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  1. Article ; Online: VEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model.

    Boisserand, Ligia Simoes Braga / Geraldo, Luiz Henrique / Bouchart, Jean / El Kamouh, Marie-Renee / Lee, Seyoung / Sanganahalli, Basavaraju G / Spajer, Myriam / Zhang, Shenqi / Lee, Sungwoon / Parent, Maxime / Xue, Yuechuan / Skarica, Mario / Yin, Xiangyun / Guegan, Justine / Boyé, Kevin / Saceanu Leser, Felipe / Jacob, Laurent / Poulet, Mathilde / Li, Mingfeng /
    Liu, Xiodan / Velazquez, Sofia E / Singhabahu, Ruchith / Robinson, Mark E / Askenase, Michael H / Osherov, Artem / Sestan, Nenad / Zhou, Jiangbing / Alitalo, Kari / Song, Eric / Eichmann, Anne / Sansing, Lauren H / Benveniste, Helene / Hyder, Fahmeed / Thomas, Jean-Leon

    The Journal of experimental medicine

    2024  Volume 221, Issue 4

    Abstract: Meningeal lymphatic vessels (MLVs) promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelial growth factor-C (VEGF-C) regulates MLV development and maintenance and has therapeutic potential for treating ... ...

    Abstract Meningeal lymphatic vessels (MLVs) promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelial growth factor-C (VEGF-C) regulates MLV development and maintenance and has therapeutic potential for treating neurological disorders. Herein, we investigated the effects of VEGF-C overexpression on brain fluid drainage and ischemic stroke outcomes in mice. Intracerebrospinal administration of an adeno-associated virus expressing mouse full-length VEGF-C (AAV-mVEGF-C) increased CSF drainage to the deep cervical lymph nodes (dCLNs) by enhancing lymphatic growth and upregulated neuroprotective signaling pathways identified by single nuclei RNA sequencing of brain cells. In a mouse model of ischemic stroke, AAV-mVEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage, associated with mitigated microglia-mediated inflammation and increased BDNF signaling in brain cells. Neuroprotective effects of VEGF-C were lost upon cauterization of the dCLN afferent lymphatics and not mimicked by acute post-stroke VEGF-C injection. We conclude that VEGF-C prophylaxis promotes multiple vascular, immune, and neural responses that culminate in a protection against neurological damage in acute ischemic stroke.
    MeSH term(s) Animals ; Mice ; Vascular Endothelial Growth Factor C ; Neuroinflammatory Diseases ; Ischemic Stroke ; Drainage ; Stroke
    Chemical Substances Vascular Endothelial Growth Factor C
    Language English
    Publishing date 2024-03-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20221983
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Inflammasome activation in infected macrophages drives COVID-19 pathology.

    Sefik, Esen / Qu, Rihao / Junqueira, Caroline / Kaffe, Eleanna / Mirza, Haris / Zhao, Jun / Brewer, J Richard / Han, Ailin / Steach, Holly R / Israelow, Benjamin / Blackburn, Holly N / Velazquez, Sofia E / Chen, Y Grace / Halene, Stephanie / Iwasaki, Akiko / Meffre, Eric / Nussenzweig, Michel / Lieberman, Judy / Wilen, Craig B /
    Kluger, Yuval / Flavell, Richard A

    Nature

    2022  Volume 606, Issue 7914, Page(s) 585–593

    Abstract: Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA and a sustained interferon (IFN) response, all of which are recapitulated and required for pathology in the SARS-CoV-2-infected MISTRG6-hACE2 ... ...

    Abstract Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA and a sustained interferon (IFN) response, all of which are recapitulated and required for pathology in the SARS-CoV-2-infected MISTRG6-hACE2 humanized mouse model of COVID-19, which has a human immune system
    MeSH term(s) Angiotensin-Converting Enzyme 2 ; Animals ; COVID-19/pathology ; COVID-19/physiopathology ; COVID-19/virology ; Humans ; Inflammasomes/metabolism ; Interleukin-1 ; Interleukin-18 ; Lung/pathology ; Lung/virology ; Macrophages/metabolism ; Macrophages/pathology ; Macrophages/virology ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Pneumonia/metabolism ; Pneumonia/virology ; Pyroptosis ; Receptors, IgG ; SARS-CoV-2/metabolism ; SARS-CoV-2/pathogenicity
    Chemical Substances Inflammasomes ; Interleukin-1 ; Interleukin-18 ; NLR Family, Pyrin Domain-Containing 3 Protein ; Receptors, IgG ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Language English
    Publishing date 2022-04-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-022-04802-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke.

    Lyden, Patrick D / Diniz, Márcio A / Bosetti, Francesca / Lamb, Jessica / Nagarkatti, Karisma A / Rogatko, André / Kim, Sungjin / Cabeen, Ryan P / Koenig, James I / Akhter, Kazi / Arbab, Ali S / Avery, Brooklyn D / Beatty, Hannah E / Bibic, Adnan / Cao, Suyi / Simoes Braga Boisserand, Ligia / Chamorro, Angel / Chauhan, Anjali / Diaz-Perez, Sebastian /
    Dhandapani, Krishnan / Dhanesha, Nirav / Goh, Andrew / Herman, Alison L / Hyder, Fahmeed / Imai, Takahiko / Johnson, Conor W / Khan, Mohammad B / Kamat, Pradip / Karuppagounder, Senthilkumar S / Kumskova, Mariia / Mihailovic, Jelena M / Mandeville, Joseph B / Morais, Andreia / Patel, Rakesh B / Sanganahalli, Basavaraju G / Smith, Cameron / Shi, Yanrong / Sutariya, Brijesh / Thedens, Daniel / Qin, Tao / Velazquez, Sofia E / Aronowski, Jaroslaw / Ayata, Cenk / Chauhan, Anil K / Leira, Enrique C / Hess, David C / Koehler, Raymond C / McCullough, Louise D / Sansing, Lauren H

    Science translational medicine

    2023  Volume 15, Issue 714, Page(s) eadg8656

    Abstract: Human diseases may be modeled in animals to allow preclinical assessment of putative new clinical interventions. Recent, highly publicized failures of large clinical trials called into question the rigor, design, and value of preclinical assessment. We ... ...

    Abstract Human diseases may be modeled in animals to allow preclinical assessment of putative new clinical interventions. Recent, highly publicized failures of large clinical trials called into question the rigor, design, and value of preclinical assessment. We established the Stroke Preclinical Assessment Network (SPAN) to design and implement a randomized, controlled, blinded, multi-laboratory trial for the rigorous assessment of candidate stroke treatments combined with intravascular thrombectomy. Efficacy and futility boundaries in a multi-arm multi-stage statistical design aimed to exclude from further study highly effective or futile interventions after each of four sequential stages. Six independent research laboratories performed a standard focal cerebral ischemic insult in five animal models that included equal numbers of males and females: young mice, young rats, aging mice, mice with diet-induced obesity, and spontaneously hypertensive rats. The laboratories adhered to a common protocol and efficiently enrolled 2615 animals with full data completion and comprehensive animal tracking. SPAN successfully implemented treatment masking, randomization, prerandomization inclusion and exclusion criteria, and blinded assessment of outcomes. The SPAN design and infrastructure provide an effective approach that could be used in similar preclinical, multi-laboratory studies in other disease areas and should help improve reproducibility in translational science.
    MeSH term(s) Female ; Humans ; Male ; Rats ; Animals ; Mice ; Ischemic Stroke ; Rodentia ; Laboratories ; Reproducibility of Results ; Stroke/therapy
    Language English
    Publishing date 2023-09-20
    Publishing country United States
    Document type Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.adg8656
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage.

    Askenase, Michael H / Goods, Brittany A / Beatty, Hannah E / Steinschneider, Arthur F / Velazquez, Sofia E / Osherov, Artem / Landreneau, Margaret J / Carroll, Shaina L / Tran, Tho B / Avram, Victor S / Drake, Riley S / Gatter, G James / Massey, Jordan A / Karuppagounder, Saravanan S / Ratan, Rajiv R / Matouk, Charles C / Sheth, Kevin N / Ziai, Wendy C / Parry-Jones, Adrian R /
    Awad, Issam A / Zuccarello, Mario / Thompson, Richard E / Dawson, Jesse / Hanley, Daniel F / Love, J Christopher / Shalek, Alex K / Sansing, Lauren H

    Science immunology

    2021  Volume 6, Issue 56

    Abstract: Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients ... ...

    Abstract Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14
    MeSH term(s) Adult ; Aged ; Brain/immunology ; Brain/pathology ; Cells, Cultured ; Cerebral Hemorrhage/complications ; Cerebral Hemorrhage/immunology ; Cerebral Hemorrhage/pathology ; Female ; Healthy Volunteers ; Hematoma ; Humans ; Longitudinal Studies ; Macrophages/immunology ; Male ; Middle Aged ; Neuroinflammatory Diseases/immunology ; Neuroinflammatory Diseases/pathology ; Neutrophils/immunology ; Primary Cell Culture ; RNA-Seq ; Transcriptome/immunology
    Language English
    Publishing date 2021-02-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2470-9468
    ISSN (online) 2470-9468
    DOI 10.1126/sciimmunol.abd6279
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results.

    Lyden, Patrick D / Bosetti, Francesca / Diniz, Márcio A / Rogatko, André / Koenig, James I / Lamb, Jessica / Nagarkatti, Karisma A / Cabeen, Ryan P / Hess, David C / Kamat, Pradip K / Khan, Mohammad B / Wood, Kristofer / Dhandapani, Krishnan / Arbab, Ali S / Leira, Enrique C / Chauhan, Anil K / Dhanesha, Nirav / Patel, Rakesh B / Kumskova, Mariia /
    Thedens, Daniel / Morais, Andreia / Imai, Takahiko / Qin, Tao / Ayata, Cenk / Boisserand, Ligia S B / Herman, Alison L / Beatty, Hannah E / Velazquez, Sofia E / Diaz-Perez, Sebastian / Sanganahalli, Basavaraju G / Mihailovic, Jelena M / Hyder, Fahmeed / Sansing, Lauren H / Koehler, Raymond C / Lannon, Steven / Shi, Yanrong / Karuppagounder, Senthilkumar S / Bibic, Adnan / Akhter, Kazi / Aronowski, Jaroslaw / McCullough, Louise D / Chauhan, Anjali / Goh, Andrew

    Stroke

    2022  Volume 53, Issue 5, Page(s) 1802–1812

    Abstract: Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated ... ...

    Abstract Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues-such as incomplete mechanistic knowledge and faulty clinical trial design-a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.
    MeSH term(s) Aged ; Animals ; Brain ; Brain Ischemia/therapy ; Feasibility Studies ; Humans ; Infarction, Middle Cerebral Artery/therapy ; Male ; Mice ; Stroke/therapy
    Language English
    Publishing date 2022-03-31
    Publishing country United States
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80381-9
    ISSN 1524-4628 ; 0039-2499 ; 0749-7954
    ISSN (online) 1524-4628
    ISSN 0039-2499 ; 0749-7954
    DOI 10.1161/STROKEAHA.121.038047
    Database MEDical Literature Analysis and Retrieval System OnLINE

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