Medicine and Health Sciences Commons^™

Saponin Tql1055 Adjuvant-Containing Vaccine Confers Protection Upon Mycobacterium Tuberculosis Challenge In Mice, Mushtaq Ahmed, Eric Farris, Rosemary V Swanson, Shibali Das, Yan Yang, Tyler Martin, Shabaana A Khader

2020-Current year OA Pubs

Tuberculosis (TB), caused by the intracellular pathogen

Human Neutralizing Antibodies Target A Conserved Lateral Patch On H7n9 Hemagglutinin Head, Manxue Jia, Hanjun Zhao, Nicholas C Morano, Hong Lu, Yin-Ming Lui, Haijuan Du, Jordan E Becker, Kwok-Yung Yuen, David D Ho, Peter D Kwong, Lawrence Shapiro, Kelvin Kai-Wang To, Xueling Wu

Journal Articles

Avian influenza A virus H7N9 causes severe human infections with >30% fatality. Currently, there is no H7N9-specific prevention or treatment for humans. Here, from a 2013 H7N9 convalescent case in Hong Kong, we isolate four hemagglutinin (HA)-reactive monoclonal antibodies (mAbs), with three directed to the globular head domain (HA1) and one to the stalk domain (HA2). Two clonally related HA1-directed mAbs, H7.HK1 and H7.HK2, potently neutralize H7N9 and protect female mice from lethal H7N9/AH1 challenge. Cryo-EM structures reveal that H7.HK1 and H7.HK2 bind to a β14-centered surface and disrupt the 220-loop that makes hydrophobic contacts with sialic acid on an …

Common Single-Base Insertions In The Vntr Of The Carboxyl Ester Lipase (Cel) Gene Are Benign And Also Likely To Arise Somatically In The Exocrine Pancreas, Ranveig S Brekke, Anny Gravdal, Khadija El Jellas, Grace E Curry, Jianguo Lin, Steven J Wilhelm, Solrun J Steine, Eric Mas, Stefan Johansson, Mark E Lowe, Bente B Johansson, Xunjun Xiao, Karianne Fjeld, Anders Molven

2020-Current year OA Pubs

The CEL gene encodes carboxyl ester lipase, a pancreatic digestive enzyme. CEL is extremely polymorphic due to a variable number tandem repeat (VNTR) located in the last exon. Single-base deletions within this VNTR cause the inherited disorder MODY8, whereas little is known about VNTR single-base insertions in pancreatic disease. We therefore mapped CEL insertion variants (CEL-INS) in 200 Norwegian patients with pancreatic neoplastic disorders. Twenty-eight samples (14.0%) carried CEL-INS alleles. Most common were insertions in repeat 9 (9.5%), which always associated with a VNTR length of 13 repeats. The combined INS allele frequency (0.078) was similar to that observed in …

C-Terminal Binding Protein 2 Is A Novel Tumor Suppressor Targeting The Myc-Irf4 Axis In Multiple Myeloma, Coty Hing Yau Cheung, Chi Keung Cheng, Kam Tong Leung, Chi Zhang, Chi Yan Ho, Xi Luo, Angel Yuet Fong Kam, Tian Xia, Thomas Shek Kong Wan, Herbert Augustus Pitts, Natalie Pui Ha Chan, Joyce Sin Cheung, Raymond Siu Ming Wong, Xiao-Bing Zhang, Margaret Heung Ling Ng

Journal Articles

Multiple myeloma (MM) cells are addicted to MYC and its direct transactivation targets IRF4 for proliferation and survival. MYC and IRF4 are still considered "undruggable," as most small-molecule inhibitors suffer from low potency, suboptimal pharmacokinetic properties, and undesirable off-target effects. Indirect inhibition of MYC/IRF4 emerges as a therapeutic vulnerability in MM. Here, we uncovered an unappreciated tumor-suppressive role of C-terminal binding protein 2 (CTBP2) in MM via strong inhibition of the MYC-IRF4 axis. In contrast to epithelial cancers, CTBP2 is frequently downregulated in MM, in association with shortened survival, hyperproliferative features, and adverse clinical outcomes. Restoration of CTBP2 exhibited potent …

A Rat-Based Preclinical Platform Facilitating Transcatheter Hepatic Arterial Infusion In Immunodeficient Rats With Liver Xenografts Of Patient-Derived Pancreatic Ductal Adenocarcinoma, Masanori Ozaki, Ken Kageyama, Kenjiro Kimura, Shinpei Eguchi, Akira Yamamoto, Ryota Tanaka, Takehito Nota, Hiroki Yonezawa, Hideyuki Nishiofuku, Yuki Sakai, Naoki Tani, Atsushi Jogo, Mizue Terai, Takami Sato, Takeaki Ishizawa, Yukio Miki

Department of Medical Oncology Faculty Papers

Liver metastases from pancreatic ductal adenocarcinoma (PDAC) are highly fatal. A rat-based patient-derived tumor xenograft (PDX) model is available for transcatheter therapy. This study aimed to create an immunodeficient rat model with liver xenografts of patient-derived primary PDAC and evaluate efficacy of hepatic arterial infusion chemotherapy with cisplatin in this model. Three patient-derived PDACs were transplanted into the livers of 21 rats each (totally, 63 rats), randomly assigned into hepatic arterial infusion, systemic venous infusion, and control groups (n = 7 each) four weeks post-implantation. Computed tomography evaluated tumor volumes before and four weeks after treatment. Post-euthanasia, resected tumor specimens …

Deficiency Of Il-22-Binding Protein Enhances The Ability Of The Gut Microbiota To Protect Against Enteric Pathogens, José L Fachi, Blanda Di Luccia, Susan Gilfillan, Hao-Wei Chang, Christina Song, Jiye Cheng, Marina Cella, Marco Aurelio Vinolo, Jeffrey I Gordon, Marco Colonna

2020-Current year OA Pubs

Interleukin 22 (IL-22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including the production of antimicrobial peptides. IL-22 binding protein (IL-22BP) is a soluble decoy encoded by the

Wormbase 2024: Status And Transitioning To Alliance Infrastructure, Paul W Sternberg, Tim Schedl, Et Al.

2020-Current year OA Pubs

WormBase has been the major repository and knowledgebase of information about the genome and genetics of Caenorhabditis elegans and other nematodes of experimental interest for over 2 decades. We have 3 goals: to keep current with the fast-paced C. elegans research, to provide better integration with other resources, and to be sustainable. Here, we discuss the current state of WormBase as well as progress and plans for moving core WormBase infrastructure to the Alliance of Genome Resources (the Alliance). As an Alliance member, WormBase will continue to interact with the C. elegans community, develop new features as needed, and curate …

Novel Loss-Of-Function Variants Expand Abcc9-Related Intellectual Disability And Myopathy Syndrome, Stephanie Efthymiou, Robert C Tryon, Colin G Nichols, Et Al.

2020-Current year OA Pubs

Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle …

Interferons And Tuft Cell Numbers Are Bottlenecks For Persistent Murine Norovirus Infection, Somya Aggarwal, Forrest C. Walker, James S. Weagley, Broc T. Mccune, Xiaofen Wu, Lawrence A. Schriefer, Heyde Makimaa, Dylan Lawrence, Pratyush Sridhar, Megan T. Baldridge

2020-Current year OA Pubs

Noroviruses (NoVs) are a leading cause of viral gastroenteritis. Despite global clinical relevance, our understanding of how host factors, such as antiviral cytokines interferons (IFNs), modulate NoV population dynamics is limited. Murine NoV (MNoV) is a tractable in vivo model for the study of host regulation of NoV. A persistent strain of MNoV, CR6, establishes a reservoir in intestinal tuft cells for chronic viral shedding in stool. However, the influence of host innate immunity and permissive cell numbers on viral population dynamics is an open question. We generated a pool of 20 different barcoded viruses (CR6BC) by inserting 6-nucleotide barcodes …

Complement Regulation In The Eye: Implications For Age-Related Macular Degeneration, Georgia A. Wilke, Rajendra S. Apte

2020-Current year OA Pubs

Careful regulation of the complement system is critical for enabling complement proteins to titrate immune defense while also preventing collateral tissue damage from poorly controlled inflammation. In the eye, this balance between complement activity and inhibition is crucial, as a low level of basal complement activity is necessary to support ocular immune privilege, a prerequisite for maintaining vision. Dysregulated complement activation contributes to parainflammation, a low level of inflammation triggered by cellular damage that functions to reestablish homeostasis, or outright inflammation that disrupts the visual axis. Complement dysregulation has been implicated in many ocular diseases, including glaucoma, diabetic retinopathy, and …

Targeting Dendritic Cell Dysfunction To Circumvent Anti-Pd1 Resistance In Head And Neck Cancer, Shin Saito, Michihisa Kono, Hoang C B Nguyen, Ann Marie Egloff, Cameron Messier, Patrick Lizotte, Cloud Paweletz, Douglas Adkins, Ravindra Uppaluri

2020-Current year OA Pubs

PURPOSE: Neoadjuvant anti-PD1 (aPD1) therapies are being explored in surgically resectable head and neck squamous cell carcinoma (HNSCC). Encouraging responses have been observed, but further insights into the mechanisms underlying resistance and approaches to improve responses are needed.

EXPERIMENTAL DESIGN: We integrated data from syngeneic mouse oral carcinoma (MOC) models and neoadjuvant pembrolizumab HNSCC patient tumor RNA-sequencing data to explore the mechanism of aPD1 resistance. Tumors and tumor-draining lymph nodes (DLN) from MOC models were analyzed for antigen-specific priming. CCL5 expression was enforced in an aPD1-resistant model.

RESULTS: An aPD1-resistant mouse model showed poor priming in the tumor DLN due …

Decorin Suppresses Tumor Lymphangiogenesis: A Mechanism To Curtail Cancer Progression, Dipon K. Mondal, Christopher Xie, Gabriel J. Pascal, Simone Buraschi, Renato V. Iozzo

Kimmel Cancer Center Faculty Papers

The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, …

Pml::Rara And Gata2 Proteins Interact Via Dna Templates To Induce Aberrant Self-Renewal In Mouse And Human Hematopoietic Cells, Casey D S Katerndahl, Olivia R S Rogers, Ryan B Day, Ziheng Xu, Nichole M Helton, Sai Mukund Ramakrishnan, Christopher A Miller, Timothy J Ley

2020-Current year OA Pubs

The underlying mechanism(s) by which the PML::RARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of PML::RARA in primary mouse and human hematopoietic progenitor cells with V5-tagged PML::RARA, using anti-V5-PML::RARA chromatin immunoprecipitation sequencing and CUT&RUN approaches. Most genomic PML::RARA binding sites were found in regions that were already chromatin-accessible (defined by ATAC-seq) in unmanipulated, wild-type promyelocytes, suggesting that these regions are "open" prior to PML::RARA expression. We found that GATA binding motifs, and the direct binding of the chromatin "pioneering factor" GATA2, were significantly enriched near PML::RARA binding sites. Proximity labeling studies …

Xpo1 Blockade With Kpt-330 Promotes Apoptosis In Cutaneous T-Cell Lymphoma By Activating The P53-P21 And P27 Pathways, Nitin Chakravarti, Amy Boles, Rachel Burzinski, Paola Sindaco, Colleen Isabelle, Kathleen Mcconnell, Anjali Mishra, Pierluigi Porcu

Kimmel Cancer Center Faculty Papers

Dysregulated nuclear-cytoplasmic trafficking has been shown to play a role in oncogenesis in several types of solid tumors and hematological malignancies. Exportin 1 (XPO1) is responsible for the nuclear export of several proteins and RNA species, mainly tumor suppressors. KPT-330, a small molecule inhibitor of XPO1, is approved for treating relapsed multiple myeloma and diffuse large B-cell lymphoma. Cutaneous T-cell lymphoma (CTCL) is an extranodal non-Hodgkin lymphoma with an adverse prognosis and limited treatment options in advanced stages. The effect of therapeutically targeting XPO1 with KPT-330 in CTCL has not been established. We report that XPO1 expression is upregulated in …

Large-Scale Annotated Dataset For Cochlear Hair Cell Detection And Classification, Christopher J Buswinka, Jinkyung Kim, Anthony J Ricci, Mark A Rutherford, Et Al.

2020-Current year OA Pubs

Our sense of hearing is mediated by cochlear hair cells, of which there are two types organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains 5-15 thousand terminally differentiated hair cells, and their survival is essential for hearing as they do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. Machine learning can be used to automate the quantification process but requires a vast and diverse dataset for effective training. …

Topographical And Cell Type-Specific Connectivity Of Rostral And Caudal Forelimb Corticospinal Neuron Populations, Lina Marcela Carmona, Eric D Thomas, Kimberly Smith, Bosiljka Tasic, Rui M Costa, Anders Nelson

Journal Articles

Corticospinal neurons (CSNs) synapse directly on spinal neurons, a diverse assortment of cells with unique structural and functional properties necessary for body movements. CSNs modulating forelimb behavior fractionate into caudal forelimb area (CFA) and rostral forelimb area (RFA) motor cortical populations. Despite their prominence, the full diversity of spinal neurons targeted by CFA and RFA CSNs is uncharted. Here, we use anatomical and RNA sequencing methods to show that CSNs synapse onto a remarkably selective group of spinal cell types, favoring inhibitory populations that regulate motoneuron activity and gate sensory feedback. CFA and RFA CSNs target similar spinal neuron types, …

Single-Cell T-Cell Receptor Repertoire Profiling In Dogs, My H Hoang, Zachary L Skidmore, Hans Rindt, Shirley Chu, Bryan Fisk, Jennifer A Foltz, Catrina Fronick, Robert Fulton, Mingyi Zhou, Nathan J Bivens, Carol N Reinero, Todd A Fehniger, Malachi Griffith, Jeffrey N Bryan, Obi L Griffith

2020-Current year OA Pubs

Spontaneous cancers in companion dogs are robust models of human disease. Tracking tumor-specific immune responses in these models requires reagents to perform species-specific single cell T cell receptor sequencing (scTCRseq). scTCRseq and integration with scRNA data have not been demonstrated on companion dogs with cancer. Here, five healthy dogs, two dogs with T cell lymphoma and four dogs with melanoma are selected to demonstrate applicability of scTCRseq in a cancer immunotherapy setting. Single-cell suspensions of PBMCs or lymph node aspirates are profiled using scRNA and dog-specific scTCRseq primers. In total, 77,809 V(D)J-expressing cells are detected, with an average of 3498 …

Bioresorbable, Wireless, Passive Sensors For Continuous Ph Measurements And Early Detection Of Gastric Leakage, Shuo Li, Yameng Xu, Ying Yan, Jorge Zárate Rodriguez, Mitchell A Pet, Chet W Hammill, Matthew R Macewan, Wilson Z Ray, Et Al.

2020-Current year OA Pubs

Continuous monitoring of biomarkers at locations adjacent to targeted internal organs can provide actionable information about postoperative status beyond conventional diagnostic methods. As an example, changes in pH in the intra-abdominal space after gastric surgeries can serve as direct indicators of potentially life-threatening leakage events, in contrast to symptomatic reactions that may delay treatment. Here, we report a bioresorbable, wireless, passive sensor that addresses this clinical need, designed to locally monitor pH for early detection of gastric leakage. A pH-responsive hydrogel serves as a transducer that couples to a mechanically optimized inductor-capacitor circuit for wireless readout. This platform enables real-time …

Novel Jak Inhibitors To Reduce Graft-Versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation In A Preclinical Mouse Model, Sena Kim, Peter Ruminski, Megh Singh, Karl Staser, Kidist Ashami, Julie Ritchey, Sora Lim, John F Dipersio, Jaebok Choi

2020-Current year OA Pubs

Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly effective, well-established treatment for patients with various hematologic malignancies and non-malignant diseases. The therapeutic benefits of allo-HCT are mediated by alloreactive T cells in donor grafts. However, there is a significant risk of graft-versus-host disease (GvHD), in which the donor T cells recognize recipient cells as foreign and attack healthy organs in addition to malignancies. We previously demonstrated that targeting JAK1/JAK2, mediators of interferon-gamma receptor (IFNGR) and IL-6 receptor signaling, in donor T cells using baricitinib and ruxolitinib results in a significant reduction in GvHD after allo-HCT. Furthermore, we showed that balanced …

Host Response During Unresolved Urinary Tract Infection Alters Female Mammary Tissue Homeostasis Through Collagen Deposition And Timp1, Samantha Henry, Xue-Yan He, Et Al.

2020-Current year OA Pubs

Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explore how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell transcriptomics, and flow cytometry, we identify that mammary tissue from UTI-bearing mice displays collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells are absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue are mediated by the systemic host response to local infection. Furthermore, broad …

Acetaminophen Influences Musculoskeletal Signaling But Not Adaptations To Endurance Exercise Training, Brandon Roberts, Alyssa Geddis, Alexandra Ciuciu, Marinaliz Reynoso, Nikhil Mehta, Alyssa Varanoske, Alyssa Kelley, Raymond Walker, Rigoberto Munoz, Alexander Kolb, Jeffery Staab, Marshall Naimo, Ryan Tomlinson

Department of Orthopaedic Surgery Faculty Papers

Acetaminophen (ACE) is a widely used analgesic and antipyretic drug with various applications, from pain relief to fever reduction. Recent studies have reported equivocal effects of habitual ACE intake on exercise performance, muscle growth, and risks to bone health. Thus, this study aimed to assess the impact of a 6-week, low-dose ACE regimen on muscle and bone adaptations in exercising and non-exercising rats. Nine-week-old Wistar rats (n = 40) were randomized to an exercise or control (no exercise) condition with ACE or without (placebo). For the exercise condition, rats ran 5 days per week for 6 weeks at a 5% …

Multisensory Flicker Modulates Widespread Brain Networks And Reduces Interictal Epileptiform Discharges, Lou T Blanpain, Eric R Cole, Emily Chen, James K Park, Michael Y Walelign, Robert E Gross, Brian T Cabaniss, Jon T Willie, Annabelle C Singer

2020-Current year OA Pubs

Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect …

Chemotherapy Activates Inflammasomes To Cause Inflammation-Associated Bone Loss, Chun Wang, Khushpreet Kaur, Canxin Xu, Yousef Abu-Amer, Gabriel Mbalaviele

2020-Current year OA Pubs

Chemotherapy is a widely used treatment for a variety of solid and hematological malignancies. Despite its success in improving the survival rate of cancer patients, chemotherapy causes significant toxicity to multiple organs, including the skeleton, but the underlying mechanisms have yet to be elucidated. Using tumor-free mouse models, which are commonly used to assess direct off-target effects of anti-neoplastic therapies, we found that doxorubicin caused massive bone loss in wild-type mice, a phenotype associated with increased number of osteoclasts, leukopenia, elevated serum levels of danger-associated molecular patterns (DAMPs; e.g. cell-free DNA and ATP) and cytokines (e.g. IL-1β and IL-18). Accordingly, …

Lung Type 3 Innate Lymphoid Cells Respond Early Following Mycobacterium Tuberculosis Infection, Shibali Das, Kuldeep Singh Chauhan, Mushtaq Ahmed, Sadia Akter, Lan Lu, Marco Colonna, Shabaana A Khader

2020-Current year OA Pubs

UNLABELLED: Tuberculosis is the leading cause of death due to an infectious disease worldwide. Innate lymphoid type 3 cells (ILC3s) mediate early protection during

IMPORTANCE: Tuberculosis is a leading cause of death due to a single infectious agent accounting for 1.6 million deaths each year. In our study, we determined the role of type 3 innate lymphoid cells in early immune events necessary for achieving protection during

Transcription Factor C/Ebpα Is Required For The Development Of Ly6chi Monocytes But Not Ly6clo Monocytes, Sunkyung Kim, Jing Chen, Feiya Ou, Tian-Tian Liu, Suin Jo, William E Gillanders, Theresa L Murphy, Kenneth M Murphy

2020-Current year OA Pubs

Monocytes comprise two major subsets, Ly6C

Mir-574-5p Activates Human Tlr8 To Promote Autoimmune Signaling And Lupus, Tao Wang, Dan Song, Xuejuan Li, Yu Luo, Dianqiang Yang, Xiaoyan Liu, Xiaodan Kong, Yida Xing, Shulin Bi, Yan Zhang, Tao Hu, Yunyun Zhang, Shuang Dai, Zhiqiang Shao, Dahan Chen, Jinpao Hou, Esteban Ballestar, Jianchun Cai, Feng Zheng, James Y Yang

Journal Articles

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling …

Pparα Is One Of The Key Targets For Dendrobine To Improve Hepatic Steatosis In Nafld., Yanzhe Xu, Miao Wang, Yi Luo, Hao Liu, Hua Ling, Yuqi He, Yanliu Lu

PCOM Scholarly Papers

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium nobile Lindl. (DNL) is a traditional Chinese ethnobotanical herb. Dendrobine (DNE) has been designated as a quality indicator for DNL in the Chinese Pharmacopoeia. DNE exhibits various pharmacological activities, including the reduction of blood lipids, regulation of blood sugar levels, as well as anti-inflammatory and antioxidant properties.

AIM OF THE STUDY: The objective of this study is to explore the impact of DNE on lipid degeneration in nonalcoholic fatty liver disease (NAFLD) liver cells and elucidate its specific mechanism. The findings aim to offer theoretical support for the development of drugs related to DNL.

MATERIALS AND METHODS: …

Subcellular Pathways Through Vglut3-Expressing Mouse Amacrine Cells Provide Locally Tuned Object-Motion-Selective Signals In The Retina, Karl Friedrichsen, Jen-Chun Hsiang, Chin-I Lin, Liam Mccoy, Katia Valkova, Daniel Kerschensteiner, Josh L Morgan

2020-Current year OA Pubs

VGluT3-expressing mouse retinal amacrine cells (VG3s) respond to small-object motion and connect to multiple types of bipolar cells (inputs) and retinal ganglion cells (RGCs, outputs). Because these input and output connections are intermixed on the same dendrites, making sense of VG3 circuitry requires comparing the distribution of synapses across their arbors to the subcellular flow of signals. Here, we combine subcellular calcium imaging and electron microscopic connectomic reconstruction to analyze how VG3s integrate and transmit visual information. VG3s receive inputs from all nearby bipolar cell types but exhibit a strong preference for the fast type 3a bipolar cells. By comparing …

Blocking Senescence And Tolerogenic Function Of Dendritic Cells Induced By Γδ Treg Cells Enhances Tumor-Specific Immunity For Cancer Immunotherapy, Fusheng Si, Xia Liu, Yan Tao, Yuanqin Zhang, Feiya Ma, Eddy C Hsueh, Sidharth V Puram, Guangyong Peng

2020-Current year OA Pubs

BACKGROUND: Regulatory T (Treg) cells are a key component in maintaining the suppressive tumor microenvironment and immune suppression in different types of cancers. A precise understanding of the molecular mechanisms used by Treg cells for immune suppression is critical for the development of effective strategies for cancer immunotherapy.

METHODS: Senescence development and tolerogenic functions of dendritic cells (DCs) induced by breast cancer tumor-derived γδ Treg cells were fully characterized using real-time PCR, flow cytometry, western blot, and functional assays. Loss-of-function strategies with pharmacological inhibitor and/or neutralizing antibody were used to identify the potential molecule(s) and pathway(s) involved in DC senescence …

Vista Checkpoint Inhibition By Ph-Selective Antibody Sns-101 With Optimized Safety And Pharmacokinetic Profiles Enhances Pd-1 Response, Thomas Thisted, Yoshiko Takeuchi, Robert D Schreiber, Et Al.

2020-Current year OA Pubs

VISTA, an inhibitory myeloid-T-cell checkpoint, holds promise as a target for cancer immunotherapy. However, its effective targeting has been impeded by issues such as rapid clearance and cytokine release syndrome observed with previous VISTA antibodies. Here we demonstrate that SNS-101, a newly developed pH-selective VISTA antibody, addresses these challenges. Structural and biochemical analyses confirmed the pH-selectivity and unique epitope targeted by SNS-101. These properties confer favorable pharmacokinetic and safety profiles on SNS-101. In syngeneic tumor models utilizing human VISTA knock-in mice, SNS-101 shows in vivo efficacy when combined with a PD-1 inhibitor, modulates cytokine and chemokine signaling, and alters the …