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Heliyon May 2024Galectins-8 (Gal-8), the tandem repeat sequences of the galectin family, can influence the pathophysiologic processes in neurological disorders. However, its effect on...
Inhibition of sugar-binding activity of Galectins-8 by thiogalactoside (TDG) attenuates secondary brain damage and improves long-term prognosis following intracerebral hemorrhage.
Galectins-8 (Gal-8), the tandem repeat sequences of the galectin family, can influence the pathophysiologic processes in neurological disorders. However, its effect on intracerebral hemorrhage and related mechanisms remains nebulous. Using collagenase VII-S-induced ICH in the left striatum of mice, we investigated the effects of Gal-8 on cellular and molecular immune inflammatory responses in hemorrhagic brain and evaluated the severity of short- and long-term brain injury. Our results showed that activated microglia in the periphery of hematoma in mice with intracerebral hemorrhage expressed Gal-8, while Gal-8 could regulate the expression of cytokines, such as HMGB-1 ( = 0.0032), TNF-α ( = 0.0158), and IL-10 ( = 0.0379). Inhibition of the glucose-binding activity of Gal-8 by thiogalactoside (TDG) significantly reduced the volume of cerebral hematoma ( = 0.0241) and hydrocephalus ( = 0.0112) during the acute phase of cerebral hemorrhage and improved the long-term prognosis. TDG can reduce acute-phase brain tissue injury and improve the prognosis by inhibiting the activation of immune-inflammatory cells in the periphery of hematoma and reducing the release of pro-inflammatory factors.
PubMed: 38737270
DOI: 10.1016/j.heliyon.2024.e30422 -
Therapeutic Advances in Hematology 2024People with severe hemophilia A usually experience their first bleed early in life. In children with severe hemophilia A, primary prophylaxis is recommended to prevent... (Review)
Review
People with severe hemophilia A usually experience their first bleed early in life. In children with severe hemophilia A, primary prophylaxis is recommended to prevent recurrent and potentially life-threatening bleeds that significantly impact day-to-day life. Factor VIII (FVIII) prophylaxis is well-established in children and has been shown to reduce the development of hemophilic arthropathy. However, a major challenge of FVIII therapy is the development of neutralizing anti-FVIII antibodies (FVIII inhibitors). Simoctocog alfa (Nuwiq) is a human cell line-derived recombinant FVIII (rFVIII) whose immunogenicity, efficacy, and safety have been studied in 167 children with severe hemophilia A across two prospective clinical trials and their long-term extensions. In 105 previously untreated children, the inhibitor rate of 16.2% for high-titer inhibitors (26.7% for all inhibitors) was lower than published rates for hamster cell line-derived rFVIII products. There was no inhibitor development in previously untreated children with non-null mutations and in previously treated children. In a case series of 10 inhibitor patients, 8 (80%) underwent successful immune tolerance induction with simoctocog alfa with a median time to undetectable inhibitor of 3.5 months. In an analysis of 96 children who enrolled in the extension studies and received long-term simoctocog alfa prophylaxis for up to 5 years, median spontaneous, joint, and total annualized bleeding rates were 0.3, 0.4, and 1.8, respectively. No thromboembolisms were reported in any of the 167 children, and there were no treatment-related deaths. Optimal care of children should consider several factors, including minimization of inhibitor development risk, maintaining tolerance to FVIII, highly effective bleed prevention and treatment, safety, and impact on long-term outcomes such as bone and joint health. In this context we review the pediatric clinical data and ongoing studies with simoctocog alfa.
PubMed: 38737006
DOI: 10.1177/20406207241245511 -
International Journal of General... 2024This study aims to investigate the incidence, clinical characteristics, and prognosis of thrombosis in Chinese patients with immune thrombocytopenia (ITP).
INTRODUCTION
This study aims to investigate the incidence, clinical characteristics, and prognosis of thrombosis in Chinese patients with immune thrombocytopenia (ITP).
METHODS
This was a single-center, retrospective study of adult patients with ITP at the Henan Provincial People's Hospital from January 2018 to June 2023.
RESULTS
A total of 3216 adult patients with primary ITP were included in the study period, with 25 (0.93%) having thrombotic events. The average age of 25 patients with thrombosis is 62.76±12.79 years, including 11 males and 14 females. In addition, among the 25 thrombotic events, 19 cases were arterial thrombosis (AT), and 6 cases were venous thrombosis (VT). The incidence of AT is higher than that of VT (P=0.009). There was no obvious difference in clinical characteristics between the two groups. The median platelet count at the time of thrombosis in 25 patients was 35 (23, 52) ×10/L. At the onset of thrombosis, 23 patients (92.0%) had a low PLT (<100×10/L). One patient with ischemic stroke died in the hospital due to severe infection.
CONCLUSION
ITP may be considered a bleeding disorder with a high risk of thrombosis, and AT is more common than VT in the Chinese population.
PubMed: 38736666
DOI: 10.2147/IJGM.S462276 -
Chinese Neurosurgical Journal May 2024In bypass surgery for moyamoya disease (MMD), the superficial temporal artery's (STA) pressure needs to surpass that of the cortical M4 recipient of the middle cerebral...
BACKGROUND
In bypass surgery for moyamoya disease (MMD), the superficial temporal artery's (STA) pressure needs to surpass that of the cortical M4 recipient of the middle cerebral artery (MCA), boosting cerebral blood flow into the MCA and enhancing cerebral circulation. This study investigates the STA-MCA arterial pressure parameters and gradients during bypass surgery, aiming to deepen our understanding of hemodynamic shifts pre- and post-operation.
METHODS
DSA imaging data were prospectively collected from patients diagnosed with bilateral MMD who underwent STA-MCA bypass surgery between 2022 and 2023 and stratified according to the Suzuki stage. The mean arterial pressure (MAP) of the donor and recipient arteries was directly measured during the STA-MCA bypass procedure, and these data were statistically analyzed and evaluated.
RESULTS
Among 48 MMD patients, Suzuki grading revealed that 43.8% were in early stages (II and III), while 56.2% were in advanced stages (IV, V, and VI). Predominantly, 77.1% presented with ischemic-type MMD and 22.9% with hemorrhagic type. Pre-bypass assessments showed that 62.5% exhibited antegrade blood flow direction, and 37.5% had retrograde. The mean recipient artery pressure was 35.0 ± 2.3 mmHg, with a mean donor-recipient pressure gradient (δP) of 46.4 ± 2.5 mmHg between donor and recipient arteries. Post-bypass, mean recipient artery pressure increased to 73.3 ± 1.6 mmHg. No significant correlation (r = 0.18, P = 0.21) was noted between δP and Suzuki staging.
CONCLUSION
Our study elucidated that cerebral blood pressure significantly decreases beyond the moyamoya network at the distal M4 segment. Furthermore, we observed bidirectional flow in MCA territories and a significant positive pressure gradient between the STA and M4 segments. The lack of correlation between Suzuki stages and M4 pressures indicates that angiographic severity may not reflect hemodynamic conditions before surgery, highlighting the need for customized surgical approaches.
PubMed: 38734681
DOI: 10.1186/s41016-024-00367-2 -
Nutrients Apr 2024The available evidence on vitamin K status in cystic fibrosis (CF) is scarce, lacking data on vitamin K2 (menaquinones-MK). Therefore, we assessed vitamin K1, MK-4 and...
The available evidence on vitamin K status in cystic fibrosis (CF) is scarce, lacking data on vitamin K2 (menaquinones-MK). Therefore, we assessed vitamin K1, MK-4 and MK-7 concentrations (LC-MS/MS) in 63 pancreatic insufficient and modulator naïve CF patients, and compared to 61 healthy subjects (HS). Vitamin K1 levels did not differ between studied groups. MK-4 concentrations were higher (median <1st-3rd quartile>: 0.778 <0.589-1.086> vs. 0.349 <0.256-0.469>, < 0.0001) and MK-7 levels lower (0.150 <0.094-0.259> vs. 0.231 <0.191-0.315>, = 0.0007) in CF patients than in HS. MK-7 concentrations were higher in CF patients receiving K1 and MK-7 supplementation than in those receiving vitamin K1 alone or no supplementation. Moreover, vitamin K1 concentrations depended on the supplementation regime. Based on multivariate logistic regression analysis, we have found that MK-7 supplementation dose has been the only predictive factor for MK-7 levels. In conclusion, vitamin K1 levels in CF are low if not currently supplemented. MK-4 concentrations in CF patients supplemented with large doses of vitamin K1 are higher than in HS. MK-7 levels in CF subjects not receiving MK-7 supplementation, with no regard to vitamin K1 supplementation, are low. There do not seem to be any good clinical predictive factors for vitamin K status.
Topics: Humans; Cystic Fibrosis; Female; Male; Vitamin K 2; Cross-Sectional Studies; Prothrombin; Adolescent; Adult; Vitamin K 1; Young Adult; Nutritional Status; Dietary Supplements; Vitamin K Deficiency; Vitamin K
PubMed: 38732584
DOI: 10.3390/nu16091337 -
International Journal of Molecular... May 2024Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell)... (Meta-Analysis)
Meta-Analysis Review
An Assessment of the Effectiveness and Safety of Chimeric Antigen Receptor T-Cell Therapy in Multiple Myeloma Patients with Relapsed or Refractory Disease: A Systematic Review and Meta-Analysis.
Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy's efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy.
Topics: Multiple Myeloma; Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Treatment Outcome; Quality of Life; Neoplasm Recurrence, Local; Cytokine Release Syndrome
PubMed: 38732213
DOI: 10.3390/ijms25094996 -
International Journal of Molecular... Apr 2024Multiple myeloma is an incurable plasma cell malignancy. Most patients end up relapsing and developing resistance to antineoplastic drugs, like bortezomib. Antibiotic...
Multiple myeloma is an incurable plasma cell malignancy. Most patients end up relapsing and developing resistance to antineoplastic drugs, like bortezomib. Antibiotic tigecycline has activity against myeloma. This study analyzed tigecycline and bortezomib combination on cell lines and plasma cells from myeloma patients. Apoptosis, autophagic vesicles, mitochondrial mass, mitochondrial superoxide, cell cycle, and hydrogen peroxide were studied by flow cytometry. In addition, mitochondrial antioxidants and electron transport chain complexes were quantified by reverse transcription real-time PCR (RT-qPCR) or western blot. Cell metabolism and mitochondrial activity were characterized by Seahorse and RT-qPCR. We found that the addition of tigecycline to bortezomib reduces apoptosis in proportion to tigecycline concentration. Supporting this, the combination of both drugs counteracts bortezomib in vitro individual effects on the cell cycle, reduces autophagy and mitophagy markers, and reverts bortezomib-induced increase in mitochondrial superoxide. Changes in mitochondrial homeostasis and upregulation may account for some of these findings. These data not only advise to avoid considering tigecycline and bortezomib combination for treating myeloma, but caution on the potential adverse impact of treating infections with this antibiotic in myeloma patients under bortezomib treatment.
Topics: Bortezomib; Humans; Multiple Myeloma; Tigecycline; Mitochondria; Reactive Oxygen Species; Apoptosis; Cell Line, Tumor; Antineoplastic Agents; Autophagy; Mitophagy; Cell Cycle
PubMed: 38732105
DOI: 10.3390/ijms25094887 -
International Journal of Molecular... Apr 2024Cerebral cavernous malformations (CCMs) are a neurological disorder characterized by enlarged intracranial capillaries in the brain, increasing the susceptibility to...
Cerebral cavernous malformations (CCMs) are a neurological disorder characterized by enlarged intracranial capillaries in the brain, increasing the susceptibility to hemorrhagic strokes, a major cause of death and disability worldwide. The limited treatment options for CCMs underscore the importance of prognostic biomarkers to predict the likelihood of hemorrhagic events, aiding in treatment decisions and identifying potential pharmacological targets. This study aimed to identify blood biomarkers capable of diagnosing and predicting the risk of hemorrhage in CCM1 patients, establishing an initial set of circulating biomarker signatures. By analyzing proteomic profiles from both human and mouse CCM models and conducting pathway enrichment analyses, we compared groups to identify potential blood biomarkers with statistical significance. Specific candidate biomarkers primarily associated with metabolism and blood clotting pathways were identified. These biomarkers show promise as prognostic indicators for CCM1 deficiency and the risk of hemorrhagic stroke, strongly correlating with the likelihood of hemorrhagic cerebral cavernous malformations (CCMs). This lays the groundwork for further investigation into blood biomarkers to assess the risk of hemorrhagic CCMs.
Topics: Hemangioma, Cavernous, Central Nervous System; Humans; Animals; Mice; Prognosis; Biomarkers; Proteomics; Cerebral Hemorrhage; KRIT1 Protein; Disease Models, Animal; Female; Male
PubMed: 38731959
DOI: 10.3390/ijms25094740 -
International Journal of Molecular... Apr 2024Multiple myeloma is a malignancy characterized by the accumulation of malignant plasma cells in bone marrow and the production of monoclonal immunoglobulin. A hallmark...
Multiple myeloma is a malignancy characterized by the accumulation of malignant plasma cells in bone marrow and the production of monoclonal immunoglobulin. A hallmark of cancer is the evasion of immune surveillance. Histone deacetylase inhibitors have been shown to promote the expression of silenced molecules and hold potential to increase the anti-MM efficacy of immunotherapy. The aim of the present work was to assess the potential effect of tinostamustine (EDO-S101), a first-in-class alkylating deacetylase inhibitor, in combination with daratumumab, an anti-CD38 monoclonal antibody (mAb), through different preclinical studies. Tinostamustine increases CD38 expression in myeloma cell lines, an effect that occurs in parallel with an increment in CD38 histone H3 acetylation levels. Also, the expression of MICA and MICB, ligands for the NK cell activating receptor NKG2D, augments after tinostamustine treatment in myeloma cell lines and primary myeloma cells. Pretreatment of myeloma cell lines with tinostamustine increased the sensitivity of these cells to daratumumab through its different cytotoxic mechanisms, and the combination of these two drugs showed a higher anti-myeloma effect than individual treatments in ex vivo cultures of myeloma patients' samples. In vivo data confirmed that tinostamustine pretreatment followed by daratumumab administration significantly delayed tumor growth and improved the survival of mice compared to individual treatments. In summary, our results suggest that tinostamustine could be a potential candidate to improve the efficacy of anti-CD38 mAbs.
Topics: Multiple Myeloma; Humans; ADP-ribosyl Cyclase 1; Animals; Antibodies, Monoclonal; Mice; Cell Line, Tumor; NK Cell Lectin-Like Receptor Subfamily K; Xenograft Model Antitumor Assays; Histone Deacetylase Inhibitors; Membrane Glycoproteins; Drug Synergism; Histocompatibility Antigens Class I; Up-Regulation
PubMed: 38731936
DOI: 10.3390/ijms25094718 -
Medicine May 2024Primary Sjögren Syndrome (pSS) is a chronic autoimmune disease that primarily affects exocrine glands and can lead to various extraglandular manifestations, including... (Observational Study)
Observational Study
Comprehensive analysis of the clinical manifestations and hematological parameters associated with secondary immune thrombocytopenia in patients with primary Sjögren syndrome: An observational study.
Primary Sjögren Syndrome (pSS) is a chronic autoimmune disease that primarily affects exocrine glands and can lead to various extraglandular manifestations, including secondary immune thrombocytopenia (ITP). Understanding the clinical and hematological differences in pSS patients with and without secondary ITP is crucial for improved patient management and treatment strategies. This retrospective study, conducted from January 2020 to December 2023, involved a cohort of pSS patients, dividing them into 2 groups: those with secondary ITP and those without. Patients were evaluated using the European League Against Rheumatism Sjögren Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren Syndrome Patient-Reported Index (ESSPRI), Health Assessment Questionnaire, and other hematological parameters. Inclusion criteria were based on the American-European Consensus Group or ACR/EULAR classification criteria for pSS. Exclusion criteria included other autoimmune or hematological disorders, prior splenectomy, recent blood transfusions, and lack of informed consent. Statistical analysis was performed using SPSS software, with various tests applied to analyze the data, including logistic regression to identify risk factors for secondary ITP. Significant differences were noted in fatigue, lymphadenopathy, arthritis, mean age, and ESSDAI scores between the secondary ITP and non-secondary ITP groups. Patients with secondary ITP exhibited higher platelet counts, more prevalent lymphopenia, higher immunoglobulin G (IgG) levels, lower complement 3 levels, and reduced white blood cell and hemoglobin levels. Logistic regression analysis identified lymphadenopathy as a risk factor and arthritis as a protective factor for the development of secondary ITP. The study reveals distinct clinical and hematological characteristics in pSS patients with secondary ITP, suggesting a higher disease activity in this subset. These findings underscore the need for further exploration of these associations to develop more precise treatment approaches for pSS, focusing on preventing secondary ITP and improving patient outcomes.
Topics: Humans; Sjogren's Syndrome; Female; Purpura, Thrombocytopenic, Idiopathic; Middle Aged; Retrospective Studies; Male; Adult; Aged; Risk Factors; Platelet Count; Severity of Illness Index
PubMed: 38728456
DOI: 10.1097/MD.0000000000037909