Abstract
Objectives
HCQ has been described as having a beneficial effect in patients with APS but its mechanism of action is unclear. We hypothesized that HCQ may have effects on subnormal ...angiogenesis, inflammation and haemostatic biomarkers seen in APS. The aim of our study was to assess laboratory markers annexin A5 (AnxA5) anticoagulant activity, tissue factor (TF) levels, thromboelastography (TEG), CRP, Bb, C3a and VEGF in HCQ-naïve patients with aPL at baseline and after commencing HCQ.
Methods
Twenty-two patients with aPL 20 female, 2 male, median age 55 (range 18-70) years had blood taken pre- and 3 months after starting HCQ 200 mg daily.
Results
Soluble TF levels were significantly reduced comparing baseline and 3 months after HCQ commencement 401.8 (152.8) vs 300.9 (108) pg/ml (P = 0.010). No significant changes were found in the following reported as pre- and post-HCQ commencement, mean (s.d.): AnxA5 anticoagulant ratio 187.1 (29.5) vs 193 (31) (P = 0.157), anti-domain1 β2 glycoprotein1 IgG activity 1.8 (2) vs 1.2 (1.4) μg/ml (P = 0.105), complement C3a-des-Arg 147.8 (84.5) vs 154.4 (88.1) ng/ml (P = 0.905), complement Bb 1.3 (0.7) vs 1.1 (0.7) μg/ml (P = 0.422), VEGF 68.8 (40) vs 59.4 (19.6) pg/ml (P = 0.454) and CRP 7 (3.5) vs 7 (3.9) μg/ml (P = 0.917). TEG results including TEG reaction time, achievement of clot firmness, TEG maximum amplitude and TEG percentage lysis 30 and 60 min after maximum amplitude showed no significant difference.
Conclusion
HCQ significantly reduced soluble TF levels in patients with aPL. No significant change was observed in AnxA5 activity, anti-domain 1 IgG activity, TEG, CRP, complement Bb and C3a-des-Arg, and VEGF. Further studies of a larger patient cohort are needed.
Rationale
Stable isotope analysis (SIA) can provide important insights into food web structure and is a widely used tool in ecological conservation and management. It has recently been augmented by ...compound‐specific stable isotope analysis of amino acids (CSIA‐AA), an innovation that can provide greater precision when analyzing trophic level and food web connectivity. The utility of SIA rests on confidence in its constituent parameters such as the trophic enrichment factor (TEF). There is increasing emphasis on the need to experimentally derive species and tissue specific TEFs for studies utilizing SIA. Chinook salmon, Oncorhynchus tshawytscha, is a species with high potential for study using SIA due to the difficulty in observing its ecology during its marine phase and the significance of the conservation consequences of recent population declines.
Methods
Bulk and amino acid‐specific TEFs were determined for juvenile and adult Chinook salmon fed specific diets. Three controlled feeding studies were performed: adult salmon were fed a biofeed, juvenile salmon were fed a biofeed, and juvenile salmon were fed krill. Bulk and compound‐specific stable isotope data were collected from diet samples and from salmon muscle tissue after a minimum of 8 weeks of controlled feeding. Bulk isotope signatures were measured using EA‐IRMS and CSIA‐AA signatures using GC/C‐IRMS, allowing the TEFs to be calculated.
Results
The bulk isotope TEFs were higher than those predicted for similar marine organisms and averaged 3.5‰ for ∆15N and 1.3‰ for ∆13C. The TEFs derived for nitrogen isotopes of amino acids were in line with expectations for this approach: the mean value for ∆15NGlu − ∆15NPhe was 7.06‰ and, using a multi‐AA approach, the value for ∆15NTrophic − ∆15NSource was 6.67‰. For carbon isotopes of amino acids, the derived TEFs of Iso, Leu and Phe were near 0‰, as was that of Met, supporting their use of as source amino acids in future CSIA studies.
Conclusions
This study presents Chinook salmon‐specific TEFs for bulk and amino acid SIA. It supports the application of future research applying SIA to the study of Chinook salmon and validates previous research on species‐specific TEFs.
Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may ...therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes.
A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span.
Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute base pairs (bp) and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories (“young”: 18–60 y; “middle”: 61–75 y; and “old”: >75 y), sex, and ethnicity.
Each unit increase in BMI corresponded to a −3.99 bp (95% CI: −5.17, −2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a −7.67 bp (95% CI: −10.03, −5.31 bp) difference. Each unit increase in BMI corresponded to a −1.58 × 10−3 unit T/S ratio (0.16% decrease; 95% CI: −2.14 × 10−3, −1.01 × 10−3) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a −2.58 × 10−3 unit T/S ratio (0.26% decrease; 95% CI: −3.92 × 10−3, −1.25 × 10−3). The associations were predominantly for the white pooled population. No sex differences were observed.
A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.
Human immunodeficiency virus 1 (HIV-1) infection is associated with heightened inflammation and excess risk of cardiovascular disease, cancer and other complications. These pathologies persist ...despite antiretroviral therapy. In two independent cohorts, we found that innate lymphoid cells (ILCs) were depleted in the blood and gut of people with HIV-1, even with effective antiretroviral therapy. ILC depletion was associated with neutrophil infiltration of the gut lamina propria, type 1 interferon activation, increased microbial translocation and natural killer (NK) cell skewing towards an inflammatory state, with chromatin structure and phenotype typical of WNT transcription factor TCF7-dependent memory T cells. Cytokines that are elevated during acute HIV-1 infection reproduced the ILC and NK cell abnormalities ex vivo. These results show that inflammatory cytokines associated with HIV-1 infection irreversibly disrupt ILCs. This results in loss of gut epithelial integrity, microbial translocation and memory NK cells with heightened inflammatory potential, and explains the chronic inflammation in people with HIV-1.
Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic ...neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine's polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100-12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of 'pleiotropic' variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.
Artemisone (ART) has been successfully tested
and in animal models against several diseases. However, its poor aqueous solubility and limited chemical stability are serious challenges. We developed a ...self-microemulsifying drug delivery system (SMEDDS) that overcomes these limitations. Here, we demonstrate the efficacy of this formulation against experimental cerebral malaria in mice and the impact of its administration using different routes (gavage, intranasal delivery, and parenteral injections) and frequency on the efficacy of the treatment. The minimal effective daily oral dose was 20 mg/kg. We found that splitting a dose of 20 mg/kg ART given every 24 h, by administering two doses of 10 mg/kg each every 12 h, was highly effective and gave far superior results compared to 20 mg/kg once daily. We obtained the best results with nasal treatment; oral treatment was ranked second, and the least effective route of administration was intraperitoneal injection. A complete cure of experimental cerebral malaria could be achieved through choosing the optimal route of application, dose, and dosing interval. Altogether, the developed formulation combines easy manufacturing with high stability and could be a successful and very versatile carrier for the delivery of ART in the treatment of human severe malaria.
Monkeypox virus has recently infected more than 88 000 people, raising concerns about our preparedness against this emerging viral pathogen. Licensed and approved for mpox, the JYNNEOS vaccine has ...fewer side-effects than previous smallpox vaccines and has shown immunogenicity against monkeypox in animal models. This study aims to elucidate human immune responses to JYNNEOS vaccination compared with mpox-induced immunity.
Peripheral blood mononuclear cells and sera were obtained from ten individuals vaccinated with one or two doses of JYNNEOS and six individuals diagnosed with monkeypox virus infection. Samples were obtained from seven individuals before vaccination to serve as a baseline. We examined the polyclonal serum (ELISA) and single B-cell (heavy chain gene and transcriptome data) antibody repertoires and T-cell responses (activation-induced marker and intracellular cytokine staining assays) induced by the JYNNEOS vaccine versus monkeypox virus infection.
All participants were men between the ages of 21 and 60 years, except for one woman in the group of mpox-convalescent individuals, and none had previous orthopoxvirus exposure. All mpox cases were mild. Vaccinee samples were collected 6–33 days after the first dose and 5–40 days after the second dose. Mpox-convalescent samples were collected 20–102 days after infection. In vaccine recipients, gene-level plasmablast and antibody responses were negligible and sera displayed moderate binding to recombinant orthopoxviral proteins (A29L, A35R, E8L, A30L, A27L, A33R, B18R, and L1R) and native proteins from the 2022 monkeypox outbreak strain. By contrast, recent monkeypox virus infection (within 20–102 days) induced robust serum antibody responses to monkeypox virus proteins and to native monkeypox virus proteins from a viral isolate obtained during the 2022 outbreak. JYNNEOS vaccine recipients presented robust orthopoxviral CD4+ and CD8+ T-cell responses.
Infection with monkeypox virus resulted in robust B-cell and T-cell responses, whereas immunisation with JYNNEOS elicited more robust T-cell responses. These data can help to inform vaccine design and policies for preventing mpox in humans.
National Cancer Institute (National Institutes of Health), National Institute of Allergy and Infectious Diseases (National Institutes of Health), and Icahn School of Medicine.
Purpose: In patients with septic shock and elevated lactate, there is limited evidence evaluating supplementary vasopressor use beyond vasopressin (AVP) and norepinephrine (NE). The purpose of this ...study is to describe vasopressor utilization and clinical outcomes based on lactate level. Methods: We conducted a retrospective study of patients with septic shock requiring NE. Patients were divided into 2 groups: baseline lactate level of ≥4 mmol/L (lactate group) or <4 mmol/L (control group). The primary outcome was supplementary utilization of AVP, phenylephrine (PE), epinephrine, and dopamine, in addition to background NE therapy between the 2 patient groups. Results: A total of 100 patients in each group were included. Mean baseline lactate was 7.6 mmol/L and 2.3 mmol/L in the study and control groups, respectively (P < .01). Combination therapy with NE plus AVP (55% vs 26%; P < .01), NE plus PE (26% vs 3%; P < .01), and NE, AVP, plus PE (17% vs 0%; P < .01) was more common in the lactate group. On regression analysis, lactate group was a predictor of using AVP (OR 3.0; 95% CI 1.6-5.9), PE (OR 7.5; 95% CI 2.1-26.7), and AVP plus PE (OR 11.1; 95% CI 2.5-49.7). Conclusions: In this small retrospective study, multiple vasopressor use was high in patients with severely elevated lactate. The optimal vasopressor regimen in this patient population needs further investigation.
In HIV-1-infected patients, increased numbers of circulating CD8+ T cells are linked to increased risk of morbidity and mortality. Here, we identified a bystander mechanism that promotes CD8 T cell ...activation and expansion in untreated HIV-1-infected patients. Compared with healthy controls, untreated HIV-1-infected patients have an increased population of proliferating, granzyme B+, CD8+ T cells in circulation. Vβ expression and deep sequencing of CDR3 revealed that in untreated HIV-1 infection, cycling memory CD8 T cells possess a broad T cell repertoire that reflects the repertoire of the resting population. This suggests that cycling is driven by bystander activation, rather than specific antigen exposure. Treatment of peripheral blood mononuclear cells with IL-15 induced a cycling, granzyme B+ phenotype in CD8+ T cells. Moreover, elevated IL-15 expression in the lymph nodes of untreated HIV-1-infected patients correlated with circulating CD8+ T cell counts and was normalized in these patients following antiretroviral therapy. Together, these results suggest that IL-15 drives bystander activation of CD8+ T cells, which predicts disease progression in untreated HIV-1-infected patients and suggests that elevated IL-15 may also drive CD8+ T cell expansion that is linked to increased morbidity and mortality in treated patients.
Purpose
Triple-negative breast cancer (TNBC) is an aggressive, lethal, heterogeneous type of breast cancer (BC). TNBC tends to have a lower response rate to chemotherapy and a lower 5-year survival ...rate than other types of BC due to recurrence and metastasis. Our previous study revealed that a combination of gemcitabine, romidepsin, and cisplatin was efficacious in controlling TNBC tumor development. In this study, we extended our investigation of gemcitabine + romidepsin + cisplatin in controlling TNBC tumor recurrence and metastasis.
Methods
We investigated the ability of gemcitabine + romidepsin + cisplatin to control cell survival and invasiveness using cell viability, soft agar colony formation, and transwell invasion assays. We determined the efficacy of gemcitabine + romidepsin + cisplatin in controlling tumor recurrence and metastasis using cell-derived xenograft animal models. We used immunoblotting to study signaling modulators regulated by gemcitabine + romidepsin + cisplatin in TNBC cells and tumor tissues.
Results
Treatment with gemcitabine + romidepsin + cisplatin reduced the TNBC MDA-MB231 and MDA-MB468 cell survival to ~ 50% and ~ 15%, as well as invasiveness to ~ 31% and ~ 13%, respectively. Gemcitabine + romidepsin + cisplatin suppressed modulators involved in epithelial-mesenchymal transition in an ROS-dependent manner. Controlling tumor recurrence, the Gem plus Rom + Cis regimen (~ 112%) was more efficacious than the Gem plus Cis regimen (~ 21%) in tumor growth inhibition. The Gem plus Rom + Cis regimen efficaciously reduced the development of metastatic nodules to 20% in animals.
Conclusion
The gemcitabine plus romidepsin + cisplatin regimen was highly efficacious in controlling TNBC tumor development, recurrence, and metastasis in animals. The combination regimen should be poised for efficient translation into clinical trials for controlling the recurrence and metastasis, ultimately contributing to reducing mortality and improving TNBC patients’ quality of life.
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