the sympathetic nervous system activity. Moreover, the bulbospongiosus muscle-electromyogram was recorded and analyzed. To test whether perifornical/lateral hypothalamic area orexinergic neurons directly projected to the paraventricular nucleus, virus retrograde tracing technology was utilized. Orexin A significantly enhanced sexual performance by shortening the intromission and ejaculation latencies, and increasing the mount and intromission frequencies, while the opposite outcomes appeared with SB334867. However, TCS-OX2-29 had no significant effects on sexual behaviors. Moreover, orexin A increased lumbar sympathetic nerve activity and the levels of serum norepinephrine, while SB334867 decreased lumbar sympathetic nerve activity and norepinephrine, which caused a significant decrease in sympathetic nervous system outflow. Meanwhile, a robust increase in the bulbospongiosus muscle-electromyogram activity was identified after microinjecting orexin A. Furthermore, cFos immunopositive cells were increased and double stained with orexin 1 receptor-expressing neurons in the mating group. Additionally, the retrograde tracing results demonstrated that orexinergic neurons in the perifornical/lateral hypothalamic area directly projected to the paraventricular nucleus. Orexin 1 receptor in the paraventricular nucleus could influence the ejaculatory reflex via mediating the sympathetic nervous system activity, which might be of great importance in the treatment of premature ejaculation in the future.

Long Non-Coding RNA Nuclear Paraspeckle Assembly Transcript 1: A Regulator of Trophoblast Cells in the Progression of Gestational Diabetes Mellitus

The potential function of NEAT1 in the progression of Gestational diabetes mellitus (GDM) and the molecular mechanisms are explored. NEAT1 levels in multiple types of cell lines and placental tissues collected from healthy, GDM and preeclampsia pregnancies were detected by quantitative real-time polymerase chain reaction (qRT-PCR). After intervening NEAT1 level in HTR-8/SVneo cells, proliferative, migratory and apoptotic potentials were examined by cell counting kit-8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EdU), transwell assay and flow cytometry. The regulatory effect of NEAT1 on the transcriptional activity of NSD1 was predicted by bioinformatic analysis and further confirmed by dual-luciferase reporter assay. In addition, histone modifications of NEAT1 on NSD1 transcription were examined by chromatin immunoprecipitation (ChIP). NEAT1 was upregulated in placental tissues collected from GDM patients. Overexpression of NEAT1 stimulated proliferative and migratory potentials, but inhibited apoptosis in HTR-8/SVneo cells. Knockdown of NEAT1 had the opposite outcomes. NEAT1 was able to regulate the transcriptional activity of NSD1 through histone modifications on H3K27Me3 and H3K27Cro. NEAT1 is upregulated in GDM cases, which triggers proliferative and migratory potentials in trophoblast cells mainly through regulating transcriptional activity of NSD1 via histone modification.

SPAG9 Expression Predicts Good Prognosis in Patients with Clear-Cell Renal Cell Carcinoma: A Bioinformatics Analysis with Experimental Validation.

Clear-cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal-cell carcinoma (RCC). Sperm-associated antigen 9 (SPAG9) has been reported to promote the progression of a variety of tumors and is thus a potential prognostic marker. This study combined a bioinformatics analysis with an experimental validation, exploring the prognostic value of SPAG9 expression in ccRCC patients and the possible underlying mechanisms. The SPAG9 expression was associated with a poor prognosis in pan-cancer patients, but with a good prognosis and slow tumor progression in ccRCC patients. To explore the underlying mechanism, we investigated the roles of SPAG9 in ccRCC and bladder urothelial carcinoma (BLCA). The latter was chosen for comparison with ccRCC to represent the tumor types in which SPAG9 expression suggests a poor prognosis. The overexpression of SPAG9 increased the expression of autophagy-related genes in 786-O cells but not in HTB-9 cells, and SPAG9 expression was significantly correlated with a weaker inflammatory response in ccRCC but not in BLCA. Through an integrated bioinformatics analysis, we screened out seven key genes (AKT3, MAPK8, PIK3CA, PIK3R3, SOS1, SOS2, and STAT5B) in this study. The correlation between SPAG9 expression and ccRCC prognosis depends on the expression of key genes. Since most of the key genes were PI3K-AKT-pathway members, we used the PI3K agonist 740Y-P to stimulate the 786-O cells, to mimic the effect of key-gene overexpression. Compared with the Ov-SPAG9 786-O cells, the 740Y-P further increased the expression of autophagy-related genes by more than twofold. Moreover, we constructed a nomogram based on SPAG9/key genes and other clinical features, which was proven to have some predictive value. Our study found that SPAG9 expression predicted opposite clinical outcomes in pan-cancer and ccRCC patients, and we speculated that SPAG9 suppresses tumor progression by promoting autophagy and inhibiting inflammatory responses in ccRCC. We further found that some genes might cooperate with SPAG9 to promote autophagy, and that these were highly expressed in the tumor stroma and could be represented by key genes. The SPAG9-based nomogram can help to estimate the long-term prognosis of ccRCC patients, indicating that SPAG9 is a potential prognostic marker for ccRCC.