Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion “cytokine storm” with severe sometimes life-threatening consequences typically encountered toxic shock syndrome (TSS). Given the rapidity which TSS develops, designing timely truly targeted therapies for this requires identification key mediators cytokine storm’s initial wave. Equally important, early host responses SAgs can be...

Abstract Objective Although biomedical informatics has multiple roles to play in addressing the climate crisis, collaborative action and research agendas have yet be developed. As a first step, AMIA’s new Climate, Health, Informatics Working Group held mini-summit entitled Climate health: How can help? during AMIA 2023 Fall Symposium define an initial set of areas interest begin mobilizing informaticians confront urgent challenges change. Materials Methods The (at time, Discussion Forum),...

Staphylococcus aureus is a foremost bacterial pathogen responsible for vast array of human diseases. Staphylococcal superantigens (SAgs) constitute family exotoxins from S. that bind directly to major histocompatibility complex (MHC) class II and T cell receptors drive extensive activation cytokine release. Although these toxins have been implicated in serious disease, including toxic shock syndrome, the specific pathological mechanisms remain unclear. Herein, we aimed elucidate how SAgs...

The deleterious effects of psychological stress on mainstream T lymphocytes are well documented. However, how impacts innate-like cells is unclear. We report that long-term surprisingly abrogates both helper 1 (TH1)- and TH2-type responses orchestrated by invariant natural killer (iNKT) cells. This not due to iNKT cell death because these unusually refractory stress-inflicted apoptosis. Activated in stressed mice exhibit a "split" inflammatory signature trigger sudden serum interleukin-10...

Abstract RNA splicing dysregulation plays a critical role in tumorigenesis, cancer progression, and therapeutic resistance. Components of the spliceosome machinery are frequently mutated myeloid malignancies, affecting 40-85% patients with Myelodysplastic Syndrome (MDS), 10‒25% Acute Myeloid Leukemia (AML) cases. Recurrent aberrant alternative (AS) patterns have also been detected AML even absence somatic gene mutations. Furthermore, genetic screens shown that loss factors sensitizes to BCL2...

Abstract Outcomes on tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant NSCLC fall short of the durable benefit observed with next-generation targeted therapies ALK and ROS1-driven NSCLC. We reviewed chemical structures 30+ existing EGFR TKIs pursuit a novel scaffold that could offer more response. First-generation (1G) (e.g. gefitinib) second-generation (2G) afatinib) share an anilinoquinazoline which is vulnerable to T790M gatekeeper resistance. Third-generation (3G) osimertinib)...

Sepsis-elicited immunosuppression elevates the risk of secondary infections. We used a clinically relevant mouse model and serial peripheral blood samples from patients to assess antimicrobial activities mucosa-associated invariant T (MAIT) cells in sepsis. Hepatic splenic MAIT B6-MAITCAST mice displayed increased CD69 expression robust interferon-γ (IFNγ) production capacity shortly after sublethal cecal ligation puncture, but not at late timepoint. Peripheral cell frequencies were reduced...

ABSTRACT A Gram-negative pathogen Haemophilus influenzae has a truncated endotoxin known as lipooligosaccharide (LOS). Recent studies on H. LOS highlighted its structural and compositional implications for bacterial virulence; however, the role of in activation innate adaptive immunity is poorly understood. THP-1 monocytes were stimulated with either lipopolysaccharide (LPS) from Escherichia coli or compounds derived Eagan, Rd, Rd lic1 lpsA strains. Cell surface expression key...

During toxic shock syndrome (TSS), bacterial superantigens trigger a polyclonal T -cell response leading to potentially catastrophic "cytokine storm". Whether innate-like invariant natural killer (iNKT) cells, with remarkable immunomodulatory properties, participate in TSS is unclear. Using genetic and cell depletion approaches, we generated iNKT cell-deficient, superantigen-sensitive HLA-DR4-transgenic (DR4tg) mice, which were compared their iNKT-sufficient counterparts for responsiveness...

As Pseudomonas aeruginosa infections are characterized by strong inflammation of infected tissues, anti-inflammatory therapies in combination with antibiotics have been considered for the treatment associated diseases. Syk tyrosine kinase is an important regulator inflammatory responses, and its specific inhibition was explored as a therapeutic option several conditions; however, this has not studied bacterial infections. We used model vitro infection human monocytic cell line THP-1 lung...

During the last two decades, Haemophilus influenzae serotype a (Hia) emerged as an important cause of invasive disease in Canadian First Nations and Inuit, Alaskan Native populations, with highest rates reported young children. Immunocompetent adults, contrast to children, do not typically develop Hia disease. To clarify factors responsible for increased burden certain population groups we studied serum bactericidal activity (SBA) against quantified IgG IgM specific capsular polysaccharide...

Invariant NKT (iNKT) cells are innate-like T lymphocytes that recognize and respond to glycolipid Ags such as α-galactosylceramide (α-GalCer). This unique property has been exploited in clinical trials for multiple malignancies. While investigating mouse iNKT cell responses α-GalCer vivo, we found a dramatically enlarged tissue-resident population surprisingly coexpressing select dendritic cell, NK B markers. Further phenotypic functional analyses revealed the identity of this B220+CD11c+MHC...

Carboxyfluorescein succinimidyl ester (CFSE)-based in vivo cytotoxicity assays enable sensitive and accurate quantitation of CD8+ cytolytic T lymphocyte (CTL) responses elicited against tumor- pathogen-derived peptides. They offer several advantages over traditional killing assays. First, they permit the monitoring CTL-mediated within architecturally intact secondary lymphoid organs, typically spleen. Second, allow for mechanistic studies during priming, effector recall phases CTL responses....

Sepsis results from a heavy-handed response to infection that may culminate in organ failure and death. Many patients who survive acute sepsis become immunosuppressed succumb opportunistic infections. Therefore, be successful, immunotherapies must target both the initial protracted phase of syndrome relieve early immunopathology late immunosuppression, respectively. Invariant NKT (iNKT) cells are attractive therapeutic targets sepsis. However, repeated treatments with α-galactosylceramide,...

Climate change is an alarming global threat to individual and public health. This commentary addresses how the field of climate health informatics can spearhead research innovation guide adaptation mitigation efforts.

Carboxyfluorescein succinimidyl ester (CFSE)-based in vivo cytotoxicity assays enable sensitive and accurate quantitation of CD8+ cytolytic T lymphocyte (CTL) responses elicited against tumor- pathogen-derived peptides. They offer several advantages over traditional killing assays. First, they permit the monitoring CTL-mediated within architecturally intact secondary lymphoid organs, typically spleen. Second, allow for mechanistic studies during priming, effector recall phases CTL responses....

Abstract The nervous system serves critical roles in the regulation of immune responses. Consequently, neuroimmune functional interface can be disrupted by psychological stress, potentially impeding our ability to combat malignancies. Invariant natural killer T (iNKT) cells are innate-like that, upon activation glycolipid antigens and/or select environmental cues such as inflammatory cytokines, participate antitumor However, how mediators stress may impact iNKT cell functions this context...

Abstract Precursors of mature natural killer (pre-mNK) cells, initially called IFN-producing dendritic have been recently characterized as a novel intermediate in NK cell differentiation. Typified by unique B220+NK1.1+CD11c+MHCII+ phenotype, pre-mNK cells exhibit prolific anti-tumor cytotoxicity while retaining the ability to present antigens thereby activating neighbouring T cells. Invariant NKT (iNKT) are another population highlighted for their potential anti-cancer immunity. They...

Long-term stress disrupts the neuroimmune interface, often resulting in immunosuppression. The deleterious effects of on mainstream T cells are well-documented. However, innate-like invariant have been overlooked. Chief among these natural killer (iNKT) and mucosa-associated (MAIT) cells, which fulfill important functions anticancer antimicrobial immunity. We found to surprisingly abrogate both TH1- TH2-type responses mediated by iNKT cells. This was not due cell death since were unusually...