Relationship between the morphology of A-1 segment of anterior cerebral artery and anterior communicating artery aneurysms

Background: The anterior communicating artery (ACoA) is one of the most frequent sites for cerebral aneurysm. The peculiar directions of projection of aneurysms offer great challenges to clinical treatment. Objetives: To establish the relationship between morphology of A-1 segment of anterior cerebral artery (ACA) and aneurismal projection. Methods: Randomly selected digital subtraction angiography data of 264 anterior communicating artery aneurysms (ACoAA) cases and 296 cases of other cerebral vascular diseases in the same period were retrospectively analyzed. Results: Among 264 ACoAA patients, the morphology of A-1 segment showed type Ⅰa in 158 sides, type Ⅰb in 11, type Ⅱa in 35, type Ⅱb in 87, type Ⅲ in 171 and absence in 66. The morphology of A-1 segment in 296 patients with other cerebral vascular diseases displayed type Ⅰa in 195 sides, type Ⅰb in 20, type Ⅱa in 47, type Ⅱ b in 74, type Ⅲ in 217 and absence in 39. The non-visualization of A-1 segment in the group of ACoAA occurred more than in the control group (χ2=11.482, p=0.001). The classifications of ACoAAs in 264 patients were confirmed as anterior-superior type in 121 cases, anterior-inferior type in 105, complicated type in 16, posterior-inferior type in 12 and posterior-superior type in 10. The correlation between morphology of A-1 segment of ACA and classifications of ACoAA was significant (p=0.000; C=0.619, p=0.000). The direction of ACoAA was downward when the A-1 segment of ACA was Type Ⅰa or Type Ⅱa, and was upward when it was Type Ⅰb or Type Ⅱb，and was upward or downward or complicated when it was Type Ⅲ. Conclusion: The relationship between morphology of A-1 segment of ACA and classification of ACoAA is clarified in the present study, which is helpful to surgical treatment.Keywords: anterior cerebral artery; morphology of A-1 segment; projection of anterior communicating artery aneurysmAfrican Health sciences Vol 14 No. 1 March 201

609 Combining bintrafusp alfa with abituzumab enhances suppression of the TGF-β signaling pathway

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor fused to a human IgG1 antibody blocking PD-L1. The TGF-βRII moiety of bintrafusp alfa functions as a "trap" to sequester active TGF-β but does not block TGF-β release from its latent form. Multiple mechanisms lead to the release of active TGF-β. Integrins control local activation of latent TGF-β stored in the extracellular matrix and cell-surface reservoirs in the tumor microenvironment (TME). Alpha v integrin mRNA expression is correlated with multiple TGF-β gene signatures. It has been shown that αvβ8 integrin mediates TGF-β activation without releasing it from the latent TGF-β complex, suggesting that the TGF-βRII moiety of bintrafusp alfa may be unable to sequester TGF-β activated by αvβ8 integrin. Therefore, we hypothesize that combining abituzumab, a pan–αv integrin antibody, with bintrafusp alfa may lead to enhanced suppression of TGF-β signaling.MethodsThe expression of αv and β6 integrin mRNA was determined by RNA sequencing of triple-negative breast cancer (TNBC) tumor samples from a phase 1 clinical trial of bintrafusp alfa and correlated with patient response to bintrafusp alfa. The combination of bintrafusp alfa and abituzumab was investigated in vitro and in vivo in a TGF-β–dependent human tumor model, Detroit 562. In this study, CellTiter-Glo 2.0 Assay measured cell proliferation in vitro and enzyme-linked immunosorbent assay measured the level of latency-associated protein (LAP). A TGF-β reporter cell line MDA-MB-231 measured the level of active TGF-β. Antitumor activity in vivo was evaluated via tumor growth of Detroit 562 xenograft model in SCID mice.ResultsIn TNBC, increased expression of αv and β6 integrin mRNA was associated with poor response to bintrafusp alfa, suggesting that TGF-β activated by αv integrin may not be blocked by bintrafusp alfa. In Detroit 562 cells, abituzumab increased LAP levels in the cell culture medium, confirming modulation of the TGF-β pathway. As a result, the amount of active TGF-β released into culture medium was reduced by abituzumab. In vitro, both abituzumab and bintrafusp alfa suppressed Detroit 562 cell proliferation, and the combination suppressed cell proliferation further. In vivo, the combination led to increased tumor growth inhibition of Detroit 562 xenograft tumors relative to either monotherapy, further supporting the potential of this combination.ConclusionsCollectively, these preclinical findings support clinical development of bintrafusp alfa and abituzumab combination therapy to maximally suppress TGF-β signaling in the TME.AcknowledgementsWe thank George Locke for his analysis of the RNAseq data.Ethics ApprovalThis study was approved by the Institutional Animal Care and Use Committee at EMD Serono, Inc.; approval number [17–008]

Genetic testing and prognosis of sarcomatoid hepatocellular carcinoma patients

BackgroundSarcomatoid hepatocellular carcinoma (SHC) is a rare epithelial malignancy with high invasiveness and poor prognosis. However, the molecular characteristics and main driver genes for SHC have not been determined. The aim of this study is to explore the potentially actionable mutations of driver genes, which may provide more therapeutic options for SHC.MethodsIn this study, DNA extraction and library preparation were performed using tumor tissues from 28 SHC patients. Then we used Miseq platform (Illumina) to sequence the target-enriched library, and we aligned and processed the sequencing data. The gene groups were tested for SNVs/Indels/CNVs. Tumor mutation burden (TMB) was assessed by the 425-cancer-relevant gene panel. Multivariate analysis of COX’s model was used for survival analysis (OS) of patients’ clinical characteristics.ResultThe median overall survival (OS) of the patients was only 4.4 months. TP53, TERT, and KRAS were the top three frequently mutated genes, with frequencies of 89.3%, 64.3%, and 21.4%, respectively. A considerable number of patients carried mutations in genes involved in the TP53 pathway (96%) and DNA Damage Repair (DDR) pathway (21%). Multiple potentially actionable mutations, such as NTRK1 fusions and BRCA1/2 mutations, were identified in SHCs.ConclusionsThis study shows a landscape of gene mutations in SHC. SHC has high mutation rates in TP53 pathway and DDR pathway. The potentially actionable mutations of driver genes may provide more therapeutic options for SHC. Survival analysis found that age, smoking, drinking, and tumor diameter may be independent prognostic predictors of SHC

Reactivation of mutant p53 in esophageal squamous cell carcinoma by isothiocyanate inhibits tumor growth

p53 mutations are prevalent in human cancers; approximately half of patients with esophageal cancer present these mutations. Mutant p53 (mutp53) exerts oncogenic functions that promote malignant tumor progression, invasion, metastasis, and drug resistance, resulting in poor prognosis. Some small molecules have been shown to mitigate the oncogenic function of mutp53 by restoring its wild-type activity. Although these molecules have been evaluated in clinical trials, none have been successfully used in the clinic. Here, we investigated the antitumor effects of phenethyl isothiocyanate (PEITC) in p53-mutant esophageal squamous cell carcinoma (ESCC) and elucidated its mechanism to identify new therapeutic strategies. We observed that p53R248Q is a DNA contact mutation and a structural mutation and that PEITC can restore the activity of p53R248Qin vitro and in vivo, further clarifying the antitumor activity of PEITC in cancers with different types of p53 mutations. PEITC can inhibit ESCC growth, induce apoptosis, and arrest cell cycle progression and has a preferential selectivity for ESCC with p53 mutations. Mechanistic studies showed that PEITC induced apoptosis and arrested cells at G2/M transition in cells expressing the p53R248Q mutant by restoring the wild-type conformation and transactivation function of p53; these effects were concentration dependent. Furthermore, PEITC inhibited the growth of subcutaneous xenografts in vivo and restored p53 mutant activity in xenografts. According to these findings, PEITC has antitumor effects, with its ability to restore p53R248Q activity being a key molecular event responsible for these effects

Ticagrelor vs Clopidogrel in CYP2C19 loss-of-function carriers with Stroke or TIA

BACKGROUNDComparisons between ticagrelor- aspirin and clopidogrel-aspirin in CYP2C19 loss-of-function carriers have not been well studied for secondary stroke prevention.METHODSWe conducted a randomized, double-blind, placebo-controlled trial of 6,412 patients with a minor ischemic stroke or TIA who carried CYP2C19 LOF alleles determined by point-of-care testing. Patients were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio to receive ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or clopidogrel (300 mg loading dose on day 1 followed by 75 mg per day for days 2 through 90), plus aspirin (75-300 mg loading dose followed by 75 mg daily for 21 days). The primary efficacy outcome was stroke and the primary safety outcome was severe or moderate bleeding, both within 90 days. RESULTSStroke occurred within 90 days in 191 (6.0%) versus 243 (7.6%), respectively (hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P=0.008). Moderate or severe bleeding occurred in 9 patients (0.3%) in the ticagrelor-aspirin group and in 11 patients (0.3%) in the clopidogrel-aspirin group; any bleeding event occurred in 170 patients (5.3%) vs 80 (2.5%), respectively. CONCLUSIONSAmong Chinese patients with minor ischemic stroke or TIA within 24 hours after symptoms onset who were carriers of CYP2C19 loss-of-function alleles, ticagrelor- aspirin was modestly better than clopidogrel-aspirin for reducing the risk of stroke but was associated with more total bleeding events at 90 days. (CHANCE-2 ClinicalTrials.gov number, NCT04078737.

Annual (2023) taxonomic update of RNA-directed RNA polymerase-encoding negative-sense RNA viruses (realm Riboviria: kingdom Orthornavirae: phylum Negarnaviricota)

55 Pág.In April 2023, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by one new family, 14 new genera, and 140 new species. Two genera and 538 species were renamed. One species was moved, and four were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.This work was supported in part through the Laulima Government Solutions, LLC, prime contract with the U.S. National Institute of Allergy and Infec tious Diseases (NIAID) under Contract No. HHSN272201800013C. J.H.K. performed this work as an employee of Tunnell Government Services (TGS), a subcontractor of Laulima Government Solutions, LLC, under Contract No. HHSN272201800013C. U.J.B. was supported by the Division of Intramural Resarch, NIAID. This work was also funded in part by Contract No. HSHQDC15-C-00064 awarded by DHS S and T for the management and operation of The National Biodefense Analysis and Countermeasures Centre, a federally funded research and development centre operated by the Battelle National Biodefense Institute (V.W.); and NIH contract HHSN272201000040I/HHSN27200004/D04 and grant R24AI120942 (N.V., R.B.T.). S.S. acknowl edges support from the Mississippi Agricultural and Forestry Experiment Station (MAFES), USDA-ARS project 58-6066-9-033 and the National Institute of Food and Agriculture, U.S. Department of Agriculture, Hatch Project, under Accession Number 1021494. The funders had no role in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the U.S. Department of the Army, the U.S. Department of Defence, the U.S. Department of Health and Human Services, including the Centres for Disease Control and Prevention, the U.S. Department of Homeland Security (DHS) Science and Technology Directorate (S and T), or of the institutions and companies affiliated with the authors. In no event shall any of these entities have any responsibility or liability for any use, misuse, inability to use, or reliance upon the information contained herein. The U.S. departments do not endorse any products or commercial services mentioned in this publication. The U.S. Government retains and the publisher, by accepting the article for publication, acknowledges that the U.S.Government retains a non-exclusive, paid up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for U.S. Government purposes.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Simulating the Effects of Different Textural Soils and N Management on Maize Yield, N Fates, and Water and N Use Efficiencies in Northeast China

Determining the best management practices (BMPs) for farmland under different soil textures can provide technical support for improving maize yield, water- and nitrogen-use efficiencies (WUE and NUE), and reducing environmental N losses. In this study, a two-year (2013–2014) maize cultivation experiment was conducted on two pieces of farmland with different textural soils (loamy clay and sandy loam) in the Phaeozems zone of Northeast China. Three N fertilizer treatments were designed for each farmland: N168, N240, and N312, with N rates of 168, 240, and 312 kg ha−1, respectively. The WHCNS (soil Water Heat Carbon Nitrogen Simulator) model was calibrated and validated using the observed soil water content, soil nitrate concentration, and crop biological indicators. Then, the effects of soil texture combined with different N rates on maize yield, water consumption, and N fates were simulated. The integrated index considering the agronomic, economic, and environmental impacts was used to determine the BMPs for two textural soils. Results indicated that simulated soil water content and nitrate concentration at different soil depths, leaf area index, dry matter, and grain yield all agreed well with the measured values. Both soil texture and N rates significantly affected maize yield, N fates, WUE, and NUE. The annual average grain yield, WUE, and NUE under three N rates in sandy loam soil were 8257 kg ha−1, 1.9 kg m−3, and 41.2 kg kg−1, respectively, which were lower than those of loam clay, 11440 kg ha−1, 2.7 kg m−3, and 46.7 kg kg−1. The order of annual average yield and WUE under two textural soils was N240 > N312 > N168. The average evapotranspiration of sandy loam (447.3 mm) was higher than that of loamy clay (404.9 mm). The annual average N-leaching amount of different N treatments for sandy loam ranged from 5.1 to 13.2 kg ha−1, which was higher than that of loamy clay soil, with a range of 1.8–5.0 kg ha−1. The gaseous N loss in sandy loam soil accounted for 14.7% of the fertilizer N application rate, while it was 11.1%in loamy clay soil. The order of the NUEs of two textural soils was: N168 > N240 > N312. The recommended N fertilizer rates for sandy loam and loamy clay soils determined by the integrated index were 180 and 200 kg ha−1, respectively

co-creativepen toolkit: a pen-based 3d toolkit for children cooperatly designing virtual environment

Co-CreativePen Toolkit is a pen-based 3D toolkit for children cooperatly designing virtual environment. This toolkit is used to construct different applications involved with distributedpen-based 3D interaction. In this toolkit,sketch method is encapsulated as kinds of interaction techniques. Children can use pen to construct 3D and IBR objects, to navigate in the virtual world, to select and manipulate virtual objects, and to communicate with other children. Children can use pen to select other children in the virtual world, and use pen to write message to children selected The distributed architecture of Co-CreativePen Toolkit is based on the CORBA. A common scene graph is managed in the server with several copies of this graph are managed in every client.Every changes of the scene graph in client will cause the change in the server and other client