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1.
J Hazard Mater ; 468: 133803, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38377910

RESUMO

Micro and nanosized plastics (MNPs), and a range of associated additive chemicals, have become pervasive contaminants that humans and the environment are exposed to everyday. However, one of the principal challenges in their analysis is adequate strategies to minimise background contamination. Here a blueprint for a specialised plastics and additive-minimised clean room laboratory built for this purpose is presented. Common laboratory construction materials (n = 23) were tested, including acoustic baffles, ceiling materials, floor materials, glazing rubber, and silicone sealant. The % polymer content ranged from 2-76% w/w while the sum concentration of six phthalates ranged from 0.81 (0.73-0.86) to 21000 (15000-27000) mg/kg, assigning many of these materials as inappropriate for use in a clean room environment. The final design of the laboratory consisted of three interconnected rooms, operated under positive pressure with the inner rooms constructed almost entirely of stainless steel. Background concentrations of MNPs and phthalates in the new laboratory were compared to two Physical Containment Level 2 (PC2) laboratory environments, with concentrations of MNPs reduced by > 100 times and phthalates reduced by up to 120 times. This study reports the first known clean room of its kind and provides a blueprint for reference and use by future plastics research.

2.
EBioMedicine ; 100: 104991, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38301482

RESUMO

BACKGROUND: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10-8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") <0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) >70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. FINDINGS: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10-1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20-1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53-0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88-0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48-4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. INTERPRETATION: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. FUNDING: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias , Adulto , Humanos , Análise da Randomização Mendeliana , Risco , Neoplasias/epidemiologia , Neoplasias/genética , Inflamação/genética , Polimorfismo de Nucleotídeo Único
3.
Int J Cancer ; 154(1): 94-103, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-37578112

RESUMO

Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.


Assuntos
Neoplasias Colorretais , Eosinófilos , Humanos , Contagem de Leucócitos , Neutrófilos , Fenótipo , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Análise da Randomização Mendeliana/métodos , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único
4.
Int J Epidemiol ; 53(1)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38110618

RESUMO

BACKGROUND: The incidence of differentiated thyroid cancer (DTC) is higher in women than in men but whether sex steroid hormones contribute to this difference remains unclear. Studies of reproductive and hormonal factors and thyroid cancer risk have provided inconsistent results. METHODS: Original data from 1 252 907 women in 16 cohorts in North America, Europe, Australia and Asia were combined to evaluate associations of DTC risk with reproductive and hormonal factors. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: During follow-up, 2142 women were diagnosed with DTC. Factors associated with higher risk of DTC included younger age at menarche (<10 vs 10-11 years; HR, 1.28; 95% CI, 1.00-1.64), younger (<40; HR, 1.31; 95% CI, 1.05-1.62) and older (≥55; HR, 1.33; 95% CI, 1.05-1.68) ages at menopause (vs 40-44 years), ever use of menopausal hormone therapy (HR, 1.16; 95% CI, 1.02-1.33) and previous hysterectomy (HR, 1.25; 95% CI, 1.13-1.39) or bilateral oophorectomy (HR, 1.14; 95% CI, 1.00-1.29). Factors associated with lower risk included longer-term use (≥5 vs <5 years) of oral contraceptives (HR, 0.86; 95% CI, 0.76-0.96) among those who ever used oral contraception and baseline post-menopausal status (HR, 0.82; 95% CI, 0.70-0.96). No associations were observed for parity, duration of menopausal hormone therapy use or lifetime number of reproductive years or ovulatory cycles. CONCLUSIONS: Our study provides some evidence linking reproductive and hormonal factors with risk of DTC. Results should be interpreted cautiously considering the modest strength of the associations and potential for exposure misclassification and detection bias. Prospective studies of pre-diagnostic circulating sex steroid hormone measurements and DTC risk may provide additional insight.


Assuntos
Adenocarcinoma , Neoplasias da Glândula Tireoide , Gravidez , Masculino , Feminino , Humanos , Criança , Estudos Prospectivos , Paridade , Fatores de Risco , Estudos de Coortes , Menopausa , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/etiologia , Menarca
5.
BMC Pregnancy Childbirth ; 23(1): 841, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-38062415

RESUMO

BACKGROUND: The maternal continuum of care (CoC) (antenatal care, facility-based delivery, postnatal care) is critical to maternal and neonatal health and reducing mortality, but completion in rural areas of low- and middle-income countries is often limited. We used repeated cross-sectional household surveys from a rural Liberian county to explore changes in rates of completion of all steps and no steps in the maternal CoC after implementation of the National Community Health Assistant Program (NCHAP), a community health worker (CHW) intervention designed to increase care uptake for families over five kilometers from a facility. METHODS: We analyzed repeated cross-sectional household surveys of women aged 18-49 served by NCHAP in Rivercess County, Liberia. We measured survey-weighted, before-to-after implementation difference in completion of all steps and no steps in the maternal CoC. We used multivariable regression to explore covariates associated with completion rates before and after NCHAP implementation. RESULTS: Data from surveys conducted at three timepoints (2015, n = 354; 2018, n = 312; 2021, n = 302) were analyzed. A significant increase in completing the full maternal CoC (2015:23.6%, 2018:53.4%, change:29.7% points (pp), 95% confidence interval (CI) [21.0,38.4]) and a decrease in completing no steps in the CoC (2015:17.6%, 2018:4.0%, change: -12.4pp [-17.6, -7.2]) after implementation of NCHAP were observed from 2015 to 2018, with rates maintained from 2018 to 2021. Living farther from a facility was consistently associated with less care across the continuum. Following implementation, living in a motorbike accessible community was associated with completing the CoC while living in a mining community was negatively associated with omitting the CoC. Household wealth was associated with differences in rates pre-NCHAP but not post-NCHAP. CONCLUSIONS: Following NCHAP implementation, completion rate of the full maternal CoC in Rivercess County more than doubled while the rate of completing no steps in the continuum fell below 5%. These rates were sustained over time including during COVID-19 with reduced differences across wealth groups, although far distances remained a risk for less care. CHW programs providing active outreach to remote communities can be important tools for improving uptake of interventions and reducing risk of no formal care during and after pregnancy.

6.
Clin Cancer Res ; 2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-38127282

RESUMO

PURPOSE: Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histological appearance, these neoplasms exhibit diverse evolutionary trajectories, with a subset progressing to malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathological features and CDKN2A copy number loss. While genomic studies have uncovered key driver events promoting tumor progression, the transcriptional changes preceding malignant transformation remain poorly defined. EXPERIMENTAL DESIGN: Here we resolve gene expression profiles in PNSTs across the neurofibroma-to-MPNST continuum in NF1 patients and mouse models, revealing early molecular features associated with neurofibroma evolution and transformation. RESULTS: Our findings demonstrate that ANF exhibit enhanced signatures of antigen presentation and immune response, which are suppressed as malignant transformation ensues. MPNSTs further displayed deregulated survival and mitotic fidelity pathways, and targeting key mediators of these pathways, CENPF and BIRC5, disrupted growth and viability of human MPNST cells lines and primary murine Nf1-Cdkn2a mutant Schwann cell precursors. Finally, neurofibromas contiguous with MPNST manifested distinct alterations in core oncogenic and immune surveillance programs, suggesting that early molecular events driving disease progression may precede histopathological evidence of malignancy. CONCLUSIONS: If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathological diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.

7.
Artigo em Inglês | MEDLINE | ID: mdl-38112776

RESUMO

BACKGROUND: High red meat and/or processed meat consumption are established colorectal cancer (CRC) risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations. METHODS: A pooled sample of 29,842 CRC cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan. RESULTS: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with CRC risk (per quartile red meat OR = 1.30; 95%CI = 1.21-1.41; processed meat OR = 1.40; 95%CI = 1.20-1.63). Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95%CI = 1.29-1.46), 1.20 (95%CI = 1.12 -1.27), and 1.07 (95%CI = 0.95 - 1.19) for CC, CG and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95%CI = 1.11-1.24), 1.35 (95%CI = 1.26-1.44), and 1.46 (95%CI = 1.26-1.69) for CC, CT, and TT, respectively. CONCLUSIONS: We propose two novel biomarkers that support the role of meat consumption with an increased risk of CRC. IMPACT: The reported GxE interactions may explain the increased risk of CRC in certain population subgroups.

8.
Nat Commun ; 14(1): 6147, 2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37783704

RESUMO

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.


Assuntos
Neoplasias Colorretais , Etnicidade , Humanos , Etnicidade/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Herança Multifatorial , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética
9.
Front Microbiol ; 14: 1243818, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37808276

RESUMO

The emergence of antibiotic resistance is a growing threat to human health, and therefore, alternatives to existing compounds are urgently needed. In this context, a novel fluorescent photoactivatable diarylacetylene has been identified and characterised for its antibacterial activity, which preferentially eliminates Gram-positive over Gram-negative bacteria. Experiments confirmed that the Gram-negative lipopolysaccharide-rich outer surface is responsible for tolerance, as strains with reduced outer membrane integrity showed increased susceptibility. Additionally, bacteria deficient in oxidative damage repair pathways also displayed enhanced sensitivity, confirming that reactive oxygen species production is the mechanism of antibacterial activity. This new diarylacetylene shows promise as an antibacterial agent against Gram-positive bacteria that can be activated in situ, potentially for the treatment of skin infections.

10.
Atmos Environ X ; 313: 1-14, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37840812

RESUMO

Quantifying atmospheric loadings of total phosphorus (TP) to freshwater environments is essential to improve understanding of its fate and transport, and to mitigate the effects of excessive levels in freshwater ecosystems. To date, atmospheric deposition of TP in the U.S. is poorly characterized due to the lack of long-term deposition observations. Here, we integrate several historical datasets to develop an estimate of dry and wet deposition to the Great Lakes region. For dry deposition, we use TP concentrations in fine particulate matter (PM2.5) samples from fourteen land-based IMPROVE sites (2013-2020) upwind of the Great Lakes to provide new fine particle phosphorus dry deposition estimates. For wet deposition, we use TP concentrations in wet-only precipitation samples collected at eleven land-based sites (2001-2009) in the Great Lakes region. For both wet and dry deposition, a seasonal cycle is evident with higher concentrations in warmer and wetter months when compared to colder months. Additionally, there is an increasing gradient from north to south in wet deposition, likely driven by both higher precipitation and increased emissions near southern sites. Despite different sampling time periods, these updated observations can provide further constraints on the TP loadings to each of the five Great Lakes. We estimate annual deposition of TP to Lakes Superior, Michigan, Huron, Erie and Ontario at 526, 702, 495, 212, and 185 MTA per year, which is lower than prior estimates for Lakes Superior, Erie and Ontario, comparable for Lake Huron, and about two times greater for Lake Michigan. When considering only the contribution of fine particulate PM to the dry deposition, wet deposition dominated over dry at all lakes except for Lake Huron. However, prior global estimates suggest greater contributions from larger particles (PM10 and PM100), yet observations to validate these estimates over the Great Lakes are not available. Our findings indicate that dry deposition of a range of particle sizes are needed to constrain the total atmospheric deposition of TP over the Great Lakes.

11.
World J Clin Pediatr ; 12(4): 162-170, 2023 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-37753495

RESUMO

Investigating gastrointestinal (GI) motility disorders relies on diagnostic tools to assess muscular contractions, peristalsis propagation and the integrity and coordination of various sphincters. Manometries are the gold standard to study the GI motor function but it is increasingly acknowledged that manometries do not provide a complete picture in relation to sphincters competencies and muscle fibrosis. Endolumenal functional lumen imaging probe (EndoFLIP) an emerging technology, uses impedance planimetry to measure hollow organs cross sectional area, distensibility and compliance. It has been successfully used as a complementary tool in the assessment of the upper and lower oesophageal sphincters, oesophageal body, the pylorus and the anal canal. In this article, we aim to review the uses of EndoFLIP as a tool to investigate GI motility disorders with a special focus on paediatric practice. The majority of EndoFLIP studies were conducted in adult patients but the uptake of the technology in paediatrics is increasing. EndoFLIP can provide a useful complementary data to the existing GI motility investigation in both children and adults.

12.
Artigo em Inglês | MEDLINE | ID: mdl-37697718

RESUMO

Mineral and bone disorders (MBD) are common in patients with chronic kidney disease (CKD), contributing to significant morbidity and mortality. For several decades, the first-line approach to control hyperparathyroidism in CKD was by exogenous calcium loading. Since the turn of the millennium, however, a growing awareness of vascular calcification risk has led to a paradigm shift in management and a move away from calcium-based phosphate binders. As a consequence, contemporary CKD patients may be at risk of a negative calcium balance, which, in turn, may compromise bone health, contributing to renal bone disease and increased fracture risk. A calcium intake below a certain threshold may be as problematic as a high intake, worsening the MBD syndrome of CKD, but is not addressed in current clinical practice guidelines. The CKD-MBD and European Renal Nutrition working groups of the European Renal Association (ERA), together with the CKD-MBD and Dialysis working groups of the European Society for Pediatric Nephrology (ESPN) developed key evidence points and clinical practice points on calcium management in children and adults with CKD across stages of disease. These were reviewed by a Delphi panel consisting of ERA and ESPN working groups members. Main clinical practice points include a suggested total calcium intake from diet and medications of 800-1000 mg/d and not exceeding 1500 mg/d to maintain a neutral calcium balance in adults with CKD. In children with CKD, total calcium intake should be kept within the age-appropriate normal range. These statements provide information and may assist in decision-making, but in the absence of high-level evidence must be carefully considered and adapted to individual patient needs.

13.
Heliyon ; 9(8): e18618, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37600402

RESUMO

Rationale and objectives: Lung transplantation is a potentially life-saving treatment option for patients with idiopathic pulmonary fibrosis (IPF); however, not all eligible candidates get referred and listed for transplantation. Amongst IPF patients within the Pulmonary Fibrosis Foundation Patient Registry (PFF-R), we sought to determine the proportion of patients who undergo lung transplant listing and the characteristics associated with transplant listing. Methods: An analysis of IPF patients with at least six months of follow-up data was performed. Patients with well-established contraindications to lung transplantation were excluded. Two complementary analyses were performed. The "prevalent" population included all patients with IPF at time of enrollment into the registry. The "incident severe" population included all patients with IPF who progressed to GAP Stage 3. Results: Of the 2003 patients in the PFF-R, 475 patients were included in the "prevalent" population. Of this group, only 42 (8.8%) were either listed for or underwent lung transplant. Univariable analysis of the "prevalent" population found age (per 10 year increase, OR 0.531, p = 0.0025), percent predicted FVC (OR 0.572, p=<0.0001), percent predicted DLCO (OR 0.606, p < 0.0001), 6-min walk distance (per 50 m, OR 0.831, p = 0.019), and oxygen use at rest (OR 5.157, p < 0.0001) were predictive of listing. On multivariable analysis, age (per 10 year increase, OR 0.558, p = 0.0088), percent predicted FVC (OR 0.728, p = 0.0161), and oxygen use at rest (OR 3.264, p = 0.0029) remained significant predictors for lung transplant listing. The "incident severe" group consisted of 176 patients (8.8%). 24 patients (13.6%) from this cohort were either listed for or received a transplant. Only age (per 10 year increase, OR 0.0286, p = 0.0465) was associated with transplant listing on univariable analysis in the Incident severe population. Conclusion: Only a small proportion of potentially eligible patients with IPF are listed for lung transplantation, even when seen at pulmonary fibrosis centers of excellence. Advanced age appears to be the primary factor associated with failure to be listed. Further refinement of future registry data is required to more clearly delineate exact reasons for low rates of listing.

14.
Biomedicines ; 11(7)2023 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-37509548

RESUMO

Patients with end-stage liver disease exhibit progressive skeletal muscle atrophy, highlighting a negative crosstalk between the injured liver and muscle. Our study was to determine whether TGFß ligands function as the mediators. Acute or chronic liver injury was induced by a single or repeated administration of carbon tetrachloride. Skeletal muscle injury and repair was induced by intramuscular injection of cardiotoxin. Activin type IIB receptor (ActRIIB) ligands and growth differentiation factor 8 (Gdf8) were neutralized with ActRIIB-Fc fusion protein and a Gdf8-specific antibody, respectively. We found that acute hepatic injury induced rapid and adverse responses in muscle, which was blunted by neutralizing ActRIIB ligands. Chronic liver injury caused muscle atrophy and repair defects, which were prevented or reversed by inactivating ActRIIB ligands. Furthermore, we found that pericentral hepatocytes produce excessive Gdf8 in injured mouse liver and cirrhotic human liver. Specific inactivation of Gdf8 prevented liver injury-induced muscle atrophy, similar to neutralization of ActRIIB ligands. Inhibition of Gdf8 also reversed muscle atrophy in a treatment paradigm following chronic liver injury. Direct injection of exogenous Gdf8 protein into muscle along with acute focal muscle injury recapitulated similar dysregulated muscle regeneration as that observed with liver injury. The results indicate that injured liver negatively communicate with the muscle largely via Gdf8. Unexpectedly, inactivation of Gdf8 simultaneously ameliorated liver fibrosis in mice following chronic liver injury. In vitro, Gdf8 induced human hepatic stellate (LX-2) cells to form a septa-like structure and stimulated expression of profibrotic factors. Our findings identified Gdf8 as a novel hepatomyokine contributing to injured liver-muscle negative crosstalk along with liver injury progression.

15.
Clin Nutr ; 42(8): 1462-1474, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37321901

RESUMO

BACKGROUND & AIMS: Diet may play an essential role in the aetiology of bladder cancer (BC). Vitamin D is involved in various biological functions which have the potential to prevent BC development. Besides, vitamin D also influences the uptake of calcium and phosphorus, thereby possibly indirectly influencing the risk of BC. The aim of the present study was to investigate the relation between vitamin D intake and BC risk. METHODS: Individual dietary data were pooled from ten cohort studies. Food item intake was converted to daily intakes of vitamin D, calcium and phosphorus. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) were obtained using Cox-regression models. Analyses were adjusted for gender, age and smoking status (Model 1), and additionally for the food groups fruit, vegetables and meat (Model 2). Dose-response relationships (Model 1) were examined using a nonparametric test for trend. RESULTS: In total, 1994 cases and 518,002 non-cases were included in the analyses. The present study showed no significant associations between individual nutrient intake and BC risk. A significant decreased BC risk was observed for high vitamin D intake with moderate calcium and low phosphorus intake (Model 2: HRhigh vitD, mod Ca, low P: 0.77, 95% CI: 0.59-1.00). No significant dose-response analyses were observed. CONCLUSION: The present study showed a decreased BC risk for high dietary vitamin D intake in combination with low calcium intake and moderate phosphorus intake. The study highlights the importance of examining the effect of a nutrient in combination with complementary nutrients for risk assessment. Future research should focus on nutrients in a wider context and in nutritional patterns.


Assuntos
Fósforo na Dieta , Neoplasias da Bexiga Urinária , Humanos , Cálcio , Estudos Prospectivos , Dieta , Vitamina D , Vitaminas , Cálcio da Dieta , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/prevenção & controle , Neoplasias da Bexiga Urinária/etiologia , Estudos de Coortes , Fósforo , Fatores de Risco
16.
Cancer Epidemiol Biomarkers Prev ; 32(9): 1265-1269, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37351909

RESUMO

BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Neoplasias Pancreáticas , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Neoplasias Pancreáticas/genética , Obesidade , Polimorfismo de Nucleotídeo Único , Neoplasias Pancreáticas
17.
Cancer Epidemiol Biomarkers Prev ; 32(9): 1153-1159, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37364297

RESUMO

BACKGROUND: DEPendency of association on the number of Top Hits (DEPTH) is an approach to identify candidate susceptibility regions by considering the risk signals from overlapping groups of sequential variants across the genome. METHODS: We applied a DEPTH analysis using a sliding window of 200 SNPs to colorectal cancer data from the Colon Cancer Family Registry (CCFR; 5,735 cases and 3,688 controls), and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO; 8,865 cases and 10,285 controls) studies. A DEPTH score > 1 was used to identify candidate susceptibility regions common to both analyses. We compared DEPTH results against those from conventional genome-wide association study (GWAS) analyses of these two studies as well as against 132 published susceptibility regions. RESULTS: Initial DEPTH analysis revealed 2,622 (CCFR) and 3,686 (GECCO) candidate susceptibility regions, of which 569 were common to both studies. Bootstrapping revealed 40 and 49 candidate susceptibility regions in the CCFR and GECCO data sets, respectively. Notably, DEPTH identified at least 82 regions that would not be detected using conventional GWAS methods, nor had they been identified by previous colorectal cancer GWASs. We found four reproducible candidate susceptibility regions (2q22.2, 2q33.1, 6p21.32, 13q14.3). The highest DEPTH scores were in the human leukocyte antigen locus at 6p21 where the strongest associated SNPs were rs762216297, rs149490268, rs114741460, and rs199707618 for the CCFR data, and rs9270761 for the GECCO data. CONCLUSIONS: DEPTH can identify candidate susceptibility regions for colorectal cancer not identified using conventional analyses of larger datasets. IMPACT: DEPTH has potential as a powerful complementary tool to conventional GWAS analyses for discovering susceptibility regions within the genome.


Assuntos
Neoplasias Colorretais , Predisposição Genética para Doença , Humanos , Estudo de Associação Genômica Ampla/métodos , Fatores de Risco , Neoplasias Colorretais/genética , Neoplasias Colorretais/epidemiologia , Proteínas , Polimorfismo de Nucleotídeo Único
18.
Artigo em Inglês | MEDLINE | ID: mdl-37197257

RESUMO

Background: Gastrointestinal complaints are common in children with neurodisabilities, vomiting, retching and poor feed tolerance are frequently reported. Endolumenal functional lumen imaging probe (EndoFLIP) is used to assess compliance and distensibility of the pylorus and can predict response to Botulinum Toxin in adult with gastroparesis. We aimed to review pyloric muscle measurements using EndoFLIP in children with neuromuscular disabilities and significant foregut symptoms and to assess the clinical response to intrapyloric Botulinum Toxin. Methods: Retrospective review of clinical notes of all children who underwent pyloric EndoFLIP assessment in Evelina London Children's Hospital from March 2019 to January 2022. EndoFLIP catheter was inserted at the time of endoscopy via existing gastrostomy tract. Results: A total of 335 measurement from 12 children were obtained, mean age 10.7±4.2 years. Measurements (pre and post Botox) were obtained with 20, 30 and 40 mL balloon volume. Diameter (6.5, 6.6), (7.8, 9.4) and (10.1, 11.2), compliance (92.3, 147.9), (89.7, 142.9) and (77, 85.4) mm3/mmHg, distensibility (2.6, 3.8), (2.7, 4.4) and (2.1, 3) mm2/mmHg and balloon pressure was (13.6, 9.6), (20.9, 16.2) and (42.3, 35) mmHg. Eleven children reported clinical symptom improvement after Botulinum Toxin injection. Balloon pressure was positively correlated to diameter (r=0.63, P<0.001). Conclusions: Children with neurodisabilities who present with symptoms suggestive of poor gastric emptying do have a low pyloric distensibility and poor compliance. EndoFLIP via existing gastrostomy tract is quick and easy to perform. Intrapyloric Botulinum Toxin appears to be safe and effective in this cohort of children leading to clinical and measurements improvement.

19.
medRxiv ; 2023 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-37205426

RESUMO

Background: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,162 cancer cases and up to 824,556 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 x 10-8) cis-acting SNPs (i.e. in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") < 0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) > 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Results: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR 1.19, 95% CI 1.10-1.29, q-value=0.033, PPH4=84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR 1.42, 95% CI 1.20-1.69, q-value=0.055, PPH4=73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR 0.66, 95% CI 0.53-0.81, q-value=0.067, PPH4=81.8%), macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR 1.14, 95% CI 1.05-1.23, q-value=0.072, PPH4=76.1%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR 0.92, 95% CI 0.88-0.97, q-value=0.15), PPH4=85.6%). For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥ 0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Conclusion: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 5 circulating inflammatory markers in risk of 5 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.

20.
JAMA Neurol ; 80(6): 624-633, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37093609

RESUMO

Importance: Progressive multifocal leukoencephalopathy can occur in the context of systemic sarcoidosis (S-PML) in the absence of therapeutic immune suppression and can initially be mistaken for neurosarcoidosis or other complications of sarcoidosis. Earlier recognition of S-PML could lead to more effective treatment of the disease. Objective: To describe characteristics of patients with S-PML. Design, Setting, and Participants: For this case series, records from 8 academic medical centers in the United States were reviewed from 2004 to 2022. A systematic review of literature from 1955 to 2022 yielded data for additional patients. Included were patients with S-PML who were not receiving therapeutic immune suppression. The median follow-up time for patients who survived the acute range of illness was 19 months (range, 2-99). Data were analyzed in February 2023. Exposures: Sarcoidosis without active therapeutic immune suppression. Main Outcomes and Measures: Clinical, laboratory, and radiographic features of patients with S-PML. Results: Twenty-one patients with S-PML not receiving therapeutic immune suppression were included in this study, and data for 37 patients were collected from literature review. The median age of the 21 study patients was 56 years (range, 33-72), 4 patients (19%) were female, and 17 (81%) were male. The median age of the literature review patients was 49 years (range, 21-74); 12 of 34 patients (33%) with reported sex were female, and 22 (67%) were male. Nine of 21 study patients (43%) and 18 of 31 literature review patients (58%) had simultaneous presentation of systemic sarcoidosis and PML. Six of 14 study patients (43%) and 11 of 19 literature review patients (58%) had a CD4+ T-cell count greater than 200/µL. In 2 study patients, a systemic flare of sarcoidosis closely preceded S-PML development. Ten of 17 study patients (59%) and 21 of 35 literature review patients (60%) died during the acute phase of illness. No meaningful predictive differences were found between patients who survived S-PML and those who did not. Conclusions and Relevance: In this case series, patients with sarcoidosis developed PML in the absence of therapeutic immune suppression, and peripheral blood proxies of immune function were often only mildly abnormal. Systemic sarcoidosis flares may rarely herald the onset of S-PML. Clinicians should consider PML in any patient with sarcoidosis and new white matter lesions on brain magnetic resonance imaging.


Assuntos
Leucoencefalopatia Multifocal Progressiva , Sarcoidose , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Encéfalo/patologia , Sarcoidose/complicações , Imageamento por Ressonância Magnética , Resultado do Tratamento
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