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Proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage in prenatal human brain

NATURE NEUROSCIENCE 2024年第11期27卷 2115页

作者： Chen, Jiapei Crouch, Elizabeth E. Zawadzki, Miriam E. Jacobs, Kyle A. Mayo, Lakyn N. Choi, Jennifer Ja-Yoon Lin, Pin-Yeh Shaikh, Saba Tsui, Jessica Gonzalez-Granero, Susana Waller, Shamari Kelekar, Avani Kang, Gugene Valenzuela, Edward J. Birrueta, Janeth Ochoa Diafos, Loukas N. Wedderburn-Pugh, Kaylee Di Marco, Barbara Xia, Wenlong Han, Claudia Z. Coufal, Nicole G. Glass, Christopher K. Fancy, Stephen P. J. Alfonso, Julieta Kriegstein, Arnold R. Oldham, Michael C. Garcia-Verdugo, Jose Manuel Kutys, Matthew L. Lehtinen, Maria K. Combes, Alexis J. Huang, Eric J. Univ Calif San Francisco Dept Pathol San Francisco CA 94143 USA Univ Calif San Francisco Weill Inst Neurosci San Francisco CA 94143 USA Univ Calif San Francisco Biomed Sci Grad Program San Francisco CA 94143 USA Univ Calif San Francisco Dept Pediat San Francisco CA USA Univ Calif San Francisco Eli & Edythe Broad Ctr Regenerat Med & Stem Cell R San Francisco CA 94143 USA Boston Childrens Hosp Dept Pathol Boston MA USA Harvard Med Sch Boston MA USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA USA Harvard Med Sch Grad Program Biol & Biomed Sci Boston MA USA Univ Calif San Francisco Dept Cell & Tissue Biol San Francisco CA USA Univ Calif San Francisco UCSF UC Berkeley Joint Grad Program Bioengn San Francisco CA USA Univ Calif San Francisco UCSF CoLab San Francisco CA USA Univ Valencia Cavanilles Inst Biodivers & Evolutionary Biol Lab Comparat Neurobiol Valencia Spain ISCIII CIBERNED Valencia Spain Univ Calif San Francisco Dept Neurol Surg San Francisco CA USA Univ Calif San Francisco Dev & Stem Cell Biol Grad Program San Francisco CA 94143 USA Univ Calif San Francisco Med Scientist Training Program San Francisco CA USA Univ Hosp Heidelberg Dept Clin Neurobiol Heidelberg Germany German Canc Res Ctr Heidelberg Germany Univ Calif San Francisco Dept Neurol San Francisco CA USA Univ Calif San Diego Dept Cellular & Mol Med La Jolla CA USA Univ Calif San Diego Dept Pediat San Diego CA USA San Francisco VA Hlth Care Syst Pathol Serv 113B San Francisco CA 94121 USA

Germinal matrix hemorrhage (GMH) is a devastating neurodevelopmental condition affecting preterm infants, but why blood vessels in this brain region are vulnerable to rupture remains unknown. Here we show that microglia in prenatal mouse and human brain interact with nascent vasculature in an age-dependent manner and that ablation of these cells in mice reduces angiogenesis in the ganglionic eminences, which correspond to the human germinal matrix. Consistent with these findings, single-cell transcriptomics and flow cytometry show that distinct subsets of CD45+ cells from control preterm infants employ diverse signaling mechanisms to promote vascular network formation. In contrast, CD45+ cells from infants with GMH harbor activated neutrophils and monocytes that produce proinflammatory factors, including azurocidin 1, elastase and CXCL16, to disrupt vascular integrity and cause hemorrhage in ganglionic eminences. These results underscore the brain's innate immune cells in region-specific angiogenesis and how aberrant activation of these immune cells promotes GMH in preterm infants. Chen et al. show that subtypes of immune cells in prenatal human brain promote angiogenesis in the germinal matrix. Conversely, in preterm infants, proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage.

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PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson's disease

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MOLECULAR NEURODEGENERATION 2020年第1期15卷 20-20页

作者： Ge, Preston Dawson, Valina L. Dawson, Ted M. Johns Hopkins Univ Neuroregenerat & Stem Cell Programs Solomon H Snyder Dept NeurosciSch MedDept Physi Inst Cell EngnDept Pharmacol & Mol SciDept Neur 733 North BroadwaySuite 731 Baltimore MD 21205 USA Adrienne Helis Malvin Med Res Fdn New Orleans LA 70130 USA Diana Helis Henry Med Res Fdn New Orleans LA 70130 USA MIT Dept Brain & Cognit Sci E25-618 Cambridge MA 02139 USA Picower Inst Learning & Memory Cambridge MA 02139 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA

That certain cell types in the central nervous system are more likely to undergo neurodegeneration in Parkinson's disease is a widely appreciated but poorly understood phenomenon. Many vulnerable subpopulations, including dopamine neurons in the substantia nigra pars compacta, have a shared phenotype of large, widely distributed axonal networks, dense synaptic connections, and high basal levels of neural activity. These features come at substantial bioenergetic cost, suggesting that these neurons experience a high degree of mitochondrial stress. In such a context, mechanisms of mitochondrial quality control play an especially important role in maintaining neuronal survival. In this review, we focus on understanding the unique challenges faced by the mitochondria in neurons vulnerable to neurodegeneration in Parkinson's and summarize evidence that mitochondrial dysfunction contributes to disease pathogenesis and to cell death in these subpopulations. We then review mechanisms of mitochondrial quality control mediated by activation of PINK1 and Parkin, two genes that carry mutations associated with autosomal recessive Parkinson's disease. We conclude by pinpointing critical gaps in our knowledge of PINK1 and Parkin function, and propose that understanding the connection between the mechanisms of sporadic Parkinson's and defects in mitochondrial quality control will lead us to greater insights into the question of selective vulnerability.

关键词： Parkinson disease Parkin PINK1 mitochondria mitophagy Selective vulnerability Substantia nigra

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Katanin p80 Regulates Human Cortical Development by Limiting Centriole and Cilia Number

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NEURON 2014年第6期84卷 1240-1257页

作者： Hu, Wen F. Pomp, Oz Ben-Omran, Tawfeg Kodani, Andrew Henke, Katrin Mochida, Ganeshwaran H. Yu, Timothy W. Woodworth, Mollie B. Bonnard, Carine Raj, Grace Selva Tan, Thong Teck Hamamy, Hanan Masri, Amira Shboul, Mohammad Al Saffar, Muna Partlow, Jennifer N. Al-Dosari, Mohammed Alazami, Anas Alowain, Mohammed Alkuraya, Fowzan S. Reiter, Jeremy F. Harris, Matthew P. Reversade, Bruno Walsh, Christopher A. Boston Childrens Hosp Dept Med Div Genet & Genom Boston MA 02115 USA Boston Childrens Hosp Manton Ctr Orphan Dis Res Boston MA 02115 USA Boston Childrens Hosp Howard Hughes Med Inst Boston MA 02115 USA Boston Childrens Hosp Dept Orthoped Res Boston MA 02115 USA Harvard Univ Sch Med Program Neurosci Boston MA 02115 USA Harvard Univ Sch Med Harvard MD PhD MSTP Program Boston MA 02115 USA Harvard Univ Sch Med Dept Pediat Boston MA 02115 USA Harvard Univ Sch Med Dept Neurol Boston MA 02115 USA Harvard Univ Sch Med Dept Genet Boston MA 02115 USA Massachusetts Gen Hosp Dept Neurol Pediat Neurol Unit Boston MA 02114 USA Broad Inst MIT & Harvard Univ Program Med & Populat Genet Cambridge MA 02142 USA Hamad Med Corp Dept Pediat Clin & Metab Genet Div Doha 3050 Qatar United Arab Emirates Univ Fac Med & Hlth Sci Dept Pediat Al Ain U Arab Emirates King Faisal Specialist Hosp & Res Ctr Dept Genet Riyadh 11211 Saudi Arabia King Faisal Specialist Hosp & Res Ctr Dept Med Genet Riyadh 11211 Saudi Arabia Alfaisal Univ Coll Med Dept Anat & Cell Biol Riyadh 11533 Saudi Arabia King Saud Univ Coll Pharm Dept Pharmacognosy Riyadh 11451 Saudi Arabia Univ Calif San Francisco Cardiovasc Res Inst Dept Biochem & Biophys San Francisco CA 94158 USA ASTAR Human Genet & Embryol Lab Med Biol Inst Singapore 138648 Singapore ASTAR Inst Mol & Cellular Biol Singapore 138648 Singapore Univ Geneva Dept Genet Med & Dev CH-1211 Geneva Switzerland Natl Univ Singapore Dept Paediat Singapore 119260 Singapore Univ Jordan Fac Med Dept Paediat Amman 11942 Jordan

Katanin is a microtubule-severing complex whose catalytic activities are well characterized, but whose in vivo functions are incompletely understood. Human mutations in KATNB1, which encodes the noncatalytic regulatory p80 subunit of katanin, cause severe microlissencephaly. Loss of Katnb1 in mice confirms essential roles in neurogenesis and cell survival, while loss of zebrafish katnb1 reveals specific roles for katnin p80 in early and late developmental stages. Surprisingly, Katnb1 null mutant mouse embryos display hallmarks of aberrant Sonic hedgehog signaling, including holoprosencephaly. KATNB1-deficient human cells show defective proliferation and spindle structure, while Katnb1 null fibroblasts also demonstrate a remarkable excess of centrioles, with supernumerary cilia but deficient Hedgehog signaling. Our results reveal unexpected functions for KATNB1 in regulating overall centriole, mother centriole, and cilia number, and as an essential gene for normal Hedgehog signaling during neocortical development.

关键词： Adenosine Triphosphatases/genetics Adenosine Triphosphatases/physiology Animals Case-Control Studies Cell Proliferation/genetics Cell Proliferation/physiology Centrioles/genetics Centrioles/genetics Centrioles/physiology Centrioles/physiology Cerebral Cortex/abnormalities Cerebral Cortex/cytology Cerebral Cortex/embryology Cerebral Cortex/metabolism Cilia/genetics Cilia/physiology Embryo, Mammalian Embryonic Development/genetics European Continental Ancestry Group/genetics Fibroblasts/metabolism Hedgehog Proteins/genetics Hedgehog Proteins/metabolism Humans Mice Microcephaly/genetics Mutation Pedigree RNA Splicing/genetics Zebrafish

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Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus

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NEURON 2023年第10期111卷 1591-1608.e4页

作者： Sadegh, Cameron Xu, Huixin Sutin, Jason Fatou, Benoit Gupta, Suhasini Pragana, Aja Taylor, Milo Kalugin, Peter N. Zawadzki, Miriam E. Alturkistani, Osama Shipley, Frederick B. Dani, Neil Fame, Ryann M. Wurie, Zainab Talati, Pratik Schleicher, Riana L. Klein, Eric M. Zhang, Yong Holtzman, Michael J. Moore, Christopher I. Lin, Pei-Yi Patel, Aman B. Warf, Benjamin C. Kimberly, W. Taylor Steen, Hanno Andermann, Mark L. Lehtinen, Maria K. Boston Childrens Hosp Dept Pathol Boston MA 02115 USA Harvard Med Sch Boston MA 02115 USA Massachusetts Gen Hosp Dept Neurosurg Boston MA 02114 USA Harvard Med Sch Boston Childrens Hosp Fetal Neonatal Neuroimaging & Dev Sci Ctr Boston MA 02115 USA Boston Childrens Hosp Cellular Imaging Core Boston MA 02115 USA Harvard Univ Harvard Coll Cambridge MA 02138 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Med Sch Grad Program Neurosci Boston MA 02115 USA Harvard Med Sch Grad Program Biol & Biomed Sci Boston MA 02115 USA Harvard Univ Grad Program Biophys Cambridge MA 02138 USA Massachusetts Gen Hosp Dept Neurol Boston MA 02114 USA Brown Univ Carney Inst Brain Sci Providence RI 02912 USA Washington Univ Dept Med Pulm & Crit Care Med St Louis MO 63110 USA Boston Childrens Hosp Dept Neurosurg Boston MA 02115 USA Boston Childrens Hosp Precis Vaccines Program Boston MA 02115 USA Beth Israel Deaconess Med Ctr Dept Med Div Endocrinol Diabet & Metab Boston MA USA

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably pro-gressive condition has hampered the development of new therapies beyond serial neurosurgical interven-tions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K+] and triggered cyto-solic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to miti-gate ventriculomegaly. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in hu-mans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.

关键词： Cerebrospinal fluid choroid plexus hydrocephalus gene therapy ventricles intraventricular hemorrhage NKCC1 adeno-associated virus epithelial cells

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SARS-CoV-2 epitope-specific CD4(+) memory T cell responses across COVID-19 disease severity and antibody durability

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SCIENCE IMMUNOLOGY 2022年第73期7卷 eabl9464页

作者： Nelson, Ryan W. Chen, Yuezhou Venezia, Olivia L. Majerus, Richard M. Shin, Daniel S. Carrington, Mary N. Yu, Xu G. Wesemann, Duane R. Moon, James J. Luster, Andrew D. Harvard Med Sch Ctr Immunol & Inflammatory Dis Massachusetts Gen Hosp Boston MA 02115 USA Harvard Med Sch Div Rheumatol Allergy & Immunol Massachusetts Gen Hosp Boston MA 02115 USA Harvard Med Sch Boston Childrens Hosp Div Immunol Boston MA 02115 USA Harvard Med Sch Brigham & Womens Hosp Dept Med Div Allergy & Clin Immunol Boston MA 02115 USA Harvard Med Sch Brigham & Womens Hosp Div Genet Boston MA 02115 USA Harvard Med Sch Brigham & Womens Hosp Infect Dis Div Boston MA 02115 USA Queens Univ Charlotte Charlotte NC USA Ragon Inst MGH MIT & Harvard Cambridge MA USA NCI Basic Sci Program Frederick Natl Lab Canc Res Frederick MD 21701 USA NCI Lab Integrat Canc Immunol Ctr Canc Res Bethesda MD USA Harvard Med Sch Div Pulm & Crit Care Med Massachusetts Gen Hosp Boston MA 02115 USA Harvard Immunol PhD Program Boston MA USA

CD4(+) T cells are central to long-term immunity against viruses through the functions of T helper 1 (T(H)1) and T follicular helper (TFH) cell subsets. To better understand the role of these subsets in coronavirus disease 2019 (COVID-19) immunity, we conducted a longitudinal study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4(+) T cell and antibody responses in convalescent individuals who seroconverted during the first wave of the pandemic in Boston, MA, USA, across a range of COVID-19 disease severities. Analyses of spike (S) and nucleocapsid (N) epitope-specific CD4(+) T cells using peptide and major histocompatibility complex class II (pMHCII) tetramers demonstrated expanded populations of T cells recognizing the different SARS-CoV-2 epitopes in most individuals compared with prepandemic controls. Individuals who experienced a milder disease course not requiring hospitalization had a greater percentage of circulating T-FH (cT(FH)) and T(H)1 cells among SARS-CoV-2-specific cells. Analysis of SARS-CoV-2-specific CD4(+) T cells responses in a subset of individuals with sustained anti-S antibody responses after viral clearance also revealed an increased proportion of memory cT(FH) cells. Our findings indicate that efficient early disease control also predicts favorable long-term adaptive immunity.

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Smoking and Risk of Colorectal Cancer Sub-classified by Tumor-infiltrating T Cells (vol 111, pg 42, 2019)

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JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE 2019年第12期111卷 1365-1365页

作者： Hamada, Tsuyoshi Department of Oncologic Pathology Department of Medical Oncology Dana-Farber Cancer Institute and Harvard Medical School Boston MAProgram in Molecular Pathological Epidemiology Department of Pathology Department of Oncologic Pathology Clinical and Translational Epidemiology Unit and Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA Clinical and Translational Epidemiology Unit and Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MADepartment of Nutrition Clinical and Translational Epidemiology Unit and Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MADepartment of NutritionDivision of Public Health Sciences Department of Surgery Washington University School of Medicine St. Louis MO Department of Oncologic Pathology Department of Medical Oncology Dana-Farber Cancer Institute and Harvard Medical School Boston MA Department of Oncologic Pathology Department of Oncologic PathologyDepartment of NutritionDivision of Public Health Sciences Department of Surgery Washington University School of Medicine St. Louis MODepartment of Epidemiology and Biostatistics and the Ministry of Education Key Lab of Environment and Health School of Public Health Huazhong University of Science and Technology Hubei P.R. China Department of Oncologic PathologyDepartment of Medical Oncology Chinese PLA General Hospital Beijing P.R. China Department of Oncologic Pathology Department of Oncologic PathologyCollege of Pharmacy Zhejiang Chinese Medical University Zhejiang P.R. China Department of Oncologic Pathology Department of Gastroenterology Rheumatology and Clinical Immunology Sapporo Medical University School of Medicine Sapporo Japan Department of NutritionDepartment of Food Science and Biotechnology Dongguk University Goyang the Republic of Korea Department of Medical Oncology Dana-Farber Cancer Institute and Harvard Medical School Boston MADepartment of

BackgroundEvidence indicates not only carcinogenic effect of cigarette smoking but also its immunosuppressive effect. We hypothesized that the association of smoking with colorectal cancer risk might be stronger for tumors with lower anti-tumor adaptive immune *** follow-up of 134 981 participants (3 490 851 person-years) in the Nurses’ Health Study and Health Professionals Follow-up Study, we documented 729 rectal and colon cancer cases with available data on T-cell densities in tumor microenvironment. Using the duplication-method Cox regression model, we examined a differential association of smoking status with risk of colorectal carcinoma subclassified by densities of CD3⁺ cells, CD8⁺ cells, CD45RO (PTPRC)⁺ cells, or FOXP3⁺ cells. All statistical tests were *** association of smoking status with colorectal cancer risk differed by CD3⁺ cell density (P_{heterogeneity} = .007). Compared with never smokers, multivariable-adjusted hazard ratios for CD3⁺ cell-low colorectal cancer were 1.38 (95% confidence interval = 1.09 to 1.75) in former smokers and 1.59 (95% confidence interval = 1.14 to 2.23) in current smokers (P_trend = .002, across smoking status categories). In contrast, smoking status was not associated with CD3⁺ cell-high cancer risk (P_trend = .52). This differential association appeared consistent in strata of microsatellite instability, CpG island methylator phenotype, or BRAF mutation status. There was no statistically significant differential association according to densities of CD8⁺ cells, CD45RO⁺ cells, or FOXP3⁺ cells (P_{heterogeneity} > .04, with adjusted α of 0.01).ConclusionsColorectal cancer risk increased by smoking was stronger for tumors with lower T-lymphocyte response, suggesting an interplay of smoking and immunity in colorectal carcinogenesis.

关键词： Association (Psychology) cancer risk Smoking Colorectal Cancer Cancer of Colon Cigarette Smoking Immunosuppression (Physiology) Adaptive Immune Response Tumours T-Lymphocytes cigarette smoke

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Targeting oncoproteins with a positive selection assay for protein degraders

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SCIENCE ADVANCES 2021年第6期7卷 000-000页

作者： Koduri, Vidyasagar Duplaquet, Leslie Lampson, Benjamin L. Wang, Adam C. Sabet, Amin H. Ishoey, Mette Paulk, Joshiawa Teng, Mingxing Harris, Isaac S. Endress, Jennifer E. Liu, Xiaoxi Dasilva, Ethan Paulo, Joao A. Briggs, Kimberly J. Doench, John G. Ott, Christopher J. Zhang, Tinghu Donovan, Katherine A. Fischer, Eric S. Gygi, Steven P. Gray, Nathanael S. Bradner, James Medin, Jeffrey A. Buhrlage, Sara J. Oser, Matthew G. Kaelin, William G., Jr. Dana Farber Canc Inst Dept Med Oncol Boston MA 02215 USA Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA Harvard Med Sch Dept Biol Chem & Mol Pharmacol Boston MA 02115 USA Ludwig Canc Ctr Boston MA 02115 USA Harvard Med Sch Dept Cell Biol Boston MA 02115 USA Dana Farber Canc Inst Linde Program Chem Biol Boston MA 02215 USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Novartis Inst Biomed Res Cambridge MA 02139 USA Med Coll Wisconsin Dept Pediat 8701 Watertown Plank Rd Milwaukee WI 53226 USA Med Coll Wisconsin Dept Biochem Milwaukee WI 53226 USA Dana Farber Canc Inst Lowe Ctr Thorac Oncol Boston MA 02215 USA Harvard Med Sch Brigham & Womens Hosp Dept Med Boston MA 02215 USA Howard Hughes Med Inst Chevy Chase MD 20815 USA Univ Rochester Med Ctr Dept Biomed Genet 601 Elmwood Ave Rochester NY 14642 USA Univ Rochester Med Ctr Wilmot Canc Inst 601 Elmwood Ave Rochester NY 14642 USA Weill Cornell Med Meyer Canc Ctr New York NY 10021 USA Weill Cornell Med Biochem Struct Dev Cell & Mol Biol Allied PhD Pro New York NY 10021 USA Tango Therapeut Cambridge MA 02142 USA

Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcription factors IKZF1 and IKZF3 by recruiting them to the cereblon E3 ubiquitin ligase. Current loss of signal ("down") assays for identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic ranges, and false positives from compounds that nonspecifically suppress transcription or translation. Here, we describe a gain of signal ("up") assay for degraders. In arrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner. In a pooled CRISPR-Cas9-based screen, we found that CDK2 regulates the abundance of the ASCL1 oncogenic transcription factor. This methodology should facilitate the identification of drugs that directly or indirectly degrade undruggable proteins.

关键词： Transcription factors

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Parametric modeling of cellular state transitions as measured with flow cytometry

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BMC BIOINFORMATICS 2012年第s5期13卷 S5-S5页

作者： Ho, Hsiu J. Lin, Tsung I. Chang, Hannah H. Haase, Steven B. Huang, Sui Pyne, Saumyadipta Natl Chung Hsing Univ Dept Appl Math Taichung 402 Taiwan Natl Chung Hsing Univ Inst Stat Taichung 402 Taiwan China Med Univ Dept Publ Hlth Taichung 404 Taiwan Harvard Univ Sch Med Childrens Hosp Boston Dept Pathol & Surg Boston MA 02115 USA Harvard Univ Program Biophys Cambridge MA 02139 USA Harvard Univ Sch Med MD PhD Program Boston MA 02115 USA Duke Univ Dept Biol Durham NC USA Univ Calgary Inst Biocomplex & Informat Calgary AB T2N 1N4 Canada Broad Inst MIT & Harvard Univ Cambridge MA 02142 USA Harvard Univ Sch Med Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA

Background: Gradual or sudden transitions among different states as exhibited by cell populations in a biological sample under particular conditions or stimuli can be detected and profiled by flow cytometric time course data. Often such temporal profiles contain features due to transient states that present unique modeling challenges. These could range from asymmetric non-Gaussian distributions to outliers and tail subpopulations, which need to be modeled with precision and rigor. Results: To ensure precision and rigor, we propose a parametric modeling framework StateProfiler based on finite mixtures of skew t-Normal distributions that are robust against non-Gaussian features caused by asymmetry and outliers in data. Further, we present in StateProfiler a new greedy EM algorithm for fast and optimal model selection. The parsimonious approach of our greedy algorithm allows us to detect the genuine dynamic variation in the key features as and when they appear in time course data. We also present a procedure to construct a well-fitted profile by merging any redundant model components in a way that minimizes change in entropy of the resulting model. This allows precise profiling of unusually shaped distributions and less well-separated features that may appear due to cellular heterogeneity even within clonal populations. Conclusions: By modeling flow cytometric data measured over time course and marker space with StateProfiler, specific parametric characteristics of cellular states can be identified. The parameters are then tested statistically for learning global and local patterns of spatio-temporal change. We applied StateProfiler to identify the temporal features of yeast cell cycle progression based on knockout of S-phase triggering cyclins Clb5 and Clb6, and then compared the S-phase delay phenotypes due to differential regulation of the two cyclins. We also used StateProfiler to construct the temporal profile of clonal divergence underlying lineage selection in m

关键词： Probability Density Function Finite Mixture Clonal Population Parsimonious Approach Merging Procedure

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Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors

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SCIENCE ADVANCES 2023年第39期9卷 eadd9668页

作者： Hoffman, Samantha E. Dowrey, Todd W. Villacorta Martin, Carlos Bi, Kevin Titchen, Breanna Johri, Shreya Dellostritto, Laura Patel, Miraj Mackichan, Colin Inga, Stephanie Chen, Judy Grimaldi, Grace Napolitano, Sara Wakiro, Isaac Wu, Jingyi Yeung, Jason Rotem, Asaf Sicinska, Ewa Shannon, Erin Clancy, Thomas Wang, Jiping Denning, Sarah Brais, Lauren Besson, Naomi R. Pfaff, Kathleen L. Huang, Ying Kao, Katrina Z. Rodig, Scott Hornick, Jason L. Vigneau, Sebastien Park, Jihye Kulke, Matthew H. Chan, Jennifer Van Allen, Eliezer M. Murphy, George J. Harvard Med Sch Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA Broad Inst Harvard & MIT Cambridge MA 02142 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Med Sch PhD Program Biol & Biomed Sci Div Med Sci Boston MA 02115 USA Boston Univ Sch Med Sect Hematol & Med Oncol Boston MA 02118 USA Boston Med Ctr Boston MA 02118 USA Boston Univ Ctr Regenerat Med Boston MA 02118 USA Harvard Pilgrim Hlth Care Inst Boston MA 02215 USA Dana Farber Canc Inst Ctr Canc Genom Boston MA 02115 USA Harvard Med Sch Brigham & Womens Hosp Dept Pathol Boston MA 02115 USA Harvard Med Sch Brigham & Womens Hosp Dept Surg Boston MA 02115 USA Dana Farber Canc Inst Ctr Immunooncol Boston MA 02115 USA Dana Farber Canc Inst Mol Diagnost Lab Boston MA 02115 USA Viome Bothell WA 98011 USA Yale Sch Publ Hlth New Haven CT 06510 USA Mem Sloan Kettering Canc Ctr New York NY 10065 USA Univ Rochester Rochester NY 14627 USA Boston Univ Boston MA 02215 USA AstraZeneca Waltham MA 02451 USA Novartis Inst Biomed Res Cambridge MA 02139 USA Ginkgo Bioworks Boston MA 02210 USA

Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)-NET growth remain incompletely elucidated;however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation, and fate determination stages. Tumor and lymphoid compartments sparsely expressed immunosuppressive targets commonly investigated in clinical trials, such as the programmed cell death protein-1/programmed death ligand-1 axis. However, infiltrating myeloid cell types within both primary and metastatic GEP-NETs were enriched for genes encoding other immune checkpoints, including VSIR (VISTA), HAVCR2 (TIM3), LGALS9 (Gal-9), and SIGLEC10. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.

关键词： Tumors

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Recent oncolytic virotherapy clinical trials outline a roadmap for the treatment of high-grade glioma

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NEURO-ONCOLOGY ADVANCES 2023年第1期5卷 vdad081页

作者： Bernstock, Joshua D. Blitz, Sarah E. Hoffman, Samantha E. Gerstl, Jakob V. E. Chiocca, E. Antonio Friedman, Gregory K. Harvard Med Sch Brigham & Womens Hosp Dept Neurosurg Boston MA USA Boston Childrens Hosp Harvard Med Sch Dept Neurosurg Boston MA USA MIT David H Koch Inst Integrat Canc Res Cambridge MA USA Harvard Med Sch Boston MA USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA USA Univ Alabama Birmingham Dept Pediat Div Pediat Hematol & Oncol Birmingham AL USA Univ Alabama Birmingham Comprehens Canc Ctr Birmingham AL USA Harvard Med Sch Brigham & Womens Hosp Boston Childrens Hosp Dept Neurosurg Hale Bldg60 Fenwood Rd Boston MA 02115 USA

Adult and pediatric high-grade gliomas (HGGs) are aggressive cancers of the central nervous system that confer dismal clinical prognoses. Standard radiation and chemotherapy have demonstrated only limited efficacy in HGGs, motivating the accelerated investigation of novel modalities such as oncolytic virus (OV) therapies. OV centered therapies work through a mixed mechanism centered on oncolysis and the stimulation of an antitumor immune response. Three recent clinical trials utilizing herpes simplex virus-1 and adenovirus-based oncolytic virotherapy demonstrated not only the safety and efficacy of OVs but also novel dosing strategies that augment OV response potential. Considering these recent trials, herein we present a roadmap for future clinical trials of oncolytic immunovirotherapy in both adult and pediatric HGG, as well as persistent roadblocks related to the assessment of OV efficacy within and between trials.

关键词： brain tumors high-grade glioma immunotherapy neuro-oncology neurosurgery oncolytic virotherapy pediatrics

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