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Histone deacetylase inhibitors (HDACis) are drugs that target the epigenetic state of cells by modifying the compaction of chromatin through effects on histone acetylation. Gliomas often harbor a mutation of isocitrate dehydrogenase (IDH) 1 or 2 that leads to changes in their epigenetic state presenting a hypermethylator phenotype. We postulated that glioma cells with IDH mutation, due to the presence of epigenetic changes, will show increased sensitivity to HDACis. This hypothesis was tested by expressing mutant IDH1 with a point alteration—converting arginine 132 to histidine—within glioma cell lines that contain wild-type IDH1. Glioma cells engineered to express mutant IDH1 produced D-2-hydroxyglutarate as expected. When assessed for response to the pan-HDACi drug belinostat, mutant IDH1-expressing glioma cells were subjected to more potent inhibition of growth than the corresponding control cells. Increased sensitivity to belinostat correlated with the increased induction of apoptosis. Finally, a phase I trial assessing the addition of belinostat to standard-of-care therapy for newly diagnosed glioblastoma patients included one patient with a mutant IDH1 tumor. This mutant IDH1 tumor appeared to display greater sensitivity to the addition of belinostat than the other cases with wild-type IDH tumors based on both standard magnetic resonance imaging (MRI) and advanced spectroscopic MRI criteria. These data together suggest that IDH mutation status within gliomas may serve as a biomarker of response to HDACis.

Glioblastoma (GBM) is a fatal disease, with poor prognosis exacerbated by difficulty in assessing tumor extent with imaging. Spectroscopic MRI (sMRI) is a non-contrast imaging technique measuring endogenous metabolite levels of the brain that can serve as biomarkers for tumor extension. We completed a three-site study to assess survival benefits of GBM patients when treated with escalated radiation dose guided by metabolic abnormalities in sMRI. Escalated radiation led to complex post-treatment imaging, requiring unique approaches to discern tumor progression from radiation-related treatment effect through our quantitative imaging platform. The purpose of this study is to determine true tumor recurrence timepoints for patients in our dose-escalation multisite study using novel methodology and to report on median progression-free survival (PFS). Follow-up imaging for all 30 trial patients were collected, lesion volumes segmented and graphed, and imaging uploaded to our platform for visual interpretation. Eighteen months post-enrollment, the median PFS was 16.6 months with a median time to follow-up of 20.3 months. With this new treatment paradigm, incidence rate of tumor recurrence one year from treatment is 30% compared to 60–70% failure under standard care. Based on the delayed tumor progression and improved survival, a randomized phase II trial is under development (EAF211).

Standard of care for lower-grade glioma (LGG) is maximal safe resection and risk-adaptive adjuvant therapy. While patients who benefit the most from adjuvant chemotherapy have been elucidated in prospective randomized studies, comparable insights for adjuvant radiotherapy (RT) are lacking. We sought to identify and validate patterns of gene expression that are associated with differential outcomes among LGG patients treated by RT from two large genomics databases.Patients from The Cancer Genome Atlas (TCGA) with LGG (WHO grade II-III glioma) treated by surgery and adjuvant RT were randomized 1:1 to a discovery cohort or an internal validation cohort. Using the discovery cohort only, associations between tumor RNA-seq expression and progression-free survival (PFS) as well as overall survival (OS) were evaluated with adjustment for clinicopathologic covariates. A Genomic Risk Score (GRS) was then constructed from the expression levels of top genes also screened for involvement in glioma carcinogenesis. The prognostic value of GRS was further assessed in the internal validation cohort of TCGA and a second distinct database, compiled by the Chinese Glioma Genome Association (CGGA).From TCGA, 289 patients with LGG received adjuvant RT alone (38 grade II, 30 grade III) or chemoradiotherapy (CRT) (51 grade II, 170 grade III) between 2009 and 2015. From CGGA, 178 patients with LGG received adjuvant RT alone (40 grade II, 13 grade III) or CRT (41 grade II, 84 grade III) between 2004 and 2016. The genes comprising GRS are involved in MAP kinase activity, T cell chemotaxis, and cell cycle transition: MAP3K15, MAPK10, CCL3, CCL4, and ADAMTS1. High GRS, defined as having a GRS in the top third, was significantly associated with poorer outcomes independent of age, sex, glioma histology, WHO grade, IDH mutation, 1p/19q co-deletion, and chemotherapy status in the discovery cohort (PFS HR 1.61, 95% CI 1.10-2.36, P = 0.014; OS HR 2.74, 95% CI 1.68-4.47, P 0.001). These findings were replicated in the internal validation cohort (PFS HR 1.58, 95% CI 1.05-2.37, P = 0.027; OS HR 1.84, 95% CI 1.13-3.00, P = 0.015) and the CGGA external validation cohort (OS HR 1.72, 95% CI 1.27-2.34, P 0.001). Association between GRS and outcomes was observed only among patients who underwent RT, in both TCGA and CGGA.This study successfully identified an expression signature of five genes that stratified outcomes among LGG patients who received adjuvant RT, with two rounds of validation leveraging independent genomics databases. Expression levels of the highlighted genes were associated with PFS and OS only among patients whose treatment included RT, but not among those with omission of RT, suggesting that expression of these genes may be predictive of radiation treatment response. While additional prospective studies are warranted, interrogation of these genes may be considered in the multidisciplinary management of LGG.

Despite aggressive treatment, glioblastoma has a poor prognosis due to its infiltrative nature. Spectroscopic MRI-measured brain metabolites, particularly the choline to N-acetylaspartate ratio (Cho/NAA), better characterizes the extent of tumor infiltration. In a previous pilot trial (NCT03137888), brain regions with Cho/NAA ≥ 2x normal were treated with high-dose radiation for newly diagnosed glioblastoma patients. This report is a secondary analysis of that trial where spectroscopic MRI-based biomarkers are evaluated for how they correlate with progression-free and overall survival (PFS/OS). Subgroups were created within the cohort based on pre-radiation treatment (pre-RT) median cutoff volumes of residual enhancement (2.1 cc) and metabolically abnormal volumes used for treatment (19.2 cc). We generated Kaplan–Meier PFS/OS curves and compared these curves via the log-rank test between subgroups. For the subgroups stratified by metabolic abnormality, statistically significant differences were observed for PFS (p = 0.019) and OS (p = 0.020). Stratification by residual enhancement did not lead to observable differences in the OS (p = 0.373) or PFS (p = 0.286) curves. This retrospective analysis shows that patients with lower post-surgical Cho/NAA volumes had significantly superior survival outcomes, while residual enhancement, which guides high-dose radiation in standard treatment, had little significance in PFS/OS. This suggests that the infiltrating, non-enhancing component of glioblastoma is an important factor in patient outcomes and should be treated accordingly.

Accurate radiation therapy (RT) targeting is crucial for glioblastoma treatment but may be challenging using clinical imaging alone due to the infiltrative nature of glioblastomas. Precise targeting by whole-brain spectroscopic MRI, which maps tumor metabolites including choline (Cho) and N-acetylaspartate (NAA), can quantify early treatment-induced molecular changes that other traditional modalities cannot measure. We developed a pipeline to determine how spectroscopic MRI changes during early RT are associated with patient outcomes to provide insight into the utility of adaptive RT planning. Data were obtained from a study (NCT03137888) where glioblastoma patients received high-dose RT guided by the pre-RT Cho/NAA twice normal (Cho/NAA ≥ 2x) volume, and received spectroscopic MRI scans pre- and mid-RT. Overlap statistics between pre- and mid-RT scans were used to quantify metabolic activity changes after two weeks of RT. Log-rank tests were used to quantify the relationship between imaging metrics and patient overall and progression-free survival (OS/PFS). Patients with lower Jaccard/Dice coefficients had longer PFS (p = 0.045 for both), and patients with lower Jaccard/Dice coefficients had higher OS trending towards significance (p = 0.060 for both). Cho/NAA ≥ 2x volumes changed significantly during early RT, putting healthy tissue at risk of irradiation, and warranting further study into using adaptive RT planning.

Multidisciplinary tumor boards (TB) are an essential part of brain tumor care, but quantifying the impact of imaging on patient management is challenging due to treatment complexity and a lack of quantitative outcome measures. This work uses a structured reporting system for classifying brain tumor MRIs, the brain tumor reporting and data system (BT-RADS), in a TB setting to prospectively assess the impact of imaging review on patient management. Published criteria were used to prospectively assign three separate BT-RADS scores (an initial radiology report, secondary TB presenter review, and TB consensus) to brain MRIs reviewed at an adult brain TB. Clinical recommendations at TB were noted and management changes within 90 days after TB were determined by chart review. In total, 212 MRIs in 130 patients (median age = 57 years) were reviewed. Agreement was 82.2% between report and presenter, 79.0% between report and consensus, and 90.1% between presenter and consensus. Rates of management change increased with increasing BT-RADS scores (0—3.1%, 1a—0%, 1b—66.7%, 2—8.3%, 3a—38.5%, 3b—55.9, 3c—92.0%, and 4—95.6%). Of 184 (86.8%) cases with clinical follow-up within 90 days after the tumor board, 155 (84.2%) of the recommendations were implemented. Structured scoring of MRIs provides a quantitative way to assess rates of agreement interpretation alongside how often management changes are recommended and implemented in a TB setting.

Supplementary Fig. 2 - PDF file 101K, Src and p38-MAPK induces FOXM1 and COX-2 expression and COX-2 regulation requires FOXM1

Cyclooxygenase-2 (COX-2) is linked to poor prognosis in patients with malignant gliomas. Amplification/overexpression of epidermal growth factor receptor (EGFR) is commonly seen in these tumors. EGFR signaling, through activation of the p38-MAPK/PKC-δ/Sp1 cascade, plays an essential role in the regulation of COX-2 expression in glioma cells. Here, we report that Src kinase contributes upstream to this signaling cascade. In addition, more detailed analysis revealed the involvement of FOXM1, a member of the forkhead box family of transcriptional activators, in EGF-dependent COX-2 induction. FOXM1 protein increased after stimulation with EGF, although its role in modulating COX-2 expression does not depend on this increase. While a conventional FOXM1 responsive element resides in a distal region (−2872/−2539 relative to the transcriptional start site) of the COX-2 promoter, this is not required for EGF-dependent induction of COX-2. Instead, FOXM1 forms a cooperative interaction with Sp1 at the Sp1-binding site (-245/-240 relative to the start site) of the COX-2 promoter to mediate EGF-induced COX-2 expression. Definition of this novel interaction provides a clearer understanding of the mechanistic basis for EGF induction of COX-2.Implications: These data provide a guide for the evaluation of potential newer therapeutic targets that have relevance in this disease. Mol Cancer Res; 11(8); 875–86. ©2013 AACR.

Supplementary Fig. 3 - PDF file 87K, Src kinase is upstream of the p38-MAPK/PKC-delta signaling cascade

Supplementary Fig. 6 - PDF file 30K, P2.6 reporter construct display EGF-induced activity

Supplementary Fig. 1 - PDF file 91K, EGFRvIII expression correlates with elevated COX-2 levels

Supplementary Fig. 7 - PDF file 84K,The Sp1-FOXM1 complex is regulated by p38-MAPK but not ERK1/2

Supplementary Fig. 8 - PDF file 207K, FOXM1 overexpression induces COX-2 levels independent of Sp1

Supplementary Fig. 5 - PDF file 146K, PKC-delta and Sp1 are downstream of Src signaling

Supplementary Fig. 4 - PDF file 96K, EGF-dependent signaling to p38-MAPK requires Src activity

Supplementary Figure 1 from Celecoxib Can Induce Vascular Endothelial Growth Factor Expression and Tumor Angiogenesis

Increased COX-2 expression has been linked to increased angiogenesis and a worse prognosis in patients with malignant gliomas and other tumor types. This led to our interest in assessing the response of glioma cell lines to treatment with celecoxib, a selective COX-2 inhibitor. However, contrary to its reported antiangiogenic effects, treatment with celecoxib actually induced the expression of VEGF in multiple glioma as well as other cancer cell lines. This induction of VEGF was comparable to, if not greater than, that found after exposure of cells to hypoxia. Pharmacologic inhibition and siRNA silencing of p38-mitogen-activated protein kinase and the Sp1 transcription factor revealed their involvement in this celecoxib-induced VEGF expression. Consistent with the documented role of Sp1 in this effect, VEGF induction was found to involve transcriptional activation and not to change the stability of VEGF mRNA. The biological significance of this effect was confirmed in vivo by showing both induction of VEGF expression and microvessel density in tumor xenografts and increased angiogenesis in a matrigel plug assay in nude mice that were administered celecoxib. We speculate that treatment with celecoxib may, in some instances, enhance tumor cell expression of VEGF as well as angiogenesis and, consequently, may have detrimental effects on the response of tumors to this drug. Mol Cancer Ther; 10(1); 138–47. ©2011 AACR.

In the United States, flood events are the most economically damaging type of natural disaster. Some of the most widely used tools for understanding property flood risk in the United States are the Flood Insurance Rate Maps (FIRMs) produced by the Federal Emergency Management Agency (FEMA). Numerous previous studies have attempted to estimate the impact on property valuation from a home’s being mapped into a Special Flood Hazard Area (SFHA) within FIRMs. However, as these maps have widely served as the source of data about true flood risk, there have been limits on the ability of researchers to disentangle these zone designation impacts as due to actual flood risk or as due to perceived flood risk. New advancements in flood modeling have allowed for the prediction of high-quality property-level flood inundation, both now and in the future. By integrating these flood modeling advancements, true flood risk may be controlled for in models looking to explore the avenues by which property valuation impacts occur. To this end, this study builds on insights from recent research looking at the valuation of single-family residential properties in Miami-Dade County (MDC), which utilizes a high-resolution floodplain model to estimate the impact of actual property inundation on sales prices. By controlling for actual property flood risk, impacts of SFHA designations are estimated in MDC through implementation of a difference in difference model which utilizes the release of updated FIRMS in 2009 and the 217,222 transactions and 120,693 property designation changes which occurred within the dataset.

Environmental changes are predicted to exacerbate changes in flood events, resulting in consequences for exposed systems. While the availability and quality of flood risk analyses are generally increasing, very little attention has been paid to flood impacts related to the commercial market. This is notable given that the commercial market is often made up of the most valuable physical structures in communities, employs much of the local labor force, and generally plays a key role in the sustainability of economies. This study provides the first national spatial model of flood risk for commercial and multi-unit residential buildings at a property level resolution within the United States. This is achieved through the use of high-resolution inputs (hazard and property data), flood hazard information for the four major flood types, multi-return period hazard information, component-based depth-damage functions, GDP and economic multipliers information, and future facing projections. This study estimates that over the next 30 years, the absolute count of commercial and multi-unit buildings with risk will increase 8%, structural damage costs will increase 25.4%, downtime days will increase 29.1%, and economic impacts will increase 26.5%. Additionally, these impacts are concentrated in certain spatial locations. A high resolution model capturing flood risk as related to these commercial buildings is important for a comprehensive understanding of overall flood risk within the United States.Classification CodesJEL C30, E00, G17, M20, R10, R30

Autoignition and detonation development are foundational events in the combustion community and are fundamentally relevant to engine knocking and detonation propulsion. Autoignition-induced reaction front propagation modes have been extensively investigated, addressing the role of thermal and concentration inhomogeneities. In this work, we have further investigated the nonmonotonic response of detonation development to temperature gradients for low-carbon fuels (hydrogen and syngas) and have found additional detonation regimes, which can depict the panorama of reaction front propagation modes. Results show that separate detonation regimes can be observed when hotspot sizes are below some critical thresholds, with the first corresponding to the known “Bradley detonation peninsula” and the second newly identified featuring broader detonation regions. Despite this, distinct combustion characteristics are observed in the demarcation of detonation regimes between hydrogen and syngas fuels. Specifically, the upper branch of the first detonation regimes for hydrogen is sensitive to temperature gradients at various hotspot sizes, while it exhibits similar behaviors in the lower branch of the second one for syngas, which results in narrower detonation regions. Meanwhile, hydrogen possesses a larger critical hotspot size compared to syngas, and the underlying mechanism is ascribed to the chemical reactivity when hotspot autoignition and the difference of energy density between hotspot interior and exterior. Finally, various detonation regimes are summarized in dimensionless detonation diagrams, in which hydrogen and syngas show similar distributions of detonation peninsula. Despite this, those distinctions in the detonation characteristics between hydrogen and syngas can still be manifested quantitatively. The current work can provide useful insights into knocking inhabitation and detonation promotion.

Background Glioblastomas (GBMs) are aggressive brain tumors despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Spectroscopic magnetic resonance imaging (sMRI), which measures levels of specific brain metabolites, can delineate regions at high risk for GBM recurrence not visualized on contrast-enhanced (CE) MRI. We conducted a clinical trial to assess the feasibility, safety, and efficacy of sMRI-guided RT dose escalation to 75 Gy for newly diagnosed GBMs. Methods Our pilot trial (NCT03137888) enrolled patients at 3 institutions (Emory University, University of Miami, Johns Hopkins University) from September 2017 to June 2019. For RT, standard tumor volumes based on T2-FLAIR and T1w-CE MRIs with margins were treated in 30 fractions to 50.1 and 60 Gy, respectively. An additional high-risk volume based on residual CE tumor and Cho/NAA (on sMRI) ≥2× normal was treated to 75 Gy. Survival curves were generated by the Kaplan–Meier method. Toxicities were assessed according to CTCAE v4.0. Results Thirty patients were treated in the study. The median age was 59 years. 30% were MGMT promoter hypermethylated; 7% harbored IDH1 mutation. With a median follow-up of 21.4 months for censored patients, median overall survival (OS) and progression-free survival were 23.0 and 16.6 months, respectively. This regimen appeared well-tolerated with 70% of grade 3 or greater toxicity ascribed to TMZ and 23% occurring at least 1 year after RT. Conclusion Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for patients with newly diagnosed GBMs. OS outcome is promising and warrants additional testing. Based on these results, a randomized phase II trial is in development.

Fat deposition is higher in fast growing chickens than in slow growing chickens. The liver is the major organ for lipogenesis and fat deposition in chickens, although genetic background, age, and gender also influence fat deposition. In the present study, we aimed to explore the molecular mechanisms underlying fat deposition in liver and abdominal fat. We determined the expression abundances of the key genes regulating fat metabolism in fast-growing (FG) broilers (Cobb) and slow-growing (SG) broilers (HS1) and found that ACC, FAS, PGC-1α, PPARγ, SREBP-1c and PLIN1genes were expressed in the abdominal fat and liver tissues of FG and SG. ANOVA analysis showed that the breed, age, and tissue factors influenced the expressions of ACC, FAS, PGC-1α, PPARγ, SREBP-1c, and PLIN1 genes in the liver and abdominal fat of FG and SG. Also, the expressions of PPARγ and PLIN1 in the liver of SG were higher than that of FG. The results suggest that the differences in adipocyte development and adipose deposition between breeds are due to genetic factors.

Homoepitaxial diamond growth may proceed with stops and resumptions to produce thick (a few millimeters or even larger) crystals or structures with different layers (e.g., doped and intrinsic diamonds). Here, we studied the effect of interrupting and resuming the growth of single crystal diamond films by microwave plasma CVD in CH4–H2 mixtures, with a focus on the change in the surface morphology with the process time. We found a strong impact of the transition period from a pure H2 plasma to a steady state gas composition on the surface relief evolution. The growth resumption starting from a well-ordered step structure is shown to proceed via the destruction of the steps with further recovery. The velocity of the step propagation, ∼32 μm h−1, was determined from the comparison of the step pattern images obtained after each short (30 min) deposition period. For epitaxy on a polished substrate surface, we observed the growth rate retarding very early in the process stage presumably because of the incomplete macroscopic step formation. Using photoluminescence (PL) mapping in the cross-sections of a multilayer epi-film, the depth profiles of silicon-vacancy (SiV) and nitrogen-vacancy (NV) PL intensities were found to show a modulation correlated with the growth history. These results shed light on the origin of defects on inner interfaces in diamond crystals grown in halt-resumption mode.

Analyze the impact of implementing a structured reporting system for primary brain tumors, the Brain Tumor Reporting and Data System, on attitudes toward radiology reports at a single institution.Following Institutional Review Board approval, an initial 22 question, 5 point (1-worst to 5-best), survey was sent to faculty members, house staff members, and nonphysician providers at our institution who participate in the direct care of brain tumor patients. Results were used to develop a structured reporting strategy for brain tumors which was implemented across an entire neuroradiology section in a staged approach. Nine months following structured reporting implementation, a follow-up 27 question survey was sent to the same group of providers. Keyword search of radiology reports was used to assess usage of Brain Tumor Reporting and Data System over time.Fifty-three brain tumor care providers responded to the initial survey and 38 to the follow-up survey. After implementing BT-RADS, respondents reported improved attitudes across multiple areas including: report consistency (4.3 vs. 3.4; p0.001), report ambiguity (4.2 vs. 3.2, p0.001), radiologist/physician communication (4.5 vs. 3.8; p0.001), facilitation of patient management (4.2 vs. 3.6; p = 0.003), and confidence in reports (4.3 vs. 3.5; p0.001). Providers were more satisfied with the BT-RADS structured reporting system (4.3 vs. 3.7; p = 0.04). Use of the reporting template progressively increased with 81% of brain tumor reports dictated using the new template by 9 months.Implementing a structured template for brain tumor imaging improves perception of radiology reports among radiologists and referring providers involved in the care of brain tumor patients.

PURPOSE: Automated synthetic CT (sCT) generation based on magnetic resonance imaging (MRI) images would allow for MRI-only based treatment planning in radiation therapy, eliminating the need for CT simulation and simplifying the patient treatment workflow. In this work, the authors propose a novel method for generation of sCT based on dense cycle-consistent generative adversarial networks (cycle GAN), a deep-learning based model that trains two transformation mappings (MRI to CT and CT to MRI) simultaneously. METHODS AND MATERIALS: The cycle GAN-based model was developed to generate sCT images in a patch-based framework. Cycle GAN was applied to this problem because it includes an inverse transformation from CT to MRI, which helps constrain the model to learn a one-to-one mapping. Dense block-based networks were used to construct generator of cycle GAN. The network weights and variables were optimized via a gradient difference loss and a novel distance loss metric between sCT and original CT. RESULTS: Leave-one-out cross-validation was performed to validate the proposed model. The mean absolute error (MAE), peak signal-to-noise ratio (PSNR) and normalized cross correlation (NCC) indexes were used to quantify the differences between the sCT and original planning CT images. For the proposed method, the mean MAE between sCT and CT were 55.7 Hounsfield units (HU) for 24 brain cancer patients and 50.8 HU for 20 prostate cancer patients. The mean PSNR and NCC were 26.6 dB and 0.963 in the brain cases, and 24.5 dB and 0.929 in the pelvis. CONCLUSION: We developed and validated a novel learning-based approach to generate CT images from routine MRIs based on dense cycle GAN model to effectively capture the relationship between the CT and MRIs. The proposed method can generate robust, high-quality sCT in minutes. The proposed method offers strong potential for supporting near real-time MRI-only treatment planning in the brain and pelvis.

BackgroundStudies including our own have shown that the Medullary Visceral Zone (MVZ) can effectively regulate systemic inflammation and immunity through the Cholinergic Anti-inflammatory Pathway (CAP). Sepsis usually causes neuroinflammation in the Central Nervous System (CNS), which will inevitably affect the structure and function in related brain areas such as MVZ, whether the intervention of CAP can affect the structure and function of the MVZ in sepsis needs to be further verified. Methods64 adults, specific pathogens free Sprague-Dawley male rats were used in this study. The septic models were prepared by cecum ligation and puncture (CLP) method, GTS-21 (a selective α7 nicotinic acetylcholine receptor agonist which can mimic CAP’s activation) and MLA (a powerful and selective nicotine acetylcholine receptor antagonist which can mimic CAP’s blocking) were used to interfere CAP. The pathological changes, apoptosis, the expressions of Tyrosine Hydroxylase (TH) and Choline acetyltransferase (CHAT), the expression levels of GAP-43 mRNA, Olig-2 mRNA, VEGF mRNA, GFAP mRNA, MMP-9 mRNA in MVZ were analyzed among different groups. ResultsIn this study, we found that sepsis induced apoptosis and functional suppression of catecholaminergic and cholinergic neurons and gliosis in MVZ, up-regulated key genes’ expressions such as GAP-43 mRNA，GFAP mRNA，VEGF mRNA，MMP-9 mRNA, down-regulated the expression of Olig-2 mRNA. GTS-21, a selective α7 nicotinic acetylcholine receptor agonist, obviously mitigated the above changes; whereas, methyllycaconitine (MLA), a powerful and selective nicotine acetylcholine receptor antagonist, significantly aggravated these changes. ConclusionsOur research shows that activating CAP can effectively mitigate the neural remodeling and neuronal suppression induced by early sepsis in MVZ, the mechanism may involve with its control of systemic and local inflammation. This study reveals that MVZ and CAP may be potential targets to curb the inflammatory storm in early sepsis.

Background The aim of this study was to assess the reader variability in quantitatively assessing pre- and post-treatment 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) scans in a defined set of images of cancer patients using the same semi-automated analytical software (Auto-PERCIST™), which identifies tumor peak standard uptake value corrected for lean body mass (SULpeak) to determine [18F]FDG PET quantitative parameters. Methods Paired pre- and post-treatment [18F]FDG PET/CT images from 30 oncologic patients and Auto-PERCIST™ semi-automated software were distributed to 13 readers across US and international sites. One reader was aware of the relevant medical history of the patients (readreference), whereas the 12 other readers were blinded to history but had access to the correlative images. Auto-PERCIST™ was set up to first automatically identify the liver and compute the threshold for tumor measurability (1.5 × liver mean) + (2 × liver standard deviation [SD]) and then detect all sites with SULpeak greater than the threshold. Next, the readers selected sites they believed to represent tumor lesions. The main performance metric assessed was the percent change in the SULpeak (%ΔSULpeak) of the hottest tumor identified on the baseline and follow-up images. Results The intra-class correlation coefficient (ICC) for the %ΔSULpeak of the hottest tumor was 0.87 (95%CI: [0.78, 0.92]) when all reads were included (n = 297). Including only the measurements that selected the same target tumor as the readreference (n = 224), the ICC for %ΔSULpeak was 1.00 (95%CI: [1.00, 1.00]). The Krippendorff alpha coefficient for response (complete or partial metabolic response, versus stable or progressive metabolic disease on PET Response Criteria in Solid Tumors 1.0) was 0.91 for all reads (n = 380) and 1.00 including for reads with the same target tumor selection (n = 270). Conclusion Quantitative tumor [18F]FDG SULpeak changes measured across multiple global sites and readers utilizing Auto-PERCIST™ show very high correlation. Harmonization of methods to single software, Auto-PERCIST™, resulted in virtually identical extraction of quantitative tumor response data from [18F]FDG PET images when the readers select the same target tumor.

Nuclear instruments & methods in physics research / A 1004, 165344 (1-9) (2021). doi:10.1016/j.nima.2021.165344, Multiphysics simulations are widely used in designing high average power RF cavities, which require iterations of RF simulation, thermal simulation and mechanical simulation in a closed loop. The reliability and accuracy of the multiphysics simulations are crucial, otherwise extra design margins are needed for simulation uncertainties. We present an experimental benchmark for the multiphysics simulations of a 40 kW L-band RF gun at the Photo Injector Test facility at DESY in Zeuthen (PITZ). The gun temperature distribution and frequency shift due to average RF heating power are measured and compared with multiphysics simulations., Published by North-Holland Publ. Co., Amsterdam

Background: The aim of this study was to assess the reader variability in quantitatively assessing pre- and post-treatment F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scans in a defined set of images of cancer patients using the same semi-automated analytical software (Auto-PERCIST™), which identifies tumor peak standard uptake value corrected for lean body mass (SULpeak) to determine 18F-FDG PET quantitative parameters.Methods: Paired pre- and post-treatment FDG PET/CT images from 30 oncologic patients and Auto-PERCIST™ semi-automated software were distributed to 13 readers across US and international sites. One reader was aware of the relevant medical history of the patients (readreference), whereas the 12 other readers were blinded to history but had access to the correlative images. Auto-PERCIST™ was set up to first automatically identify the liver and compute the threshold for tumor measurability (1.5 x liver mean) + (2 x liver standard deviation [SD]), and then detect all sites with SULpeak greater than the threshold. Next, the readers selected sites they believed to represent tumor lesions. The main performance metric assessed was the percent change in the SULpeak (%ΔSULpeak) of the hottest tumor identified on the baseline and follow up images. Results: The intra-class correlation coefficient (ICC) for the %ΔSULpeak of the hottest tumor was 0.87 (95%CI: [0.78, 0.92]) when all reads were included (n=297). Including only the measurements that selected the same target tumor as the readreference (n=224), the ICC for %ΔSULpeak was 1.00 (95%CI: [1.00, 1.00]). The Krippendorff alpha coefficient for response (complete or partial metabolic response, versus stable or progressive metabolic disease on PET Response Criteria in Solid Tumors 1.0) was 0.91 for all reads (n=380), and 1.00 including for reads with the same target tumor selection (n=270).Conclusion: Quantitative tumor FDG SULpeak changes measured across multiple global sites and readers utilizing Auto-PERCIST™ show very high correlation. Harmonization of methods to single software, Auto-PERCIST™, resulted in virtually identical extraction of quantitative tumor response data from FDG PET images when the readers select the same target tumor.

Background The aim of this study was to assess the reader variability in quantitatively assessing pre- and post-treatment 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) scans in a defined set of images of cancer patients using the same semi-automated analytical software (Auto-PERCIST™), which identifies tumor peak standard uptake value corrected for lean body mass (SULpeak) to determine [18F]FDG PET quantitative parameters. Methods Paired pre- and post-treatment [18F]FDG PET/CT images from 30 oncologic patients and Auto-PERCIST™ semi-automated software were distributed to 13 readers across US and international sites. One reader was aware of the relevant medical history of the patients (readreference), whereas the 12 other readers were blinded to history but had access to the correlative images. Auto-PERCIST™ was set up to first automatically identify the liver and compute the threshold for tumor measurability (1.5 × liver mean) + (2 × liver standard deviation [SD]) and then detect all sites with SULpeak greater than the threshold. Next, the readers selected sites they believed to represent tumor lesions. The main performance metric assessed was the percent change in the SULpeak (%ΔSULpeak) of the hottest tumor identified on the baseline and follow-up images. Results The intra-class correlation coefficient (ICC) for the %ΔSULpeak of the hottest tumor was 0.87 (95%CI: [0.78, 0.92]) when all reads were included (n = 297). Including only the measurements that selected the same target tumor as the readreference (n = 224), the ICC for %ΔSULpeak was 1.00 (95%CI: [1.00, 1.00]). The Krippendorff alpha coefficient for response (complete or partial metabolic response, versus stable or progressive metabolic disease on PET Response Criteria in Solid Tumors 1.0) was 0.91 for all reads (n = 380) and 1.00 including for reads with the same target tumor selection (n = 270). Conclusion Quantitative tumor [18F]FDG SULpeak changes measured across multiple global sites and readers utilizing Auto-PERCIST™ show very high correlation. Harmonization of methods to single software, Auto-PERCIST™, resulted in virtually identical extraction of quantitative tumor response data from [18F]FDG PET images when the readers select the same target tumor.

The last two decades have witnessed two large-scale pandemics caused by coronaviruses, including severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). At the end of 2019, another novel coronavirus, designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hit Wuhan, a city in the center of China, and subsequently spread rapidly to the whole world. Latest reports revealed that more than 800 thousand people in over 200 countries are involved in the epidemic disease by SARS-CoV-2. Due to the high mortality rate and the lack of optimum therapeutics, it is crucial to understand the biological characteristics of the virus and its possible pathogenesis to respond to the SARS-CoV-2. Rapid diagnostics and effective therapeutics are also important interventions for the management of infection control. However, the rapid evolution of SARS-CoV-2 exerted tremendous challenges on its diagnostics and therapeutics. Therefore, there is an urgent need to summarize the existing research results to guide decision-making on the prioritization of resources for research and development. In this review, we focus on our current understanding of epidemiology, pathogenesis, diagnostics and therapeutics of coronavirus disease 2019 (COVID-19).

Nuclear instruments & methods in physics research / A 1027, 166220 (2022). doi:10.1016/j.nima.2021.166220, A three-cell 1.3 GHz, Normal Conducting (NC) buncher is designed for a possible future upgrade of the European X-ray Free Electron Laser (Eu-XFEL) to operate in a continuous-wave (CW)/ long pulse (LP) mode. The RF geometry of the buncher is optimized for high shunt impedance, large mode separation as well as multipacting free in the operation range. The nominal buncher voltage is 400 kV with an RF power dissipation of 14 kW, and its shunt impedance is ∼50% higher than existing CW bunchers. The RF power coupler cell is optimized for field symmetry to minimize coupler kick effect on beam dynamics. The thermal load due to RF power dissipation is analyzed using Multiphysics simulations in CSTMWS and a cooling scheme is designed., Published by North-Holland Publ. Co., Amsterdam

Purpose Radiation oncologists are frequently involved in providing palliative and supportive care (PSC) for patients with advanced cancers through delivery of palliative radiation. Whether they are confident in their ability to assess and initiate treatments for pain, nonpain, and psychosocial distress is unknown. The American Society for Radiation Oncology surveyed its practicing members in the United States on self-assessment of their primary PSC skills and access to continuing medical education on PSC. Methods We electronically surveyed 4093 practicing radiation oncologists in the United States. The survey consisted of 16-questions in 5 sections 1 : demographics, 2 PSC training, 3 domains of PSC, 4 perceived barriers as a radiation oncologist to initiate advanced care planning, and 5 discussion of prognosis. Results The survey was e-mailed to 4093 American Society for Radiation Oncology members, and 649 responses were received (response rate 16%). The majority (91%) of radiation oncologists surveyed believe PSC is an important competency for radiation oncologists. Most radiation oncologists reported that they are moderately confident in their ability to assess and manage pain and gastrointestinal symptoms, but less confident in their ability to manage anorexia, anxiety, and depression. Despite areas of decreased confidence, a large number (42%) of radiation oncologists do not receive any additional PSC education beyond their residency training. Lastly, a perceived fear of upsetting referring medical oncologists and lack of clinic time are concerns for radiation oncologists who may want to initiate goals of care/advance care planning discussions with patients and their families. Conclusion Radiation oncologists are more confident in their ability to assess and manage pain than in their ability to manage depression, anxiety, anorexia, and fatigue. There is a need for increasing continuing medical educational efforts in PSC for practicing radiation oncologists, and strengthening PSC training in residency programs.

The beam power of the CEPC Collider is about 60 MW, so an efficiency of an RF power source is very important for cost of project implementation. The most popular source for an accelerator is a klystron, which has the advantage that it can be operated at high power with a reasonable high efficiency. IHEP is developing 650 MHz klystron with 800 kW CW output power and 80% efficiency. To reach this goal, a couple of klystron prototypes will be manufactured in the near future. The first prototype is completely manufactured by Institute of Electronics (IE) and GLVAC Company and the first step of high-power conditioning and commissioning is also completed in IHEP. The design schemes of high-efficiency klystron are also in progress.

This study evaluated the effects of different amounts (0, 2.5, 5, 10 g/kg) of dietary yeast extract (YE, including 102 g/kg nucleotides) on the milk composition, oxidative stress status, and performance of sows and their offspring. A total of 80 multiparous Large White sows (2-3 of parity) were allotted to 1 of the 4 dietary treatments (0, 2.5, 5, 10 g/kg YE, with 0 g/kg YE used as control (CON)) based on body weight at day 85 of gestation (n=20 per treatment), and the experiment lasted from day 85 of gestation to day 21 of lactation. The reproductive performance of sows and growth performance of piglets were measured. Blood samples were collected from sows and weaning piglets for measuring the level of oxidative stress parameters. The general composition and nucleotide concentrations of colostrum and milk were also measured. Results indicated that, with increasing YE amount in the diet, sows had a linear increase (P ≤ 0.05) in average daily feed intake (ADFI) during the first week of lactation, while a linear decrease (P ≤ 0.01) in body weight loss during lactation. Additionally, the 10 g/kg YE treatment tended to increase the number of weaned piglets per litter (P = 0.08). Furthermore, with increasing YE, the milk exhibited a linear increase (P

BACKGROUND Stereotactic radiosurgery (SRS) is an increasingly common modality used with surgery for resectable brain metastases (BM). OBJECTIVE To present a multi-institutional retrospective comparison of outcomes and toxicities of preoperative SRS (Pre-SRS) and postoperative SRS (Post-SRS). METHODS We reviewed the records of patients who underwent resection of BM and either Pre-SRS or Post-SRS alone between 2005 and 2013 at 2 institutions. Pre-SRS used a dose-reduction strategy based on tumor size, with planned resection within 48 hours. Cumulative incidence with competing risks was used to determine estimated rates. RESULTS A total of 180 patients underwent surgical resection for 189 BM: 66 (36.7%) underwent Pre-SRS and 114 (63.3%) underwent Post-SRS. Baseline patient characteristics were balanced except for higher rates of performance status 0 (62.1% vs 28.9%, P < .001) and primary breast cancer (27.2% vs 10.5%, P = .010) for Pre-SRS. Pre-SRS had lower median planning target volume margin (0 mm vs 2 mm) and peripheral dose (14.5 Gy vs 18 Gy), but similar gross tumor volume (8.3 mL vs 9.2 mL, P = .85). The median imaging follow-up period was 24.6 months for alive patients. Multivariable analyses revealed no difference between groups for overall survival (P = .1), local recurrence (P = .24), and distant brain recurrence (P = .75). Post-SRS was associated with significantly higher rates of leptomeningeal disease (2 years: 16.6% vs 3.2%, P = .010) and symptomatic radiation necrosis (2 years: 16.4% vs 4.9%, P = .010). CONCLUSION Pre-SRS and Post-SRS for resected BM provide similarly favorable rates of local recurrence, distant brain recurrence, and overall survival, but with significantly lower rates of symptomatic radiation necrosis and leptomeningeal disease in the Pre-SRS cohort. A prospective clinical trial comparing these treatment approaches is warranted. ABBREVIATIONS BM, brain metastasesCI, confidence intervalCTV, clinical target volumeDBR, distant brain recurrenceGTV, gross tumor volumeLC, local controlLMD, leptomeningeal diseaseLR, local recurrenceMVA, multivariable analysisOS, overall survivalPost-SRS, postoperative stereotactic radiosurgeryPre-SRS, preoperative stereotactic radiosurgeryPTV, planning target volumeRN, radiation necrosisSRN, symptomatic radiation necrosisSRS, stereotactic radiosurgeryWBRT, whole-brain radiation therapy.

10th International Particle Accelerator Conference, IPAC'19, Melbourne, Australia, 19 May 2019 - 24 May 2019; Journal of physics / Conference series Conference series [...] 1350, 012036 - (2019). doi:10.1088/1742-6596/1350/1/012036, A free-electron laser based THz source is undergoing design studies at the Photo Injector Test facility at DESY in Zeuthen (PITZ). It is considered as a prototype for pump-probe experiments at the European XFEL, benefiting from the fact that the electron beam from the PITZ facility has an identical pulse train structure as the XFEL pulses. In the proposed proof-of-principle experiment, the electron beam (up to 4 nC bunch charge and 200 A peak current) will be accelerated to 16-22 MeV/c to generate SASE radiations in an LCLS-I undulator in the THz range between 60 and 100 pm with an expected energy of up to ~1 mJ/pulse. In this paper, we report our simulations on the optimization of the photo-injector and the design of the transport and matching beamline. Experimental investigations on the generation, characterization and matching of the high charge beam in the existing 22-m-long beamline will also be presented., Published by IOP Publ.20382, Bristol

Local slope, as one of the key attributes of locally coherent events, has been a hot research issue for decades in seismic data processing. However, the estimation of local slopes for intersecting events is still challenging. In this paper, we first detail the multimodality of coherency of intersecting events in the slope domain, and then introduce a multimodal optimization method called neighborhood based crowding differential evolution (NCDE) algorithm to capture their local slopes simultaneously. We demonstrate the effectiveness of the proposed method on both normal gather and super-gather.