Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to ...allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.
Allogeneic hematopoietic cell transplantation is increasingly utilized in older adults. This study prospectively evaluated the prognostic utility of geriatric assessment domains prior to allogeneic ...transplantation in recipients aged 50 years and over. Geriatric assessment was performed prior to transplant, and included validated measures across domains of function and disability, comorbidity, frailty, mental health, nutritional status, and systemic inflammation. A total of 203 patients completed geriatric assessment and underwent transplant. Median age was 58 years (range 50-73). After adjusting for established prognostic factors, limitations in instrumental activities of daily living (HR 2.38, 95%CI: 1.59-3.56; P<0.001), slow walk speed (HR 1.80, 95%CI: 1.14-2.83; P=0.01), high comorbidity by hematopoietic cell transplantation-specific comorbidity index (HR 1.56, 95%CI: 1.07-2.28; P=0.02), low mental health by short-form-36 mental component summary (HR 1.67, 95%CI: 1.13-2.48; P=0.01), and elevated serum C-reactive protein (HR 2.51, 95%CI: 1.54-4.09; P<0.001) were significantly associated with inferior overall survival. These associations were more pronounced in the cohort 60 years and over. Geriatric assessment measures confer independent prognostic utility in older allogeneic transplant recipients. Implementation of geriatric assessment prior to allogeneic transplantation may aid appropriate selection of older adults.
To determine genomic alterations in head and neck squamous cell carcinoma (HNSCC) using formalin-fixed, paraffin-embedded (FFPE) tumors obtained through routine clinical practice, selected ...cancer-related genes were evaluated and compared with alterations seen in frozen tumors obtained through research studies.
DNA samples obtained from 252 FFPE HNSCC were analyzed using next-generation sequencing-based (NGS) clinical assay to determine sequence and copy number variations in 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. Human papillomavirus (HPV) status was determined by presence of the HPV DNA sequence in all samples and corroborated with high-risk HPV in situ hybridization (ISH) and p16 immunohistochemical (IHC) staining in a subset of tumors. Sequencing data from 399 frozen tumors in The Cancer Genome Atlas and University of Chicago public datasets were analyzed for comparison.
Among 252 FFPE HNSCC, 84 (33%) were HPV positive and 168 (67%) were HPV negative by sequencing. A subset of 40 tumors with HPV ISH and p16 IHC results showed complete concordance with NGS-derived HPV status. The most common genes with genomic alterations were PIK3CA and PTEN in HPV-positive tumors and TP53 and CDKN2A/B in HPV-negative tumors. In the pathway analysis, the PI3K pathway in HPV-positive tumors and DNA repair-p53 and cell cycle pathways in HPV-negative tumors were frequently altered. The HPV-positive oropharynx and HPV-positive nasal cavity/paranasal sinus carcinoma shared similar mutational profiles.
The genomic profile of FFPE HNSCC tumors obtained through routine clinical practice is comparable with frozen tumors studied in research setting, demonstrating the feasibility of comprehensive genomic profiling in a clinical setting. However, the clinical significance of these genomic alterations requires further investigation through application of these genomic profiles as integral biomarkers in clinical trials.
The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and ...environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC.
We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR.
We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors—such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin—higher alcohol drinking, and lower education attainment with increased EOCRC risk.
Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.
•We conducted GWAS and MR analyses to identify the causes of EOCRC.•We identified two novel risk loci specific to EOCRC and confirmed the involvement of several known CRC risk variants in EOCRC.•We also identified new EOCRC risk genes and highlighted the prominent role of pathways such as insulin signaling in EOCRC.•We identified probable causal associations for body size, fasting insulin, alcohol intake, and educational level with EOCRC.
Urbanisation critically alters wildlife habitat and resource distribution, leading to shifts in trophic dynamics. The loss of apex predators in human-transformed landscapes can result in changes in ...the ecological roles of the remaining mesocarnivores. Decreased top-down control together with increased bottom-up forcing through greater availability of anthropogenic foods can result in a predation paradox. Understanding these changes is important for conserving ecological function and biodiversity in rapidly urbanising systems. Here, we use stable isotope analysis to provide insight into longer term changes in trophic position, niche width and overlap of an elusive, medium-sized urban adapter, the caracal (Caracal caracal) in and around the city of Cape Town, South Africa. Using fur samples (n = 168) from individuals along a gradient of urbanisation we find that overall caracals have a broad isotopic dietary niche that reflects their large variation in resource use. When accounting for underlying environmental differences, the intensity of anthropogenic pressure, measured using the Human Footprint Index (HFI), explained variation in both food subsidy use (δ
C values) and trophic status (δ
N values). The significantly higher δ
C values (P < 0.01) and lower δ
N values (P < 0.001) of caracals in more urbanised areas suggest that predator subsidy consumption occurs via predictable, anthropogenic resource subsidies to synanthropic prey. These prey species are predominantly primary consumers, resulting in shifts in diet composition towards lower trophic levels. Further, caracals using areas with higher HFI had narrower isotope niches than those in less impacted areas, likely due to their hyperfocus on a few lower trophic level prey species. This pattern of niche contraction in urban areas is retained when accounting for caracal demographics, including sex and age. The removal of apex predators in human-transformed landscapes together with reliable resource availability, including abundant prey, may paradoxically limit the ecological influence of the remaining predators, and bring about a degree of predator trophic downgrading. The dampening of top-down control, and thus ecosystem regulation, likely points to widespread disruption of trophic dynamics in rapidly developing areas globally.
Context:
Bone mass is low and fracture risk is higher in obese children. Hormonal changes in relation to skeletal microstructure and biomechanics have not been studied in obese children.
Objective:
...The objective of the study was to ascertain the relationships of obesity-related changes in hormones with skeletal microstructure and biomechanics.
Design:
High resolution peripheral quantitative computed tomography (HR-pQCT) was used to compare three-dimensional cortical and trabecular microstructure and biomechanics at load-bearing and nonload bearing sites in obese and lean children. The relationship between leptin, adiponectin, testosterone, estrogen, osteocalcin and sclerostin and skeletal microstructure was also determined.
Setting:
The study was conducted at a tertiary pediatric endocrine unit in the United Kingdom.
Participants:
Obese and lean children were matched by gender and pubertal stage.
Results:
Radial cortical porosity (mean difference −0.01 95% CI: −0.02, −0.004, P = .003) and cortical pore diameter (mean difference −0.005 mm 95% CI: −0.009, −0.001, P = .011) were lower in obese children. Tibial trabecular thickness was lower (mean difference −0.009 mm 95% CI: −0.014, −0.004, P = .003), and trabecular number was higher (mean difference 0.23 mm−1 95% CI: 0.08, 0.38, P = .004) in obese children. At the radius, fat mass percentage negatively correlated with cortical porosity (r = −0.57, P < .001) and pore diameter (r = −0.38, P = .02) and negatively correlated with trabecular thickness (r = −0.62, P < .001) and trabecular von Mises stress (r = −0.39, P = .019) at the tibia. No difference was observed in the other biomechanical parameters of the radius and tibia. Leptin was higher in obese children (805.3 ± 440.6 pg/ml vs 98.1 ± 75.4 pg/ml, P < .001) and was inversely related to radial cortical porosity (r = 0.60, 95% CI: −0.80, −0.30, P < .001), radial cortical pore diameter (r = 0.51, 95% CI −0.75, −0.16, P = .002), tibial trabecular thickness (r = 0.55, 95% CI: −0.78, −0.21, P = .001) and tibial trabecular von Mises stress (r = −0.39, 95% CI: −0.65, 0.04, P = .02).
Conclusion:
Childhood obesity alters radial and tibial microstructure. Leptin may direct these changes. Despite this, the biomechanical properties of the radius and tibia do not adapt sufficiently in obese children to withstand the increased loading potential from a fall. This may explain the higher incidence of fracture in obese children.
Background Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation ...characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. Methods We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. Results Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 95% confidence interval = 3.60 to 9.46 vs 2.25 95% confidence interval = 1.44 to 3.52; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10−6 ≤ P ≤ .02). Conclusion Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.
Background Melanoma risk is related to sun exposure; we have investigated risk variation by tumour site and latitude. Methods We performed a pooled analysis of 15 case–control studies (5700 melanoma ...cases and 7216 controls), correlating patterns of sun exposure, sunburn and solar keratoses (three studies) with melanoma risk. Pooled odds ratios (pORs) and 95% Bayesian confidence intervals (CIs) were estimated using Bayesian unconditional polytomous logistic random-coefficients models. Results Recreational sun exposure was a risk factor for melanoma on the trunk (pOR = 1.7; 95% CI: 1.4–2.2) and limbs (pOR = 1.4; 95% CI: 1.1–1.7), but not head and neck (pOR = 1.1; 95% CI: 0.8–1.4), across latitudes. Occupational sun exposure was associated with risk of melanoma on the head and neck at low latitudes (pOR = 1.7; 95% CI: 1.0–3.0). Total sun exposure was associated with increased risk of melanoma on the limbs at low latitudes (pOR = 1.5; 95% CI: 1.0–2.2), but not at other body sites or other latitudes. The pORs for sunburn in childhood were 1.5 (95% CI: 1.3–1.7), 1.5 (95% CI: 1.3–1.7) and 1.4 (95% CI: 1.1–1.7) for melanoma on the trunk, limbs, and head and neck, respectively, showing little variation across latitudes. The presence of head and neck solar keratoses was associated with increased risk of melanoma on the head and neck (pOR = 4.0; 95% CI: 1.7–9.1) and limbs (pOR = 4.0; 95% CI: 1.9–8.4). Conclusion Melanoma risk at different body sites is associated with different amounts and patterns of sun exposure. Recreational sun exposure and sunburn are strong predictors of melanoma at all latitudes, whereas measures of occupational and total sun exposure appear to predict melanoma predominately at low latitudes.
Aim
This study explored the effects of blood flow restriction (BFR) on mRNA responses of PGC‐1α (total, 1α1, and 1α4) and Na+,K+‐ATPase isoforms (NKA; α1‐3, β1‐3, and FXYD1) to an interval running ...session and determined whether these effects were related to increased oxidative stress, hypoxia, and fibre type‐specific AMPK and CaMKII signalling, in human skeletal muscle.
Methods
In a randomized, crossover fashion, 8 healthy men (26 ± 5 year and 57.4 ± 6.3 mL kg−1 min−1) completed 3 exercise sessions: without (CON) or with blood flow restriction (BFR), or in systemic hypoxia (HYP, ~3250 m). A muscle sample was collected before (Pre) and after exercise (+0 hour, +3 hours) to quantify mRNA, indicators of oxidative stress (HSP27 protein in type I and II fibres, and catalase and HSP70 mRNA), metabolites, and α‐AMPK Thr172/α‐AMPK, ACC Ser221/ACC, CaMKII Thr287/CaMKII, and PLBSer16/PLB ratios in type I and II fibres.
Results
Muscle hypoxia (assessed by near‐infrared spectroscopy) was matched between BFR and HYP, which was higher than CON (~90% vs ~70%; P < .05). The mRNA levels of FXYD1 and PGC‐1α isoforms (1α1 and 1α4) increased in BFR only (P < .05) and were associated with increases in indicators of oxidative stress and type I fibre ACC Ser221/ACC ratio, but dissociated from muscle hypoxia, lactate, and CaMKII signalling.
Conclusion
Blood flow restriction augmented exercise‐induced increases in muscle FXYD1 and PGC‐1α mRNA in men. This effect was related to increased oxidative stress and fibre type‐dependent AMPK signalling, but unrelated to the severity of muscle hypoxia, lactate accumulation, and modulation of fibre type‐specific CaMKII signalling.
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