المؤلفون: Polidan, Ronald S., Burns, Jack O., Ignatiev, Alex, Hegedus, Alex, Pober, Jonathan, Mahesh, Nivedita, Chang, Tzu-Ching, Hallinan, Gregg, Ning, Yuhong, Bowman, Judd

مصطلحات موضوعية: Astrophysics - Instrumentation and Methods for Astrophysics, Astrophysics - Cosmology and Nongalactic Astrophysics

الوصف: FarView is an early-stage concept for a large, low-frequency radio observatory, manufactured in-situ on the lunar far side using metals extracted from the lunar regolith. It consists of 100,000 dipole antennas in compact subarrays distributed over a large area but with empty space between subarrays in a core-halo structure. FarView covers a total area of ~200 km2, has a dense core within the inner ~36 km2, and a ~power-law falloff of antenna density out to ~14 km from the center. With this design, it is relatively easy to identify multiple viable build sites on the lunar far side. The science case for FarView emphasizes the unique capabilities to probe the unexplored Cosmic Dark Ages - identified by the 2020 Astrophysics Decadal Survey as the discovery area for cosmology. FarView will deliver power spectra and tomographic maps tracing the evolution of the Universe from before the birth of the first stars to the beginning of Cosmic Dawn, and potentially provide unique insights into dark matter, early dark energy, neutrino masses, and the physics of inflation. What makes FarView feasible and affordable in the timeframe of the 2030s is that it is manufactured in-situ, utilizing space industrial technologies. This in-situ manufacturing architecture utilizes Earth-built equipment that is transported to the lunar surface to extract metals from the regolith and will use those metals to manufacture most of the array components: dipole antennas, power lines, and silicon solar cell power systems. This approach also enables a long functional lifetime, by permitting servicing and repair of the observatory. The full 100,000 dipole FarView observatory will take 4 - 8 years to build, depending on the realized performance of the manufacturing elements and the lunar delivery scenario.
Comment: 26 pages, 7 figures, 2 tables

الوصول الحر: http://arxiv.org/abs/2404.03840Test

المؤلفون: Sjöström, Martin, Zhao, Shuang G, Levy, Samuel, Zhang, Meng, Ning, Yuhong, Shrestha, Raunak, Lundberg, Arian, Herberts, Cameron, Foye, Adam, Aggarwal, Rahul, Hua, Junjie T, Li, Haolong, Bergamaschi, Anna, Maurice-Dror, Corinne, Maheshwari, Ashutosh, Chen, Sujun, Ng, Sarah WS, Ye, Wenbin, Petricca, Jessica, Fraser, Michael, Chesner, Lisa, Perry, Marc D, Moreno-Rodriguez, Thaidy, Chen, William S, Alumkal, Joshi J, Chou, Jonathan, Morgans, Alicia K, Beer, Tomasz M, Thomas, George V, Gleave, Martin, Lloyd, Paul, Phillips, Tierney, McCarthy, Erin, Haffner, Michael C, Zoubeidi, Amina, Annala, Matti, Reiter, Robert E, Rettig, Matthew B, Witte, Owen N, Fong, Lawrence, Bose, Rohit, Huang, Franklin W, Luo, Jianhua, Bjartell, Anders, Lang, Joshua M, Mahajan, Nupam P, Lara, Primo N, Evans, Christopher P, Tran, Phuoc T, Posadas, Edwin M, He, Chuan, Cui, Xiao-Long, Huang, Jiaoti, Zwart, Wilbert, Gilbert, Luke A, Maher, Christopher A, Boutros, Paul C, Chi, Kim N, Ashworth, Alan, Small, Eric J, He, Housheng H, Wyatt, Alexander W, Quigley, David A, Feng, Felix Y

المصدر: Cancer Research. 82(21)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Aging, Prostate Cancer, Human Genome, Urologic Diseases, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Male, Humans, 5-Methylcytosine, Prostatic Neoplasms, Prostate, Biopsy, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis

الوصف: Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease.SignificanceIn prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.

الوصول الحر: https://escholarship.org/uc/item/4mx5410zTest

المؤلفون: Almualla, Mouza, Ning, Yuhong, Salehi, Pouyan, Bulla, Mattia, Dietrich, Tim, Coughlin, Michael W., Guessoum, Nidhal

مصطلحات موضوعية: Astrophysics - High Energy Astrophysical Phenomena

الوصف: On the 17th of August, 2017 came the simultaneous detections of GW170817, a gravitational wave that originated from the coalescence of two neutron stars, along with the gamma-ray burst GRB170817A, and the kilonova counterpart AT2017gfo. Since then, there has been much excitement surrounding the study of neutron star mergers, both observationally, using a variety of tools, and theoretically, with the development of complex models describing the gravitational-wave and electromagnetic signals. In this work, we improve upon our pipeline to infer kilonova properties from observed light-curves by employing a Neural-Network framework that reduces execution time and handles much larger simulation sets than previously possible. In particular, we use the radiative transfer code POSSIS to construct 5-dimensional kilonova grids where we employ different functional forms for the angular dependence of the dynamical ejecta component. We find that incorporating an angular dependence improves the fit to the AT2017gfo light-curves by up to ~50% when quantified in terms of the weighted Mean Square Error.

الوصول الحر: http://arxiv.org/abs/2112.15470Test

المؤلفون: Guler, Gulfem D, Ning, Yuhong, Coruh, Ceyda, Mognol, Giuliana P, Phillips, Tierney, Nabiyouni, Maryam, Hazen, Kyle, Scott, Aaron, Volkmuth, Wayne, Levy, Samuel

المساهمون: ClearNote Health

المصدر: Journal for ImmunoTherapy of Cancer ; volume 12, issue 1, page e008028 ; ISSN 2051-1426

الوصف: Background Treatment with immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) can yield durable antitumor responses, yet not all patients respond to ICIs. Current approaches to select patients who may benefit from anti-PD-1 treatment are insufficient. 5-hydroxymethylation (5hmC) analysis of plasma-derived cell-free DNA (cfDNA) presents a novel non-invasive approach for identification of therapy response biomarkers which can tackle challenges associated with tumor biopsies such as tumor heterogeneity and serial sample collection. Methods 151 blood samples were collected from 31 patients with non-small cell lung cancer (NSCLC) before therapy started and at multiple time points while on therapy. Blood samples were processed to obtain plasma-derived cfDNA, followed by enrichment of 5hmC-containing cfDNA fragments through biotinylation via a two-step chemistry and binding to streptavidin coated beads. 5hmC-enriched cfDNA and whole genome libraries were prepared in parallel and sequenced to obtain whole hydroxymethylome and whole genome plasma profiles, respectively. Results Comparison of on-treatment time point to matched pretreatment samples from same patients revealed that anti-PD-1 treatment induced distinct changes in plasma cfDNA 5hmC profiles of responding patients, as judged by Response evaluation criteria in solid tumors, relative to non-responders. In responders, 5hmC accumulated over genes involved in immune activation such as inteferon (IFN)-γ and IFN-α response, inflammatory response and tumor necrosis factor (TNF)-α signaling, whereas in non-responders 5hmC increased over epithelial to mesenchymal transition genes. Molecular response to anti-PD-1 treatment, as measured by 5hmC changes in plasma cfDNA profiles were observed early on, starting with the first cycle of treatment. Comparison of pretreatment plasma samples revealed that anti-PD-1 treatment response and resistance associated genes can be captured by 5hmC profiling of plasma-derived cfDNA. Furthermore, 5hmC profiling of ...

الإتاحة: https://doi.org/10.1136/jitc-2023-008028Test

المؤلفون: Haan, David, Bergamaschi, Anna, Friedl, Verena, Guler, Gulfem D., Ning, Yuhong, Reggiardo, Roman, Kesling, Michael, Collins, Micah, Gibb, Bill, Hazen, Kyle, Bates, Steve, Antoine, Michael, Fraire, Carolina, Lopez, Vanessa, Malta, Roger, Nabiyouni, Maryam, Nguyen, Albert, Phillips, Tierney, Riviere, Michael, Leighton, Anna, Ellison, Christopher, McCarthy, Erin, Scott, Aaron, Gigliotti, Lauren, Nilson, Eric, Sheard, Judith, Peters, Melissa, Bethel, Kelly, Chowdhury, Shimul, Volkmuth, Wayne, Levy, Samuel

المصدر: Clinical Gastroenterology and Hepatology ; volume 21, issue 7, page 1802-1809.e6 ; ISSN 1542-3565

مصطلحات موضوعية: Gastroenterology, Hepatology

الإتاحة: https://doi.org/10.1016/j.cgh.2023.03.016Test
https://api.elsevier.com/content/article/PII:S1542356523002240?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1542356523002240?httpAccept=text/plainTest

المؤلفون: Cui, Xiao-Long, Nie, Ji, Ku, Jeremy, Dougherty, Urszula, West-Szymanski, Diana C., Collin, Francois, Ellison, Christopher K., Sieh, Laura, Ning, Yuhong, Deng, Zifeng, Zhao, Carolyn W. T., Bergamaschi, Anna, Pekow, Joel, Wei, Jiangbo, Beadell, Alana V., Zhang, Zhou, Sharma, Geeta, Talwar, Raman, Arensdorf, Patrick, Karpus, Jason, Goel, Ajay, Bissonnette, Marc, Zhang, Wei, Levy, Samuel, He, Chuan

المساهمون: U.S. Department of Health & Human Services | National Institutes of Health

المصدر: Nature Communications ; volume 11, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: DNA 5-hydroxymethylcytosine (5hmC) modification is known to be associated with gene transcription and frequently used as a mark to investigate dynamic DNA methylation conversion during mammalian development and in human diseases. However, the lack of genome-wide 5hmC profiles in different human tissue types impedes drawing generalized conclusions about how 5hmC is implicated in transcription activity and tissue specificity. To meet this need, we describe the development of a 5hmC tissue map by characterizing the genomic distributions of 5hmC in 19 human tissues derived from ten organ systems. Subsequent sequencing results enabled the identification of genome-wide 5hmC distributions that uniquely separates samples by tissue type. Further comparison of the 5hmC profiles with transcriptomes and histone modifications revealed that 5hmC is preferentially enriched on tissue-specific gene bodies and enhancers. Taken together, the results provide an extensive 5hmC map across diverse human tissue types that suggests a potential role of 5hmC in tissue-specific development; as well as a resource to facilitate future studies of DNA demethylation in pathogenesis and the development of 5hmC as biomarkers.

الإتاحة: https://doi.org/10.1038/s41467-020-20001-wTest
https://www.nature.com/articles/s41467-020-20001-w.pdfTest
https://www.nature.com/articles/s41467-020-20001-wTest

المؤلفون: Guler, Gulfem D., Ning, Yuhong, Ku, Chin-Jen, Phillips, Tierney, McCarthy, Erin, Ellison, Christopher K., Bergamaschi, Anna, Collin, Francois, Lloyd, Paul, Scott, Aaron, Antoine, Michael, Wang, Wendy, Chau, Kim, Ashworth, Alan, Quake, Stephen R., Levy, Samuel

المصدر: Nature Communications ; volume 11, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort ( n = 64) in comparison with a non-cancer cohort ( n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function ( GATA4 , GATA6 , PROX1 , ONECUT1 , MEIS2 ), and cancer pathogenesis ( YAP1 , TEAD1 , PROX1 , IGF1 ). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53 . Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n = 79) and 0.92–0.94 (two independent test sets, n = 228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC = 0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.

الإتاحة: https://doi.org/10.1038/s41467-020-18965-wTest
https://www.nature.com/articles/s41467-020-18965-w.pdfTest
https://www.nature.com/articles/s41467-020-18965-wTest

المؤلفون: Guler, Gulfem, Ning, Yuhong, Haan, David, Kesling, Michael, Coruh, Ceyda, Mognol, Giuliana, Phillips, Tierney, Hazen, Kyle, Volkmuth, Wayne, Levy, Samuel

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2022-sitc2022.0007Test

مستخلص: Provided herein are methods for treating and/or preventing a cancer or a tumor syndrome in a patient, comprising administering an effective amount of a TOR kinase inhibitor to a patient having cancer or a tumor syndrome, characterized by a LKB1 and/or AMPK gene or protein loss or mutation.

المؤلفون: Rychak, Emily, Mendy, Derek, Shi, Tao, Ning, Yuhong, Leisten, Jim, Lu, Ling, Miller, Karen, Narla, Rama K., Orlowski, Robert Z., Raymon, Heather K., Bjorklund, Chad C., Thakurta, Anjan, Gandhi, Anita K., Cathers, Brian E., Chopra, Rajesh, Daniel, Thomas O., Lopez‐Girona, Antonia

المساهمون: Celgene

المصدر: British Journal of Haematology ; volume 172, issue 6, page 889-901 ; ISSN 0007-1048 1365-2141

الوصف: Summary Pomalidomide is an IMiD ® immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rr MM ) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al , ; San Miguel et al , 2013; Richardson et al , 2014; Scott, ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti‐proliferative and pro‐apoptotic activity in both lenalidomide‐sensitive and lenalidomide‐resistant MM cell lines. PomDex also synergistically inhibited tumour growth compared with single‐agent treatment in xenografts of lenalidomide‐resistant H929 R10‐1 cells. Typical hallmarks of IM iD compound activity, including IKZF 3 (Aiolos) degradation, and the downregulation of interferon regulatory factor (IRF) 4 and MYC , seen in lenalidomide‐sensitive H929 MM cell lines, were also observed in PomDex‐treated lenalidomide‐resistant H929 MM cells. Remarkably, this resulted in strong, synergistic effects on the induction of apoptosis in both lenalidomide‐sensitive and resistant MM cells. Furthermore, gene expression profiling revealed a unique differential gene expression pattern in PomDex‐treated samples, highlighted by the modulation of pro‐apoptotic pathways in lenalidomide‐resistant cells. These results provide key insights into molecular mechanisms of PomDex in the lenalidomide‐resistant setting.

الإتاحة: https://doi.org/10.1111/bjh.13905Test