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384 Background: Polo-Like Kinase-1(PLK1) is one of the key regulators in G2/M cell cycle. Preclinical studies have shown that PLK1 might be involved in treatment resistance in prostate cancer (PCa). PLK1 overexpression by immunohistochemistry is associated with higher Gleason grade and thus PLK1 could play a role in PCa tumorigenesis. In this study, we utilized a different methodology by using RNA-seq PLK1 expression and correlated with clinical outcomes. Methods: Patients with all stages of prostate adenocarcinoma diagnosed between 2014 and 2020 from nine participating members of the Oncology Research Information Exchange Network (ORIEN) were included in the study. Tumor RNA-seq was analyzed for PLK1 expression and associated with clinical data obtained from ORIEN AVATAR. PLK1 expression was stratified into high expression (defined as ≥75th percentile of PLK1 mRNA expression) vs. low expression (≤75th percentile). Univariate and multivariate Cox proportional hazard model were used to compare overall survival between patients with low vs high PLK1 expression adjusting for age, race, PSA and stage. Results: A total of 452 tumors were evaluated for PLK1 expression. Of those, 241 (53.3%) had high PLK1 and 211 (46.7%) had low PLK1 expression. Median age at diagnosis for high and low PLK1 expression was 64.5 and 63.2 years respectively. The majority of patients were Caucasian in both groups. In high PLK1 group, 93 (65%) had localized high risk/very high risk disease, 27 (19%) had localized intermediate risk, 20 (14%) had metastatic vs. 97 (63%), 38 (25%) and 18(12%) respectively in low PLK1 group. Gleason ≥ 8 and PSA

The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high-grade, serous epithelial ovarian cancer tumor organoid lines from tissue obtained during debulking surgery (two neoadjuvant-carboplatin-exposed and four chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1, and 0.1 µM). Cell viability curves and resultant EC50 values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC50 value (50.2 µM) being above clinically achievable Cmax. UK1254 had a significantly shorter PFS than the rest of the subjects (p = 0.0253) and was treated as a platinum-resistant recurrence. Subsequent gene expression analysis revealed extensively interconnected, differentially expressed pathways related to NF-kB, cellular differentiation (PRDM6 activation), and the linkage of B-cell receptor signaling to the PI3K–Akt signaling pathway (PI3KAP1 activation). This study demonstrates that patient-derived tumor organoids can be developed from patients at the time of primary or interval debulking surgery and may be used to predict clinical platinum sensitivity status or to investigate drivers of carboplatin resistance.

Intracerebral hemorrhage (ICH) is a serious public health problem which causes high rates of disability and mortality in adults. Cell apoptosis is a sign of secondary brain injury (SBI) following ICH. Mammalian sterile 20-like kinase-1 (MST1), an apoptosis-promoting kinase, is a part of the Hippo signaling pathway and involved in cell death, oxidative stress, and inflammation. However, the role and underlying mechanism of MST1 in SBI induced by ICH have not yet been fully explained. The main purpose of present research was to explore the role of MST1 and its potential mechanism in SBI after ICH. An ICH model was established by injecting autologous blood into the right basal ganglia in male SD rats. We found that MST1 phosphorylation was significantly increased in brain tissues of rats after ICH. Additionally, inhibition of MST1 phosphorylation by a chemical inhibitor (Xmu-mp-1) and genetic knockdown could effectively reduce the activation of P-LATS1 and P-YAP which are downstream proteins of MST1 and decrease neuronal cell death and inflammation reaction in ICH rats. Furthermore, the decreased of MST1 phosphorylation reduced brain edema, blood-brain barrier (BBB) damage, and neurobehavioral impairment during ICH. Over-expression of MST1 resulted in opposite effects. Finally, deletion of MST1 significantly reduced neuronal apoptosis in vitro. In summary, our study revealed that MST1 played an important role in the SBI following ICH, and inhibition of MST1 could alleviate ICH-induced SBI. Therefore, MST1 may be considered as a potential therapeutic target for SBI following ICH.

Sodium/hydrogen exchanger 1 (NHE1) plays an essential role in maintaining intracellular pH (pHi) homeostasis in the central nervous system (CNS) under physiological conditions, and it is also associated with neuronal death and intracellular Na+ and Ca2+ overload induced by cerebral ischemia. However, its roles and underlying mechanisms in early brain injury (EBI) induced by subarachnoid hemorrhage (SAH) have not been fully explored. In this research, a SAH model in adult male rat was established through injecting autologous arterial blood into prechiasmatic cistern. Meanwhile, primary cultured cortical neurons of rat treated with 5 μM oxygen hemoglobin (OxyHb) for 24 h were applied to mimic SAH in vitro. We find that the protein levels of NHE1 are significantly increased in brain tissues of rats after SAH. Downregulation of NHE1 by HOE642 (a specific chemical inhibitor of NHE1) and genetic-knockdown can effectively alleviate behavioral and cognitive dysfunction, brain edema, blood-brain barrier (BBB) injury, inflammatory reactions, oxidative stress, neurondegeneration, and neuronal apoptosis, all of which are involved in EBI following SAH. However, upregulation of NHE1 by genetic-overexpression can produce opposite effects. Additionally, inhibiting NHE1 significantly attenuates OxyHb-induced neuronal apoptosis in vitro and reduces interaction of NHE1 and CHP1 both in vivo and in vitro. Collectively, we can conclude that NHE1 participates in EBI induced by SAH through mediating inflammation, oxidative stress, behavioral and cognitive dysfunction, BBB injury, brain edema, and promoting neuronal degeneration and apoptosis.

Summary Aims To investigate the critical role of Tim‐3 in the polarization of microglia in intracerebral hemorrhage (ICH)‐induced secondary brain injury (SBI). Methods An in vivo ICH model was established by autologous whole blood injection into the right basal ganglia in rats. The primary cultured microglia were treated with oxygen‐hemoglobin (OxyHb) to mimic ICH in vitro. In this experiment, specific siRNA for Tim‐3 and recombinant human TIM‐3 were exploited both in vivo and in vitro. Results Tim‐3 was increased in the brain after ICH, which mainly distributed in microglia, but not neurons and astrocytes. However, the blockade of Tim‐3 by siRNA markedly reduced secretion of inflammatory factors, neuronal degeneration, neuronal cell death, and brain edema. Meanwhile, downregulation of Tim‐3 promoted the transformation of microglia phenotype from M1 to M2 after ICH. Furthermore, upregulation of Tim‐3 can increase the interaction between Tim‐3 and Galectin‐9 (Gal‐9) and activate Toll‐like receptor 4 (TLR‐4) pathway after ICH. Increasing the expression of Tim‐3 may be related to the activation of HIF‐1α. Conclusion Tim‐3 may be an important link between neuroinflammation and microglia polarization through Tim‐3/Gal‐9 and TLR‐4 signaling pathways which induced SBI after ICH.

Oxidative stress plays an important role in secondary brain injury (SBI) after intracerebral hemorrhage (ICH), but the underling mechanism has not been fully elucidated. Recently, the antioxidant enzyme glutathione peroxidase 4 (GPX4), has attracted increasing attention due to its ability to degrade reactive oxygen species (ROS) which are the major indicator of oxidative stress; However, the role of GPX4 in ICH has not been reported. This study was designed to investigate the changes in protein levels, as well as potential role and mechanism of GPX4 in SBI following ICH using a Sprague-Dawley (SD) rat model of ICH induced by autologous blood injection into the right basal ganglia. Firstly, GPX4 protein levels in the brain were reduced gradually and bottomed out at 24 h after ICH, compared with the Sham group. Secondly, genetic-overexpression of GPX4 effectively increased level of GPX4 in the brain, and clearly relieved neuronal dysfunction, brain edema, blood brain barrier (BBB) injury, oxidative stress and inflammation after ICH. In contrast, inhibiting GPX4 with a specific pharmacological inhibitor or genetic knockdown exacerbated SBI after ICH. Finally, Ferrostatin-1, a chemical inhibitor of ferroptosis, was used to explore the role of ferroptosis in brain injury after ICH. The results suggest that inhibiting ferroptosis can significantly alleviate SBI after ICH. In summary, our work indicated that GPX4 contributes to SBI following ICH by mediating ferroptosis. Therefore, inhibiting ferroptosis with specific inhibitors or upregulation of GPX4 may be a potential strategy to ameliorate brain injury induced by ICH.

Leucine-rich repeat kinase 2 (LRRK2) is the genetic cause of both familial and idiopathic Parkinson's disease (PD), and it is associated with neuronal death, vesicle trafficking, mitochondrial dysfunction, and inflammation. However, its role in secondary brain injury (SBI) induced by intracerebral hemorrhage (ICH) has not been evaluated. In this study, an ICH model was induced by injecting autologous whole blood into the right basal ganglia of adult rats. Meanwhile, primary rat cortical neurons treated with Oxyhemoglobin (OxyHb) were used as an in vitro ICH model. Protein levels of LRRK2 increased significantly in brain tissues after ICH. Upregulation of LRRK2 by genetic overexpression augmented inflammatory responses, behavioral and cognitive dysfunction, brain edema, blood-brain barrier (BBB) injury, and cell death involved in SBI following ICH. Downregulation of LRRK2 by GNE7915 (a specific chemical inhibitor of LRRK2) and genetic knockdown yielded opposite effects. Additionally, inhibiting LRRK2 by GNE7915 obviously reduced OxyHb-induced neuronal apoptosis in vitro and attenuated phosphorylation of p38 MAPK and Drosha both in vivo and in vitro. Therefore, we concluded that LRRK2 participated in ICH-induced SBI by mediating inflammatory responses, behavioral and cognitive dysfunction, brain edema, and BBB injury and by modulating neuronal death and dysfunction and regulating the p38 MAPK/Drosha pathway.

Background A challenge for R2 and R2* methods in measuring liver iron concentration (LIC) is that fibrosis, fat, and other hepatic cellular pathology contribute to R2 and R2* and interfere with LIC estimation. Purpose To examine the interfering effects of fibrosis, fat, and other lesions on R2* LIC estimation and to use quantitative susceptibility mapping (QSM) to reduce these distortions. Study type Prospective. Phantoms, subjects Water phantoms with various concentrations of gadolinium (Gd), collagen (Cl, modeling fibrosis), and fat; nine healthy controls with no known hepatic disease, nine patients with known or suspected hepatic iron overload, and nine patients with focal liver lesions. Field strength/sequence The phantoms and human subjects were imaged using a 3D multiecho gradient-echo on clinical 1.5T and 3T MRI systems. Assessment QSM and R2* images were postprocessed from the same gradient-echo data. Fat contributions to susceptibility and R2* were corrected in signal models for LIC estimation. Statistical tests Polynomial regression analyses were performed to examine relations among susceptibility, R2* and true [Gd] and [Cl] in phantoms, and among susceptibility and R2* in patient livers. Results In phantoms, R2* had a strong nonlinear dependency on [Cl], [fat], and [Gd], while susceptibility was linearly dependent (R2 > 0.98). In patients, R2* was highly sensitive to liver pathological changes, including fat, fibrosis, and tumors, while QSM was relatively insensitive to these abnormalities (P = 0.015). With moderate iron overload, liver susceptibility and R2* were not linearly correlated over a common R2* range [0, 100] sec-1 (P = 0.35). Data conclusion R2* estimation of LIC is prone to substantial nonlinear interference from fat, fibrosis, and other lesions. QSM processing of the same gradient echo MRI data can effectively minimize the effects of cellular pathology. Level of evidence 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1069-1079.

The purpose of this study was to evaluate the sensitivities of quantitative susceptibility mapping (QSM) and R2* mapping in clinical diagnoses of Parkinson’s disease (PD). QSM images and R2* maps from 29 patients with PD and 25 healthy controls were obtained on a clinical 3T magnetic resonance imaging (MRI) system using a three-dimensional multi-echo gradient-echo sequence. Two-tailed t tests and receiver operating characteristic curves analyses were applied to the mean values of QSM and R2* of the two groups. In the PD group, a two-tailed Pearson correlation analysis was used to investigate the correlations between MRI measures (susceptibility and R2* values) and the Unified Parkinson’s Disease Rating Scale-III (UPDRS-III) score. In the substantia nigra (SN), a significant difference between patients with PD and healthy controls was found on QSM (154.80 ± 43.36 vs. 127.50 ± 21.05 ppb, P = 0.006) but not on R2* mapping. The receiver operating characteristic curves showed that QSM was more sensitive than R2* mapping to distinguish PD patients from healthy controls, with areas under the curve equal to 0.68 and 0.51, respectively. The UPDRS-III motor scores did not correlate with mean susceptibility or R2* values in the PD group. In conclusion, QSM is a more accurate and sensitive method than R2* mapping to detect the pathologic changes in the SN of patients with PD.

Base bleed is an important extended-range technology wherein low-speed mass flux is injected with high temperature by using an ammonium perchlorate (AP)-based burning composite propellant. The range of a projectile can be increased effectively by controlling the burning rate of the propellant. In this study, the burning rate of a type of bimodal AP/hydroxyl-terminated polybutadiene (HTPB) base-bleed composite propellant was measured under ground free ambient pressure (0.99 atm) by using laser ignition, high-speed video, and image-processing technology. As it is difficult to determine the existing burning rate of this bimodal AP/HTPB base-bleed composite propellant, a numerical calculation model of the burning rate was constructed. The numerical calculation result, that is, 1.59 mm/s, agrees well with the experimental value of 1.607 mm/s.

Coke oven blowing cooler system is one of the important parts in the process of coking production. It is a complex system with the characteristics of nonlinear time-varying, multi-variable, strong random disturbance and so on which cause the system to be difficult to establish the accurate mathematics model. In this paper, a predictive control strategy based on support vector machine regression (SVR) is proposed. The support vector machine regression (SVR) modeling based on the structural risk minimization is used to predict model and the adaptive weight particle swarm optimization (APSO) algorithm is used to optimize SVR parameters. Then using online rolling optimization and feedback correction to forecast and compensate the error in the future. The simulation results show that the control strategy has strong anti-interference and robustness, and ensure the rapid and effective stability of the pre-cooling device pressure in the process.

Supplemental_material for Sodium/Hydrogen Exchanger 1 Participates in Early Brain Injury after Subarachnoid Hemorrhage both in vivo and in vitro via Promoting Neuronal Apoptosis by Huangcheng Song, Shuai Yuan, Zhuwei Zhang, Juyi Zhang, Peng Zhang, Jie Cao, Haiying Li, Xiang Li, Haitao Shen, Zhong Wang, and Gang Chen in Cell Transplantation

BACKGROUND: A challenge for R2 and R2* methods in measuring liver iron concentration (LIC) is that fibrosis, fat, and other hepatic cellular pathology contribute to R2 and R2* and interfere with LIC estimation. PURPOSE: To examine the interfering effects of fibrosis, fat and other lesions on R2* LIC estimation and to use quantitative susceptibility mapping (QSM) to reduce these distortions. STUDY TYPE: Prospective PHANTOMS AND SUBJECTS: Water phantoms with various concentrations of gadolinium (Gd), collagen (Cl, modeling fibrosis) and fat, 9 healthy controls with no known hepatic disease, 9 patients with known or suspected hepatic iron overload, and 9 patients with focal liver lesions. FIELD STRENGTH/SEQUENCE: The phantoms and human subjects were imaged using a 3D multi-echo gradient-echo on clinical 1.5T and 3T MRI systems. ASSESSMENT: QSM and R2* images were postprocessed from the same gradient-echo data. Fat contributions to susceptibility and R2* were corrected in signal models for LIC estimation. STATISTICAL TESTS: Polynomial regression analyses were performed to examine relations among susceptibility, R2* and true [Gd] and [Cl] in phantoms, and among susceptibility and R2* in patient livers. RESULTS: In phantoms, R2* had a strong nonlinear dependency on [Cl], [fat] and [Gd], while susceptibility was linearly dependent (R(2)>0.98). In patients, R2* was highly sensitive to liver pathological changes, including fat, fibrosis and tumors, while QSM was relatively insensitive to these abnormalities (P=0.015). With moderate iron overload, liver susceptibility and R2* were not linearly correlated over a common R2* range [0, 100] sec(−1) (P=0.35). DATA CONCLUSION: R2* estimation of LIC is prone to substantial nonlinear interference from fat, fibrosis and other lesions. QSM processing of the same gradient echo MRI data can effectively minimize the effects of cellular pathology.

Stroke, also known as "cerebrovascular accident", is an acute cerebrovascular disease that is caused by a sudden rupture of blood vessels in the brain or obstruction of the blood supply by blockage of blood vessels, thus including hemorrhagic and ischemic strokes. The incidence of ischemic stroke is higher than that of hemorrhagic stroke, and accounts for 80% of the total number of strokes. However, the mortality rate of hemorrhagic stroke is relatively high. Internal carotid artery and vertebral artery occlusion and stenosis can cause ischemic stroke, and especially males over 40 years of age are at a high risk of morbidity. According to the survey, stroke in urban and rural areas has become the first cause of death in China. It is also the leading cause of disability in Chinese adults. In a word, stroke is characterized by high morbidity, high mortality and high disability rates. Studies have shown that many noble gases have the neuroprotective effects. For example, xenon has been extensively studied in various animal models of neurological injury including stroke, hypoxic-ischemic encephalopathy. Compared to xenon, Argon, as a noble gas, is abundant, cheap and widely applicable, and has been also demonstrated to be neuroprotective in many research studies. In a variety of models, ranging from oxygen-glucose deprivation in cell culture to complex models of mid-cerebral artery occlusion, subarachnoid hemorrhage or retinal ischemia-reperfusion injury in animals. Argon administration after individual injury demonstrated favorable effects, particularly increased cell survival and even improved neuronal function. Therefore the neuroprotective effects of argon may be of possible clinical use for opening a potential therapeutic window in stroke. It is important to illuminate the mechanisms of argon in nerve function and to explore the best use of this gas in stroke treatment.

Background: Empathy is a multidimensional construct referring to the capacity to understand and share the emotional and affective states of another person. Cerebral γ-aminobutyric acid (GABA)-ergic levels are associated with a variety of neurological and psychiatric disorders. However, the role of the GABA system in different dimensions of empathy has not been investigated. Materials and Methods: Thirty-two right-handed healthy volunteers took part in this study. We used proton magnetic resonance spectroscopy to determine GABA concentrations in the anterior insula (AI) and the anterior cingulate cortex (ACC) and to examine the relationship between the GABA concentrations and the subcomponents of empathy evaluated by the Interpersonal Reactivity Index (IRI). Result: Pearson correlation analyses (two-tailed) showed that AI GABA was significantly associated with the empathy concern score (r = 0.584, p

The influence of underlay thickness on the wrinkle period has been explored in this paper. The wrinkle period has been reduced to about 600 nm on an ultrathin Au upper-layer/polystyrene (PS) underlay system. The experimental data show that the wrinkle period is decrease with the underlay thickness. The previous theory can not give an adequate explanation of the relationship between the underlay thickness and the wrinkle period. A new analytical solution containing finite underlay thickness and a stretching energy item is obtained based on Landau's elastic theory. The analytical solution can well explain the relationship between the underlay thickness and the small period, and is consistent with the experimental data.