OBJECTIVE: The objective of the study was to delineate a process in human ZG, which may regulate both aldosterone production and cell turnover.
DESIGN: This study included a comparison of 20 pairs of ZG and zona fasciculata transcriptomes from adrenals adjacent to an APA (n = 13) or a pheochromocytoma (n = 7).
INTERVENTIONS: Interventions included an overexpression of the top ZG gene (LGR5) or stimulation by its ligand (R-spondin-3).
MAIN OUTCOME MEASURES: A transcriptome profile of ZG and zona fasciculata and aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin-3-stimulated cells were measured.
RESULTS: LGR5 was the top gene up-regulated in ZG (25-fold). The gene for its cognate ligand R-spondin-3, RSPO3, was 5-fold up-regulated. In total, 18 genes associated with the Wnt pathway were greater than 2-fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by quantitative PCR and immunohistochemistry. Both R-spondin-3 stimulation and LGR5 transfection of human adrenal cells suppressed aldosterone production. There was reduced proliferation and increased apoptosis of transfected cells, and the noncanonical activator protein-1/Jun pathway was stimulated more than the canonical Wnt pathway (3-fold vs 1.3-fold). ZG of adrenal sections stained positive for apoptosis markers.
CONCLUSION: LGR5 is the most selectively expressed gene in human ZG and reduces aldosterone production and cell number. Such conditions may favor cells whose somatic mutation reverses aldosterone inhibition and cell loss.
METHODS: Eleven case-control studies within the International Pancreatic Cancer Case-control Consortium took part in the present study, including in total 2838 case and 4748 control women. Pooled estimates of odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated using a 2-step logistic regression model and adjusting for relevant covariates.
RESULTS: An inverse OR was observed in women who reported having had hysterectomy (ORyesvs.no, 0.78; 95% CI, 0.67-0.91), remaining significant in postmenopausal women and never-smoking women, adjusted for potential PC confounders. A mutually adjusted model with the joint effect for hormone replacement therapy (HRT) and hysterectomy showed significant inverse associations with PC in women who reported having had hysterectomy with HRT use (OR, 0.64; 95% CI, 0.48-0.84).
CONCLUSIONS: Our large pooled analysis suggests that women who have had a hysterectomy may have reduced risk of PC. However, we cannot rule out that the reduced risk could be due to factors or indications for having had a hysterectomy. Further investigation of risk according to HRT use and reason for hysterectomy may be necessary.
APPROACH AND RESULTS: Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E-deficient (ApoE-/-) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE-/- mice overexpressing the mitochondrial helicase Twinkle (Tw+/ApoE-/-). Tw+/ApoE-/- mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw+/ApoE-/- mice had decreased necrotic core and increased fibrous cap areas, and Tw+/ApoE-/- bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress-induced apoptosis.
CONCLUSIONS: Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen species and may be a promising therapeutic strategy in atherosclerosis.
METHODS: World Spine Care convened the GSCI to develop an evidence-based, practical, and sustainable healthcare model for spinal care. The initiative aims to improve the management, prevention, and public health for spine-related disorders worldwide; thus, global representation was essential. A series of meetings established the initiative's mission and goals. Electronic surveys collected contributorship and demographic information, and experiences with spinal conditions to better understand perceptions and potential biases that were contributing to the model of care.
RESULTS: Sixty-eight clinicians and scientists participated in the deliberations and are authors of one or more of the GSCI articles. Of these experts, 57 reported providing spine care in 34 countries, (i.e., low-, middle-, and high-income countries, as well as underserved communities in high-income countries.) The majority reported personally experiencing or having a close family member with one or more spinal concerns including: spine-related trauma or injury, spinal problems that required emergency or surgical intervention, spinal pain referred from non-spine sources, spinal deformity, spinal pathology or disease, neurological problems, and/or mild, moderate, or severe back or neck pain. There were no substantial reported conflicts of interest.
CONCLUSION: The GSCI participants have broad professional experience and wide international distribution with no discipline dominating the deliberations. The GSCI believes this set of papers has the potential to inform and improve spine care globally. These slides can be retrieved under Electronic Supplementary Material.
METHODS: The Global Spine Care Initiative (GSCI) meetings and literature reviews were synthesized into a seed document and distributed to spine care experts. After three rounds of a modified Delphi process, all participants reached consensus on the final model of care and implementation steps.
RESULTS: Sixty-six experts representing 24 countries participated. The GSCI model of care has eight core principles: person-centered, people-centered, biopsychosocial, proactive, evidence-based, integrative, collaborative, and self-sustaining. The model of care includes a classification system and care pathway, levels of care, and a focus on the patient's journey. The six steps for implementation are initiation and preparation; assessment of the current situation; planning and designing solutions; implementation; assessment and evaluation of program; and sustain program and scale up.
CONCLUSION: The GSCI proposes an evidence-based, practical, sustainable, and scalable model of care representing eight core principles with a six-step implementation plan. The aim of this model is to help transform spine care globally, especially in low- and middle-income countries and underserved communities. These slides can be retrieved under Electronic Supplementary Material.
METHODS: Leading spine clinicians and scientists around the world were invited to participate. The interprofessional, international team consisted of 68 members from 24 countries, representing most disciplines that study or care for patients with spinal symptoms, including family physicians, spine surgeons, rheumatologists, chiropractors, physical therapists, epidemiologists, research methodologists, and other stakeholders.
RESULTS: Literature reviews on the burden of spinal disorders and six categories of evidence-based interventions for spinal disorders (assessment, public health, psychosocial, noninvasive, invasive, and the management of osteoporosis) were completed. In addition, participants developed a stratification system for surgical intervention, a classification system for spinal disorders, an evidence-based care pathway, and lists of resources and recommendations to implement the GSCI model of care.
CONCLUSION: The GSCI proposes an evidence-based model that is consistent with recent calls for action to reduce the global burden of spinal disorders. The model requires testing to determine feasibility. If it proves to be implementable, this model holds great promise to reduce the tremendous global burden of spinal disorders. These slides can be retrieved under Electronic Supplementary Material.
METHODS: The Global Spine Care Initiative (GSCI) care pathway development team extracted interventions recommended for the management of spinal disorders from six GSCI articles that synthesized the available evidence from guidelines and relevant literature. Sixty-eight international and interprofessional clinicians and scientists with expertise in spine-related conditions were invited to participate. An iterative consensus process was used.
RESULTS: After three rounds of review, 46 experts from 16 countries reached consensus for the care pathway that includes five decision steps: awareness, initial triage, provider assessment, interventions (e.g., non-invasive treatment; invasive treatment; psychological and social intervention; prevention and public health; specialty care and interprofessional management), and outcomes. The care pathway can be used to guide the management of patients with any spine-related concern (e.g., back and neck pain, deformity, spinal injury, neurological conditions, pathology, spinal diseases). The pathway is simple and can be incorporated into educational tools, decision-making trees, and electronic medical records.
CONCLUSION: A care pathway for the management of individuals presenting with spine-related concerns includes evidence-based recommendations to guide health care providers in the management of common spinal disorders. The proposed pathway is person-centered and evidence-based. The acceptability and utility of this care pathway will need to be evaluated in various communities, especially in low- and middle-income countries, with different cultural background and resources. These slides can be retrieved under Electronic Supplementary Material.
METHODS: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided.
RESULTS: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets.
CONCLUSION: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
METHODS: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics.
RESULTS: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10-6) was observed in the meta-analysis (P GxE = 1.2 ×10-6, P Joint = 4.2 ×10-7).
CONCLUSIONS: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans.
IMPACT: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.