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The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid N -acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. Furthermore, different BAs regulated CD8 + T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.

Memory T and B cells in tissues are essential for protective immunity. Here, we performed a comprehensive analysis of the tissue distribution, phenotype, durability, and transcriptional profile of COVID-19 mRNA vaccine-induced immune memory across blood, lymphoid organs, and lungs obtained from 63 vaccinated organ donors aged 23-86, some of whom experienced SARS-CoV-2 infection. Spike (S)-reactive memory T cells were detected in lymphoid organs and lungs and variably expressed tissue-resident markers based on infection history, and S-reactive B cells comprised class-switched memory cells resident in lymphoid organs. Compared with blood, S-reactive tissue memory T cells persisted for longer times post-vaccination and were more prevalent with age. S-reactive T cells displayed site-specific subset compositions and functions: regulatory cell profiles were enriched in tissues, while effector and cytolytic profiles were more abundant in circulation. Our findings reveal functional compartmentalization of vaccine-induced T cell memory where surveilling effectors and in situ regulatory responses confer protection with minimal tissue damage., Competing Interests: Declaration of interests A.S. is a consultant for Gritstone Bio, Flow Pharma, Moderna, AstraZeneca, Qiagen, Fortress, Gilead, Sanofi, Merck, RiverVest, MedaCorp, Turnstone, NA Vaccine Institute, Emervax, Gerson Lehrman Group, and Guggenheim. La Jolla Institute. has filed for patent protection for various aspects of T cell epitope and vaccine design work. Columbia University has filed patent applications related to vaccine tissue assays., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In recent years, many countries have significantly increased military spending, mainly due to geopolitical instability in several regions and the potential risk of armed conflicts spreading worldwide. In this context, understanding the nutritional needs of soldiers in different climates (warm, cold and high altitude) is important and directly impacts the performance and health of soldiers, especially in extreme environments. The amount of liquids, calories, and macro- and micronutrients contained in military rations must be determined considering the type of exercise, duration and environment. Military rations, in addition to being nutritionally adequate, must be practical, sustainable and easy to consume at any temperature and situation. Given these considerations, this study aimed to review scientific knowledge regarding the convenience, sensory attributes and nutritional components of military rations. Furthermore, this review studied the factors influencing soldiers' appetite, gut microbiota and nutritional needs during training or combat in extreme environments (warm, cold and high altitude). This exploration further advances our understanding of contemporary nutritional strategies for military personnel, contributing to future research and highlighting areas that must be developed.

Brewer's spent grain (BSG) is an abundant agro-industrial residue and a sustainable low-cost source for extracting proteins. The composition and functionality of BSG protein concentrates are affected by extraction conditions. This study examined the use of citric acid (CA) and HCl to precipitate BSG proteins. The resultant protein concentrates were compared in terms of their composition and functional properties. The BSG protein concentrate precipitated by CA had 10% lower protein content, 5.8% higher carbohydrate, and 5.4% higher lipid content than the sample precipitated by HCl. Hydrophilic/hydrophobic protein and saturated/unsaturated fatty acid ratios increased by 16.9% and 26.5% respectively, in the sample precipitated by CA. The formation of CA-cross-linkages was verified using shotgun proteomics and Fourier transform infrared spectroscopy. Precipitation by CA adversely affected protein solubility and emulsifying properties, while improving foaming properties. This study provides insights into the role of precipitants in modulating the properties of protein concentrates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Hypertension, a major health concern linked to heart disease and premature mortality, has prompted a search for alternative treatments due to side effects of existing medications. Sustainable harvesting of low-trophic marine organisms not only enhances food security but also provides a variety of bioactive molecules, including peptides. Despite comprising only a fraction of active natural compounds, peptides are ideal for drug development due to their size, stability, and resistance to degradation. Our review evaluates the anti-hypertensive properties of peptides and proteins derived from selected marine invertebrate phyla, examining the various methodologies used and their application in pharmaceuticals, supplements, and functional food. A considerable body of research exists on the anti-hypertensive effects of certain marine invertebrates, yet many species remain unexamined. The array of assessments methods, particularly for ACE inhibition, complicates the comparison of results. The dominance of in vitro and animal in vivo studies indicates a need for more clinical research in order to transition peptides into pharmaceuticals. Our findings lay the groundwork for further exploration of these promising marine invertebrates, emphasizing the need to balance scientific discovery and marine conservation for sustainable resource use., Competing Interests: The authors declare no conflicts of interest.

Human sepsis is a complex disease that manifests with a diverse range of phenotypes and inherent variability among individuals, making it hard to develop a comprehensive animal model. Despite this difficulty, numerous models have been developed that capture many key aspects of human sepsis. The robustness of these models is vital for conducting pre-clinical studies to test and develop potential therapeutics. In this article, we describe four different models of murine sepsis that can be used to address different scientific questions relevant to the pathology and immune response during and after a septic event. Basic Protocol 1 details a non-synchronous cecal ligation and puncture (CLP) model of sepsis, where mice are subjected to polymicrobial exposure through surgery at different time points within 2 weeks. This variation in sepsis onset establishes each mouse at a different state of inflammation and cytokine levels that mimics the variability observed in humans when they present in the clinic. This model is ideal for studying the long-term impact of sepsis on the host. Basic Protocol 2 is also a type of polymicrobial sepsis, where injection of a specific amount of cecal slurry from a donor mouse into the peritoneum of recipient mice establishes immediate inflammation and sepsis without any need for surgery. Basic Protocol 3 describes infecting mice with a defined gram-positive or -negative bacterial strain to model a subset of sepsis observed in humans infected with a single pathogen. Basic Protocol 4 describes administering LPS to induce sterile endotoxemia. This form of sepsis is observed in humans exposed to bacterial toxins from the environment. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Non-synchronous cecal ligation and puncture Basic Protocol 2: Cecal slurry model of murine sepsis Basic Protocol 3: Monomicrobial model of murine sepsis Basic Protocol 4: LPS model of murine sepsis., (© 2024 The Authors. Current Protocols published by Wiley Periodicals LLC.)

Sepsis, an amplified immune response to systemic infection, is characterized by a transient cytokine storm followed by chronic immune dysfunction. Consequently, sepsis survivors are highly susceptible to newly introduced infections, suggesting sepsis can influence the function and composition of the naïve CD8 T cell pool and resulting pathogen-induced primary CD8 T cell responses. Here, we explored the extent to which sepsis induces phenotypic and functional changes within the naïve CD8 T cell pool. To interrogate this, the cecal ligation and puncture (CLP) mouse model of polymicrobial sepsis was used. In normal, non-septic mice, we show type-I interferon (IFN I)-mediated signaling plays an important role in driving the phenotypic and functional heterogeneity in the naïve CD8 T cell compartment leading to increased representation of Ly6C+ naïve CD8 T cells. In response to viral infection after sepsis resolution, naïve Ly6C+ CD8 T cells generated more primary effector and memory CD8 T cells with slower conversion to a central memory CD8 T cell phenotype (Tcm) than Ly6C- naïve CD8 T cells. Importantly, as a potent inducer of cytokine storm and IFN I production, sepsis leads to increased representation of Ly6C+ naïve CD8 T cells that maintained their heightened ability to respond (i.e., effector and memory CD8 T cell accumulation and cytokine production) to primary LCMV infection. Lastly, longitudinal analyses of peripheral blood samples obtained from septic patients revealed profound changes in CD8 T cell subset composition and frequency compared to healthy controls. Thus, sepsis has the capacity to alter the composition of naïve CD8 T cells, directly influencing primary CD8 T cell responses to newly introduced infections., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Berton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

While sea cucumber is a food delicacy in Asia, these food resources are less exploited in Europe. The aim of this study was to determine the chemical composition and potential food applications of the less exploited orange-footed sea cucumber ( Cucumaria frondosa ). In particular, the antioxidative capacity and free amino acids associated with the umami flavor released by enzymatic hydrolyses by either Bromelain + Papain (0.36%, 1:1) or Alcalase (0.36%) were studied. Fresh C. frondosa contained approximately 86% water, and low levels of ash (<1%) and lipids (<0.5%). The protein content was 5%, with a high proportion of essential amino acids (43%) and thus comparable to the FAO reference protein. The high concentration of free amino acids associated with umami, sour, sweet, and bitter may contribute to flavor enhancement. Hydrolysis by Bromelain + Papain resulted in the highest protein yield, and the greatest concentration of free amino acids associated with umami and sour taste. All samples showed promising antioxidant capacity measured by FRAP, ABTS, DPPH and ORAC compared to previous reports. The inorganic arsenic concentration of fresh C. frondosa ranged from 2 to 8 mg/kg wet weight and was not affected by processing. This is comparable to other seafood and may exceed regulatory limits of consumption.

Microencapsulation of purple corn anthocyanins was carried out via an electrostatic extruder using alginate as a wall material. The influence of alginate concentration (1-2 %), extract concentration (20-30 %), and extrusion voltage (3-5 kV) on encapsulation efficiency and mean particle size was evaluated using response surface methodology. Optimal conditions were obtained to produce two different extract-loaded microbeads. Microbeads with the highest encapsulation efficiency (EE) and minimum particle size were achieved at 1 % alginate, 20 % extract, and 5 kV extrusion voltage (EE C3G  = 70.26 %, EE TPC  = 91.59 %, particle size = 1.29 mm). In comparison, the microbeads with the efficient entrapment and maximum particle size were obtained at 1 % alginate, 26 % extract, and 3 kV (EE C3G  = 81.15 %, EE TPC  = 91.01 %, particle size = 1.87 mm). Brunauer-Emmett-Teller (BET) surface area, pore size, and pore volume decreased after the inclusion of extract, with the lowest values reported for the smallest microbeads containing the extract. Scanning electron microscopy confirmed the results obtained by BET method and demonstrated fewer cracks and lower shrinkage of encapsulated samples. Fourier-transform infrared results proved the presence of anthocyanins and further possible interactions between phenolics and alginate. Stability studies revealed the color maintenance of anthocyanins-loaded microbeads during 4 weeks of storage at 4 °C and 8 °C. Moreover, the small and large particles showed a 7.6 and 3.4-fold reduction in degradation rate at 4 °C compared to their unencapsulated counterparts. Anthocyanins-loaded alginate microbeads retained over 80 % of cyanidin-3-glucoside at 4 °C and 8 °C, suggesting a promising potential of optimized microbeads for intelligent packaging applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

pH indicators have emerged as promising tools for real-time monitoring of product freshness and quality in intelligent food packaging applications. However, ensuring the stability of these indicators is critical for practical use. This study aims to evaluate the stability of anthocyanins-loaded alginate hydrogel beads of varying sizes at different temperatures under accelerated light conditions and relative humidity (RH) levels of 53% and 97% during 21 days of storage. Moreover, their sensitivity to the principal spoilage volatiles of muscle food products such as ammonia (NH 3 ), dimethylamine (DMA) and trimethylamine (TMA) was investigated. The half-life of cyanidin-3-glucoside in small hydrogel beads was roughly twice as long as that of the larger beads under accelerated light exposure at 4 °C and they were less likely to undergo noticeable color changes over time. Both sizes of hydrogel beads stored at 97% RH and 4 °C showed color stability over the 21-day period with minimal color variation (|ΔE| ≤ 3). The UV-vis spectra of the purple corn extract exhibited changes across pH 2 to 12, as evidenced by the visible color variations, ranging from pink to green. The limit of detection (LOD) for NH 3 was 25 ppm for small beads and 15 ppm for large ones. Both types of beads exhibited similar LOD for DMA and TMA, around 48 ppm. This research showed that alginate hydrogel beads containing anthocyanins from purple corn are a viable option for developing intelligent packaging of muscle foods. Furthermore, the use of hydrogel beads of different sizes can be customized to specific muscle foods based on the primary spoilage compound generated during spoilage., Competing Interests: I confirm that there are no known conflicts of interest associated with this manuscript and there has been no financial support for this work that could have influenced its outcome. I confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed., (© 2023 The Authors. Published by Elsevier B.V.)

Introduction: Sensorineural hearing loss (SNHL) is the most common birth disorder. The cause of SNHL is heterogeneous and varies in different populations. Understanding the causes of a hearing loss (HL) predict the outcome of cochlear implantation and is of great importance in understanding the mechanism of the disease and in providing the best treatment. Undiagnosed and untreated HL has a profound effect on the acquisition of early communication skills, speech, language, academic, emotional, and psychosocial development in children., Objectives: To determine the cause of HL and implantation age in pediatric cochlear implant (CI) users in a Danish population., Methods: Data of 100 children (54 females and 46 males), age 0-17 years, was analyzed. All of the children were implanted during 2020-2022., Results: Hereditary HL was diagnosed in 44 cases (44%), with pathogenic variants in the SLC26A4 gene found in 14 cases (14%). Syndromic HL was diagnosed in 23 children (23%). Non-syndromic HL was diagnosed in 21 children (21%), where the most common genetic variation was found in the GJB2 gene. Acquired prenatal and postnatal sensory disorders TORCH risk factors were associated with HL in 25 cases (25%). Congenital CMV DNA was diagnosed in 23 samples (23%). The cause of the HL remained unknown for 31 (31%) children. In 70 (70%) of the participants the HL was diagnosed at time of newborn hearing screening (NHS). Twenty-three of the children were diagnosed with congenital severe to profound bilateral HL and were simultaneously implanted between 8 and 14 months (mean age 10.5 months). In the remaining 47 cases, the HL was progressive and the children were implanted when the HL reached the criteria for implantation., Conclusions: In the current study, the major causes of HL were alterations in the SLC26A4 gene: 13% with Pendred syndrome and 1% non-syndromic. Thirty-one (31%) had HL of unknown origin and almost half of these cases had inner ear malformations (n = 16)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The increasing use of nuclear energy sources inevitably raises the risk of accidental or deliberate radiation exposure and associated immune dysfunction. However, the extent to which radiation exposure impacts memory CD8 T cells, potent mediators of immunity to recurring intracellular infections and malignancies, remains understudied. Using P14 CD8 T cell chimeric mice (P14 chimeras) with an lymphocytic choriomeningitis virus (LCMV) infection model, we observed that sublethal (5Gy) whole-body irradiation (WBI) induced a rapid decline in the number of naive (T N ) and P14 circulating memory CD8 T cells (T CIRCM ), with the former being more susceptible to radiation-induced numeric loss. While T N cell numbers rapidly recovered, as previously described, the number of P14 T CIRCM cells remained low at least 9 mo after radiation exposure. Additionally, the remaining P14 T CIRCM in irradiated hosts exhibited an inefficient transition to a central memory (CD62L + ) phenotype compared to nonirradiated P14 chimeras. WBI also resulted in long-lasting T cell intrinsic deficits in memory CD8 T cells, including diminished cytokine and chemokine production along with impaired secondary expansion upon cognate Ag reencounter. Irradiated P14 chimeras displayed significantly higher bacterial burden after challenge with Listeria monocytogenes expressing the LCMV GP 33-41 epitope relative to nonirradiated controls, likely due to radiation-induced numerical and functional impairments. Taken together, our findings suggest that sublethal radiation exposure caused a long-term numerical, impaired differentiation, and functional dysregulation in preexisting T CIRCM , rendering previously protected hosts susceptible to reinfection.

The Republic of Seychelles is located in Western-Central Indian Ocean, and marine capture fisheries play a key role in the country's economic and social life in terms of food security, employment, and cultural identity. The Seychellois are among the highest per capita fish-consuming people in the world, with a high reliance on fish for protein. However, the diet is in transition, moving towards a Western-style diet lower in fish and higher in animal meat and easily available, highly processed foods. The aim of this study was to examine and evaluate the protein content and quality of a wide range of marine species exploited by the Seychelles industrial and artisanal fisheries, as well as to further to assess the contribution of these species to the daily intake recommended by the World Health Organization (WHO). A total of 230 individuals from 33 marine species, including 3 crustaceans, 1 shark, and 29 teleost fish, were collected from the Seychelles waters during 2014-2016. All analyzed species had a high content of high-quality protein, with all indispensable amino acids above the reference value pattern for adults and children. As seafood comprises almost 50% of the consumed animal protein in the Seychelles, it is of particular importance as a source of essential amino acids and associated nutrients, and as such every effort to sustain the consumption of regional seafood should be encouraged.

Long-lasting sepsis-induced immunoparalysis has been principally studied in primary (1°) memory CD8 T cells; however, the impact of sepsis on memory CD8 T cells with a history of repeated cognate Ag encounters is largely unknown but important in understanding the role of sepsis in shaping the pre-existing memory CD8 T cell compartment. Higher-order memory CD8 T cells are crucial in providing immunity against common pathogens that reinfect the host or are generated by repeated vaccination. In this study, we analyzed peripheral blood from septic patients and show that memory CD8 T cells with defined Ag specificity for recurring CMV infection proliferate less than bulk populations of central memory CD8 T cells. Using TCR-transgenic T cells to generate 1° and higher-order (quaternary [4°]) memory T cells within the same host, we demonstrate that the susceptibility and loss of both memory subsets are similar after sepsis induction, and sepsis diminished Ag-dependent and -independent (bystander) functions of these memory subsets equally. Both the 1° and 4° memory T cell populations proliferated in a sepsis-induced lymphopenic environment; however, due to the intrinsic differences in baseline proliferative capacity, expression of receptors (e.g., CD127/CD122), and responsiveness to homeostatic cytokines, 1° memory T cells become overrepresented over time in sepsis survivors. Finally, IL-7/anti-IL-7 mAb complex treatment early after sepsis induction preferentially rescued the proliferation and accumulation of 1° memory T cells, whereas recovery of 4° memory T cells was less pronounced. Thus, inefficient recovery of repeatedly stimulated memory cells after polymicrobial sepsis induction leads to changes in memory T cell pool composition, a notion with important implications in devising strategies to recover the number and function of pre-existing memory CD8 T cells in sepsis survivors., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Low trophic species are often mentioned as additional food sources to achieve broader and more sustainable utilisation of the ocean. The aim of this study was to map the food potential of Norwegian orange-footed sea cucumber ( Cucumaria frondosa ). C. frondosa contained 7% protein, 1% lipids with a high proportion of polyunsaturated fatty acids, and a variety of micronutrients. The nutrient density scores (NDS) of C. frondosa were above average compared towards daily recommended intakes (DRI) for men and women (age 31-60) but below when capped at 100% of DRI. The concentrations of persistent organic pollutants and trace elements were in general low, except for inorganic arsenic (iAs) (0.73 mg per kg) which exceeded the limits deemed safe by food authorities. However, the small number of samples analysed for iAs lowers the ability to draw a firm conclusion. The carbon footprint from a value chain with a dredge fishery, processing in Norway and retail in Asia was assessed to 8 kg carbon dioxide equivalent (CO 2 eq.) per kg C. frondosa , the fishery causing 90%. Although, C. frondosa has some nutritional benefits, the carbon footprint or possible content of iAs may restrict the consumption.

The global production of sea cucumbers was 245 thousand tons in 2020. Sea cucumbers are important food items in Asian and Pacific cuisines, the highest proportion being consumed in China as "bêche-de-mer" dried, gutted, boiled and salted body wall. However, consumption of sea cucumbers is expanding in China and globally, and the high demand has led to decline in populations of sea cucumbers, due to overexploitation. Aquaculture, together with novel fisheries on new species in new regions is easing the demand. Thus, an assessment of food safety is warranted. A literature search on food hazards was performed. A high proportion of the selected papers concerned heavy metals and metalloid hazards, such as mercury (Hg), cadmium (Cd), lead (Pb), and arsenic (As). No specific maximum limits (MLs) have been set for contents of these in sea cucumbers. Thus, the contents were compared with maximum limits set for aquatic animals in general or bivalve molluscs if available. With regard to Hg and Cd levels, none of the samples exceeded limits set by the European Commission or the National Standard of China, while for Pb, samples from highly industrialised areas exceeded the limits. Surprisingly, data on contaminants such as POPs, including dioxins and dl-PCB, PAH and PFAS as well as microbial hazards were scarce. The availability of fresh sea cucumber has increased due to aquaculture. To preserve the original flavour some consumers are reported to prefer to eat raw sea cucumber products, sashimi and sushi, which inevitably causes challenges from the microbial food safety perspective. Altogether, this paper highlights specific needs for knowledge, in particular when harvesting new species of sea cucumbers or in industrialized regions. Systematic monitoring activities, appropriate guidelines and regulations are highly warranted to guide the utilization of sea cucumbers.

Elegant fate-mapping models to label intestinal tissue-resident memory CD8 + T (T RM ) cells demonstrate retention and lack of expansion of CD103 + T RM cells, whereas intestinal CD103 - memory cells expand, forming both new tissue-localized CD103 + and CD103 - T RM cells (see related Research Articles by Fung et al. and von Hoesslin et al. ).

Sepsis, an amplified immune response to systemic infection that leads to life-threatening organ dysfunction, affects >125,000 people/day worldwide with 20% mortality. Modest therapeutic progress for sepsis has been made, in part because of the lack of therapeutic translatability between mouse-based experimental models and humans. One potential reason for this difference stems from the extensive use of immunologically naive specific pathogen-free mice in preclinical research. To address this issue, we used sequential infections with well-defined BSL-2 pathogens to establish a novel immune-experienced mouse model (specific pathogen experienced [SPexp]) to determine the extent to which immunological experience and/or inflammation influences the host capacity to respond to subsequent infections, including sepsis. Consistent with their immunological experience, SPexp inbred or outbred mice had significant changes in the composition and activation status of multiple leukocyte populations known to influence the severity of cecal ligation and puncture-induced sepsis. Importantly, by varying the timing of sepsis induction, we found the level of basal inflammation controls sepsis-induced morbidity and mortality in SPexp mice. In addition, although a beneficial role of NK cells in sepsis was recently demonstrated in specific pathogen-free mice, NK cell depletion before cecal ligation and puncture induction in SPexp mice lead to diminished mortality, suggesting NK cells may have beneficial or detrimental roles in the response to septic insult dependent on host immune status. Thus, data highlight the importance of utilizing immune-experienced models for preclinical studies to interrogate the cellular/molecular mechanism(s) that could be therapeutically exploited during severe and dysregulated infection-induced inflammatory responses, such as sepsis., (Copyright © 2022 The Authors.)

NK cells are important mediators of viral control with the capacity to form adaptive immune features following infection. However, studies of infection-induced adaptive NK cells require adoptive cell transfer to lower the precursor frequency of "Ag-specific" NK cells, potentially limiting the diversity of the NK cell response. In seeking an unmanipulated model to probe the adaptive NK cells, we interrogated a wide range of Collaborative Cross (CC) inbred mice, inbred mouse strains that exhibit broad genetic diversity across strains. Our assessment identified and validated a putative "ideal" CC strain, CC006, which does not require manipulation to generate and maintain adaptive NK cells. Critically, CC006 mice, in contrast to C57BL/6 mice, are capable of developing enhanced NK cell-mediated protective responses to murine CMV infection following m157-mediated vaccination. This work both furthers our understanding of adaptive NK cells and demonstrates the utility of CC mice in the development and interrogation of immunologic models., (Copyright © 2022 The Authors.)

Circulating memory CD8 T cell trafficking and protective capacity during liver-stage malaria infection remains undefined. We find that effector memory CD8 T cells (Tem) infiltrate the liver within 6 hours after malarial or bacterial infections and mediate pathogen clearance. Tem recruitment coincides with rapid transcriptional upregulation of inflammatory genes in Plasmodium-infected livers. Recruitment requires CD8 T cell-intrinsic LFA-1 expression and the presence of liver phagocytes. Rapid Tem liver infiltration is distinct from recruitment to other non-lymphoid tissues in that it occurs both in the absence of liver tissue resident memory "sensing-and-alarm" function and ∼42 hours earlier than in lung infection by influenza virus. These data demonstrate relevance for Tem in protection against malaria and provide generalizable mechanistic insights germane to control of liver infections., Competing Interests: Declarations of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

We recently demonstrated how sepsis influences the subsequent development of experimental autoimmune encephalomyelitis (EAE) presented a conceptual advance in understanding the postsepsis chronic immunoparalysis state. However, the reverse scenario (autoimmunity prior to sepsis) defines a high-risk patient population whose susceptibility to sepsis remains poorly defined. In this study, we present a retrospective analysis of University of Iowa Hospital and Clinics patients demonstrating increased sepsis prevalence among multiple sclerosis (MS), relative to non-MS, patients. To interrogate how autoimmune disease influences host susceptibility to sepsis, well-established murine models of MS and sepsis and EAE and cecal ligation and puncture, respectively, were used. EAE, relative to non-EAE, mice were highly susceptible to sepsis-induced mortality with elevated cytokine storms. These results were further recapitulated in LPS and Streptococcus pneumoniae sepsis models. This work highlights both the relevance of identifying highly susceptible patient populations and expands the growing body of literature that host immune status at the time of septic insult is a potent mortality determinant., (Copyright © 2021 The Authors.)

The global health burden due to sepsis and the associated cytokine storm is substantial. While early intervention has improved survival during the cytokine storm, those that survive can enter a state of chronic immunoparalysis defined by transient lymphopenia and functional deficits of surviving cells. Memory CD8 T cells provide rapid cytolysis and cytokine production following re-encounter with their cognate antigen to promote long-term immunity, and CD8 T cell impairment due to sepsis can pre-dispose individuals to re-infection. While the acute influence of sepsis on memory CD8 T cells has been characterized, if and to what extent pre-existing memory CD8 T cells recover remains unknown. Here, we observed that central memory CD8 T cells (T CM ) from septic patients proliferate more than those from healthy individuals. Utilizing LCMV immune mice and a CLP model to induce sepsis, we demonstrated that T CM proliferation is associated with numerical recovery of pathogen-specific memory CD8 T cells following sepsis-induced lymphopenia. This increased proliferation leads to changes in composition of memory CD8 T cell compartment and altered tissue localization. Further, memory CD8 T cells from sepsis survivors have an altered transcriptional profile and chromatin accessibility indicating long-lasting T cell intrinsic changes. The sepsis-induced changes in the composition of the memory CD8 T cell pool and transcriptional landscape culminated in altered T cell function and reduced capacity to control L. monocytogenes infection. Thus, sepsis leads to long-term alterations in memory CD8 T cell phenotype, protective function and localization potentially changing host capacity to respond to re-infection., Competing Interests: IJ, XL, PM, QS, MF, MT, JH, HX, TG, WP, VB No competing interests declared, (© 2021, Jensen et al.)

Sepsis is a life-threatening condition characterized by an acute cytokine storm followed by prolonged dysfunction of the immune system in the survivors. Post-septic lymphopenia and functional deficits of the remaining immune cells lead to increased susceptibility to secondary infections and other morbid conditions causing late death in the patients. This state of post-septic immunoparalysis may also influence disorders stemming from inappropriate or overactive immune responses, such as autoimmune and immunoinflammatory diseases, including multiple sclerosis. In addition, ongoing autoimmunity likely influences the susceptibility to and outcome of sepsis. This review article addresses the bidirectional relationship between sepsis and multiple sclerosis, with a focus on the immunologic mechanisms of the interaction and potential directions for future studies., (Copyright © 2021. Published by Elsevier B.V.)

Sepsis reduces the number and function of memory CD8 T cells within the host, contributing to the long-lasting state of immunoparalysis. Interestingly, the relative susceptibility of memory CD8 T cell subsets to quantitative/qualitative changes differ after cecal ligation and puncture (CLP)-induced sepsis. Compared with circulatory memory CD8 T cells (T CIRCM ), moderate sepsis (0-10% mortality) does not result in numerical decline of CD8 tissue-resident memory T cells (T RM ), which retain their "sensing and alarm" IFN-γ-mediated effector function. To interrogate this biologically important dichotomy, vaccinia virus-immune C57BL/6 (B6) mice containing CD8 T CIRCM and skin T RM underwent moderate or severe (∼50% mortality) sepsis. Severe sepsis led to increased morbidity and mortality characterized by increased inflammation compared with moderate CLP or sham controls. Severe CLP mice also displayed increased vascular permeability in the ears. Interestingly, skin CD103 + CD8 T RM , detected by i.v. exclusion or two-photon microscopy, underwent apoptosis and subsequent numerical loss following severe sepsis, which was not observed in mice that experienced moderate CLP or sham surgeries. Consequently, severe septic mice showed diminished CD8 T cell-mediated protection to localized skin reinfection. Finally, the relationship between severity of sepsis and demise in circulatory versus tissue-embedded memory CD8 T cell populations was confirmed by examining tumor-infiltrating and nonspecific CD8 T cells in B16 melanoma tumors. Thus, sepsis can differentially affect the presence and function of Ag-specific CD8 T cells that reside inside tissues/tumors depending on the severity of the insult, a notion with direct relevance to sepsis survivors and their ability to mount protective memory CD8 T cell-dependent responses to localized Ag re-encounter., (Copyright © 2021 by The American Association of Immunologists, Inc.)

The research investigates the problems and maps the solutions to the serious threat that plastics pose to the oceans, food safety, and human health, with more than eight million tons of plastic debris dumped in the sea every year. The aim of this study is to explore how to better improve the regulatory process of ocean plastics by integrating scientific results, regulatory strategies and action plans so as to limit the impact of plastics at sea. Adopting a problem-solving approach and identifying four areas of intervention enable the establishment of a regulatory framework from a multi-actor, multi-issue, and multi-level perspective. The research methodology consists of a two-pronged approach: 1. An analysis of the state-of-the-art definition of plastics, micro-, and nanoplastics (respectively, MPs and NPs), and 2. The identification and discussion of loopholes in the current regulation, suggesting key actions to be taken at a global, regional and national level. In particular, the study proposes a systemic integration of scientific and regulatory advancements towards the construction of an interconnected multi-tiered (MT) plastic governance framework. The milestones reached by the project SECURE at UiT - The Arctic University of Norway provide evidence of the strength of the theory of integration and rights-based approaches. The suggested model holds substantial significance for the fields of environmental protection, food security, food safety, and human health. This proposed MT plastic governance framework allows for the holistic and effective organization of complex information and scenarios concerning plastics regulation. Containing a clear definition of plastics, grounded on the precautionary principle, the MT plastic framework should provide detailed mitigation measures, with a clear indication of rights and duties, and in coordination with an effective reparatory justice system.

The dysregulated host response and organ damage following systemic infection that characterizes a septic event predisposes individuals to a chronic immunoparalysis state associated with severe transient lymphopenia and diminished lymphocyte function, thereby reducing long-term patient survival and quality of life. Recently, we observed lasting production of reactive oxygen species (ROS) in mice that survive sepsis. ROS production is a potent mechanism for targeting infection, but excessive ROS production can prove maladaptive by causing organ damage, impairing lymphocyte function, and promoting inflammaging, concepts paralleling sepsis-induced immunoparalysis. Notably, we observed an increased frequency of ROS-producing immature monocytes in septic hosts that was sustained for greater than 100 days postsurgery. Recent clinical trials have explored the use of vitamin C, a potent antioxidant, for treating septic patients. We observed that therapeutic vitamin C administration for sepsis limited ROS production by monocytes and reduced disease severity. Importantly, we also observed increased ROS production by immature monocytes in septic patients both at admission and ∼28 days later, suggesting a durable and conserved feature that may influence the host immune response. Thus, lasting ROS production by immature monocytes is present in septic patients, and early intervention strategies to reduce it may improve host outcomes, potentially reducing sepsis-induced immunoparalysis., (Copyright © 2021 The Authors.)

Protective lung tissue-resident memory CD8 + T cells (Trm) form after influenza A virus (IAV) infection. We show that IAV infection of mice generates CD69 + CD103 + and other memory CD8 + T cell populations in lung-draining mediastinal lymph nodes (mLNs) from circulating naive or memory CD8 + T cells. Repeated antigen exposure, mimicking seasonal IAV infections, generates quaternary memory (4M) CD8 + T cells that protect mLN from viral infection better than 1M CD8 + T cells. Better protection by 4M CD8 + T cells associates with enhanced granzyme A/B expression and stable maintenance of mLN CD69 + CD103 + 4M CD8 + T cells, vs the steady decline of CD69 + CD103 + 1M CD8 + T cells, paralleling the durability of protective CD69 + CD103 + 4M vs 1M in the lung after IAV infection. Coordinated upregulation in canonical Trm-associated genes occurs in circulating 4M vs 1M populations without the enrichment of canonical downregulated Trm genes. Thus, repeated antigen exposure arms circulating memory CD8 + T cells with enhanced capacity to form long-lived populations of Trm that enhance control of viral infections of the mLN., Competing Interests: SA, NV, SM, Sv, QS, RV, RS, SH, IJ, SV, NB, HX, VB, JH No competing interests declared, (© 2021, Anthony et al.)

The dysregulated sepsis-induced cytokine storm evoked during systemic infection consists of biphasic and interconnected pro- and anti-inflammatory responses. The contrasting inflammatory cytokine responses determine the severity of the septic event, lymphopenia, host survival, and the ensuing long-lasting immunoparalysis state. NK cells, because of their capacity to elaborate pro- (i.e., IFN-γ) and anti-inflammatory (i.e., IL-10) responses, exist at the inflection of sepsis-induced inflammatory responses. Thus, NK cell activity could be beneficial or detrimental during sepsis. In this study, we demonstrate that murine NK cells promote host survival during sepsis by limiting the scope and duration of the cytokine storm. Specifically, NK cell-derived IL-10, produced in response to IL-15, is relevant to clinical manifestations in septic patients and critical for survival during sepsis. This role of NK cells demonstrates that regulatory mechanisms of classical inflammatory cells are beneficial and critical for controlling systemic inflammation, a notion relevant for therapeutic interventions during dysregulated infection-induced inflammatory responses., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. We have previously demonstrated that CNS-specific CD8 T cells possess a disease-suppressive function in MS and variations of its animal model, experimental autoimmune encephalomyelitis (EAE), including the highly clinically relevant relapsing-remitting EAE disease course. Regulatory CD8 T cell subsets have been identified in EAE and other autoimmune diseases, but studies vary in defining phenotypic properties of these cells. In relapsing-remitting EAE, PLP 178-191 CD8 T cells suppress disease, whereas PLP 139-151 CD8 T cells lack this function. In this study, we used this model to delineate the unique phenotypic properties of CNS-specific regulatory PLP 178-191 CD8 T cells versus nonregulatory PLP 139-151 or OVA 323-339 CD8 T cells. Using multiparametric flow cytometric analyses of phenotypic marker expression, we identified a CXCR3 + subpopulation among activated regulatory CD8 T cells, relative to nonregulatory counterparts. This subset exhibited increased degranulation and IFN-γ and IL-10 coproduction. A similar subset was also identified in C57BL/6 mice within autoregulatory PLP 178-191 CD8 T cells but not within nonregulatory OVA 323-339 CD8 T cells. This disease-suppressing CD8 T cell subpopulation provides better insights into functional regulatory mechanisms, and targeted enhancement of this subset could represent a novel immunotherapeutic approach for MS., (Copyright © 2021 by The American Association of Immunologists, Inc.)

In this paper, we present updated data on proximate composition, amino acid, and fatty acid composition, as well as concentrations of dioxins, polychlorinated biphenyls (PCBs), and selected heavy metals, in fillets from farmed ( n = 20), escaped ( n = 17), and wild ( n = 23) Atlantic salmon ( Salmo salar L.). The concentrations of dioxins (0.53 ± 0.12 pg toxic equivalents (TEQ)/g), dioxin-like PCBs (0.95 ± 0.48 pg TEQ/g), mercury (56.3 ± 12.9 µg/kg) and arsenic (2.56 ± 0.87 mg/kg) were three times higher in wild compared to farmed salmon, but all well below EU-uniform maximum levels for contaminants in food. The six ICES (International Council for the Exploration of the Sea) PCBs concentrations (5.09 ± 0.83 ng/g) in wild salmon were higher than in the farmed fish (3.34 ± 0.46 ng/g). The protein content was slightly higher in wild salmon (16%) compared to the farmed fish (15%), and the amount of essential amino acids were similar. The fat content of farmed salmon (18%) was three times that of the wild fish, and the proportion of marine long-chain omega-3 fatty acids was a substantially lower (8.9 vs. 24.1%). The omega-6 to omega-3 fatty acid ratio was higher in farmed than wild salmon (0.7 vs. 0.05). Both farmed and wild Atlantic salmon are still valuable sources of eicosapentaenoic acid and docosahexaenoic acid. One 150 g portion per week will contribute to more (2.1 g and 1.8 g) than the recommended weekly intake for adults.

Numerous models are available for the preclinical study of sepsis, and they fall into one of three general categories: (1) administration of exogenous toxins (e.g., lipopolysaccharide, zymosan), (2) virulent bacterial or viral challenge, and (3) host barrier disruption, e.g., cecal ligation and puncture (CLP) or colon ascendens stent peritonitis (CASP). Of the murine models used to study the pathophysiology of sepsis, CLP combines tissue necrosis and polymicrobial sepsis secondary to autologous fecal leakage, as well as hemodynamic and biochemical responses similar to those seen in septic humans. Further, a transient numerical reduction of multiple immune cell types, followed by development of prolonged immunoparalysis, occurs in CLP-induced sepsis just as in humans. Use of the CLP model has led to a vast expansion in knowledge regarding the intricate physiological and cellular changes that occur during and after a septic event. This updated article details the steps necessary to perform this survival surgical technique, as well as some of the obstacles that may arise when evaluating the sepsis-induced changes within the immune system. It also provides representative monoclonal antibody (mAb) panels for multiparameter flow cytometric analysis of the murine immune system in the septic host. © 2020 Wiley Periodicals LLC. Basic Protocol: Cecal ligation and puncture in the mouse., (© 2020 Wiley Periodicals LLC.)

Evaluation of sepsis-induced immunoparalysis has highlighted how decreased lymphocyte number/function contribute to worsened infection/cancer. Yet, an interesting contrast exists with autoimmune disease development, wherein diminishing pathogenic effectors may benefit the post-septic host. Within this framework, the impact of cecal ligation and puncture (CLP)-induced sepsis on the development of experimental autoimmune encephalomyelitis (EAE) was explored. Notably, CLP mice have delayed onset and reduced disease severity, relative to sham mice. Reduction in disease severity was associated with reduced number, but not function, of autoantigen (MOG)-specific pathogenic CD4 T cells in the CNS during disease and draining lymph node during priming. Numerical deficits of CD4 T cell effectors are associated with the loss of MOG-specific naive precursors. Critically, transfer of MOG-TCR transgenic (2D2) CD4 T cells after, but not before, CLP led to EAE disease equivalent to sham mice. Thus, broad impairment of antigenic responses, including autoantigens, is a hallmark of sepsis-induced immunoparalysis., Competing Interests: IJ, SJ, FS, KG, TD, TG, AM, VB No competing interests declared, (© 2020, Jensen et al.)

The central nervous system (CNS) is classically viewed as immune-privileged; however, recent advances highlight interactions between the peripheral immune system and CNS in controlling infections and tissue homeostasis. Tissue-resident memory (T RM ) CD8 + T cells in the CNS are generated after brain infections, but it is unknown whether CNS infection is required to generate brain T RM cells. We show that peripheral infections generate antigen-specific CD8 + memory T cells in the brain that adopt a unique T RM signature. Upon depletion of circulating and perivascular memory T cells, this brain signature was enriched and the surveilling properties of brain T RM cells was revealed by intravital imaging. Notably, peripherally induced brain T RM cells showed evidence of rapid activation and enhanced cytokine production and mediated protection after brain infections. These data reveal that peripheral immunizations can generate brain T RM cells and will guide potential use of T cells as therapeutic strategies against CNS infections and neurological diseases.

Microbial exposures can define an individual's basal immune state. Cohousing specific pathogen-free (SPF) mice with pet store mice, which harbor numerous infectious microbes, results in global changes to the immune system, including increased circulating phagocytes and elevated inflammatory cytokines. How these differences in the basal immune state influence the acute response to systemic infection is unclear. Cohoused mice exhibit enhanced protection from virulent Listeria monocytogenes (LM) infection, but increased morbidity and mortality to polymicrobial sepsis. Cohoused mice have more TLR2 + and TLR4 + phagocytes, enhancing recognition of microbes through pattern-recognition receptors. However, the response to a TLR2 ligand is muted in cohoused mice, whereas the response to a TLR4 ligand is greatly amplified, suggesting a basis for the distinct response to Listeria monocytogenes and sepsis. Our data illustrate how microbial exposure can enhance the immune response to unrelated challenges but also increase the risk of immunopathology from a severe cytokine storm., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients who survive sepsis experience long-term immunoparalysis characterized by numerical and/or functional lesions in innate and adaptive immunity that increase the host's susceptibility to secondary complications. The extent to which tumor development/growth is affected in sepsis survivors remains unknown. In this study, we show cecal ligation and puncture (CLP) surgery renders mice permissive to increased B16 melanoma growth weeks/months after sepsis induction. CD8 T cells provide partial protection in this model, and tumors from sepsis survivors had a reduced frequency of CD8 tumor-infiltrating lymphocytes (TILs) concomitant with an increased tumor burden. Interestingly, the postseptic environment reduced the number of CD8 TILs with high expression of activating/inhibitory receptors PD-1 and LAG-3 (denoted PD-1 hi ) that define a tumor-specific CD8 T cell subset that retain some functional capacity. Direct ex vivo analysis of CD8 TILs from CLP hosts showed decreased proliferation, IFN-γ production, and survival compared with sham counterparts. To increase the frequency and/or functional capacity of PD-1 hi CD8 TILs in tumor-bearing sepsis survivors, checkpoint blockade therapy using anti-PD-L1/anti-LAG-3 mAb was administered before or after the development of sepsis-induced lesions in CD8 TILs. Checkpoint blockade did not reduce tumor growth in CLP hosts when therapy was administered after PD-1 hi CD8 TILs had become reduced in frequency and/or function. However, early therapeutic intervention before lesions were observed significantly reduced tumor growth to levels seen in nonseptic hosts receiving therapy. Thus, sepsis-induced immunoparalysis is defined by diminished CD8 T cell-mediated antitumor immunity that can respond to timely checkpoint blockade, further emphasizing the importance of early cancer detection in hosts that survive sepsis., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Background: The epidermal growth factor receptor (EGFR) monoclonal IgG 1 antibody cetuximab is approved for first-line treatment of recurrent and metastatic (R/M) HNSCC as a part of the standard of care EXTREME regimen (platinum/5-fluorouracil/cetuximab). This regimen has relatively high response and disease control rates but is generally not curative and many patients will experience recurrent disease and/or metastasis. Therefore, there is a great need to identify predictive biomarkers for recurrence and disease progression in cetuximab-treated HNSCC patients to facilitate patient management and allow for treatment modification. The goal of this work is to assess the potential of activating interleukin-1 (IL-1) ligands (IL-1 alpha [IL-1α], IL-1 beta [IL-1β]) as predictive biomarkers of survival outcomes in HNSCC patients treated with cetuximab-based chemotherapy., Methods: Baseline gene, serum and tumor expression of interleukin-1 (IL-1) ligands were analyzed from The Cancer Genome Atlas (TCGA) database or clinical trials of cetuximab-based therapies and interrogated for associations with clinical outcome data., Results: High tumor gene expression of IL-1β was associated with a more favorable overall survival in cetuximab-treated HNSCC patients but not in non-cetuximab-treated patients. In HNSCC patients treated with cetuximab-based chemotherapy, higher gene and circulating levels of IL-1α and IL-1β were correlated with a more favorable progression free survival compared to patients with low or undetectable levels of IL-1 ligands., Conclusions: These findings suggest that IL-1 ligands may function as predictive biomarkers for tumor response to cetuximab-based chemotherapy in HNSCC patients and warrants further investigation and validation in larger clinical studies., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Induction of memory CD8 T cells is important for controlling infections such as malaria HIV/AIDS, and for cancer immunotherapy. Accurate assessment of antigen (Ag)-specific CD8 T-cells is critical for vaccine optimization and defining correlates of protection. However, conditions for determining Ag-specific CD8 T-cell responses ex-vivo using ICS may be variable, especially in humans with complex antigens. Here, we used an attenuated whole parasite malaria vaccine model in humans and various experimental infections in mice to show that the duration of antigenic stimulation and timing of brefeldin A (BFA) addition influences the magnitude of Ag-specific and bystander T cell responses. Indeed, following immunization with an attenuated whole sporozoite malaria vaccine in humans, significantly higher numbers of IFN-γ producing memory CD8 T-cells comprised of antigen specific and bystander responses were detected by increasing the duration of Ag-stimulation prior to addition of BFA. Mechanistic analyses of virus-specific CD8 T-cells in mice revealed that the increase in IFNg producing CD8 T-cells was due to bystander activation of Ag-experienced memory CD8 T-cells, and correlated with the proportion of Ag-experienced CD8 T-cells in the stimulated populations. Incubation with anti-cytokine antibodies (ex. IL-12) improved accuracy in detecting bona-fide memory CD8 T-cell responses suggesting this as the mechanism for the bystander activation. These data have important implications for accurate assessment of immune responses generated by vaccines intended to elicit protective memory CD8 T-cells.

Malignancy increases sepsis incidence 10-fold and elevates sepsis-associated mortality. Advances in treatment have improved survival of cancer patients shortly after sepsis, but there is a paucity of information on how sepsis impacts cancer growth, development, and prognosis. To test this, cecal ligation and puncture surgery was performed on B16 melanoma-bearing mice to show that sepsis has detrimental effects in hosts with advanced tumors, leading to increased mortality. Surprisingly, mice experiencing cecal ligation and puncture-induced sepsis earlier during tumor development exhibited CD8 T cell-dependent attenuation of tumor growth. Sepsis-resistant CD8 tumor-infiltrating T cells showed increased in vivo activation, effector IFN-γ cytokine production, proliferation, and expression of activation/inhibitory PD-1/LAG-3 receptors because of a sepsis-induced liberation of tumor Ags. Sepsis-reinvigorated CD8 tumor-infiltrating T cells were also amenable to (anti-PD-L1/LAG-3) checkpoint blockade therapy, further prolonging cancer-associated survival in sepsis survivors. Thus, sepsis has the capacity to improve tumor-specific CD8 T cell responses, leading to better cancer prognosis and increased survival., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Background: Despite the high prevalence of epidermal growth factor receptor (EGFR) overexpression in head and neck squamous cell carcinomas (HNSCCs), incorporation of the EGFR inhibitor cetuximab into the clinical management of HNSCC has not led to significant changes in long-term survival outcomes. Therefore, the identification of novel therapeutic approaches to enhance the clinical efficacy of cetuximab could lead to improved long-term survival for HNSCC patients. Our previous work suggests that EGFR inhibition activates the interleukin-1 (IL-1) pathway via tumor release of IL-1 alpha (IL-1α), although the clinical implications of activating this pathway are unclear in the context of cetuximab therapy. Given the role of IL-1 signaling in anti-tumor immune response, we hypothesized that increases in IL-1α levels would enhance tumor response to cetuximab., Methods: Parental and stable myeloid differentiation primary response gene 88 (MyD88) and IL-1 receptor 1 (IL-1R1) knockdown HNSCC cell lines, an IL-1R antagonist (IL-1RA), neutralizing antibodies to IL-1α and IL-1β, and recombinant IL-1α and IL-1β were used to determine cytokine production (using ELISA) in response to cetuximab in vitro. IL-1 pathway modulation in mouse models was accomplished by administration of IL-1RA, stable overexpression of IL-1α in SQ20B cells, administration of rIL-1α, and administration of a polyanhydride nanoparticle formulation of IL-1α. CD4 + and CD8 + T cell-depleting antibodies were used to understand the contribution of T cell-dependent anti-tumor immune responses. Baseline serum levels of IL-1α were measured using ELISA from HNSCC patients treated with cetuximab-based therapy and analyzed for association with progression free survival (PFS)., Results: Cetuximab induced pro-inflammatory cytokine secretion from HNSCC cells in vitro which was mediated by an IL-1α/IL-1R1/MyD88-dependent signaling pathway. IL-1 signaling blockade did not affect the anti-tumor efficacy of cetuximab, while increased IL-1α expression using polyanhydride nanoparticles in combination with cetuximab safely and effectively induced a T cell-dependent anti-tumor immune response. Detectable baseline serum levels of IL-1α were associated with a favorable PFS in cetuximab-based therapy-treated HNSCC patients compared to HNSCC patients with undetectable levels., Conclusions: Altogether, these results suggest that IL-1α in combination with cetuximab can induce a T cell-dependent anti-tumor immune response and may represent a novel immunotherapeutic strategy for EGFR-positive HNSCCs.

The sepsis-induced cytokine storm leads to severe lymphopenia and reduced effector capacity of remaining/surviving cells. This results in a prolonged state of immunoparalysis, that contributes to enhanced morbidity/mortality of sepsis survivors upon secondary infection. The impact of sepsis on several lymphoid subsets has been characterized, yet its impact on NK-cells remains underappreciated-despite their critical role in controlling infection(s). Here, we observed numerical loss of NK-cells in multiple tissues after cecal-ligation-and-puncture (CLP)-induced sepsis. To elucidate the sepsis-induced lesions in surviving NK-cells, transcriptional profiles were evaluated and indicated changes consistent with impaired effector functionality. A corresponding deficit in NK-cell capacity to produce effector molecules following secondary infection and/or cytokine stimulation (IL-12,IL-18) further suggested a sepsis-induced NK-cell intrinsic impairment. To specifically probe NK-cell receptor-mediated function, the activating Ly49H receptor, that recognizes the murine cytomegalovirus (MCMV) m157 protein, served as a model receptor. Although relative expression of Ly49H receptor did not change, the number of Ly49H+ NK-cells in CLP hosts was reduced leading to impaired in vivo cytotoxicity and the capacity of NK-cells (on per-cell basis) to perform Ly49H-mediated degranulation, killing, and effector molecule production in vitro was also severely reduced. Mechanistically, Ly49H adaptor protein (DAP12) activation and clustering, assessed by TIRF microscopy, was compromised. This was further associated with diminished AKT phosphorylation and capacity to flux calcium following receptor stimulation. Importantly, DAP12 overexpression in NK-cells restored Ly49H/D receptors-mediated effector functions in CLP hosts. Finally, as a consequence of sepsis-dependent numerical and functional lesions in Ly49H+ NK-cells, host capacity to control MCMV infection was significantly impaired. Importantly, IL-2 complex (IL-2c) therapy after CLP improved numbers but not a function of NK-cells leading to enhanced immunity to MCMV challenge. Thus, the sepsis-induced immunoparalysis state includes numerical and NK-cell-intrinsic functional impairments, an instructive notion for future studies aimed in restoring NK-cell immunity in sepsis survivors., Competing Interests: The authors have declared that no competing interest exist.

Sepsis results in a deluge of pro- and anti-inflammatory cytokines, leading to lymphopenia and chronic immunoparalysis. Sepsis-induced long-lasting immunoparalysis is defined, in part, by impaired CD4 and CD8 αβ T cell responses in the postseptic environment. The dysfunction in T cell immunity affects naive, effector, and memory T cells and is not restricted to classical αβ T cells. Although sepsis-induced severe and transient lymphopenia is a contributory factor to diminished T cell immunity, T cell-intrinsic and -extrinsic factors/mechanisms also contribute to impaired T cell function. In this review, we summarize the current knowledge of how sepsis quantitatively and qualitatively impairs CD4 and CD8 T cell immunity of classical and nonclassical T cell subsets and discuss current therapeutic approaches being developed to boost the recovery of T cell immunity postsepsis induction., (Copyright © 2018 by The American Association of Immunologists, Inc.)

The reported protein content of foods depends on the analytical method used for determination, making a direct comparison between studies difficult. The aim of this study was to examine and compare protein analytical methods. Some of these methods require extraction preceding analysis. The efficacy of protein extraction differs depending on food matrices and thus extraction yield was determined. Overall, most analytical methods overestimated the protein contents. The inaccuracies were linked to indirect measurements, i.e. nitrogen determination and subsequent conversion to protein, or interference from other chemical substances. Amino acid analysis is the only protein analysis method where interfering substances do not affect the results. Although there is potential for improvement in regards to the hydrolysis method, we recommend that this method should be the preferred for food protein determination., Competing Interests: The authors declare no conflict of interest.

Sepsis is a systemic infection that enhances host vulnerability to secondary infections normally controlled by T cells. Using CLP sepsis model, we observed that sepsis induces apoptosis of circulating memory CD8 T-cells (TCIRCM) and diminishes their effector functions, leading to impaired CD8 T-cell mediated protection to systemic pathogen re-infection. In the context of localized re-infections, tissue resident memory CD8 T-cells (TRM) provide robust protection in a variety of infectious models. TRM rapidly 'sense' infection in non-lymphoid tissues and 'alarm' the host by enhancing immune cell recruitment to the site of the infection to accelerate pathogen clearance. Here, we show that compared to pathogen-specific TCIRCM, sepsis does not invoke significant numerical decline of Vaccinia virus induced skin-TRM keeping their effector functions (e.g., Ag-dependent IFN-γ production) intact. IFN-γ-mediated recruitment of immune cells to the site of localized infection was, however, reduced in CLP hosts despite TRM maintaining their 'sensing and alarming' functions. The capacity of memory CD8 T-cells in the septic environment to respond to inflammatory cues and arrive to the site of secondary infection/antigen exposure remained normal suggesting T-cell-extrinsic factors contributed to the observed lesion. Mechanistically, we showed that IFN-γ produced rapidly during sepsis-induced cytokine storm leads to reduced IFN-γR1 expression on vascular endothelium. As a consequence, decreased expression of adhesion molecules and/or chemokines (VCAM1 and CXCL9) on skin endothelial cells in response to TRM-derived IFN-γ was observed, leading to sub-optimal bystander-recruitment of effector cells and increased susceptibility to pathogen re-encounter. Importantly, as visualized by intravital 2-photon microscopy, exogenous administration of CXCL9/10 was sufficient to correct sepsis-induced impairments in recruitment of effector cells at the localized site of TRM antigen recognition. Thus, sepsis has the capacity to alter skin TRM anamnestic responses without directly impacting TRM number and/or function, an observation that helps to further define the immunoparalysis phase in sepsis survivors.

Intake of long-chain omega-3 polyunsaturated fatty acids (LC-n3-PUFA) is commonly recognized to reduce cardiovascular disease (CVD). In previous studies, cold-pressed whale oil (CWO) and cod liver oil (CLO) were given as a dietary supplement to healthy volunteers. Even though CWO contains less than half the amount of LC-n3-PUFA of CLO, CWO supplement resulted in beneficial effects on anti-inflammatory and CVD risk markers compared to CLO. In the present study, we prepared virtually lipid-free extracts from CWO and CLO and evaluated the antioxidative capacity (AOC) and anti-inflammatory effects. Oxygen radical absorbance capacity (ORAC) and ferric reducing antioxidant power (FRAP) assays were used to test the AOC, and the results indicated high levels of antioxidants present in all extracts. The anti-inflammatory effects of the extracts were tested with lipopolysaccharide- (LPS-) treated THP-1 cells, measuring its ability to reduce cytokine and chemokine secretion. Several CWO extracts displayed anti-inflammatory activity, and a butyl alcohol extract of CWO most effectively reduced TNF- α (50%, p < 0.05) and MCP-1 (85%, p < 0.001) secretion. This extract maintained a stable effect of reducing MCP-1 secretion (60%, p < 0.05) even after long-term storage. In conclusion, CWO has antioxidant and anti-inflammatory activities that may act in addition to its well-known LC-n3-PUFA effects.

High seafood consumption has traditionally been linked to a reduced risk of cardiovascular diseases, mainly due to the lipid lowering effects of the long chained omega 3 fatty acids. However, fish and seafood are also excellent sources of good quality proteins and emerging documentation show that, upon digestion, these proteins are sources for bioactive peptides with documented favorable physiological effects such as antioxidative, antihypertensive and other cardioprotective effects. This documentation is mainly from in vitro studies, but also animal studies are arising. Evidence from human studies evaluating the positive health effects of marine proteins and peptides are scarce. In one study, a reduction in oxidative stress after intake of cod has been documented and a few human clinical trials have been performed evaluating the effect on blood pressure. The results are, however, inconclusive. The majority of the human clinical trials performed to investigate positive health effects of marine protein and lean fish intake, has focused on blood lipids. While some studies have documented a reduction in triglycerides after intake of lean fish, others have documented no effects., Competing Interests: The authors declare no conflict of interest.

Several common protein extraction protocols have been applied on seaweeds, but extraction yields have been limited. The aims of this study were to further develop and optimize existing extraction protocols and to examine the effect of enzymatic pre-treatment on bioaccessibility and extractability of seaweed proteins. Enzymatic pre-treatment of seaweed samples resulted in a three-fold increase in amino acids available for extraction. Combining enzymatic pre-treatment with alkaline extraction resulted in a 1.6-fold increase in the protein extraction yield compared to a standard alkaline extraction protocol. A simulated in vitro gastrointestinal digestion model showed that enzymatic pre-treatment of seaweed increased the amount of amino acids available for intestinal absorption 3.2-fold. In conclusion, enzymatic pre-treatment of seaweeds is effective for increasing the amount of amino acids available for utilization and may thus be an effective means for increasing the utilization potential of seaweed proteins. However, both the enzymatic pre-treatment protocol and the protein extraction protocol need further optimization in order to obtain optimal cost-benefit and results from the in vitro gastrointestinal digestion model need to be confirmed in clinical models., Competing Interests: None of the authors report any conflicts of interest.