A5050645853- Viral-associated cancers and disorders
- Immune Cell Function and Interaction
- Lymphoma Diagnosis and Treatment
- Neuroinflammation and Neurodegeneration Mechanisms
- T-cell and B-cell Immunology
- Immune cells in cancer
- Renal Diseases and Glomerulopathies
- HIV Research and Treatment
- Cancer-related molecular mechanisms research
- Reproductive System and Pregnancy
- Pressure Ulcer Prevention and Management
- Epigenetics and DNA Methylation
- Single-cell and spatial transcriptomics
- Chronic Lymphocytic Leukemia Research
- Immune Response and Inflammation
- Acute Myeloid Leukemia Research
- Wound Healing and Treatments
- Immunotherapy and Immune Responses
- Genetic and phenotypic traits in livestock
- Platelet Disorders and Treatments
- Burn Injury Management and Outcomes
- Glioma Diagnosis and Treatment
- CNS Lymphoma Diagnosis and Treatment
- Polyomavirus and related diseases
- IL-33, ST2, and ILC Pathways
University of Pennsylvania
1999-2025
California University of Pennsylvania
2022-2025
Children's Hospital of Philadelphia
2016-2024
Abramson Center for Jewish Life
2022
University of Havana
2018
Washington State University
2013-2017
Howard Hughes Medical Institute
2014
United States Department of Agriculture
2013
Agricultural Research Service
2013
Royal Marsden NHS Foundation Trust
2013
Neurotrophins and tyrosine receptor kinase (Trk) receptors are expressed in skeletal muscle, but it is unclear what functional role Trk-mediated signaling plays during postnatal life. Full-length TrkB (trkB.FL) as well truncated (trkB.t1) were found to be localized primarily the postsynaptic acetylcholine receptor– (AChR-) rich membrane at neuromuscular junctions. In vivo, dominant-negative manipulation of using adenovirus overexpress trkB.t1 mouse sternomastoid muscle fibers resulted...
Background and AimsBowel function requires coordinated activity of diverse enteric neuron subtypes. Our aim was to define gene expression in these subtypes facilitate development novel therapeutic approaches treat devastating neuropathies, learn more about nervous system function.MethodsTo identify subtype–specific genes, we performed single-nucleus RNA-seq on adult mouse human colon myenteric plexus, single-cell E17.5 ENS cells from whole bowel. We used immunohistochemistry, select mutant...
The mechanisms by which FOXP3+ T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe or vaccine recognition and away from self-reactivity remain incompletely understood. To explore underappreciated heterogeneity in human Tfr cell development, function, localization, we used paired TCRVA/TCRVB sequencing to distinguish tonsillar that are clonally related natural (nTfr) those likely induced helper (Tfh) (iTfr). proteins iTfr nTfr differentially expressed...
HIV-associated neurocognitive disorders (HAND) affect over half of HIV-infected individuals, despite antiretroviral therapy (ART). Therapeutically targetable mechanisms underlying HAND remain elusive, partly due to a lack representative model. We developed human-induced pluripotent stem cell (hiPSC)-based model, independently differentiating hiPSCs into neurons, astrocytes, and microglia, systematically combining generate tri-culture with or without HIV infection ART. Single-cell RNA...
The TAFRO clinical subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO) is a rare hematologic illness involving episodic flares thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly (TAFRO) progressive multiple organ dysfunction. We previously showed that the mTOR signaling pathway elevated in lymph nodes iMCD-TAFRO patients an inhibitor effective small cohort patients. However, upstream mechanisms, cell types, mediators involved...
The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. deficiency fatally arrests lymphopoiesis myelopoiesis in mice, but human congenital disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients...
A GM-CSF + T helper cell subset develops from naïve precursors and switch to a H 1 phenotype during neuroinflammation.
Tumor-associated macrophages (TAMs) play an important role in tumor immunity and comprise of subsets that have distinct phenotype, function, ontology. Transcriptomic analyses human medulloblastoma, the most common malignant pediatric brain cancer, showed medulloblastomas (MBs) with activated sonic hedgehog signaling (SHH-MB) significantly more TAMs than other MB subtypes. Therefore, we examined MB-associated by single-cell RNA sequencing autochthonous murine SHH-MB at steady state under two...
Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly-understood cytokine storm-driven inflammatory disorder. Interleukin-6 (IL-6) known driver in some patients, but anti-IL-6 therapy with siltuximab not effective all biomarkers indicating success at an early time point following treatment initiation are lacking. Here we show, by comparison of levels 1,178 proteins sera healthy participants (N = 42), patients iMCD 88), related diseases 60), comprehensive landscape candidate...
Summary Idiopathic multicentric Castleman disease (iMCD) is a rare haematological disorder characterized by generalized lymphadenopathy with atypical histopathological features and systemic inflammation caused cytokine storm involving interleukin‐6 (IL‐6). Three clinical subtypes are recognized: thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly (iMCD‐TAFRO); idiopathic plasmacytic (iMCD‐IPL), thrombocytosis hypergammaglobulinaemia; iMCD‐not otherwise specified (iMCD‐NOS),...
CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired migration enhanced tumor progression; however, impacts of individual ECM molecules on function microenvironment (TME) only beginning be elucidated. Upstream regulators aberrant deposition organization tumors equally ill-defined. Therefore, we investigated how modulates undifferentiated...
Significance Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are diseases characterized by accumulation of myeloid cells in the central nervous system (CNS). Both harmful beneficial present EAE/MS, a goal MS therapy is to preferentially remove cells. The receptor for CSF-1 (CSF-1R) found on important their survival. CSF-1R can bind two ligands, IL-34, but it not known whether functions EAE/MS differ. We that blocking depleted only CNS suppressed...
Linked-read sequencing provides long-range information on short-read data by barcoding reads originating from the same DNA molecule, and can improve detection breakpoint identification for structural variants (SVs). Here we present LinkedSV SV linked-read data. considers barcode overlapping enriched fragment endpoints as signals to detect large SVs, while it leverages read depth, paired-end local assembly small SVs. Benchmarking studies demonstrate that outperforms existing tools, especially...
Abstract In mice engineered to express enhanced green fluorescent protein (eGFP) under the control of entire glutamate transporter 1 (GLT1) gene, eGFP is found in all ‘adult’ cortical astrocytes. However, when 8.3 kilobases human GLT1/EAAT2 promoter used expression tdTomato (tdT), tdT only a subpopulation these eGFP-expressing The have been define mechanisms transcriptional regulation using astrocytes cultured from cortex 1–3 day old mice. Using same cultures, we were never able induce +...
Abstract Castleman disease (CD) is a rare hematologic disorder characterized by pathologic lymph node changes and range of symptoms due to excessive cytokine production. While uncontrolled infection with human herpesvirus-8 (HHV-8) responsible for the storm in portion multicentric CD (HHV-8-associated MCD) cases, etiology unicentric (UCD) HHV-8-negative/idiopathic MCD (iMCD) unknown. Several hypotheses have been proposed regarding pathogenesis UCD iMCD, including occult given precedent...
Abstract How IRF7 promotes autoimmune B cell responses and systemic autoimmunity is unclear. Analysis of spontaneous SLE-prone mice deficient in uncovered the role regulating germinal center (GC), plasma (PC) autoantibody disease. IRF7, however, was dispensable for foreign antigen driven GC, PC antibody responses. Competitive bone marrow (BM) chimeras highlighted importance hematopoietic cells GC differentiation. Single-cell-RNAseq indicated mediated differentiation through fates....
Introduction Idiopathic Multicentric Castleman Disease (iMCD) is a polyclonal lymphoproliferative disorder involving cytokine storms that can lead to organ failure and death. The cause of iMCD unknown, but some clinical evidence suggests an autoimmune etiology. For example, connective tissue disorders (CTDs) share many features, autoantibodies have been anecdotally reported in individual patients. This study investigates whether common are shared across Methods We assembled custom bead-based...
3004 Background: AZD2014 is a potent, dual mTORC1/mTORC2 inhibitor with clear activity in vivo and vitro experimental models. Methods: This 2-part study consisted of "rolling six" dose escalation (Part A) expansion B) phases. Part A: 3–6 pts per cohort received an oral solution BD starting at 50 mg. A further 6 were treated below the MTD to changes pharmacodynamic (PD) biomarkers. B: additional dosed MTD, including group ER+/PR+ or HER2+ patients breast cancer. Primary endpoint: safety...
The dissemination of HIV from an initial site infection is facilitated by motile HIV-infected CD4+ T-cells. However, the impact infected target cell migration on antigen recognition HIV-specific CD8+ T-cells unclear. Using a 3D in vitro model tissue, we visualized dynamic interactions between or peptide-pulsed and CTLs engaged targets, but ∼50% targets broke contact escaped. In contrast, immobilized cells were readily killed, indicating motility directly inhibits T-cell function. Strong...
The intestine is a highly dynamic environment that requires tight control of the various inputs to maintain homeostasis and allow for proper responses injury. It was recently found stem cell niche epithelium regenerated after injury by de-differentiated adult cells, through process gives rise Sca1+ fetal-like cells driven transient population Clu
Idiopathic multicentric Castleman disease is a rare lymphoproliferative disorder that clinically classified into idiopathic plasmacytic lymphadenopathy (IPL); thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO); not otherwise specified (NOS). Although each subtype shows varying degrees of hypervascularity, no statistical data on the degree vascularization have been reported. Additionally, mechanisms underlying in clinical are poorly understood. Here, we aimed to...
The full GM-CSF expression spectrum in immune cells remains unclear, while CD4+ T are the primary source. Using novel reporter/fate reporter transgenic mice, we tracked ongoing and past (YFP+) various cells. was produced by diverse cells, including CD4+, CD8+, γδ T, NK, B, CD11b+ with patterns varying cell type organ, liver NK showing highest history both naive mice EAE. transient permanently lost most over time. In a mouse model of multiple sclerosis, effector memory were dominant CNS...
During alcohol consumption, the esophageal mucosa is directly exposed to high concentrations of ethanol (EtOH). We therefore investigated response normal human epithelial cell lines EPC1, EPC2 and EPC3 acute EtOH exposure. While these cells were able tolerate 2% for 8 h in both three-dimensional organoids monolayer culture conditions, RNA sequencing suggested that induced mitochondrial dysfunction. With treatment, EPC1 also demonstrated decreased ATPB protein expression by immunofluorescence...