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Neuro-oncology Advances 2024This retrospective study compares the real-world performance of cerebrospinal fluid (CSF) CNSide™ versus cytology in leptomeningeal disease (LMD).
BACKGROUND
This retrospective study compares the real-world performance of cerebrospinal fluid (CSF) CNSide™ versus cytology in leptomeningeal disease (LMD).
METHODS
Consecutive patients with suspected LMD who underwent lumbar punctures for CSF cytology and CNSide™ from January 2020 to December 2022 were reviewed. LMD was classified by EANO criteria. Descriptive statistics, confusion matrix, Kaplan-Meier curves, and Cox proportional regression were used.
RESULTS
Median age for 87 evaluable patients was 63 years (range: 23-93); 82 (94%) met EANO criteria for possible/probable/confirmed LMD (EANO/LMD). The commonest primary cancers were breast (36,44.0%) and lung (34,41.5%). Primary lung harbored actionable mutations in 18 (53.0%); primary breast expressed hormone receptors in 27 (75%), and HER2 amplification in 8 (22%). Uncontrolled systemic disease was detected in 35 (40%), while 25 (46%) received systemic therapy with medium/high CNS penetrance at LMD diagnosis. The median time from initial cancer to LMD diagnosis was 31 months (range: 13-73). LMD was confirmed by CSF cytology in 23/82 (28%), all identified by CNSide™. CNSide™ identified 13 additional cases (36/82, 43.9%), increasing diagnostic yield by 56.5%. Median overall survival (mOS) was 31 weeks (95%CI: 21-43), significantly worse for CNSide™ positive versus negative: 4.0 versus 16.0 weeks, respectively (HR = 0.50, = .010). While survival since LMD diagnosis did not differ by histology, time to LMD diagnosis from initial cancer diagnosis was longer for breast (48.5 months, IQR: 30.0-87.5) versus lung (8 months, IQR:0.5-16.0) cohorts. mOS was longer for patients eligible for intrathecal chemotherapy (HR: 0.189, 95%CI: 0.053-0.672, = .010).
CONCLUSIONS
This retrospective, real-world analysis of CNSide™ showed increased sensitivity versus cytology and provided clinically relevant molecular CSF analyses.
PubMed: 38957163
DOI: 10.1093/noajnl/vdae071 -
Cancer Research Communications Jul 2024Various lines of investigation support a signaling interphase shared by receptor tyrosine kinases and the DNA damage response. However, the underlying network nodes and...
Various lines of investigation support a signaling interphase shared by receptor tyrosine kinases and the DNA damage response. However, the underlying network nodes and their contribution to the maintenance of DNA integrity remain unknown. We explored MET-related metabolic pathways whose interruption compromises proper resolution of DNA damage. Discovery metabolomics combined with transcriptomics identified changes in pathways relevant to DNA repair following MET inhibition (METi). METi by tepotinib was associated with formation of γH2AX foci and with significant alterations in major metabolic circuits such as glycolysis, gluconeogenesis, and purine, pyrimidine, amino acids, and lipids metabolism. 5'-Phosphoribosyl-N-formylglycinamide (FGAR), a de novo purine synthesis pathway metabolite, was consistently decreased in in vitro and in vivo MET-dependent models, and a METi-related depletion of dNTPs was observed. METi instigated the downregulation of critical purine synthesis enzymes including phosphoribosylglycinamide formyltransferase (GART) which catalyzes FGAR synthesis. Genes encoding these enzymes are regulated through E2F1, whose levels decrease upon METi in MET-driven cells and xenografts. Transient E2F1 overexpression prevented dNTPs depletion and the concomitant METi-associated DNA damage in MET-driven cells. We conclude that DNA damage following METi results from dNTPs reduction via downregulation of E2F1 and a consequent decline of de novo purine synthesis.
PubMed: 38957115
DOI: 10.1158/2767-9764.CRC-23-0370 -
Journal of Cellular and Molecular... Jul 2024Pruritus is often accompanied with bacterial infections, but the underlying mechanism is not fully understood. Although previous studies revealed that...
Pruritus is often accompanied with bacterial infections, but the underlying mechanism is not fully understood. Although previous studies revealed that lipopolysaccharides (LPS) could directly activate TRPV4 channel and TRPV4 is involved in the generation of both acute itch and chronic itch, whether and how LPS affects TRPV4-mediated itch sensation remains unclear. Here, we showed that LPS-mediated TRPV4 sensitization exacerbated GSK101-induced scratching behaviour in mice. Moreover, this effect was compromised in TLR4-knockout mice, suggesting LPS acted through a TLR4-dependent mechanism. Mechanistically, LPS enhanced GSK101-evoked calcium influx in mouse ear skin cells and HEK293T cells transfected with TRPV4. Further, LPS sensitized TRPV4 channel through the intracellular TLR4-PI3K-AKT signalling. In summary, our study found a modulatory role of LPS in TRPV4 function and highlighted the TLR4-TRPV4 interaction in itch signal amplification.
Topics: TRPV Cation Channels; Animals; Toll-Like Receptor 4; Pruritus; Lipopolysaccharides; Humans; Signal Transduction; Mice; HEK293 Cells; Phosphatidylinositol 3-Kinases; Mice, Knockout; Mice, Inbred C57BL; Male; Calcium; Proto-Oncogene Proteins c-akt
PubMed: 38957035
DOI: 10.1111/jcmm.18509 -
Organic & Biomolecular Chemistry Jul 2024We describe the synthesis of two tetra-α aryl-extended calix[4]pyrroles (C[4]Ps) 4a-b bearing four terminal carboxylic groups in their -propyl chains defining the lower...
We describe the synthesis of two tetra-α aryl-extended calix[4]pyrroles (C[4]Ps) 4a-b bearing four terminal carboxylic groups in their -propyl chains defining the lower rims. The synthesized C[4]Ps became soluble (1-3 mM) in water at pD = 10. We probed the interaction of 4a towards tetra-methylammonium (G1) chloride in water using H NMR spectroscopy. The C[4]P 4a includes G1 in the shallow aromatic cavity defined by the pyrrole rings in cone conformation forming a 1 : 1 complex G1⊂4a. Pyridine--oxide (PNO) binding in the larger polar aromatic cavity of 4a results in the quantitative self-assembly of the supramolecular receptor PNO@4a featuring the pyrrole rings preorganized in cone conformation. The PNO@4a receptor displays improved binding properties towards G1 than the parent C[4]P 4a. We thermodynamically characterized (H NMR titrations and ITC experiments) the 1 : 1 complexes of PNO@4a with a series of tetra-alkylammonium salts, including biologically relevant examples. The PNO@4a supramolecular receptor displays significant affinity (log = 3-4) but lacks selectivity in water binding of methyl trialkyl ammonium cations. Cation-π and coulombic interactions are the main intermolecular forces stabilizing the complexes. We also performed DFT calculations to gain some insights into the complexes' structures.
PubMed: 38957010
DOI: 10.1039/d4ob00843j -
Fundamental & Clinical Pharmacology Jul 2024Currently, there is no effective therapy for takotsubo syndrome (stress-induced cardiac injury in humans) in the clinics. It has previously been shown that β-adrenergic...
BACKGROUND
Currently, there is no effective therapy for takotsubo syndrome (stress-induced cardiac injury in humans) in the clinics. It has previously been shown that β-adrenergic receptor (β-AR) agonist formoterol reduces cardiomyocyte injury in experimental takotsubo syndrome.
OBJECTIVES
The aim of this study was to investigate whether formoterol prevents apoptosis and necrosis of cardiomyocytes and endothelial cells in stress-induced cardiomyopathy.
METHODS
Stress-induced cardiac injury was induced by immobilization of rats for 2, 6, and 24 hours.
RESULTS
The myocardium of stressed rats showed a reduction in contractility and histological manifestations of cardiomyocyte damage: karyopyknosis, perinuclear edema of cardiomyocytes and endothelial cells, and microcirculation disturbances augmented with extended exposure to stress. In addition, apoptosis of endothelial cells was detected 6 hours after the onset of stress and peaked at 24 hours. Apoptosis of cardiomyocytes significantly gained only after 24 hours of stress exposure. These morphological alterations were associated with increased levels of serum creatine kinase-MB, syndecan-1, and thrombomodulin after 24 hours of stress. Administration of β-AR agonist formoterol (50 μg/kg) four times during 24-hour stress exposure led to the improvement in myocardial inotropy, decrease in the severity of histological signatures, reduction in the number of TUNEL-positive cardiomyocytes, serum creatine kinase-MB, syndecan-1, and thrombomodulin levels.
CONCLUSION
Present data suggest that apoptosis and necrosis of cardiomyocytes and necrosis of endothelial cells in stress-induced cardiac injury can be mitigated by activation of the β-AR. However, formoterol did not eliminate completely cardiomyocyte apoptosis, histological alterations, or endothelium injury markers under stress.
PubMed: 38956972
DOI: 10.1111/fcp.13026 -
International Neurourology Journal Jun 2024To critically analyse the relationship of bladder pain syndrome (BPS/IC), as defined, to the posterior fornix syndrome, "PFS" predictably co-occurring bladder urgency,...
To critically analyse the relationship of bladder pain syndrome (BPS/IC), as defined, to the posterior fornix syndrome, "PFS" predictably co-occurring bladder urgency, frequency, nocturia, chronic pelvic pain, emptying symptoms/retention, caused by uterosacral ligament (USL) laxity and cured by USL repair. The starting and end points of this paper are the questions, "Are there arguments that BPS/IC can, in some cases, be linked to PFS?" And if so, "To what extent?" We used the criteria required by Ueda for proper diagnosis: "understanding symptoms, detecting abnormal findings and verifying them as a cause of the symptoms." Literature, diagnostic and surgical, indicate that chronic pelvic pain "of unknown origin" can be caused by unsupported visceral pelvic plexuses because of weak USLs; these cause fire of afferent impulses, which the brain mistakenly interprets as coming from the end-organ itself (i.e., genitourinary pain, lower urinary tract symptoms). The same lax USLs can also weaken the pelvic muscles which contract to stretch the vagina to support the urothelial stretch receptors from below: these may prematurely fire off afferent impulses to activate micturition at lower bladder volumes, interpreted as urgency. A speculum placed in the vagina can relieve pain and urgency by mechanically supporting the vaginal wall and USLs, thus predicting an eventual cure by USL repair. There is need to evaluate what percentage of women with known BPS/IC also pass the criteria for PFS. Identifying a significant percentage of BPS/IC women with the causative relation between PFS pathogenesis and BPS/ IC may open a new way of diagnosing and treating BPS/IC in some women.
PubMed: 38956769
DOI: 10.5213/inj.2346344.172 -
Parasites & Vectors Jul 2024Toxoplasma gondii infection affects a significant portion of the global population, leading to severe toxoplasmosis and, in immunocompromised patients, even death....
BACKGROUND
Toxoplasma gondii infection affects a significant portion of the global population, leading to severe toxoplasmosis and, in immunocompromised patients, even death. During T. gondii infection, disruption of gut microbiota further exacerbates the damage to intestinal and brain barriers. Therefore, identifying imbalanced probiotics during infection and restoring their equilibrium can regulate the balance of gut microbiota metabolites, thereby alleviating tissue damage.
METHODS
Vimentin gene knockout (vim-/-) mice were employed as an immunocompromised model to evaluate the influence of host immune responses on gut microbiota balance during T. gondii infection. Behavioral experiments were performed to assess changes in cognitive levels and depressive tendencies between chronically infected vim-/- and wild-type (WT) mice. Fecal samples were subjected to 16S ribosomal RNA (rRNA) sequencing, and serum metabolites were analyzed to identify potential gut probiotics and their metabolites for the treatment of T. gondii infection.
RESULTS
Compared to the immunocompetent WT sv129 mice, the immunocompromised mice exhibited lower levels of neuronal apoptosis and fewer neurobehavioral abnormalities during chronic infection. 16S rRNA sequencing revealed a significant decrease in the abundance of probiotics, including several species of Lactobacillus, in WT mice. Restoring this balance through the administration of Lactobacillus murinus and Lactobacillus gasseri significantly suppressed the T. gondii burden in the intestine, liver, and brain. Moreover, transplantation of these two Lactobacillus spp. significantly improved intestinal barrier damage and alleviated inflammation and neuronal apoptosis in the central nervous system. Metabolite detection studies revealed that the levels of various Lactobacillus-related metabolites, including indole-3-lactic acid (ILA) in serum, decreased significantly after T. gondii infection. We confirmed that L. gasseri secreted much more ILA than L. murinus. Notably, ILA can activate the aromatic hydrocarbon receptor signaling pathway in intestinal epithelial cells, promoting the activation of CD8 T cells and the secretion of interferon-gamma.
CONCLUSION
Our study revealed that host immune responses against T. gondii infection severely disrupted the balance of gut microbiota, resulting in intestinal and brain damage. Lactobacillus spp. play a crucial role in immune regulation, and the metabolite ILA is a promising therapeutic compound for efficient and safe treatment of T. gondii infection.
Topics: Animals; Gastrointestinal Microbiome; Mice; Toxoplasma; Mice, Knockout; Brain Injuries; Probiotics; Brain; Lactobacillus; Disease Models, Animal; Immunocompromised Host; Toxoplasmosis; RNA, Ribosomal, 16S; Male; Intestines
PubMed: 38956725
DOI: 10.1186/s13071-024-06349-8 -
Stem Cell Research & Therapy Jul 2024Repairation of bone defects remains a major clinical problem. Constructing bone tissue engineering containing growth factors, stem cells, and material scaffolds to...
BACKGROUND
Repairation of bone defects remains a major clinical problem. Constructing bone tissue engineering containing growth factors, stem cells, and material scaffolds to repair bone defects has recently become a hot research topic. Nerve growth factor (NGF) can promote osteogenesis of bone marrow mesenchymal stem cells (BMSCs), but the low survival rate of the BMSCs during transplantation remains an unresolved issue. In this study, we investigated the therapeutic effect of BMSCs overexpression of NGF on bone defect by inhibiting pyroptosis.
METHODS
The relationship between the low survival rate and pyroptosis of BMSCs overexpressing NGF in localized inflammation of fractures was explored by detecting pyroptosis protein levels. Then, the NGF/BMSCs-NSA-Sca bone tissue engineering was constructed by seeding BMSCs overexpressing NGF on the allograft bone scaffold and adding the pyroptosis inhibitor necrosulfonamide(NSA). The femoral condylar defect model in the Sprague-Dawley (SD) rat was studied by micro-CT, histological, WB and PCR analyses in vitro and in vivo to evaluate the regenerative effect of bone repair.
RESULTS
The pyroptosis that occurs in BMSCs overexpressing NGF is associated with the nerve growth factor receptor (P75NTR) during osteogenic differentiation. Furthermore, NSA can block pyroptosis in BMSCs overexpression NGF. Notably, the analyses using the critical-size femoral condylar defect model indicated that the NGF/BMSCs-NSA-Sca group inhibited pyroptosis significantly and had higher osteogenesis in defects.
CONCLUSION
NGF/BMSCs-NSA had strong osteogenic properties in repairing bone defects. Moreover, NGF/BMSCs-NSA-Sca mixture developed in this study opens new horizons for developing novel tissue engineering constructs.
Topics: Animals; Nerve Growth Factor; Mesenchymal Stem Cells; Rats; Tissue Scaffolds; Rats, Sprague-Dawley; Osteogenesis; Bone Regeneration; Allografts; Male; Tissue Engineering; Pyroptosis; Sulfonamides; Cell Differentiation; Mesenchymal Stem Cell Transplantation; Bone Transplantation
PubMed: 38956719
DOI: 10.1186/s13287-024-03807-z -
Genomics & Informatics Jul 2024Autoimmune disorders (ADs) are chronic conditions resulting from failure or breakdown of immunological tolerance, resulting in the host immune system attacking its cells...
Autoimmune disorders (ADs) are chronic conditions resulting from failure or breakdown of immunological tolerance, resulting in the host immune system attacking its cells or tissues. Recent studies report shared effects, mechanisms, and evolutionary origins among ADs; however, the possible factors connecting them are unknown. This study attempts to identify gene signatures commonly shared between different autoimmune disorders and elucidate their molecular pathways linking the pathogenesis of these ADs using an integrated gene expression approach. We employed differential gene expression analysis across 19 datasets of whole blood/peripheral blood cell samples with five different autoimmune disorders (rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, and type 1 diabetes) to get nine key genes-EGR1, RUNX3, SMAD7, NAMPT, S100A9, S100A8, CYBB, GATA2, and MCEMP1 that were primarily involved in cell and leukocyte activation, leukocyte mediated immunity, IL-17, AGE-RAGE signaling in diabetic complications, prion disease, and NOD-like receptor signaling confirming its role in immune-related pathways. Combined with biological interpretations such as gene ontology (GO), pathway enrichment, and protein-protein interaction (PPI) network, our current study sheds light on the in-depth research on early detection, diagnosis, and prognosis of different ADs.
PubMed: 38956704
DOI: 10.1186/s44342-024-00004-5 -
Journal of Animal Science and... Jul 2024Tissue non-specific alkaline phosphatase (TNSALP; encoded by the ALPL gene) has a critical role in the postnatal regulation of phosphate homeostasis, yet how TNSALP...
BACKGROUND
Tissue non-specific alkaline phosphatase (TNSALP; encoded by the ALPL gene) has a critical role in the postnatal regulation of phosphate homeostasis, yet how TNSALP activity and expression are regulated during pregnancy remain largely unknown. This study tested the hypothesis that progesterone (P4) and/or interferon tau (IFNT) regulate TNSALP activity during pregnancy in sheep.
METHODS
In Exp. 1, ewes were bred and received daily intramuscular injections of either corn oil vehicle (CO) or 25 mg progesterone in CO (P4) for the first 8 days of pregnancy and were hysterectomized on either Day 9, 12, or 125 of gestation. In Exp. 2, ewes were fitted with intrauterine catheters on Day 7 of the estrous cycle and received daily intramuscular injections of 50 mg P4 in CO and/or 75 mg progesterone receptor antagonist (RU486) in CO from Days 8 to 15, and twice daily intrauterine injections of either control proteins (CX) or IFNT (25 µg/uterine horn/d) from Days 11 to 15 (treatment groups: P4 + CX; P4 + IFNT; RU486 + P4 + CX; and RU486 + P4 + IFNT) and were hysterectomized on Day 16.
RESULTS
In Exp. 1, endometria from ewes administered P4 had greater expression of ALPL mRNA than ewes administered CO on Day 12. TNSALP activity appeared greater in the epithelia, stratum compactum stroma, and endothelium of the blood vessels in the endometrium and myometrium from ewes administered P4 than ewes administered CO on Day 12. On Day 125, TNSALP activity localized to uterine epithelial and endothelial cells, independent of P4 treatment. TNSALP activity in placentomes appeared greater in P4 treated ewes and was detected in endothelial cells and caruncular tissue in P4 treated but not CO treated ewes. In Exp. 2, endometrial homogenates from ewes administered RU486 + P4 + CX had lower TNSALP activity those for P4 + CX and P4 + IFNT ewes. Immunoreactive TNSALP protein appeared greater in the mid- and deep-glandular epithelia in RU486 + P4 + CX treated ewes as compared to the other treatment groups. Enzymatic activity appeared greater on the apical surface of the deep glandular epithelia in endometria from ewes treated with RU486 + P4 + CX compared to the other treatment groups.
CONCLUSIONS
These results suggest that P4, but not IFNT, regulates the expression and activity of TNSALP in utero-placental tissues and has the potential to contribute to the regulation of phosphate availability that is critical for conceptus development during pregnancy.
PubMed: 38956701
DOI: 10.1186/s40104-024-01048-x