ipsc-derived-epithelial-mesenchymal-endothelial-immune-cell-co

iPSC-Derived Epithelial, Mesenchymal, Endothelial, and Immune Cell Co-Culture to Model Airway Barrier Integrity in Lung Health and Disease

Human lung tissue is composed of an interconnected network of epithelium, mesenchyme, endothelium, and immune cells from the upper airway of the ...

an-open-source-normothermic-perfusion-system-designed-for-research

An Open-Source Normothermic Perfusion System Designed for Research Scientists

The integration of ex vivo perfusion machines for human organs prior to transplantation has improved outcomes for recipients and increased organ ...

Sanford Consortium for Regenerative Medicine

Sanford Burnham Prebys Medical Discovery Institute

National Institutes of Health

The licensing of herpes zoster vaccine has demonstrated that therapeutic vaccination can help control chronic viral infection. Unfortunately, human trials of immunodeficiency virus (HIV) vaccine have shown only marginal efficacy.

Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire.

This study examines the association of age and other sociodemographic variables with properties of personal networks; using samples of individuals residing in the rural western United States and the City of Los Angeles, we evaluate the degree to which these associations vary with geographical context. For both samples, we test the hypothesis that age is negatively associated with network size (i.e., degree) and positively associated with network multiplexity (the extent of overlap) on 6 different relations: core discussion members, social activity participants, emergency contacts, neighborhood safety contacts, job informants, and kin. We also examine the relationship between age and spatial proximity to alters.

The relationship of age to personal network size, relational multiplexity, and proximity to alters in the Western United States.

Nucleic acid (DNA and RNA) vaccines are among the most advanced vaccines for COVID-19 under development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of nucleic acid vaccines. This will facilitate the assessment by key stakeholders of potential safety issues and understanding of overall benefit-risk. The structured assessment provided by the template can also help improve communication and public acceptance of licensed nucleic acid vaccines.

The Brighton Collaboration standardized template for collection of key information for benefit-risk assessment of nucleic acid (RNA and DNA) vaccines.

Many of the vaccines under development for COVID-19 involve the use of viral vectors. The Brighton Collaboration Benefit-Risk Assessment of Vaccines by Technology (BRAVATO, formerly the Viral Vector Vaccine Safety Working Group, V3SWG) working group has prepared a standardized template to describe the key considerations for the benefit-risk assessment of viral vector vaccines. This will facilitate key stakeholders to anticipate potential safety issues and interpret or assess safety data. This would also help improve communication and public acceptance of licensed viral vector vaccines.

The Brighton Collaboration standardized template for collection of key information for benefit-risk assessment of viral vector vaccines.

Critical advancement is needed in the study of human milk as a biological system that intersects and interacts with myriad internal (maternal biology) and external (diet, environment, infections) factors and its plethora of influences on the developing infant. Human-milk composition and its resulting biological function is more than the sum of its parts. Our failure to fully understand this biology in a large part contributes to why the duration of exclusive breastfeeding remains an unsettled science (if not policy). Our current understanding of human-milk composition and its individual components and their functions fails to fully recognize the importance of the chronobiology and systems biology of human milk in the context of milk synthesis, optimal timing and duration of feeding, and period of lactation. The overly simplistic, but common, approach to analyzing single, mostly nutritive components of human milk is insufficient to understand the contribution of either individual components or the matrix within which they exist to both maternal and child health. There is a need for a shift in the conceptual approach to studying human milk to improve strategies and interventions to support better lactation, breastfeeding, and the full range of infant feeding practices, particularly for women and infants living in undernourished and infectious environments. Recent technological advances have led to a rising movement towards advancing the science of human-milk biology. Herein, we describe the rationale and critical need for unveiling the multifunctionality of the various nutritional, nonnutritional, immune, and biological signaling pathways of the components in human milk that drive system development and maturation, growth, and development in the very early postnatal period of life. We provide a vision and conceptual framework for a research strategy and agenda to change the field of human-milk biology with implications for global policy, innovation, and interventions.

The need to study human milk as a biological system.

The transfer of the small protein ubiquitin to a target protein is an intricately orchestrated process called ubiquitination that results in modulation of protein function or stability. Proper regulation of ubiquitination is essential, and dysregulation of this process is implicated in several human diseases. An example of a ubiquitination cascade that is a central signaling node in important disease-associated pathways is that of CBLB [a human homolog of a viral oncogene asitas -lineage ymphoma (CBL) from the Cas NS-1 murine retrovirus], a RING finger ubiquitin ligase (E3) whose substrates include a number of important cell-signaling kinases. These include kinases important in immune function that act in the T cell receptor and costimulatory pathways, the Tyro/Axl/MerTK (TAM) receptor family in natural killer (NK) cells, as well as growth factor receptor kinases like epidermal growth factor receptor (EGFR). Loss of CBLB has been shown to increase innate and adaptive antitumor immunity. This suggests that small-molecule modulation of CBLB E3 activity could enhance antitumor immunity in patients. To explore the hypothesis that enzymatic inhibition of E3s may result in modulation of disease-related signaling pathways, we established a high-throughput screen of >70,000 chemical entities for inhibition of CBLB activity. Although CBLB was chosen as a proof-of-principle target for inhibitor discovery, we demonstrate that our assay is generalizable to monitoring the activity of other ubiquitin ligases. We further extended our observed in vitro inhibition with additional cell-based models of CBLB activity. From these studies, we demonstrate that a class of natural product-based alkaloids, known as methyl ellipticiniums (MEs), is capable of inhibiting ubiquitin ligases intracellularly.

In Vitro Ubiquitination Platform Identifies Methyl Ellipticiniums as Ubiquitin Ligase Inhibitors.

An extract of the coralline demosponge  inhibited the ubiquitin ligase activity of the immunomodulatory protein Cbl-b. The bioassay-guided separation of the extract provided ten active compounds, including three new -methyladenine-containing diterpenoids, agelasines W-Y (-), a new bromopyrrole alkaloid, (1)-methylisoageliferin (), and six known ageliferin derivatives (-). The structures of the new compounds were elucidated from their spectroscopic and spectrometric data, including IR, HRESIMS, and NMR, and by comparison with spectroscopic data in the literature. While all of the isolated compounds showed Cbl-b inhibitory activities, ageliferins (-) were the most potent metabolites, with IC values that ranged from 18 to 35 μM.

Agelasine Diterpenoids and Cbl-b Inhibitory Ageliferins from the Coralline Demosponge .

Extremely low birth weight (ELBW) infants are at risk for end-organ hypoxia and ischemia. Regional tissue oxygenation of the brain and gut as monitored with near-infrared spectroscopy (NIRS) may change with postnatal age, but normal ranges are not well defined.

Early brain and abdominal oxygenation in extremely low birth weight infants.

This sequential, prospective meta-analysis sought to identify risk factors among pregnant and postpartum women with COVID-19 for adverse outcomes related to disease severity, maternal morbidities, neonatal mortality and morbidity, and adverse birth outcomes.

Clinical risk factors of adverse outcomes among women with COVID-19 in the pregnancy and postpartum period: a sequential, prospective meta-analysis.

A new dimeric alkaloid plakoramine A [(±)-] was identified from a marine sponge  sp. Chiral-phase HPLC separation of (±)- led to the purified enantiomers (+)- and (-)- which both potently inhibited CBL-B E3 ubiquitin ligase activities. The absolute configurations of the enantiomers were determined by quantum chemical calculations. Scrutinization of the purification conditions revealed a previously undescribed, nonenzymatic route to form (±)- via photochemical conversion of its naturally occurring monomeric counterpart, plakinidine B ().

Photochemical Dimerization of Plakinidine B Leads to Potent Inhibition of the E3 Ubiquitin-Protein Ligase CBL-B.

Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes.

Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants: A Secondary Near-Infrared Spectroscopy Study of the Transfusion of Prematures Randomized Clinical Trial (TOP NIRS).

Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with robust anti-tumor activity, but systemic adverse effects largely terminated therapeutic development of recombinant human IL-12 (rhIL-12). PDS01ADC is a novel human monoclonal antibody (NHS76) conjugated to two IL-12 heterodimers with established safety in phase I trials. The NHS76 antibody specifically targets histone/DNA complexes which are accessible only in regions of cell death and this antibody has been shown to accumulate locally in tumors.

Hepatic artery infusion pump (HAIP) therapy in combination with targeted delivery of IL-12 for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma: a phase II trial protocol.

The US Food and Drug Administration (FDA) and National Institutes of Health (NIH) share a mutual interest in facilitating efficient, well-designed clinical studies of drugs, devices, and biological products. Recent advances in science and technology, as well as innovative approaches to research design and methodology, provide opportunities to enhance efficiency in medical product development and improve participant engagement in clinical trials. Recent initiatives across the FDA and NIH focus on evidence modernization approaches. Fostering appropriate use of novel designs and sources of evidence, such as real-world data (RWD) to support marketing authorizations and satisfy postapproval study requirements, may be enhanced by using consensus terminology for innovative study designs.

ArticleTotal : 2	Year
Publication title	2024
Publication title Cited by 2	2025

Article	Year
Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire. The Journal of infectious diseases\| PubMed ID: 23482645	2013
The relationship of age to personal network size, relational multiplexity, and proximity to alters in the Western United States. The journals of gerontology. Series B, Psychological sciences and social sciences\| PubMed ID: 25324292	2015
The Brighton Collaboration standardized template for collection of key information for benefit-risk assessment of nucleic acid (RNA and DNA) vaccines. Vaccine\| PubMed ID: 32571717	2020
The Brighton Collaboration standardized template for collection of key information for benefit-risk assessment of viral vector vaccines. Vaccine\| PubMed ID: 32907759	2020
The need to study human milk as a biological system. The American journal of clinical nutrition\| PubMed ID: 33831952	2021
In Vitro Ubiquitination Platform Identifies Methyl Ellipticiniums as Ubiquitin Ligase Inhibitors. SLAS discovery : advancing life sciences R & D\| PubMed ID: 33882749	2021
Agelasine Diterpenoids and Cbl-b Inhibitory Ageliferins from the Coralline Demosponge . Marine drugs\| PubMed ID: 34202500	2021
Early brain and abdominal oxygenation in extremely low birth weight infants. Pediatric research\| PubMed ID: 35513716	2022
Clinical risk factors of adverse outcomes among women with COVID-19 in the pregnancy and postpartum period: a sequential, prospective meta-analysis. American journal of obstetrics and gynecology\| PubMed ID: 36027953	2023
Photochemical Dimerization of Plakinidine B Leads to Potent Inhibition of the E3 Ubiquitin-Protein Ligase CBL-B. Organic letters\| PubMed ID: 36516994	2022
Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants: A Secondary Near-Infrared Spectroscopy Study of the Transfusion of Prematures Randomized Clinical Trial (TOP NIR... JAMA network open\| PubMed ID: 37733345	2023
Hepatic artery infusion pump (HAIP) therapy in combination with targeted delivery of IL-12 for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma: a phase II trial... Journal of gastrointestinal oncology\| PubMed ID: 38989414	2024
Modernizing Research and Evidence Consensus Definitions: A Food and Drug Administration-National Institutes of Health Collaboration. JAMA network open\| PubMed ID: 40526378	2025

Emily Smith

Biography

JoVE Journal Publications

Other Publications