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- Mishra, A, et al.
(författare)
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Diminishing benefits of urban living for children and adolescents' growth and development
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7954, s. 874-883
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Tidskriftsartikel (refereegranskat)abstract
- Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.
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- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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- Dutta, D, et al.
(författare)
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Nuclear transparency with the gamma n ->pi(-)p process in He-4
- 2003
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 68:2: 021001
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Tidskriftsartikel (refereegranskat)abstract
- We have measured the nuclear transparency of the fundamental process gamman-->pi(-)p in He-4. These measurements were performed at Jefferson Lab in the photon energy range of 1.6-4.5 GeV and at theta(cm)(pi)=70degrees and 90degrees. These measurements are the first of their kind in the study of nuclear transparency in photoreactions. They also provide a benchmark test of Glauber calculations based on traditional models of nuclear physics. The transparency results suggest deviations from the traditional nuclear physics picture. The momentum transfer dependence of the measured nuclear transparency is consistent with Glauber calculations that include the quantum chromodynamics phenomenon of color transparency.
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- Wang, Y, et al.
(författare)
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Wnt/beta-catenin signaling confers ferroptosis resistance by targeting GPX4 in gastric cancer
- 2022
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Ingår i: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1476-5403 .- 1350-9047. ; 29:11, s. 2190-2202
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Tidskriftsartikel (refereegranskat)abstract
- The development of chemotherapy resistance is the most vital obstacle to clinical efficacy in gastric cancer (GC). The dysregulation of the Wnt/beta-catenin signaling pathway is critically associated with GC development and chemotherapy resistance. Ferroptosis is a form of regulated cell death, induced by an iron-dependent accumulation of lipid peroxides during chemotherapy. However, whether the Wnt/beta-catenin signaling directly controls resistance to cell death, remains unclear. Here, we show that the activation of the Wnt/beta-catenin signaling attenuates cellular lipid ROS production and subsequently inhibits ferroptosis in GC cells. The beta-catenin/TCF4 transcription complex directly binds to the promoter region of GPX4 and induces its expression, resulting in the suppression of ferroptotic cell death. Concordantly, TCF4 deficiency promotes cisplatin-induced ferroptosis in vitro and in vivo. Thus, we demonstrate that the aberrant activation of the Wnt/beta-catenin signaling confers ferroptosis resistance and suggests a potential therapeutic strategy to enhance chemo-sensitivity for advanced GC patients.
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- Zeng, DQ, et al.
(författare)
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Immunosuppressive Microenvironment Revealed by Immune Cell Landscape in Pre-metastatic Liver of Colorectal Cancer
- 2021
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 11, s. 620688-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Colorectal cancer, the fourth leading cause of cancer mortality, is prone to metastasis, especially to the liver. The pre-metastatic microenvironment comprising various resident stromal cells and immune cells is essential for metastasis. However, how the dynamic evolution of immune components facilitates pre-metastatic niche formation remains unclear.Methods: Utilizing RNA-seq data from our orthotopic colorectal cancer mouse model, we applied single sample gene set enrichment analysis and Cell type Identification By Estimating Relative Subsets Of RNA Transcripts to investigate the tumor microenvironment landscape of pre-metastatic liver, and define the exact role of myeloid-derived suppressor cells (MDSCs) acting in the regulation of infiltrating immune cells and gene pathways activation. Flow cytometry analysis was conducted to quantify the MDSCs levels in human and mice samples.Results: In the current work, based on the high-throughput transcriptome data, we depicted the immune cell infiltration pattern of pre-metastatic liver and highlighted MDSCs as the dominant altered cell type. Notably, flow cytometry analysis showed that high frequencies of MDSCs, was detected in the pre-metastatic liver of orthotopic colorectal cancer tumor-bearing mice, and in the peripheral blood of patients with stage I–III colorectal cancer. MDSCs accumulation in the liver drove immunosuppressive factors secretion and immune checkpoint score upregulation, consequently shaping the pre-metastatic niche with sustained immune suppression. Metabolic reprogramming such as upregulated glycolysis/gluconeogenesis and HIF-1 signaling pathways in the primary tumor was also demonstrated to correlate with MDSCs infiltration in the pre-metastatic liver. Some chemokines were identified as a potential mechanism for MDSCs recruitment.Conclusion: Collectively, our study elucidates the alterations of MDSCs during pre-metastatic niche transformation, and illuminates the latent biological mechanism by which primary tumors impact MDSC aggregation in the targeted liver.
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- Zeng, DQ, et al.
(författare)
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Tumor microenvironment evaluation promotes precise checkpoint immunotherapy of advanced gastric cancer
- 2021
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Ingår i: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- Durable efficacy of immune checkpoint blockade (ICB) occurred in a small number of patients with metastatic gastric cancer (mGC) and the determinant biomarker of response to ICB remains unclear.MethodsWe developed an open-source TMEscore R package, to quantify the tumor microenvironment (TME) to aid in addressing this dilemma. Two advanced gastric cancer cohorts (RNAseq, N=45 and NanoString, N=48) and other advanced cancer (N=534) treated with ICB were leveraged to investigate the predictive value of TMEscore. Simultaneously, multi-omics data from The Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD) and Asian Cancer Research Group (ACRG) were interrogated for underlying mechanisms.ResultsThe predictive capacity of TMEscore was corroborated in patient with mGC cohorts treated with pembrolizumab in a prospective phase 2 clinical trial (NCT02589496, N=45, area under the curve (AUC)=0.891). Notably, TMEscore, which has a larger AUC than programmed death-ligand 1 combined positive score, tumor mutation burden, microsatellite instability, and Epstein-Barr virus, was also validated in the multicenter advanced gastric cancer cohort using NanoString technology (N=48, AUC=0.877). Exploration of the intrinsic mechanisms of TMEscore with TCGA and ACRG multi-omics data identified TME pertinent mechanisms including mutations, metabolism pathways, and epigenetic features.ConclusionsCurrent study highlighted the promising predictive value of TMEscore for patients with mGC. Exploration of TME in multi-omics gastric cancer data may provide the impetus for precision immunotherapy.
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| 42. |
- Zhang, J, et al.
(författare)
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Inhibition of miR-1193 leads to synthetic lethality in glioblastoma multiforme cells deficient of DNA-PKcs
- 2020
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:7, s. 602-
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is the most malignant primary brain tumor and has the highest mortality rate among cancers and high resistance to radiation and cytotoxic chemotherapy. Although some targeted therapies can partially inhibit oncogenic mutation-driven proliferation of GBM cells, therapies harnessing synthetic lethality are ‘coincidental’ treatments with high effectiveness in cancers with gene mutations, such as GBM, which frequently exhibits DNA-PKcs mutation. By implementing a highly efficient high-throughput screening (HTS) platform using an in-house-constructed genome-wide human microRNA inhibitor library, we demonstrated that miR-1193 inhibition sensitized GBM tumor cells with DNA-PKcs deficiency. Furthermore, we found that miR-1193 directly targets YY1AP1, leading to subsequent inhibition of FEN1, an important factor in DNA damage repair. Inhibition of miR-1193 resulted in accumulation of DNA double-strand breaks and thus increased genomic instability. RPA-coated ssDNA structures enhanced ATR checkpoint kinase activity, subsequently activating the CHK1/p53/apoptosis axis. These data provide a preclinical theory for the application of miR-1193 inhibition as a potential synthetic lethal approach targeting GBM cancer cells with DNA-PKcs deficiency.
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- Zhu, LY, et al.
(författare)
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Cross-section measurement of charged-pion photoproduction from hydrogen and deuterium
- 2003
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Ingår i: Physical Review Letters. - 1079-7114. ; 91:2: 022003
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Tidskriftsartikel (refereegranskat)abstract
- We have measured the differential cross section for the gamman-->pi(-)p and gammap-->pi(+)n reactions at theta(c.m.)=90degrees in the photon energy range from 1.1 to 5.5 GeV at Jefferson Lab (JLab). The data at E(gamma)greater than or similar to3.3 GeV exhibit a global scaling behavior for both pi(-) and pi(+) photoproduction, consistent with the constituent counting rule and the existing pi(+) photoproduction data. Possible oscillations around the scaling value are suggested by these new data. The data show enhancement in the scaled cross section at a center-of-mass energy near 2.2 GeV. The cross section ratio of exclusive pi(-) to pi(+) photoproduction at high energy is consistent with the prediction based on one-hard-gluon-exchange diagrams.
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