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Poster Session J (+Lunch and Office Hours)

Session Information

Jun 11, 2021 02:05 PM - 02:35 PM(America/Detroit)
Venue : Posters
20210611T1405 20210611T1435 America/Detroit Poster Session J (+Lunch and Office Hours) Posters NIH Common Fund's 2021 High-Risk, High-Reward Research Symposium becky.miller2@nih.gov

Presentations

High-resolution Chemical Imaging of Cells and Tissues

Chemical Biology 02:05 PM - 02:35 PM (America/Detroit) 2021/06/11 18:05:00 UTC - 2021/06/11 18:35:00 UTC
Innovations in high-resolution optical imaging have allowed visualization of nanoscale biological structures and connections. However, super-resolution fluorescence techniques, including both optics-oriented and sample-expansion based, are relatively limited in quantification and throughput especially in tissues from photobleaching or quenching of the fluorophores, and low-efficiency or non-uniform delivery of the probes. Here, I would like to present our recent efforts in developing a general sample-expansion vibrational imaging strategy for label-free high-resolution (to below 100 nm) chemical imaging in cells and tissues. With further adoption of machine learning training, we successfully obtained label-free multi-component and volumetric prediction of nucleus, blood vessels, neuronal cells and dendrites in complex mouse brain tissues.

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Presenters
LW
Lu Wei
California Institute Of Technology

Uncovering the molecular landscape of clonal hematopoiesis using cell reprogramming

Molecular and Cellular Biology 02:05 PM - 02:35 PM (America/Detroit) 2021/06/11 18:05:00 UTC - 2021/06/11 18:35:00 UTC
Myeloid neoplasms, including myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), are genetically heterogeneous blood disorders characterized by clonal stem cell expansion. The onset of disease is often preceded by an extended period of age-related clonal hematopoiesis (CH) during which hematopoietic stem and progenitors (HSPCs) accumulate somatic mutations. CH is defined by the presence of rare oncogenic subclones in healthy individuals and is associated with increased, albeit low, risk of progression to malignancy. A comprehensive molecular description of CH is currently lacking, limiting understanding of why some individuals progress and others do not, and options for early intervention. We have previously shown that reprogramming of MDS/AML patient HSPCs to induced pluripotent stem cells (iPSCs) can identify single cell clonal intermediates (Hsu et al. 2019). Here, we isolated iPSC clones spanning normal, CH, and progression stages of disease in 12 individual MDS or AML patients. Using genome sequencing we mapped the genomic landscape and natural selection shaping somatic genomes during clonal evolution. We simultaneously reconstructed the transcriptome changes during clonal progression by differentiating isogenic iPSCs to HSPCs. We thus use cell reprogramming to for the first time map concurrent genomic and transcriptomic evolution of single cells during life-long progression from normal to pre-malignant and leukemic hematopoiesis in individual patients.

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Presenters
SD
Sergei Doulatov
University Of Washington

Building A Sentient Implantable Neurodevice: Early Progress

Clinical and Translational Research 02:05 PM - 02:35 PM (America/Detroit) 2021/06/11 18:05:00 UTC - 2021/06/11 18:35:00 UTC
Introduction
A major limitation of current implantable devices is that they do not provide feedback or inform how a host's behavior affects his or her health. In many disorders, such as epilepsy, a system that could teach patients to reduce seizure risk while teaching devices which electrophysiologic patterns are associated with ill health or increased seizure likelihood would greatly improve quality of life.
Methods
We present early progress on the main components of a sentient, implantable, epilepsy management system. We identify a cohort of 12 patients implanted with stereotactic electrodes to localize epileptic seizures. A Hidden Markov Model (HMM) is used to parse intracranial EEG (iEEG) recordings into discrete states based on covariance across channels. An Ecological Momentary Assessment (EMA) delivered via bi-directional text messaging simultaneously samples patient behavior. We develop a BERT-like NLP algorithm to interpret patient texts chronicling activities of daily living and feelings. We are exploring classifiers and learning algorithms to link these streams, so that patient and device can teach each other to optimize health.
Results
We are testing each of the above system components separately for reproducibility, ease of use and computational efficiency in preparation for an inpatient trial of the closed-loop system. Preliminary results suggest such that a trial is feasible, and a finite number of patient-specific states related to behavior and seizure risk can be identified.
Conclusion
We are developing a closed loop system that allows implanted neurodevices and patients to communicate, identify and modulate behavioral and neural state to improve seizure control and quality of life. We plan to initiate a clinical trial to test a first iteration of this system over the next 6 months.

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Presenters
BL
Brian Litt
University Of Pennsylvania
Co-Authors
AP
Akash Pattnaik
University Of Pennsylvania
KX
Kevin Xie
University Of Pennsylvania
NG
Nina Ghosn
University Of Pennsylvania
PG
Peter Galer
University Of Pennsylvania
BS
Brittany Scheid
University Of Pennsylvania
JB
John Bernabei
University Of Pennsylvania

Single-Cell RNA sequencing reveals cell states and transcriptional signatures of immune and epithelial dysregulation that define colitis associated with immune checkpoint inhibitors

Infectious Diseases and Immunology 02:05 PM - 02:35 PM (America/Detroit) 2021/06/11 18:05:00 UTC - 2021/06/11 18:35:00 UTC
Antibodies targeting immune checkpoint inhibitors CTLA-4 and PD-1/PD-L1 have revolutionized the treatment of solid tumors. However, their use is limited by a high incidence of immune-related adverse events (irAEs) affecting all organs, which can mimic autoimmune disease presentations. Beyond improving cancer patient care, studying irAEs represent a unique opportunity to study immune response regulation directly in human subjects. The colon is a frequent target of this immune attack, seen in up to 45% of patients on dual PD-1 and CTLA-4 blockade (referred to irColitis). To deeply define cell populations that could be tracked for diagnosis and characterize cell states and transcriptional programs driving irAEs that could therapeutically be manipulated to resolve irAEs, we profiled ~200,000 epithelial, mesenchymal, and immune single cells by RNA sequencing with paired TCR and BCR sequencing from the colon mucosa and blood of irColitis patients on ICI therapy (n=13) and controls that were either healthy (n=8) or on ICI therapy (n=6). Analysis of tissue immune cells from irColitis patients revealed marked expansion of T regulatory cells, effector CD4+ T cells, and three transcriptionally-distinct populations of CD8+ T cells. Single-cell TCR and BCR profiling revealed polyclonal expansion of T and B cell subsets with unique transcriptional signatures. We further showed that tissue resident T cells can transition between different cell states during active irColitis based on the observation of identical TCRs in CD8+ T cells from cytotoxic effector and memory-like cells. scRNAseq analysis of colon epithelial and mesenchymal cells revealed strong inflammatory and interferon signatures, likely driving the tissue damage observed in irColitis patients. Together, these data highlight the molecular mechanisms driving irColitis that may apply to other irAEs and shed light on the specific role of CTLA-4 and PD-1 signaling in maintaining gastrointestinal immune tolerance.

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Presenters
MT
Molly Thomas
Division Of Gastroenterology, Department Of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
Co-Authors
KS
Kamil Slowikowski
Center For Immunology And Inflammatory Diseases, Department Of Medicine, Massachusetts General Hospital, Boston, MA
KM
Kasidet Manakongtreecheep
Center For Immunology And Inflammatory Diseases, Department Of Medicine, Massachusetts General Hospital, Boston, MA
JT
Jessica Tantivit
Center For Immunology And Inflammatory Diseases, Department Of Medicine, Massachusetts General Hospital, Boston, MA
MN
Mazen Nasrallah
Division Of Rheumatology, Allergy, And Immunology, Department Of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
LZ
Leyre Zubiri
Division Of Oncology And Hematology, Department Of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
GB
Genevieve Boland
Department Of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
KR
Kerry Reynolds
Division Of Oncology And Hematology, Department Of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
MD
Michael Dougan
Division Of Gastroenterology, Department Of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
BL
Bo Li
Center For Immunology And Inflammatory Diseases, Department Of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
AV
Alexandra-Chloe Villani
Massachusetts General Hospital/Harvard Medical School

3D organoids generated from human trophoblast stem cells model early placental development and susceptibility to emerging viral infections

Molecular and Cellular Biology 02:05 PM - 02:35 PM (America/Detroit) 2021/06/11 18:05:00 UTC - 2021/06/11 18:35:00 UTC
Trophoblast organoids provide a powerful tool to study human placental development, but obtaining trophoblasts from the first trimester is complicated due to ethical and legal restrictions. Here we report that human trophoblast cells (hTSCs) obtained from primary cytotrophoblasts (CTBs) and naive human pluripotent stem cells (hPSCs) can efficiently give rise to 3D trophoblast organoids. These stem cell-derived organoids recapitulate the villous architecture of placenta-derived organoids containing an epithelial CTB shell with a syncytiotrophoblast (STB) core. Single cell RNA-sequencing (scRNA-seq) demonstrated that organoids derived from naive and primary hTSCs contained a similar cellular composition, which includes two discrete CTB clusters, two discrete STB clusters, and one extravillous trophoblast (EVT) population. Comparison with scRNA-seq data from human embryos showed a high degree of alignment with post-implantation CTB, STB, and EVT populations. Given emerging evidence regarding pregnancy complications due to COVID-19 infection, we investigated the susceptibility of hTSC-derived organoids to SARS-CoV-2 infection. Our scRNA-seq data indicate that the common entry receptors for the SARS-CoV-2 virus, ACE2 and TMPRSS2, are expressed in a subset of STBs. In accordance with these expression data, infection of trophoblast organoids with a pseudovirus expressing the SARS-CoV-2 spike protein on its surface resulted in limited infection in STBs. By comparison, infection of trophoblast organoids with Zika virus resulted in more robust infection in multiple trophoblast cell types. Our results demonstrate that SARS-CoV-2 has the ability to infect a subset of STBs, yet the underlying CTB population appears resilient to SARS-CoV-2 infection, potentially limiting the vertical transmission of the virus to the fetus. The generation of 3D trophoblast organoids from hPSCs provides a means of deriving patient-specific organoids to study placental disease and the response to emerging viral infections.

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Presenters Thorold Theunissen
Washington University School Of Medicine
Co-Authors
RK
Rowan Karvas
Washington University School Of Medicine
SV
Sonam Verma
Washington University School Of Medicine
SD
Sabine Dietmann
Washington University School Of Medicine
IM
Indira Mysorekar
Washington University School Of Medicine

Enhanced efficacy of simultaneous PD-1 and PD-L1 immune checkpoint blockade in high grade serous ovarian cancer

Molecular and Cellular Biology 02:05 PM - 02:35 PM (America/Detroit) 2021/06/11 18:05:00 UTC - 2021/06/11 18:35:00 UTC
Immune therapies have had limited efficacy in high grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single cell RNA-seq transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-PD-1/PD-L1 antibody compared to monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and NK cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC.

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Presenters
SH
Sarah Hill
Dana-Farber Cancer Institute
Co-Authors
CW
Changxin Wan
Dana-Farber Cancer Institute
SL
Suzan Lazo
Dana-Farber Cancer Institute
MB
Myles Brown
Dana-Farber Cancer Institute
XL
X. Shirley Liu
Dana-Farber Cancer Institute
BR
Bo Rueda
Massachusetts General Hospital
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1623097704SarahHill-EnhancedefficacyofsimultaneousPD-1-1.png
Enhanced efficacy of simultaneous PD-...
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Submitted by Sarah Hill
1623097562RownKarvas-3DOrganoidsgenerated-1.png
3D organoids generated from human tro...
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Submitted by Thorold Theunissen
1623080756BrianLitt-BuildingASentient-1.png
Building A Sentient Implantable Neuro...
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Submitted by Brian Litt
1623084206LuWei-Super-resolution.jpg
High-resolution Chemical Imaging of C...
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Submitted by Lu Wei
1623087371SergeiDoulatov-Uncoveringthemolecularlandscape-1.png
Uncovering the molecular landscape of...
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Submitted by Sergei Doulatov

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