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MedRxiv : the Preprint Server For... Jun 2024Sepsis is the leading cause of death of hospitalized children worldwide. Despite the established link between immune dysregulation and mortality in pediatric sepsis, it...
Sepsis is the leading cause of death of hospitalized children worldwide. Despite the established link between immune dysregulation and mortality in pediatric sepsis, it remains unclear which host immune factors contribute causally to adverse sepsis outcomes. Identifying modifiable pathobiology is an essential first step to successful translation of biologic insights into precision therapeutics. We designed a prospective, longitudinal cohort study of 88 critically ill pediatric patients with multiple organ dysfunction syndrome (MODS), including patients with and without sepsis, to define subphenotypes associated with targetable mechanisms of immune dysregulation. We first assessed plasma proteomic profiles and identified shared features of immune dysregulation in MODS patients with and without sepsis. We then employed consensus clustering to define three subphenotypes based on protein expression at disease onset and identified a strong association between subphenotype and clinical outcome. We next identified differences in immune cell frequency and activation state by MODS subphenotype and determined the association between hyperinflammatory pathway activation and cellular immunophenotype. Using single cell transcriptomics, we demonstrated STAT3 hyperactivation in lymphocytes from the sickest MODS subgroup and then identified an association between STAT3 hyperactivation and T cell immunometabolic dysregulation. Finally, we compared proteomics findings between patients with MODS and patients with inborn errors of immunity that amplify cytokine signaling pathways to further assess the impact of STAT3 hyperactivation in the most severe patients with MODS. Overall, these results identify a potentially pathologic and targetable role for STAT3 hyperactivation in a subset of pediatric patients with MODS who have high severity of illness and poor prognosis.
PubMed: 38946991
DOI: 10.1101/2024.06.11.24308709 -
FEBS Open Bio Jun 2024Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are scavenger receptors expressed by liver sinusoidal endothelial cells (LSECs). The Stabilin-mediated scavenging function is...
Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are scavenger receptors expressed by liver sinusoidal endothelial cells (LSECs). The Stabilin-mediated scavenging function is responsible for regulating the molecular composition of circulating blood in mammals. Stab1 and Stab2 have been shown to influence fibrosis in liver and kidneys and to modulate inflammation in atherosclerosis. In this context, circulating and localized TGFBi and POSTN are differentially controlled by the Stabilins as their receptors. To assess Stab1 and Stab2 functions in inflammatory and fibrotic skin disease, topical Imiquimod (IMQ) was used to induce psoriasis-like skin lesions in mice and Bleomycin (BLM) was applied subcutaneously to induce scleroderma-like effects in the skin. The topical treatment with IMQ, as expected, led to psoriasis-like changes in the skin of mice, including increased epidermal thickness and significant weight loss. Clinical severity was reduced in Stab2-deficient compared to Stab1-deficient mice. We did not observe differential effects in the skin of Stabilin-deficient mice after bleomycin injection. Interestingly, treatment with IMQ led to a significant increase of Stabilin ligand TGFBi plasma levels in Stab2 mice, treatment with BLM resulted in a significant decrease in TGFBi levels in Stab1 mice. Overall, Stab1 and Stab2 deficiency resulted in minor alterations of the disease phenotypes accompanied by alterations of circulating ligands in the blood in response to the disease models. Stabilin-mediated clearance of TGFBi was altered in these disease processes. Taken together our results suggest that Stabilin deficiency-associated plasma alterations may interfere with preclinical disease severity and treatment responses in patients.
PubMed: 38946049
DOI: 10.1002/2211-5463.13857 -
Thyroid Research Jul 2024Despite the presence of evidence that establishes a strong correlation between oxidative stress and thyroid cancer, there exists a scarcity of research that investigates...
BACKGROUND
Despite the presence of evidence that establishes a strong correlation between oxidative stress and thyroid cancer, there exists a scarcity of research that investigates the specific role of glutathione as an important antioxidant in this particular context. The objective of this study was to assess the altered balance of oxidative stress in cases of thyroid cancer, which includes both papillary thyroid carcinoma (PTC) and micro PTC (mPTC), by examining and comparing the total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), reduced glutathione (GSH), oxidized glutathione (GSSG), and GSSG/GSH ratio with those of individuals diagnosed with multinodular goiter (MNG) as well as Healthy subjects.
MATERIALS AND METHODS
Plasma samples were collected from 92 patients (23 mPTC, 23 PTC, 23 MNG, 23 Healthy). The levels of TAC, TOS, GSH, and GSSG were measured using a commercial assay kits, and the OSI and GSSG/GSH ratio were calculated for each sample. Statistical analyses were performed to compare the oxidative stress between the groups.
RESULTS
The plasma levels of TOS were significantly higher in the mPTC, PTC, and MNG groups compared to the Healthy individuals (p < 0.05). The OSI in the mPTC and PTC groups showed a significant increase compared to the Healthy group (p < 0.05). The levels of GSH in mPTC and PTC were markedly lower compared to the Healthy subjects (p < 0.01). Interestingly, the concentration of GSH in mPTC was found to be considerably lower than in PTC and MNG patients (p < 0.01).
CONCLUSION
These findings indicate that GSH may be a useful biomarker for evaluating oxidative stress and antioxidant system status in patients with PTC, especially mPTC. Low levels of GSH may indicate increased levels of oxidative stress, which may contribute to the development and progression of mPTC to PTC.
PubMed: 38946003
DOI: 10.1186/s13044-024-00204-9 -
Internal Medicine (Tokyo, Japan) 2024Thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly (TAFRO) syndrome is an inflammatory disorder with an unclear pathogenesis. We herein report a case...
Thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly (TAFRO) syndrome is an inflammatory disorder with an unclear pathogenesis. We herein report a case of TAFRO syndrome in remission in a patient who experienced recurrent intracranial bleeding despite a normal platelet count and coagulation system. A further investigation suggested the presence of anti-glycoprotein VI (GPVI) autoantibodies in the plasma, which induced platelet dysfunction and bleeding tendency. No new bleeding or relapse of TAFRO syndrome occurred after immunosuppressive therapy was initiated. These findings may help elucidate the autoimmune pathogenesis of TAFRO syndrome.
Topics: Humans; Autoantibodies; Recurrence; Syndrome; Platelet Membrane Glycoproteins; Cerebral Hemorrhage; Thrombocytopenia; Fever; Female; Middle Aged; Male; Blood Platelet Disorders
PubMed: 38945933
DOI: 10.2169/internalmedicine.2799-23 -
Journal of Oleo Science 2024In this study, we evaluated the cancer cell killing activity of koji mold-derived extracts using several solvents. The koji mold lipid extract (KML) exhibited potent...
Koji Mold-derived Lipids Disrupt the Intracellular Redox State by Decreasing the GPx4 and Intracellular Glutathione Levels, Promoting Membrane Lipid Peroxidation, and Inducing Ferroptosis in HL-60 Cells.
In this study, we evaluated the cancer cell killing activity of koji mold-derived extracts using several solvents. The koji mold lipid extract (KML) exhibited potent cytotoxicity against a human leukemia cell line. Fractionation of the KML via silica gel chromatography revealed the presence of active components in fraction (Fr.) 6. Cytotoxic effects of Fr. 6 were inhibited by the ferroptosis inhibitors, ferrostatin-1 and SRS11-92, and the iron chelator, deferoxamine. Interestingly, ferroptosis inhibitors failed to prevent the KML-induced cell death. Fr. 6 decreased the expression of glutathione peroxidase 4 (GPx4) and increased the level of peroxidized plasma membrane lipids. Furthermore, Fr. 6 decreased the intracellular glutathione levels. Overall, our results suggest that Fr. 6 included in KML induces ferroptosis in HL-60 cells.
Topics: Humans; HL-60 Cells; Phospholipid Hydroperoxide Glutathione Peroxidase; Ferroptosis; Lipid Peroxidation; Glutathione; Oxidation-Reduction; Deferoxamine; Cyclohexylamines; Lipids; Phenylenediamines; Membrane Lipids; Iron Chelating Agents
PubMed: 38945927
DOI: 10.5650/jos.ess24043 -
Japanese Journal of Infectious Diseases Jun 2024Persistent inflammation in chronic HIV infection may affect immune responses against SARS-CoV-2 infection. Plasma levels of multiple proinflammatory cytokines during...
Persistent inflammation in chronic HIV infection may affect immune responses against SARS-CoV-2 infection. Plasma levels of multiple proinflammatory cytokines during acute SARS-CoV-2 infection were assessed in people with HIV (PWH) with effective cART. There were no significant differences in any of the tested cytokines between COVID-19 severity in PWH, while most of them were significantly higher in individuals with severe disease in HIV-uninfected individuals, suggesting that excess cytokines release by hyper-inflammatory responses does not occur in severe COVID-19 with HIV infection. The strong associations between the cytokines observed in HIV-uninfected individuals, especially between IFN-α/TNF-α and other cytokines, were lost in PWH. The steady state plasma levels of IP-10, ICAM-1, and CD62E were significantly higher in PWH, indicating that PWH are in an enhanced inflammatory state. Loss of the several inter-cytokine correlations were observed in in vitro LPS stimuli-driven cytokines production in PWH. These data suggest that inflammatory responses during SARS-CoV-2 infection in PWH are distinct from those in HIV-uninfected individuals, partially due to the underlying inflammatory state and/or impairment of innate immune cells.
PubMed: 38945856
DOI: 10.7883/yoken.JJID.2024.184 -
Food Research International (Ottawa,... Aug 2024Lipids from cow milk fat globule membranes (MFGMs) and extracellular vesicles (EVs) are considered beneficial for neurodevelopment, cognitive maintenance and human...
Lipids from cow milk fat globule membranes (MFGMs) and extracellular vesicles (EVs) are considered beneficial for neurodevelopment, cognitive maintenance and human health in general. Nevertheless, it is largely unknown whether intake of infant formulas and medical nutrition products rich in these particles promote accretion of specific lipids and whether this affects metabolic homeostasis. To address this, we carried out a 16-week dietary intervention study where mice were supplemented with a MFGM/EV-rich concentrate, a control diet supplemented with a whey protein concentrate and devoid of milk lipids, or regular chow. Assessment of commonly used markers of metabolic health, including body weight, glucose intolerance and liver microanatomy, demonstrated no differences across the dietary regimes. In contrast, in-depth lipidomic analysis revealed accretion of milk-derived very long odd-chain sphingomyelins and ceramides in blood plasma and multiple tissues of mice fed the MFGM/EV diet. Furthermore, lipidomic flux analysis uncovered that mice fed the MFGM/EV diet have increased lipid metabolic turnover at the whole-body level. These findings help fill a long-lasting knowledge gap between the intake of MFGM/EV-containing foods and the health-promoting effects of their lipid constituents. In addition, the findings suggest that dietary sphingomyelins or ceramide-breakdown products with very long-chains can be used as structural components of cellular membranes, lipoprotein particles and signaling molecules that modulate metabolic homeostasis and health.
Topics: Animals; Sphingolipids; Extracellular Vesicles; Mice; Glycolipids; Lipid Metabolism; Lipid Droplets; Glycoproteins; Lipidomics; Mice, Inbred C57BL; Male; Sphingomyelins; Ceramides; Diet; Liver; Dietary Supplements
PubMed: 38945615
DOI: 10.1016/j.foodres.2024.114601 -
Antiviral Research Jun 2024The WHO declared the official end of the SARS-CoV-2 caused public health emergency on May 5, 2023, after two years in which the virus infected approximately 750 Mio...
The WHO declared the official end of the SARS-CoV-2 caused public health emergency on May 5, 2023, after two years in which the virus infected approximately 750 Mio individuals causing estimated up to 7 Mio deaths. Likely, the virus will continue to evolve in the human population as a seasonal respiratory pathogen. To now prevent severe infection outcomes in vulnerable individuals, effective antivirals are urgently needed to complement the protection provided by vaccines. SARS-CoV-2 enters its host cell via ACE2 mediated membrane fusion, either at the plasma membrane, if the protease TMPRSS2 is present or via the endosome, in a cathepsin dependent fashion. A small number of positive regulators of viral uptake were described in the literature, which are potentially useful targets for host directed antiviral therapy or biomarkers indicating increased or diminished susceptibility to infection. We identified here by cell surface proximity ligation novel proteins, required for efficient virion uptake. Importantly, chemical inhibition of one of these factors, SLC3A2, resulted in robust reduction of viral replication, to that achieved with a TMPRSS2 inhibitor. Our screen identified new host dependency factors for SARS-CoV-2 entry, which could be targeted by novel antiviral therapies.
PubMed: 38945485
DOI: 10.1016/j.antiviral.2024.105951 -
Journal of Dairy Science Jun 2024The uptake of AA in mammary tissues is affected by prolactin (PRL). To investigate whether PRL-induced AA uptake is involved in L-type AA transporter 1 (LAT1), we...
The uptake of AA in mammary tissues is affected by prolactin (PRL). To investigate whether PRL-induced AA uptake is involved in L-type AA transporter 1 (LAT1), we analyzed the changes of AA in the medium of dairy cow mammary epithelial cells in the presence of PRL or PRL plus BCH, an inhibitor of LAT1. Then Western blot and luciferase assay were used to detect the regulation mechanism of PRL on LAT1 expression and function. Our results showed that Thr, Val, Met, Ile, Leu, Tyr, Lys, Phe, and His are LAT1 substrates and could be transported into mammary epithelial cells via LAT1. PRL stimulation increased the uptake of most AA into mammary epithelial cells of dairy cows, however, inhibition of LAT1 transport activity reduced PRL-induced AA uptake, suggesting that the effect of PRL on AA transport depends on LAT1 expression and function. PRL stimulation upregulated LAT1 expression and plasma membrane location not only in dairy cow mammary epithelial cells, but also in mouse mammary epithelial cell line HC11. Western blot showed that PI3K-AKT-mTOR signaling could be activated in PRL-stimulated mammary epithelial cells. Treatment of cells with LY294002 decreased PI3K-AKT-mTOR activation, as well LAT1 expression, that in turn decreased milk protein synthesis. Luciferase assay showed PRL treatment increased the promoter activity of LAT1 promoter fragment -419∼-86 bp. Treatment of cells with LY294002, an inhibitor of PI3K, or SC79, an activator of AKT abolished or promoted the transcriptional activity of this promoter fragment in the presence of PRL. These results suggested that the -419∼-86 bp fragment of LAT1 promoter mediates the action of PI3K-AKT-mTOR signaling on LAT1 transcription in mammary epithelial cells of dairy cows, which in turn increased LAT1 expression and AA uptake.
PubMed: 38945262
DOI: 10.3168/jds.2024-24746 -
Lung Cancer (Amsterdam, Netherlands) Jun 2024Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a...
BACKGROUND
Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a small but significant fraction of NSCLC. The efficacy of these therapies in this subgroup of patients is unknown.
MATERIALS AND METHODS
Plasma and tissue samples from 116 resectable stage IIIA/B NSCLC patients, included in NADIM and NADIM II clinical trials (NADIM cohort), and from a prospective academic cohort with 84 stage IV NSCLC patients (BLI-O cohort), were analyzed by next-generation sequencing.
RESULTS
The p.G464E, p.G466R, p.G466V, p.G469V, p.L597Q, p.T599I, p.V600E (n = 2) BRAF mutations, were identified in four (3.45 %) samples from the NADIM cohort, all of which were cases treated with neoadjuvant chemoimmunotherapy (CH-IO), and four (4.76 %) samples from the BLI-O cohort, corresponding to cases treated with first-line immunotherapy (n = 2) or CH-IO (n = 2). All these patients were alive and had no evidence of disease at data cut-off. Conversely, patients with BRAF wild-type (wt) tumors in the BLI-O cohort had a median progression-free survival (PFS) of 5.49 months and a median overall survival (OS) of 12.00 months (P-LogRank = 0.013 and 0.046, respectively). Likewise, PFS and OS probabilities at 36 months were 60.5 % and 76.1 % for patients with BRAF-wt tumors in the NADIM cohort. The pathological complete response (pCR) rate after neoadjuvant CH-IO in patients with BRAF-positive tumors (n = 4) was 100 %, whereas the pCR rate in the BRAF-wt population was 44.3 % (RR: 2.26; 95 % CI: 1.78-2.85; P < 0.001).
CONCLUSION
BRAF mutations may be a good prognostic factor for advanced and locally advanced NSCLC patients undergoing immunotherapy-based treatments.
PubMed: 38945004
DOI: 10.1016/j.lungcan.2024.107865