17 research outputs found
Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists
Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure. © 2012 Koes et al
Dengue Incidence in Urban and Rural Cambodia: Results from Population-Based Active Fever Surveillance, 2006–2008
Dengue is a major public health problem in South-East Asia. Several dengue vaccine candidates are now in late-stage development and are being evaluated in clinical trials. Accurate estimates of true dengue disease burden will become an important factor in the public-health decision-making process for endemic countries once safe and effective vaccines become available. However, estimates of the true disease incidence are difficult to make, because national surveillance systems suffer from disease under-recognition and reporting. Dengue is mainly reported among children, and in some countries, such as Cambodia, the national case definition only includes hospitalized children. This study used active, community-based surveillance of febrile illness coupled with laboratory testing for DENV infection to identify cases of dengue fever in rural and urban populations. We found a high burden of dengue in young children and late adolescents in both rural and urban communities at a magnitude greater than previously described. The study also confirmed the previously observed focal nature of dengue virus transmission
Multi-parametric MR Imaging Biomarkers Associated to Clinical Outcomes in Gliomas: A Systematic Review
[EN] Purpose: To systematically review evidence regarding the association of multi-parametric biomarkers with clinical outcomes and their capacity to explain relevant subcompartments of gliomas.
Materials and Methods: Scopus database was searched for original journal papers from January 1st, 2007 to February 20th , 2017 according to PRISMA. Four hundred forty-nine abstracts of papers were reviewed and scored independently by two out of six authors. Based on those papers we analyzed associations between biomarkers, subcompartments within the tumor lesion, and clinical outcomes. From all the articles analyzed, the twenty-seven papers with the highest scores were highlighted to represent the evidence about MR imaging biomarkers associated with clinical outcomes. Similarly, eighteen studies defining subcompartments within the tumor region were also highlighted to represent the evidence of MR imaging biomarkers. Their reports were critically appraised according to the QUADAS-2 criteria.
Results: It has been demonstrated that multi-parametric biomarkers are prepared for surrogating diagnosis, grading, segmentation, overall survival, progression-free survival, recurrence, molecular profiling and response to treatment in gliomas. Quantifications and radiomics features obtained from morphological exams (T1, T2, FLAIR, T1c), PWI (including DSC and DCE), diffusion (DWI, DTI) and chemical shift imaging (CSI) are the preferred MR biomarkers associated to clinical outcomes. Subcompartments relative to the peritumoral region, invasion, infiltration, proliferation, mass effect and pseudo flush, relapse compartments, gross tumor volumes, and high-risk regions have been defined to characterize the heterogeneity. For the majority of pairwise cooccurrences, we found no evidence to assert that observed co-occurrences were significantly different from their expected co-occurrences (Binomial test with False Discovery Rate correction, alpha=0.05). The co-occurrence among terms in the studied papers was found to be driven by their individual prevalence and trends in the literature.
Conclusion: Combinations of MR imaging biomarkers from morphological, PWI, DWI and CSI exams have demonstrated their capability to predict clinical outcomes in different management moments of gliomas. Whereas morphologic-derived compartments have been mostly studied during the last ten years, new multi-parametric MRI approaches have also been proposed to discover specific subcompartments of the tumors. MR biomarkers from those subcompartments show the local behavior within the heterogeneous tumor and may quantify the prognosis and response to treatment of gliomas.This work was supported by the Spanish Ministry for Investigation, Development and Innovation project with identification number DPI2016-80054-R.Oltra-Sastre, M.; Fuster García, E.; Juan -Albarracín, J.; Sáez Silvestre, C.; Perez-Girbes, A.; Sanz-Requena, R.; Revert-Ventura, A.... (2019). Multi-parametric MR Imaging Biomarkers Associated to Clinical Outcomes in Gliomas: A Systematic Review. Current Medical Imaging Reviews. 15(10):933-947. https://doi.org/10.2174/1573405615666190109100503S9339471510Louis D.N.; Perry A.; Reifenberger G.; The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016,131(6),803-820Ostrom Q.T.; Gittleman H.; Fulop J.; CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro-oncol 2015,17(Suppl. 4),iv1-iv62Yachida S.; Jones S.; Bozic I.; Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010,467(7319),1114-1117Gerlinger M.; Rowan A.J.; Horswell S.; Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012,366(10),883-892Sottoriva A.; Spiteri I.; Piccirillo S.G.M.; Intratumor heterogeneityin human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci USA 2013,110(10),4009-4014Whiting P.F.; Rutjes A.W.; Westwood M.E.; QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011,155(8),529-536Stupp R.; Mason W.P.; van den Bent M.J.; Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005,352(10),987-996Ponte K.F.; Berro D.H.; Collet S.; In vivo relationship between hypoxia and angiogenesis in human glioblastoma: a multimodal imaging study. J Nucl Med 2017,58(10),1574-1579Pope W.B.; Kim H.J.; Huo J.; Recurrent glioblastoma multiforme: ADC histogram analysis predicts response to bevacizumab treatment. Radiology 2009,252(1),182-189Mörén L.; Bergenheim A.T.; Ghasimi S.; Brännström T.; Johansson M.; Antti H.; Metabolomic screening of tumor tissue and serum in glioma patients reveals diagnostic and prognostic information. Metabolites 2015,5(3),502-520Prager A.J.; Martinez N.; Beal K.; Omuro A.; Zhang Z.; Young R.J.; Diffusion and perfusion MRI to differentiate treatment-related changes including pseudoprogression from recurrent tumors in high-grade gliomas with histopathologic evidence. AJNR Am J Neuroradiol 2015,36(5),877-885Kickingereder P.; Burth S.; Wick A.; Radiomic profiling of glioblastoma: identifying an imaging predictor of patient survival with improved performance over established clinical and radiologic risk models. Radiology 2016,280(3),880-889Yoo R-E.; Choi S.H.; Cho H.R.; Tumor blood flow from arterial spin labeling perfusion MRI: a key parameter in distinguishing high-grade gliomas from primary cerebral lymphomas, and in predicting genetic biomarkers in high-grade gliomas. J Magn Reson Imaging 2013,38(4),852-860Liberman G.; Louzoun Y.; Aizenstein O.; Automatic multi-modal MR tissue classification for the assessment of response to bevacizumab in patients with glioblastoma. Eur J Radiol 2013,82(2),e87-e94Ramadan S.; Andronesi O.C.; Stanwell P.; Lin A.P.; Sorensen A.G.; Mountford C.E.; Use of in vivo two-dimensional MR spectroscopy to compare the biochemistry of the human brain to that of glioblastoma. Radiology 2011,259(2),540-549Xintao H.; Wong K.K.; Young G.S.; Guo L.; Wong S.T.; Support vector machine multi-parametric MRI identification of pseudoprogression from tumor recurrence in patients with resected glioblastoma. J Magn Reson Imaging 2011,33(2),296Ingrisch M.; Schneider M.J.; Nörenberg D.; Radiomic Analysis reveals prognostic information in T1-weighted baseline magnetic resonance imaging in patients with glioblastoma. Invest Radiol 2017,52(6),360-366Ulyte A.; Katsaros V.K.; Liouta E.; Prognostic value of preoperative dynamic contrast-enhanced MRI perfusion parameters for high-grade glioma patients. Neuroradiology 2016,58(12),1197-1208O’Neill A.F.; Qin L.; Wen P.Y.; de Groot J.F.; Van den Abbeele A.D.; Yap J.T.; Demonstration of DCE-MRI as an early pharmacodynamic biomarker of response to VEGF Trap in glioblastoma. J Neurooncol 2016,130(3),495-503Kickingereder P.; Bonekamp D.; Nowosielski M.; Radiogenomics of glioblastoma: machine learning-based classification of molecular characteristics by using multiparametric and multiregional mr imaging features. Radiology 2016,281(3),907-918Roberto S-R.; Antonio R-V.; Luis M-B.; Angel A-B.; Gracián G-M.; Quantitative mr perfusion parameters related to survival time in high-grade gliomas. European Radiology 2013,23(12),3456-3465Jain R.; Poisson L.; Narang J.; Genomic mapping and survival prediction in glioblastoma: molecular subclassification strengthened by hemodynamic imaging biomarkers. Radiology 2013,267(1),212-220Fathi K.A.; Mohseni M.; Rezaei S.; Bakhshandehpour G.; Saligheh R.H.; Multi-parametric (ADC/PWI/T2-W) image fusion approach for accurate semi-automatic segmentation of tumorous regions in glioblastoma multiforme. MAGMA 2015,28(1),13-22Caulo M.; Panara V.; Tortora D.; Data-driven grading of brain gliomas: a multiparametric MR imaging study. Radiology 2014,272(2),494-503Alexiou G.A.; Zikou A.; Tsiouris S.; Comparison of diffusion tensor, dynamic susceptibility contrast MRI and (99m)Tc-Tetrofosmin brain SPECT for the detection of recurrent high-grade glioma. Magn Reson Imaging 2014,32(7),854-859Van Cauter S.; De Keyzer F.; Sima D.M.; Integrating diffusion kurtosis imaging, dynamic susceptibility-weighted contrast-enhanced MRI, and short echo time chemical shift imaging for grading gliomas. Neuro-oncol 2014,16(7),1010-1021Seeger A.; Braun C.; Skardelly M.; Comparison of three different MR perfusion techniques and MR spectroscopy for multiparametric assessment in distinguishing recurrent high-grade gliomas from stable disease. Acad Radiol 2013,20(12),1557-1565Chawalparit O.; Sangruchi T.; Witthiwej T.; Diagnostic performance of advanced mri in differentiating high-grade from low-grade gliomas in a setting of routine service. J Med Assoc Thai 2013,96(10),1365-1373Li Y.; Lupo J.M.; Parvataneni R.; Survival analysis in patients with newly diagnosed glioblastoma using pre- and postradiotherapy MR spectroscopic imaging. Neuro-oncol 2013,15(5),607-617Shankar J.J.S.; Woulfe J.; Silva V.D.; Nguyen T.B.; Evaluation of perfusion CT in grading and prognostication of high-grade gliomas at diagnosis: a pilot study. AJR Am J Roentgenol 2013,200(5)Zinn P.O.; Mahajan B.; Sathyan P.; Radiogenomic mapping of edema/cellular invasion MRI-phenotypes in glioblastoma multiforme. PLoS One 2011,6(10)Matsusue E.; Fink J.R.; Rockhill J.K.; Ogawa T.; Maravilla K.R.; Distinction between glioma progression and post-radiation change by combined physiologic MR imaging. Neuroradiology 2010,52(4),297-306Juan-Albarracín J.; Fuster-Garcia E.; Manjón J.V.; Automated glioblastoma segmentation based on a multiparametric structured unsupervised classification. PLoS One 2015,10(5)Itakura H.; Achrol A.S.; Mitchell L.A.; Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities. Sci Transl Med 2015,7(303)Ion-Margineanu A.; Van Cauter S.; Sima D.M.; Tumour relapse prediction using multiparametric MR data recorded during follow-up of GBM patients. BioMed Res Int 2015,2015Durst C.R.; Raghavan P.; Shaffrey M.E.; Multimodal MR imaging model to predict tumor infiltration in patients with gliomas. Neuroradiology 2014,56(2),107-115Yoon J.H.; Kim J.H.; Kang W.J.; Grading of cerebral glioma with multi-parametric MR Imaging and 18F-FDG-PET: concordance and accuracy. European Radiol 2014,24(2),380-389Demerath T.; Simon-Gabriel C.P.; Kellner E.; Mesoscopic imaging of glioblastomas: are diffusion, perfusion and spectroscopic measures influenced by the radiogenetic phenotype? Neuroradiol J 2017,30(1),36-47Qin L.; Li X.; Stroiney A.; Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma. Neuroradiology 2017,59(2),135-145Boult J.K.R.; Borri M.; Jury A.; Investigating intracranial tumour growth patterns with multiparametric MRI incorporating Gd-DTPA and USPIO-enhanced imaging. NMR Biomed 2016,29(11),1608-1617Server A.; Kulle B.; Gadmar Ø.B.; Josefsen R.; Kumar T.; Nakstad P.H.; Measurements of diagnostic examination performance using quantitative apparent diffusion coefficient and proton MR spectroscopic imaging in the preoperative evaluation of tumor grade in cerebral gliomas. Eur J Radiol 2011,80(2),462-470Chang P.D.; Chow D.S.; Yang P.H.; Filippi C.G.; Lignelli A.; Predicting glioblastoma recurrence by early changes in the apparent diffusion coefficient value and signal intensity on FLAIR images. AJR Am J Roentgenol 2017,208(1),57-65Yi C.; Shangjie R.; Volume of high-risk intratumoralsubregions at multi-parametric MR imaging predicts overall survival and complements molecular analysis of glioblastoma. Eur Radiol 2017,27,3583-3592Khalifa J.; Tensaouti F.; Chaltiel L.; Identification of a candidate biomarker from perfusion MRI to anticipate glioblastoma progression after chemoradiation. Eur Radiol 2016,26(11),4194-4203Prateek P.; Jay P.; Partovi S.; Madabhushi A.; Tiwari P.; Radiomic features from the peritumoral brain parenchyma on treatment-naïve multi-parametric MR imaging predict long versus short-term survival in glioblastomamultiforme: preliminary findings. Eur Radiol 2017,27(10),4188-4197Lemasson B.; Chenevert T.L.; Lawrence T.S.; Impact of perfusion map analysis on early survival prediction accuracy in glioma patients. Transl Oncol 2013,6(6),766-774Inano R.; Oishi N.; Kunieda T.; Visualization of heterogeneity and regional grading of gliomas by multiple features using magnetic resonance-based clustered images. Sci Rep 2016,6,30344Delgado-Goñi T.; Ortega-Martorell S.; Ciezka M.; MRSI-based molecular imaging of therapy response to temozolomide in preclinical glioblastoma using source analysis. NMR Biomed 2016,29(6),732-743Cui Y.; Tha K.K.; Terasaka S.; Prognostic imaging biomarkers in glioblastoma: development and independent validation on the basis of multiregion and quantitative analysis of MR images. Radiology 2016,278(2),546-553Price S.J.; Young A.M.H.; Scotton W.J.; Multimodal MRI can identify perfusion and metabolic changes in the invasive margin of glioblastomas. J Magn Reson Imaging 2016,43(2),487-494Sauwen N.; Acou M.; Van Cauter S.; Comparison of unsupervised classification methods for brain tumor segmentation using multi-parametric MRI. Neuroimage Clin 2016,12,753-764Jena A.; Taneja S.; Gambhir A.; Glioma recurrence versus radiation necrosis: single-session multiparametric approach using simultaneous O-(2-18F-Fluoroethyl)-L-Tyrosine PET/MRI. Clin Nucl Med 2016,41(5),e228-e236Kim H.S.; Goh M.J.; Kim N.; Choi C.G.; Kim S.J.; Kim J.H.; Which combination of MR imaging modalities is best for predicting recurrent glioblastoma? Study of diagnostic accuracy and reproducibility. Radiology 2014,273(3),831-843Christoforidis G.A.; Yang M.; Abduljalil A.; “Tumoral pseudoblush” identified within gliomas at high-spatial-resolution ultrahigh-field-strength gradient-echo MR imaging corresponds to microvascularity at stereotactic biopsy. Radiology 2012,264(1),210-217Wang S.; Kim S.; Chawla S.; Differentiation between glioblastomas, solitary brain metastases, and primary cerebral lymphomas using diffusion tensor and dynamic susceptibility contrast-enhanced MR imaging. AJNR Am J Neuroradiol 2011,32(3),507-514Hanahan D.; Weinberg R.A.; Hallmarks of cancer: the next generation. Cell 2011,144(5),646-674Macdonald D.R.; Cascino T.L.; Schold S.C.; Cairncross J.G.; Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990,8(7),1277-1280Wen P.Y.; Macdonald D.R.; Reardon D.A.; Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010,28(11),1963-1972Sorensen A.G.; Batchelor T.T.; Wen P.Y.; Zhang W-T.; Jain R.K.; Response criteria for glioma. Nat Clin Pract Oncol 2008,5(11),634-644Rosenkrantz A.B.; Friedman K.; Chandarana H.; Current status of hybrid PET/MRI in oncologic imaging. AJR Am J Roentgenol 2016,206(1),162-172Castiglioni I.; Gallivanone F.; Canevari C.; Hybrid PET/MRI for In vivo imaging of cancer: current clinical experiences and recent advances. Curr Med Imaging 2016,12,106Mainta I.C.; Perani D.; Delattre B.M.A.; FDG PET/MR imaging in major neurocognitive disorders. Curr Alzheimer Res 2017,14,186-197Marner L.; Henriksen O.M.; Lundemann M.; Larsen V.A.; Law I.; Clinical PET/MRI in neurooncology: opportunities and challenges from a single-institution perspective. Clin Transl Imaging 2017,5(2),135-149R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria; 2015. Available from: https://www.R-project.org
Management of anaphylaxis due to COVID-19 vaccines in the elderly
Older adults, especially men and/or those with diabetes, hypertension, and/or obesity, are prone to severe COVID-19. In some countries, older adults, particularly those residing in nursing homes, have been prioritized to receive COVID-19 vaccines due to high risk of death. In very rare instances, the COVID-19 vaccines can induce anaphylaxis, and the management of anaphylaxis in older people should be considered carefully. An ARIA-EAACI-EuGMS (Allergic Rhinitis and its Impact on Asthma, European Academy of Allergy and Clinical Immunology, and European Geriatric Medicine Society) Working Group has proposed some recommendations for older adults receiving the COVID-19 vaccines. Anaphylaxis to COVID-19 vaccines is extremely rare (from 1 per 100,000 to 5 per million injections). Symptoms are similar in younger and older adults but they tend to be more severe in the older patients. Adrenaline is the mainstay treatment and should be readily available. A flowchart is proposed to manage anaphylaxis in the older patients.Peer reviewe
フィリピンの小児デングウイルス感染症の重症化に、HLA-A*33:01アレルは防御的に働く
Dengue virus infection is a leading cause of morbidity among children in the Philippines in recent years. In order to investigate the association of HLA Class I and II alleles and dengue disease severity in a cohort of Filipino children, we performed a case control study in 2 hospitals in Metro Manila from June 2008 to December 2009. A total of 250 laboratory confirmed dengue patients and 300 healthy individuals aged 5 to 15 years old were typed for HLA-A, B and DRB1 alleles. The frequency of HLA-A*33:01 was significantly decreased in severe dengue (DHF/ DSS; Pc = 0.0016)) and DSS (Pc = 0.0032) compared to the background population. These findings support a previous study that this allele may confer protection against the severe form of dengue and provide the first evidence of HLA association with dengue in the Philippines. Future studies should be directed in investigating the possible mechanisms of protection.長崎大学学位論文 学位記番号:博(医歯薬)乙第39号 学位授与年月日:平成27年6月3日Author: Edelwisa Segubre Mercado, Fe Esperanza Espino, Ma. Lucila M. Perez, Josie M. Bilar, Jemimah Dawn P. Bajaro, Nguyen Tien Huy, Benilda Q Baello, Mihoko Kikuchi, Kenji HirayamaCitation: PLOS ONE, 10(2), e0115619; 2015Nagasaki University (長崎大学)論文博
Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies
There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity