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Experimental Hematology May 2024Key studies in pre-leukemic disorders have linked increases in pro-inflammatory cytokines with accelerated phases of disease, but the precise role of the cellular...
Key studies in pre-leukemic disorders have linked increases in pro-inflammatory cytokines with accelerated phases of disease, but the precise role of the cellular microenvironment in disease initiation and evolution remains poorly understood. In myeloproliferative neoplasms (MPNs), higher levels of specific cytokines have been previously correlated with increased disease severity (TNF-α, IP-10) and decreased survival (IL-8). Whereas TNF-α and IL-8 have been studied by numerous groups, there is a relative paucity of studies on IP-10 (CXCL10). Here we explore the relationship of IP-10 levels with detailed genomic and clinical data and undertake a complementary cytokine screen alongside functional assays in a wide range of MPN mouse models. Similar to patients, levels of IP-10 were increased in mice with more severe disease phenotypes (e.g., JAK2 TET2 double mutant mice) compared to those with less severe phenotypes (e.g., CALR or JAK2 mice) and WT littermate controls. While exposure to IP-10 did not directly alter proliferation or survival in single hematopoietic stem cells (HSCs) in vitro, IP-10 mice transplanted with disease initiating HSCs developed an MPN phenotype more slowly, suggesting that the effect of IP-10 loss was non-cell autonomous. To explore the broader effects of IP-10 loss, we crossed IP-10 mice into a series of MPN mouse models and show that its loss reduces the erythrocytosis observed in mice with the most severe phenotype. Together these data point to a potential role for blocking IP-10 activity in the management of MPNs.
PubMed: 38763471
DOI: 10.1016/j.exphem.2024.104246 -
Pharmacological Research May 2024Studies have shown that the microbiota-gut-brain axis is highly correlated with the pathogenesis of depression in humans. However, whether independent oral microbiome...
Studies have shown that the microbiota-gut-brain axis is highly correlated with the pathogenesis of depression in humans. However, whether independent oral microbiome that do not depend on gut microbes could affect the progression of depression in human beings remains unclear, neither does the presence and underlying mechanisms of the microbiota-oral-brain axis in the development of the condition. Hence this study that encompasses clinical and animal experiments aims at investigating the correlation between oral microbiota and the onset of depression via mediating the microbiota-oral-brain axis. We compared the oral microbial compositions and metabolomes of 87 patients with depressive symptoms versus 70 healthy controls. We found that the oral microbial and metabolic signatures were significantly different between the two groups. Significantly, germ-free (GF) mice transplanted with saliva from mice exposing to chronic restraint stress (CRS) displayed depression-like behavior and oral microbial dysbiosis. This was characterized by a significant differential abundance of bacterial species, including the enrichment of Pseudomonas, Pasteurellaceae, and Muribacter, as well as the depletion of Streptococcus. Metabolomic analysis showed the alternation of metabolites in the plasma of CRS-exposed GF mice, especially Eicosapentaenoic Acid. Furthermore, oral and gut barrier dysfunction caused by CRS-induced oral microbiota dysbiosis may be associated with increased blood-brain barrier permeability. Pseudomonas aeruginosa supplementation exacerbated depression-like behavior, while Eicosapentaenoic Acid treatment conferred protection against depression-like states in mice. These results suggest that oral microbiome and metabolic function dysbiosis may be relevant to the pathogenesis and pathophysiology of depression. The proposed microbiota-oral-brain axis provides a new way and targets for us to study the pathogenesis of depression.
PubMed: 38763328
DOI: 10.1016/j.phrs.2024.107214 -
Journal of the American Academy of... May 2024
PubMed: 38763291
DOI: 10.1016/j.jaad.2024.05.022 -
Redox Biology May 2024Activation of inflammation is tightly associated with metabolic reprogramming in macrophages. The iron-containing tetrapyrrole heme can induce pro-oxidant and...
Activation of inflammation is tightly associated with metabolic reprogramming in macrophages. The iron-containing tetrapyrrole heme can induce pro-oxidant and pro-inflammatory effects in murine macrophages, but has been associated with polarization towards an anti-inflammatory phenotype in human macrophages. In the current study, we compared the regulatory responses to heme and the prototypical Toll-like receptor (TLR)4 ligand lipopolysaccharide (LPS) in human and mouse macrophages with a particular focus on alterations of cellular bioenergetics. In human macrophages, bulk RNA-sequencing analysis indicated that heme led to an anti-inflammatory transcriptional profile, whereas LPS induced a classical pro-inflammatory gene response. Co-stimulation of heme with LPS caused opposing regulatory patterns of inflammatory activation and cellular bioenergetics in human and mouse macrophages. Specifically, in LPS-stimulated murine, but not human macrophages, heme led to a marked suppression of oxidative phosphorylation and an up-regulation of glycolysis. The species-specific alterations in cellular bioenergetics and inflammatory responses to heme were critically dependent on the availability of nitric oxide (NO) that is generated in inflammatory mouse, but not human macrophages. Accordingly, studies with an inducible nitric oxide synthase (iNOS) inhibitor in mouse, and a pharmacological NO donor in human macrophages, reveal that NO is responsible for the opposing effects of heme in these cells. Taken together, the current findings indicate that NO is critical for the immunomodulatory role of heme in macrophages.
PubMed: 38762951
DOI: 10.1016/j.redox.2024.103191 -
BMC Musculoskeletal Disorders May 2024Surgical repair is recommended for the treatment of high-grade partial and full thickness rotator cuff tears, although evidence shows surgery is not necessarily superior... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Percutaneous bone marrow concentrate and platelet products versus exercise therapy for the treatment of rotator cuff tears: a randomized controlled, crossover trial with 2-year follow-up.
BACKGROUND
Surgical repair is recommended for the treatment of high-grade partial and full thickness rotator cuff tears, although evidence shows surgery is not necessarily superior to non-surgical therapy. The purpose of this study was to compare percutaneous orthobiologic treatment to a home exercise therapy program for supraspinatus tears.
METHODS
In this randomized-controlled, crossover design, participants with a torn supraspinatus tendon received either 'BMC treatment', consisting of a combination of autologous bone marrow concentrate (BMC) and platelet products, or underwent a home exercise therapy program. After three months, patients randomized to exercise therapy could crossover to receive BMC treatment if not satisfied with shoulder progression. Patient-reported outcomes of Numeric Pain Scale (NPS), Disabilities of the Arm, Shoulder, and Hand, (DASH), and a modified Single Assessment Numeric Evaluation (SANE) were collected at 1, 3, 6, 12, and 24 months. Pre- and post-treatment MRI were assessed using the Snyder Classification system.
RESULTS
Fifty-one patients were enrolled and randomized to the BMC treatment group (n = 34) or the exercise therapy group (n = 17). Significantly greater improvement in median ΔDASH, ΔNPS, and SANE scores were reported by the BMC treatment group compared to the exercise therapy group (-11.7 vs -3.8, P = 0.01; -2.0 vs 0.5, P = 0.004; and 50.0 vs 0.0, P < 0.001; respectively) after three months. Patient-reported outcomes continued to progress through the study's two-year follow-up period without a serious adverse event. Of patients with both pre- and post-treatment MRIs, a majority (73%) showed evidence of healing post-BMC treatment.
CONCLUSIONS
Patients reported significantly greater changes in function, pain, and overall improvement following BMC treatment compared to exercise therapy for high grade partial and full thickness supraspinatus tears.
TRIAL REGISTRATION
This protocol was registered with www.
CLINICALTRIALS
gov (NCT01788683; 11/02/2013).
Topics: Humans; Male; Female; Rotator Cuff Injuries; Middle Aged; Cross-Over Studies; Exercise Therapy; Bone Marrow Transplantation; Aged; Follow-Up Studies; Treatment Outcome; Rotator Cuff; Pain Measurement; Adult; Patient Reported Outcome Measures; Magnetic Resonance Imaging
PubMed: 38762734
DOI: 10.1186/s12891-024-07519-6 -
BMC Cardiovascular Disorders May 2024Extracorporeal blood purification has been widely used in intensive care medicine, nephrology, toxicology, and other fields. During the last decade, with the emergence...
BACKGROUND
Extracorporeal blood purification has been widely used in intensive care medicine, nephrology, toxicology, and other fields. During the last decade, with the emergence of new adsorptive blood purification devices, hemoadsorption has been increasingly applied during CPB in cardiac surgery, for patients at different inflammatory risks, or for postoperative complications. Clinical evidence so far has not provided definite answers concerning this adjunctive treatment. The current systematic review aimed to critically assess the role of perioperative hemoadsorption in cardiac surgery, by summarizing the current knowledge in this clinical setting.
METHODS
A literature search of PubMed, Cochrane library, and the database provided by CytoSorbents was conducted on June 1st, 2023. The search terms were chosen by applying neutral search keywords to perform a non-biased systematic search, including language variations of terms "cardiac surgery" and "hemoadsorption". The screening and selection process followed scientific principles (PRISMA statement). Abstracts were considered for inclusion if they were written in English and published within the last ten years. Publications were eligible for assessment if reporting on original data from any type of study (excluding case reports) in which a hemoadsorption device was investigated during or after cardiac surgery. Results were summarized according to sub-fields and presented in a tabular view.
RESULTS
The search resulted in 29 publications with a total of 1,057 patients who were treated with hemoadsorption and 988 control patients. Articles were grouped and descriptively analyzed due to the remarkable variability in study designs, however, all reported exclusively on CytoSorb therapy. A total of 62% (18/29) of the included articles reported on safety and no unanticipated adverse events have been observed. The most frequently reported clinical outcome associated with hemoadsorption was reduced vasopressor demand resulting in better hemodynamic stability.
CONCLUSIONS
The role of hemoadsorption in cardiac surgery seems to be justified in selected high-risk cases in infective endocarditis, aortic surgery, heart transplantation, and emergency surgery in patients under antithrombotic therapy, as well as in those who develop a dysregulated inflammatory response, vasoplegia, or septic shock postoperatively. Future large randomized controlled trials are needed to better define proper patient selection, dosing, and timing of the therapy.
Topics: Humans; Cardiac Surgical Procedures; Treatment Outcome; Risk Factors; Postoperative Complications; Cardiopulmonary Bypass; Male; Female; Risk Assessment; Aged; Middle Aged
PubMed: 38762715
DOI: 10.1186/s12872-024-03938-4 -
Nature Communications May 2024Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various...
Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.
Topics: HSC70 Heat-Shock Proteins; B7-H1 Antigen; Lysosomes; Animals; Mice; Humans; Female; Cell Line, Tumor; Proteolysis; Endosomes; Neoplasms; HSP90 Heat-Shock Proteins; Mice, Inbred C57BL; Immune Checkpoint Inhibitors; CTLA-4 Antigen; Cell Membrane; Myelin Proteins; MARVEL Domain-Containing Proteins
PubMed: 38762492
DOI: 10.1038/s41467-024-48597-3 -
Journal of Pediatric Nursing May 2024When a child needs a hematopoietic stem cell transplant, the seriousness of the child's illness is highlighted. The purpose of this study was to explore parents'...
PURPOSE
When a child needs a hematopoietic stem cell transplant, the seriousness of the child's illness is highlighted. The purpose of this study was to explore parents' experiences of the transplantation process when two children in the family are involved, one severely ill child as the recipient and the other as the donor.
METHODS
In this qualitative study, interviews were conducted with 18 parents of 13 healthy minor donors after successful stem cell transplants. Qualitative content analysis was used to explore parents' experiences.
FINDINGS
The parents described they were living with the threat of losing a child. They lived with an uncertain future as they were confronted with life-changing information. Whether the ill child would survive or not could not be predicted; thus, parents had to endure unpredictability, and to cope with this they chose to focus on positives. Finally, the parents managed family life in the midst of chaos, felt an inadequacy and a perception that the family became a fragmented although close team during hospital stays. They expressed a need for both tangible and emotional support.
CONCLUSIONS
When a child needs a stem cell transplant, the parents feel inadequate to their healthy children including the donating child. It is obvious that they experience an uncertain future and struggle to keep the family together amid the chaos.
PRACTICE IMPLICATIONS
Considering these results, psychosocial support should be mandatory for parents in connection with pediatric HSCT, to enable a process where parents can prepare for the outcome, whether successful or not.
PubMed: 38762421
DOI: 10.1016/j.pedn.2024.05.015 -
Transplantation Proceedings May 2024In this paper, we present organ donation and transplantation activities in Poland from 2017 to 2022. Data came from registries maintained by the Polish Transplant...
In this paper, we present organ donation and transplantation activities in Poland from 2017 to 2022. Data came from registries maintained by the Polish Transplant Coordinating Center Poltransplant and consisted of the national waiting list, deceased donor registry, transplant registry, and the live donor registry. Poltransplant is the Competent Authority in Organs, with tasks related to preparing assessments, analyses, information, and reports in transplantation medicine and publishing and disseminating these results in the country and abroad. Poltransplant edits the Poltransplant Bulletin on its web pages and presents its activities at Polish Transplantation Society congresses, published consecutively as professional papers.
PubMed: 38762405
DOI: 10.1016/j.transproceed.2024.03.027 -
Lancet (London, England) May 2024Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the...
Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.
BACKGROUND
Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021.
METHODS
The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk-outcome pairs. Pairs were included on the basis of data-driven determination of a risk-outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk-outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk-outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws.
FINDINGS
Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7-9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4-9·2]), smoking (5·7% [4·7-6·8]), low birthweight and short gestation (5·6% [4·8-6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8-6·0]). For younger demographics (ie, those aged 0-4 years and 5-14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9-27·7]) and environmental and occupational risks (decrease of 22·0% [15·5-28·8]), coupled with a 49·4% (42·3-56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9-21·7] for high BMI and 7·9% [3·3-12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6-1·9) for high BMI and 1·3% (1·1-1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4-78·8) for child growth failure and 66·3% (60·2-72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP).
INTERPRETATION
Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions.
FUNDING
Bill & Melinda Gates Foundation.
Topics: Humans; Global Burden of Disease; Risk Factors; Global Health; Female; Male; Risk Assessment; Adult; Middle Aged; Aged; Disability-Adjusted Life Years; Adolescent; Young Adult; Quality-Adjusted Life Years
PubMed: 38762324
DOI: 10.1016/S0140-6736(24)00933-4