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Science Advances May 2024Reactive oxygen species (ROS) play an important role in regulating the immune system by affecting pathogens, cancer cells, and immune cells. Recent advances in... (Review)
Review
Reactive oxygen species (ROS) play an important role in regulating the immune system by affecting pathogens, cancer cells, and immune cells. Recent advances in biomaterials have leveraged this mechanism to precisely modulate ROS levels in target tissues for improving the effectiveness of immunotherapies in infectious diseases, cancer, and autoimmune diseases. Moreover, ROS-responsive biomaterials can trigger the release of immunotherapeutics and provide tunable release kinetics, which can further boost their efficacy. This review will discuss the latest biomaterial-based approaches for both precise modulation of ROS levels and using ROS as a stimulus to control the release kinetics of immunotherapeutics. Finally, we will discuss the existing challenges and potential solutions for clinical translation of ROS-modulating and ROS-responsive approaches for immunotherapy, and provide an outlook for future research.
Topics: Humans; Reactive Oxygen Species; Immunotherapy; Animals; Neoplasms; Biocompatible Materials
PubMed: 38748805
DOI: 10.1126/sciadv.adl0479 -
Science Advances May 2024High-grade serous ovarian cancer (HGSC) is a challenging disease, especially for patients with immunologically "cold" tumors devoid of tumor-infiltrating lymphocytes...
High-grade serous ovarian cancer (HGSC) is a challenging disease, especially for patients with immunologically "cold" tumors devoid of tumor-infiltrating lymphocytes (TILs). We found that HGSC exhibits among the highest levels of expression and transcriptional signature across human cancers, which is strongly linked to diminished features of antitumor immunity. N-MYC repressed basal and induced IFN type I signaling in HGSC cell lines, leading to decreased chemokine expression and T cell chemoattraction. N-MYC inhibited the induction of IFN type I by suppressing tumor cell-intrinsic STING signaling via reduced STING oligomerization, and by blunting RIG-I-like receptor signaling through inhibition of MAVS aggregation and localization in the mitochondria. Single-cell RNA sequencing of human clinical HGSC samples revealed a strong negative association between cancer cell-intrinsic transcriptional program and type I IFN signaling. Thus, N-MYC inhibits tumor cell-intrinsic innate immune signaling in HGSC, making it a compelling target for immunotherapy of cold tumors.
Topics: Humans; Female; Ovarian Neoplasms; Signal Transduction; Immunity, Innate; Cell Line, Tumor; Interferon Type I; Cystadenocarcinoma, Serous; Gene Expression Regulation, Neoplastic; Proto-Oncogene Proteins c-myc; Membrane Proteins; Neoplasm Grading; Adaptor Proteins, Signal Transducing
PubMed: 38748789
DOI: 10.1126/sciadv.adj5428 -
Science Advances May 2024Early and precise diagnosis of α-synucleinopathies is challenging but critical. In this study, we developed a molecular beacon-based assay to evaluate...
Early and precise diagnosis of α-synucleinopathies is challenging but critical. In this study, we developed a molecular beacon-based assay to evaluate microRNA-containing extracellular vesicles (EVs) in plasma. We recruited 1203 participants including healthy controls (HCs) and patients with isolated REM sleep behavior disorder (iRBD), α-synucleinopathies, or non-α-synucleinopathies from eight centers across China. Plasma miR-44438-containing EV levels were significantly increased in α-synucleinopathies, including those in the prodromal stage (e.g., iRBD), compared to both non-α-synucleinopathy patients and HCs. However, there are no significant differences between Parkinson's disease (PD) and multiple system atrophy. The miR-44438-containing EV levels negatively correlated with age and the Hoehn and Yahr stage of PD patients, suggesting a potential association with disease progression. Furthermore, a longitudinal analysis over 16.3 months demonstrated a significant decline in miR-44438-containing EV levels in patients with PD. These results highlight the potential of plasma miR-44438-containing EV as a biomarker for early detection and progress monitoring of α-synucleinopathies.
Topics: Humans; Extracellular Vesicles; Male; Biomarkers; Female; Middle Aged; Circulating MicroRNA; Parkinson Disease; Aged; Synucleinopathies; alpha-Synuclein; Case-Control Studies; MicroRNAs; Multiple System Atrophy
PubMed: 38748787
DOI: 10.1126/sciadv.adl6442 -
PloS One 2024The role of vitamin D3 (VitD3) in modulating innate and adaptive immunity has been reported in different disease contexts. Since the start of the coronavirus...
BACKGROUND
The role of vitamin D3 (VitD3) in modulating innate and adaptive immunity has been reported in different disease contexts. Since the start of the coronavirus disease-2019 (COVID-19) pandemic, the role of VitD3 has been highlighted in many correlational and observational studies. However, the exact mechanisms of action are not well identified. One of the mechanisms via which VitD3 modulates innate immunity is by regulating the NLRP3-inflammasome pathway, being a main underlying cause of SARS-CoV-2-induced hyperinflammation.
AIMS AND MAIN METHODS
Blood specimens of severe COVID-19 patients with or without VitD3 treatment were collected during their stay in the intensive care unit and patients were followed up for 29 days. qPCR, western blot, and ELISA were done to investigate the mechanism of action of VitD3 on the NLRP3 inflammasome activation.
KEY FINDINGS
We here report the ability of VitD3 to downregulate the NLRP3-inflammsome pathway in severe COVID-19 patients. Lower inflammasome pathway activation was observed with significantly lower gene and protein expression of NLRP3, cleaved caspase-1, ASC and IL-1β among severe COVID-19 patients treated with VitD3. The reduction of the inflammasome pathway was associated with a reduction in disease severity markers and enhancement of type I IFN pathway.
SIGNIFICANCE
Our data reveals an important anti-inflammatory effect of VitD3 during SARS-CoV-2 infection. Further investigations are warranted to better characterize the ability of VitD3 to control disease pathogenesis and prevent progression to severe states. This will allow for a more efficient use of a low cost and accessible treatment like VitD3.
Topics: NLR Family, Pyrin Domain-Containing 3 Protein; Humans; COVID-19; Inflammasomes; Male; Female; Middle Aged; SARS-CoV-2; Cholecalciferol; Severity of Illness Index; Aged; Adult; Signal Transduction; Interleukin-1beta; COVID-19 Drug Treatment; Vitamin D
PubMed: 38748756
DOI: 10.1371/journal.pone.0302818 -
PloS One 2024Mental disorders account for nine percent of the overall global burden of disease and are among the top ten leading causes of disability. Mental illness and tuberculosis...
BACKGROUND
Mental disorders account for nine percent of the overall global burden of disease and are among the top ten leading causes of disability. Mental illness and tuberculosis share risk factors including poverty, overcrowding, stigma, poor nutrition, substance use and retro-viral disease co-infection. Presence of mental illness in tuberculosis delays health-seeking, affects drug adherence, increases cost of treatment, prolongs disease duration, lowers quality of life, and increases mortality. Early diagnosis, linkage, and treatment of psychiatric morbidity among patients with tuberculosis would improve outcomes for both. This study thus aimed to determine the prevalence and factors associated with psychiatric morbidity among patients on treatment for tuberculosis at a low- middle- income country.
METHODS
A cross-sectional study carried out at the tuberculosis clinic at Moi Teaching and Referral Hospital (MTRH), Eldoret, Kenya. 367 participants on TB treatment were interviewed using Mini-International Neuropsychiatric Interview (MINI) tool. The key outcome was presence of psychiatric illness. Pearson's Chi-square and logistic regression were used to assess relationships at bivariate and multivariate level respectively.
RESULTS
Majority of the respondents were male (61.3%) and overall median age was 33 years. About half of participants (48.5%) had at least one psychiatric illness. Common disorders were alcohol use disorder (30.3%), depression (23.4%), substance use disorder (12.8%) and suicidality (8.2%). Odds of 'any psychiatric illness' were increased by being male (aOR = 1.92; P = 0.04), being separated or divorced (aOR = 6.86; P = 0.002), using alcohol (aOR = 3.2; P<0.001), having been previously treated for tuberculosis (aOR = 2.76; P = 0.01), having other medical comorbidities (aOR = 4.2; P = 0.004) and family history of mental illness (aOR = 2.4; P = 0.049).
CONCLUSION
Almost half of the patients on treatment for tuberculosis had at least one psychiatric illness. Introduction of protocols for screening for mental illness and integration of mental health services with tuberculosis care would aid prompt diagnosis, referral, and quality of care.
Topics: Humans; Male; Kenya; Female; Adult; Tuberculosis; Mental Disorders; Tertiary Care Centers; Cross-Sectional Studies; Middle Aged; Young Adult; Prevalence; Adolescent; Risk Factors
PubMed: 38748751
DOI: 10.1371/journal.pone.0302744 -
PloS One 2024Out-of-hospital cardiac arrest (OHCA) affects over 360,000 adults in the United States each year with a 50-80% mortality prior to reaching medical care. Despite...
Out-of-hospital cardiac arrest (OHCA) affects over 360,000 adults in the United States each year with a 50-80% mortality prior to reaching medical care. Despite aggressive supportive care and targeted temperature management (TTM), half of adults do not live to hospital discharge and nearly one-third of survivors have significant neurologic injury. The current treatment approach following cardiac arrest resuscitation consists primarily of supportive care and possible TTM. While these current treatments are commonly used, mortality remains high, and survivors often develop lasting neurologic and cardiac sequela well after resuscitation. Hence, there is a critical need for further therapeutic development of adjunctive therapies. While select therapeutics have been experimentally investigated, one promising agent that has shown benefit is CO. While CO has traditionally been thought of as a cellular poison, there is both experimental and clinical evidence that demonstrate benefit and safety in ischemia with lower doses related to improved cardiac/neurologic outcomes. While CO is well known for its poisonous effects, CO is a generated physiologically in cells through the breakdown of heme oxygenase (HO) enzymes and has potent antioxidant and anti-inflammatory activities. While CO has been studied in myocardial infarction itself, the role of CO in cardiac arrest and post-arrest care as a therapeutic is less defined. Currently, the standard of care for post-arrest patients consists primarily of supportive care and TTM. Despite current standard of care, the neurological prognosis following cardiac arrest and return of spontaneous circulation (ROSC) remains poor with patients often left with severe disability due to brain injury primarily affecting the cortex and hippocampus. Thus, investigations of novel therapies to mitigate post-arrest injury are clearly warranted. The primary objective of this proposed study is to combine our expertise in swine models of CO and cardiac arrest for future investigations on the cellular protective effects of low dose CO. We will combine our innovative multi-modal diagnostic platform to assess cerebral metabolism and changes in mitochondrial function in swine that undergo cardiac arrest with therapeutic application of CO.
Topics: Animals; Swine; Disease Models, Animal; Carbon Monoxide; Heart Arrest; Out-of-Hospital Cardiac Arrest; Male; Cardiopulmonary Resuscitation
PubMed: 38748750
DOI: 10.1371/journal.pone.0302653 -
PloS One 2024Hepatic ischemia-reperfusion injury causes liver damage during surgery. In hepatic ischemia-reperfusion injury, the blood coagulation cascade is activated, causing...
Hepatic ischemia-reperfusion injury causes liver damage during surgery. In hepatic ischemia-reperfusion injury, the blood coagulation cascade is activated, causing microcirculatory incompetence and cellular injury. Coagulation factor Xa (FXa)- protease-activated receptor (PAR)-2 signaling activates inflammatory reactions and the cytoprotective effect of FXa inhibitor in several organs. However, no studies have elucidated the significance of FXa inhibition on hepatic ischemia-reperfusion injury. The present study elucidated the treatment effect of an FXa inhibitor, edoxaban, on hepatic ischemia-reperfusion injury, focusing on FXa-PAR-2 signaling. A 60 min hepatic partial-warm ischemia-reperfusion injury mouse model and a hypoxia-reoxygenation model of hepatic sinusoidal endothelial cells were used. Ischemia-reperfusion injury mice and hepatic sinusoidal endothelial cells were treated and pretreated, respectively with or without edoxaban. They were incubated during hypoxia/reoxygenation in vitro. Cell signaling was evaluated using the PAR-2 knockdown model. In ischemia-reperfusion injury mice, edoxaban treatment significantly attenuated fibrin deposition in the sinusoids and liver histological damage and resulted in both anti-inflammatory and antiapoptotic effects. Hepatic ischemia-reperfusion injury upregulated PAR-2 generation and enhanced extracellular signal-regulated kinase 1/2 (ERK 1/2) activation; however, edoxaban treatment reduced PAR-2 generation and suppressed ERK 1/2 activation in vivo. In the hypoxia/reoxygenation model of sinusoidal endothelial cells, hypoxia/reoxygenation stress increased FXa generation and induced cytotoxic effects. Edoxaban protected sinusoidal endothelial cells from hypoxia/reoxygenation stress and reduced ERK 1/2 activation. PAR-2 knockdown in the sinusoidal endothelial cells ameliorated hypoxia/reoxygenation stress-induced cytotoxicity and suppressed ERK 1/2 phosphorylation. Thus, edoxaban ameliorated hepatic ischemia-reperfusion injury in mice by protecting against micro-thrombosis in sinusoids and suppressing FXa-PAR-2-induced inflammation in the sinusoidal endothelial cells.
Topics: Animals; Reperfusion Injury; Factor Xa Inhibitors; Receptor, PAR-2; Pyridines; Thiazoles; Mice; Liver; MAP Kinase Signaling System; Male; Endothelial Cells; Mice, Inbred C57BL; Disease Models, Animal; Mitogen-Activated Protein Kinase 3
PubMed: 38748746
DOI: 10.1371/journal.pone.0292628 -
PloS One 2024Peptide receptor radionucleotide therapy (PRRT) with 177Lu-dotatate is widely used for the treatment of patients with neuroendocrine tumors (NETs). We analyzed data from...
Peptide receptor radionucleotide therapy (PRRT) with 177Lu-dotatate is widely used for the treatment of patients with neuroendocrine tumors (NETs). We analyzed data from 104 patients with NETs treated with 177Lu -dotatate at a US academic center between December 2017 and October 2020 to better understand patterns of long-term efficacy, safety, and toxicity in the real-world setting. 177Lu-dotatate (200 mCi) was administered every eight weeks for four doses. The most common sites of primary disease were small intestine NETs (n = 49, 47%), pancreatic NETs (n = 32, 31%), and lung NETs (n = 7, 7%). Twenty-seven percent had Ki-67 <3%, 49% had Ki-67 between 3-20%, and 13.5% had Ki-67 >20%. The cohort had been pretreated with a median of two prior lines of treatment. Forty percent had received prior liver-directed treatment. Seventy-four percent of patients completed all four doses of treatment. The objective response rate was 18%. The median time-to-treatment failure/death was significantly longer for small-bowel NETs when compared to pancreatic NETs (37.3 months vs. 13.2 months, p = 0.001). In a multivariate model, Ki-67, primary site, and liver tumor burden ≥50% were found to independently predict time-to-treatment failure/death. Around 40% of patients experienced adverse events of ≥grade 3 severity. Treatment-related adverse events leading to discontinuation of therapy happened in 10% of patients. Preexisting mesenteric/peritoneal disease was present in 33 patients; seven of these patients developed bowel-related toxicities including two grade 5 events. We also report two cases of delayed-onset minimal change nephrotic syndrome, which occurred 14 and 27 months after the last dose of PRRT. Lastly, we describe six patients who developed rapid tumor progression in the liver leading to terminal liver failure within 7.3 months from the start of PRRT, and identify potential risk factors associated with this occurrence, which will need further study.
Topics: Humans; Neuroendocrine Tumors; Male; Female; Middle Aged; Aged; Octreotide; Receptors, Peptide; Adult; Treatment Outcome; Organometallic Compounds; Aged, 80 and over; Radiopharmaceuticals; Pancreatic Neoplasms; Retrospective Studies
PubMed: 38748739
DOI: 10.1371/journal.pone.0298824 -
PloS One 2024In a recent study (doi: 10.1371/journal.pone.0265662), associations were identified between owner-reported dog health status and diet, whereby those fed a vegan diet...
In a recent study (doi: 10.1371/journal.pone.0265662), associations were identified between owner-reported dog health status and diet, whereby those fed a vegan diet were perceived to be healthier. However, the study was limited because it did not consider possible confounding from variables not included in the analysis. The aim of the current study was to extend these earlier findings, using different modelling techniques and including multiple variables, to identify the most important predictors of owner perceptions of dog health. From the original dataset, two binary outcome variables were created: the 'any health problem' distinguished dogs that owners perceived to be healthy ("no") from those perceived to have illness of any severity; the 'significant illness' variable distinguished dogs that owners perceived to be either healthy or having mild illness ("no") from those perceived to have significant or serious illness ("yes"). Associations between these health outcomes and both owner-animal metadata and healthcare variables were assessed using logistic regression and machine learning predictive modelling using XGBoost. For the any health problem outcome, best-fit models for both logistic regression (area under curve [AUC] 0.842) and XGBoost (AUC 0.836) contained the variables dog age, veterinary visits and received medication, whilst owner age and breed size category also featured. For the significant illness outcome, received medication, veterinary visits, dog age and were again the most important predictors for both logistic regression (AUC 0.903) and XGBoost (AUC 0.887), whilst breed size category, education and owner age also featured in the latter. Any contribution from the dog vegan diet variable was negligible. The results of the current study extend the previous research using the same dataset and suggest that diet has limited impact on owner-perceived dog health status; instead, dog age, frequency of veterinary visits and receiving medication are most important.
Topics: Dogs; Animals; Humans; Surveys and Questionnaires; Dog Diseases; Male; Female; Ownership; Perception; Health Status; Diet, Vegan; Logistic Models
PubMed: 38748734
DOI: 10.1371/journal.pone.0280173 -
PLoS Genetics May 2024The leiomodin (Lmod) family of actin-binding proteins play a critical role in muscle function, highlighted by the fact that mutations in all three family members...
The leiomodin (Lmod) family of actin-binding proteins play a critical role in muscle function, highlighted by the fact that mutations in all three family members (LMOD1-3) result in human myopathies. Mutations in the cardiac predominant isoform, LMOD2 lead to severe neonatal dilated cardiomyopathy. Most of the disease-causing mutations in the LMOD gene family are nonsense, or frameshift, mutations predicted to result in expression of truncated proteins. However, in nearly all cases of disease, little to no LMOD protein is expressed. We show here that nonsense-mediated mRNA decay, a cellular mechanism which eliminates mRNAs with premature termination codons, underlies loss of mutant protein from two independent LMOD2 disease-causing mutations. Furthermore, we generated steric-blocking oligonucleotides that obstruct deposition of the exon junction complex, preventing nonsense-mediated mRNA decay of mutant LMOD2 transcripts, thereby restoring mutant protein expression. Our investigation lays the initial groundwork for potential therapeutic intervention in LMOD-linked myopathies.
PubMed: 38748723
DOI: 10.1371/journal.pgen.1011279