Objective
To determine whether antihypertensives will affect diagnostic accuracy of the aldosterone-to-renin ratio (ARR) to an extent that is clinically relevant.
Methods
Confirmatory tests were used ...to confirm or exclude PA diagnosis. Area under the receiver operating characteristic curve (AUC), specificity and sensitivity of ARR performance in different conditions were calculated.
Results
208 PA and 78 essential hypertension (EH), and 125 PA and 206 EH patients, were included in the retrospective and prospective cohort, respectively. AUC of ARR on interfering medications was comparable to ARR off interfering medications (retrospective: 0.82 vs. 0.87,
p
= 0.20; prospective: 0.78 vs. 0.84,
p
= 0.07). At a threshold of 20 pg/μIU, the sensitivity of ARR on interfering medications was lower (11.1–23.2%) while the specificity was higher (10.2–15.2%) than ARR off interfering medications. However, when the ARR threshold on interfering medications was lowered to 10 pg/μIU, both the sensitivity (retrospective: 0.91 vs. 0.90,
p
= 0.61; prospective: 0.86 vs. 0.82,
p
= 0.39) and specificity (retrospective: 0.49 vs. 0.59,
p
= 0.20; prospective: 0.58 vs. 0.66,
p
= 0.10) were comparable to the ARR threshold off interfering medications.
Conclusion
Using ARR to screen for PA whilst taking interfering antihypertensive drugs is feasible in most cases, but the ARR threshold needs to be reduced.
Trial registration
ClinicalTrials.gov identifier: NCT04991961.
Temporal lobe epilepsy (TLE) is one of the most drug-resistant types of epilepsy with about 80% of TLE patients falling into this category. Increasing evidence suggests that neuroinflammation, which ...has a critical role in the epileptogenesis of TLE, is associated with microglial activation. Therefore, agents that act toward the alleviation in microglial activation and the attenuation of neuroinflammation are promising candidates to treat TLE. α-Asarone is a major active ingredient of the Acori Graminei Rhizoma used in Traditional Chinese Medicine, which has been used to improve various disease conditions including stroke and convulsions. In addition, an increasing number of studies suggested that α-asarone can attenuate microglia-mediated neuroinflammation. Thus, we hypothesized that α-asarone is a promising neuroprotective agent for the treatment of the TLE.
The present study evaluated the therapeutic effects of α-asarone on microglia-mediated neuroinflammation and neuroprotection
and
, using an untreated control group, a status epilepticus (SE)-induced group, and an SE-induced α-asarone pretreated group. A pilocarpine-induced rat model of TLE was established to investigate the neuroprotective effects of α-asarone
. For the
study, lipopolysaccharide (LPS)-stimulated primary cultured microglial cells were used.
The results indicated that the brain microglial activation in the rats of the SE rat model led to important learning and memory deficit. Preventive treatment with α-asarone restrained microglial activation and reduced learning and memory deficit. In the
studies, α-asarone significantly suppressed proinflammatory cytokine production in primary cultured microglial cells and attenuated the LPS-stimulated neuroinflammatory responses. Our mechanistic study revealed that α-asarone inhibited inflammatory processes by regulation the transcription levels of kappa-B, by blocking the degradation pathway of kappa B-alpha inhibitor kappa B-alpha (IκB-α) and kappa B-beta (IκB-β) kinase in both the SE rats and in primary cultured microglial cells.
Taken together, these data demonstrate that α-asarone is a promising neuroprotective agent for the prevention and treatment of microglia-mediated neuroinflammatory conditions including TLE, for which further assessment studies are pertinent.
At the 75th session of the United Nations General Assembly, China formally proposed the goal of achieving carbon peak by 2030 and carbon neutrality by 2060, which is called the dual-carbon strategy. ...In this study, we incorporated the dual-carbon strategy perspective into ecological product value (EPV) evaluation. The EPV is the sum of the final product and service value provided by regional ecosystems for human production and life. A significant uncertainty exists in evaluating the EPV. To bridge this gap, we explored the quantitative evaluation index system of EPV based on the dual-carbon perspective and conducted an empirical analysis relating to four subindexes (ecological protection, ecological products carbon neutral capacity transformation, ecological value, and ecological product value realization safeguard mechanism). The EPV in nine provinces of the Yellow River basin in 2020 was measured. The results showed that the total evaluation score of EPV realization in the Yellow River basin was relatively low, and the average scores of ecological product protection level, carbon neutrality capacity, value transformation level, and value realization guarantee mechanism were all at a low level. Overall, the protection level of ecological products and the guarantee mechanism to realize the EPV were relatively good. However, the carbon neutrality capacity and the value transformation level were relatively poor. From the spatial perspective, the value realization level of ecological products was roughly upstream region > downstream region > midstream region in the Yellow River basin. Finally, corresponding countermeasures and suggestions are put forward according to the comprehensive evaluation index of EPV realization and analysis of the four subindexes.
The rapid spread of carbapenemase-producing Klebsiella pneumoniae (cpKP) poses serious threats to public health; however, the underlying genetic basis for its dissemination is still unknown. We ...conducted a comprehensive genomic epidemiology analysis on 420 cpKP isolates collected from 70 hospitals in 24 provinces/autonomous regions/municipalities of China during 2009–2017 by short-/long-read sequencing. The results showed that most cpKP isolates were categorized into clonal group 258 (CG258), in which ST11 was the dominant clone. Phylogenetic analysis revealed three major clades including the top one of Clade 3 for CG258 cpKP isolates. Additionally, carbapenemase gene analysis indicated that blaKPC was dominant in the cpKP isolates, and most blaKPC genes were located in five major incompatibility (Inc) groups of blaKPC-harboring plasmids. Importantly, three advantageous combinations of host–blaKPC-carrying plasmid (Clade 3.1+3.2–IncFIIpHN7A8, Clade 3.1+3.2–IncFIIpHN7A8:IncR, and Clade 3.3–IncFIIpHN7A8:IncpA1763-KPC) were identified to confer cpKP isolates the advantages in both genotypes (strong correlation/coevolution) and phenotypes (resistance/growth/competition) to facilitate the nationwide spread of ST11/CG258 cpKP. Intriguingly, Bayesian skyline analysis illustrated that the three advantageous combinations might be directly associated with the strong population expansion during 2007–2008 and subsequent maintenance of the population of ST11/CG258 cpKP after 2008. We then examined drug resistance profiles of these cpKP isolates and proposed combination treatment regimens for CG258/non-CG258 cpKP infections. Thus, the findings of our systematical analysis shed light on the molecular epidemiology and genetic basis for the dissemination of ST11/CG258 cpKP in China, and much emphasis should be given to the close monitoring of advantageous cpKP–plasmid combinations.
High-grade serous ovarian carcinoma (HGS-OvCa) has the lowest survival rate among all gynecologic cancers and is hallmarked by a high degree of heterogeneity. The Cancer Genome Atlas network has ...described a gene expression-based molecular classification of HGS-OvCa into Differentiated, Mesenchymal, Immunoreactive and Proliferative subtypes. However, the biological underpinnings and regulatory mechanisms underlying the distinct molecular subtypes are largely unknown. Here we showed that tumor-infiltrating stromal cells significantly contributed to the assignments of Mesenchymal and Immunoreactive clusters. Using reverse engineering and an unbiased interrogation of subtype regulatory networks, we identified the transcriptional modules containing master regulators that drive gene expression of Mesenchymal and Immunoreactive HGS-OvCa. Mesenchymal master regulators were associated with poor prognosis, while Immunoreactive master regulators positively correlated with overall survival. Meta-analysis of 749 HGS-OvCa expression profiles confirmed that master regulators as a prognostic signature were able to predict patient outcome. Our data unraveled master regulatory programs of HGS-OvCa subtypes with prognostic and potentially therapeutic relevance, and suggested that the unique transcriptional and clinical characteristics of ovarian Mesenchymal and Immunoreactive subtypes could be, at least partially, ascribed to tumor microenvironment.
BackgroundLung squamous cell carcinoma (LUSC) remains a leading cause of cancer-related deaths with few therapeutic strategies. Immune checkpoint inhibitors (ICIs) have demonstrated promising ...efficacy in patients with LUSC. However, ICIs could also lead to a unique spectrum of immune-related adverse events (irAEs), which dampen the clinical outcome. In-depth characterization of the immune hallmarks of antitumor responses and irAEs remains an unmet need to maximize ICI-treatment benefits of patients.MethodsWe performed single-cell RNA sequencing (scRNA-seq) on pre-ICI and on-ICI treatment tumor biopsies. We used bulk RNA-seq data of matched pretreatment/on-treatment tumors and irAE affected organs to validate observations from scRNA-seq analysis. Two independent patient cohorts were collected to determine circulating tumor necrosis factor (TNF) protein expression levels.ResultsWe found that increased proportions of a macrophage subcluster with highly expressed secreted phosphoprotein 1 (SPP1) and two tumor cell subclusters in irAE patients, whereas proportions of two cytotoxic CD8+ T cell subclusters were higher in patients with partial response (PR). TNF signaling pathway was conversely associated with treatment efficacy and irAE development in most macrophage and tumor cell subclusters. Cell–cell communications for TNF ligand-receptor pairs between macrophage/T cells and tumor cells were also bidirectionally remodeled in responders versus non-responders and irAE versus non-irAE patients. Bulk RNA-seq analysis on matched pretreatment/on-treatment tumors and irAE affected organs revealed remarkably enhanced macrophage abundance and TNF signaling pathway in on-treatment tumors and organs developed irAEs. Furthermore, we observed significantly increased circulating TNF protein in plasma or serum of irAE patients but not ICI responders, based on analysis of two independent LUSC patient cohorts and one published ICI patient cohort.ConclusionsOur data depicts specific reprogramming of macrophage, T cells and tumor cells associated with ICI response and irAEs, elucidates divergent roles of TNF signaling in antitumor immunity and irAEs, and highlights the significance of TNF expression in irAE development in the LUSC setting.
Sarcopenia, a skeletal muscle disorder in which loss of muscle mass and function progresses with age, is associated with increased overall frailty, risk of falling and mortality in the elders. Here, ...we reveal that SESN1 safeguards skeletal muscle from ageing downstream of the longevity gene FOXO3, which we recently reported is a geroprotector in primate skeletal muscle. Knockdown of SESN1 mimicked the human myotube ageing phenotypes observed in the FOXO3‐deficient human myotubes, whereas genetic activation of SESN1 alleviated human myotube senescence. Of note, SESN1 was identified as a protective secretory factor against muscle atrophy. Administration of recombinant SESN1 protein attenuated senescence of human myotubes in vitro and facilitated muscle regeneration in vivo. Altogether, we unveil a key role of SESN1 downstream of FOXO3 in protecting skeletal muscle from ageing, providing diagnostic biomarkers and intervention strategies for counteracting skeletal muscle ageing and related diseases.
Here, we reveal that SESN1 safeguards skeletal muscle from ageing downstream of the longevity gene FOXO3, which we recently reported is a geroprotector in primate skeletal muscle. Notably, SESN1 levels were reduced in the serum of elderly human individuals, implying that SESN1 could function as a potent circulating biomarker to predict progressive skeletal muscle atrophy. More importantly, we propose that recombinant SESN1 protein may have potential as a therapeutic agent capable of attenuating myofibre senescence and promoting muscle regeneration.
In this paper, cobalt tetraaminophthalocyanine （CoPc） was successfully deposited onto a carbon nanotubes modified electrode by consecutive cyclic scanning in supporting electrolyte containing CoPc to ...form phthalocyanine-containing chemically modified electrode. The electrochemistry of sulfadiazine was studied by voltammetric method and flow injection analysis at the new modified electrode. Compared with glassy carbon electrode, the new modified electrode exhibited exciting performance including low oxidation potential, high current response and promising flow injection response.
ABSTRACT
Cell wall is the first physical barrier to aluminum (Al) toxicity. Modification of cell wall properties to change its binding capacity to Al is one of the major strategies for plant Al ...resistance; nevertheless, how it is regulated in rice remains largely unknown. In this study, we show that exogenous application of putrescines (Put) could significantly restore the Al resistance of art1, a rice mutant lacking the central regulator Al RESISTANCE TRANSCRIPTION FACTOR 1 (ART1), and reduce its Al accumulation particularly in the cell wall of root tips. Based on RNA‐sequencing, yeast‐one‐hybrid and electrophoresis mobility shift assays, we identified an R2R3 MYB transcription factor OsMYB30 as the novel target in both ART1‐dependent and Put‐promoted Al resistance. Furthermore, transient dual‐luciferase assay showed that ART1 directly inhibited the expression of OsMYB30, and in turn repressed Os4CL5‐dependent 4‐coumaric acid accumulation, hence reducing the Al‐binding capacity of cell wall and enhancing Al resistance. Additionally, Put repressed OsMYB30 expression by eliminating Al‐induced H2O2 accumulation, while exogenous H2O2 promoted OsMYB30 expression. We concluded that ART1 confers Put‐promoted Al resistance via repression of OsMYB30‐regulated modification of cell wall properties in rice.
Aluminum (Al) RESISTANCE TRANSCRIPTION FACTOR 1 represses the transcription factor gene OsMYB30, which is indirectly repressed by putrescines via eliminating Al‐induced H2O2 accumulation. OsMYB30 repression down‐regulates the 4‐coumarate:coenzyme a gene Os4CL5, increasing 4‐coumaric acid levels, which reduce Al bound to the cell wall and thus enhance rice Al resistance.
The emergence of immune checkpoint inhibitors (ICIs) has heralded a transformative era in the therapeutic landscape of non‐small cell lung cancer (NSCLC). While ICIs have demonstrated clinical ...efficacy in a portion of patients with NSCLC, these treatments concurrently precipitate a spectrum of immune‐related adverse events (irAEs), encompassing mild to severe manifestations, collectively posing a risk of significant organ damage. Consequently, there exists an imperative to augment our comprehension of the pathophysiological underpinnings of irAEs and to formulate more efficacious preventive and ameliorative strategies. In this comprehensive review, we delineate the clinical presentation of organ‐specific irAEs in patients with NSCLC and provide an in‐depth analysis of recent advancements in understanding the mechanisms driving ICI‐induced toxicity. Furthermore, we discuss potential strategies and targets for ameliorating these irAEs. Ultimately, this review aims to furnish valuable insights to guide further research endeavours in the context of irAEs in NSCLC patients.
Immunotherapy not only revolutionises lung cancer treatment but also poses serious toxicity risks.
Elucidating irAE mechanisms in NSCLC: T/B‐cell dysregulation, cytokine imbalances, autoantibody production, genetic predispositions and gut microbiome alterations.
Highlighting precise irAE interventions in NSCLC: corticosteroids, targeted immunosuppressants, monoclonal antibodies targeting lymphocytes, cytokine inhibitors and signalling pathway modulators.
PDF
