To assess the genetic consequences of induced pluripotent stem cell (iPSC) reprogramming, we sequenced the genomes of ten murine iPSC clones derived from three independent reprogramming experiments, ...and compared them to their parental cell genomes. We detected hundreds of single nucleotide variants (SNVs) in every clone, with an average of 11 in coding regions. In two experiments, all SNVs were unique for each clone and did not cluster in pathways, but in the third, all four iPSC clones contained 157 shared genetic variants, which could also be detected in rare cells (<1 in 500) within the parental MEF pool. These data suggest that most of the genetic variation in iPSC clones is not caused by reprogramming per se, but is rather a consequence of cloning individual cells, which “captures” their mutational history. These findings have implications for the development and therapeutic use of cells that are reprogrammed by any method.
► iPSC clones contain hundreds of SNVs that are unique to each clone ► Most iPSC genomes do not contain recurrently mutated genes or pathways ► Reprogramming can select for rare cells with shared genetic variants ► Most SNVs are probably preexisting mutations “captured” by cloning
Background
Cancer incidence is higher in men than in women at most shared anatomic sites for currently unknown reasons. The authors quantified the extent to which behaviors (smoking and alcohol use), ...anthropometrics (body mass index and height), lifestyles (physical activity, diet, medications), and medical history collectively explain the male predominance of risk at 21 shared cancer sites.
Methods
Prospective cohort analyses (n = 171,274 male and n = 122,826 female participants; age range, 50–71 years) in the National Institutes of Health‐AARP Diet and Health Study (1995–2011). Cancer‐specific Cox regression models were used to estimate male‐to‐female hazard ratios (HRs). The degree to which risk factors explained the observed male–female risk disparity was quantified using the Peters–Belson method.
Results
There were 26,693 incident cancers (17,951 in men and 8742 in women). Incidence was significantly lower in men than in women only for thyroid and gallbladder cancers. At most other anatomic sites, the risks were higher in men than in women (adjusted HR range, 1.3–10.8), with the strongest increases for bladder cancer (HR, 3.33; 95% confidence interval CI, 2.93–3.79), gastric cardia cancer (HR, 3.49; 95% CI, 2.26–5.37), larynx cancer (HR, 3.53; 95% CI, 2.46–5.06), and esophageal adenocarcinoma (HR, 10.80; 95% CI, 7.33–15.90). Risk factors explained a statistically significant (nonzero) proportion of the observed male excess for esophageal adenocarcinoma and cancers of liver, other biliary tract, bladder, skin, colon, rectum, and lung. However, only a modest proportion of the male excess was explained by risk factors (ranging from 50% for lung cancer to 11% for esophageal adenocarcinoma).
Conclusions
Men have a higher risk of cancer than women at most shared anatomic sites. Such male predominance is largely unexplained by risk factors, underscoring a role for sex‐related biologic factors.
The male predominance of many nonsex‐specific cancers has been explained by differences in exposure prevalence between sexes, but cancer incidence in this study remained significantly higher among men for most sites after a comprehensive adjustment for carcinogenic exposures. These findings suggest a role of sex‐related biologic mechanisms as the major determinants of sex differences in cancer risk.
DNMT3A mutations in acute myeloid leukemia Ley, Timothy J; Ding, Li; Walter, Matthew J ...
The New England journal of medicine,
12/2010, Letnik:
363, Številka:
25
Journal Article
Recenzirano
Odprti dostop
The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown.
Using massively parallel DNA sequencing, we identified a somatic mutation in ...DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations.
A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis.
DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.).
The purpose of this review is to determine the evidence base classification of schema-based instruction (SBI) as an intervention to improve word problem-solving outcomes in mathematics for students ...with learning or mathematics disabilities in Grades K–12. Using the Council for Exceptional Children’s quality indicators (QIs) and standards, we reviewed both single-case and group design studies to classify the evidence of SBI. Results of this review indicate that SBI is a potentially evidence-based practice (EBP) for students with learning disabilities. Implications and directions for research and practice are presented.
Continuity of care is broadly associated with better patient health outcomes. The relative contributions of continuity with an individual physician and with a practice, however, have not generally ...been distinguished. This retrospective observational study examined the impact of continuity of care for patients seen at their main clinic but by different family physicians.
We analyzed linked health administrative data from 2015-2018 from Alberta, Canada to explore the association of physician and clinic continuity with rates of emergency department (ED) visits and hospitalizations across varying levels of patient complexity. Physician continuity was calculated using the known provider of care index and clinic continuity with an analogous measure. We developed zero-inflated negative binomial models to assess the association of each with all-cause ED visits and hospitalizations.
High physician continuity was associated with lower ED use across all levels of patient complexity and with fewer hospitalizations for highly complex patients. Broadly, no (0%) clinic continuity was associated with increased use and complete (100%) clinic continuity with decreased use, with the largest effect seen for the most complex patients. Levels of clinic continuity between 1% and 50% were generally associated with slightly higher use, and levels of 51% to 99% with slightly lower use.
The best health care outcomes (measured by ED visits and hospitalizations) are associated with consistently seeing one's own primary family physician or seeing a clinic partner when that physician is unavailable. The effect of partial clinic continuity appears complex and requires additional research. These results provide some reassurance for part-time and shared practices, and guidance for primary care workforce policy makers.
Although dementia of the Alzheimer's type (DAT) is the most common form of dementia, the severity of dementia is only weakly correlated with DAT pathology. In contrast, postmortem measurements of ...cholinergic function and membrane ethanolamine plasmalogen (PlsEtn) content in the cortex and hippocampus correlate with the severity of dementia in DAT. Currently, the largest risk factor for DAT is age. Because the synthesis of PlsEtn occurs via a single nonredundant peroxisomal pathway that has been shown to decrease with age and PlsEtn is decreased in the DAT brain, we investigated potential relationships between serum PlsEtn levels, dementia severity, and DAT pathology. In total, serum PlsEtn levels were measured in five independent population collections comprising >400 clinically demented and >350 nondemented subjects. Circulating PlsEtn levels were observed to be significantly decreased in serum from clinically and pathologically diagnosed DAT subjects at all stages of dementia, and the severity of this decrease correlated with the severity of dementia. Furthermore, a linear regression model predicted that serum PlsEtn levels decrease years before clinical symptoms. The putative roles that PlsEtn biochemistry play in the etiology of cholinergic degeneration, amyloid accumulation, and dementia are discussed.
Flavonoids are bioactive polyphenolic compounds found in fruits, vegetables, and beverages of plant origin. Previous studies have shown that flavonoid intake reduces the risk of certain cancers; ...however, few studies to date have examined associations of flavonoids with upper gastrointestinal cancers or used prospective cohorts.
Our study examined the association between intake of flavonoids (anthocyanidins, flavan-3-ols, flavanones, flavones, flavonols, and isoflavones) and risk of head and neck, esophageal, and gastric cancers.
The NIH-AARP Diet and Health Study is a prospective cohort study that consists of 469,008 participants. Over a mean 12-y follow-up, 2453 head and neck (including 1078 oral cavity, 424 pharyngeal, and 817 laryngeal), 1165 esophageal (890 adenocarcinoma and 275 squamous cell carcinoma), and 1297 gastric (625 cardia and 672 noncardia) cancer cases were identified. We used Cox proportional hazards regression models to estimate HRs and CIs for the associations between flavonoid intake assessed at study baseline and cancer outcomes. For 56 hypotheses examined, P-trend values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control.
The highest quintile of total flavonoid intake was associated with a 24% lower risk of head and neck cancer (HR: 0.76; 95% CI: 0.66, 0.86; BH-adjusted 95% CI: 0.63, 0.91; P-trend = 0.02) compared with the lowest quintile. Notably, anthocyanidins were associated with a 28% lower risk of head and neck cancer (HR: 0.72; 95% CI: 0.62, 0.82; BH-adjusted 95% CI: 0.59, 0.87; P-trend = 0.0005), and flavanones were associated with a 22% lower risk of head and neck cancer (HR: 0.78; 95% CI: 0.68, 0.89; BH-adjusted 95% CI: 0.64, 0.94; P-trend: 0.02). No associations between flavonoid intake and risk of esophageal or gastric cancers were found.
Our results indicate that flavonoid intake is associated with lower head and neck cancer risk. These associations suggest a protective effect of dietary flavonoids on head and neck cancer risk, and thus potential as a risk reduction strategy.
•Cognitive impairment is a major comorbidity of temporal lobe epilepsy (TLE).•Three discrete cognitive phenotypes of TLE are identified here.•The phenotypes are linked to network, clinical, and ...socioeconomic characteristics.•This taxonomy advances clinical and theoretical understanding of the cognitive complications of TLE.
This study explored the taxonomy of cognitive impairment within temporal lobe epilepsy and characterized the sociodemographic, clinical and neurobiological correlates of identified cognitive phenotypes. 111 temporal lobe epilepsy patients and 83 controls (mean ages 33 and 39, 57% and 61% female, respectively) from the Epilepsy Connectome Project underwent neuropsychological assessment, clinical interview, and high resolution 3T structural and resting-state functional MRI. A comprehensive neuropsychological test battery was reduced to core cognitive domains (language, memory, executive, visuospatial, motor speed) which were then subjected to cluster analysis. The resulting cognitive subgroups were compared in regard to sociodemographic and clinical epilepsy characteristics as well as variations in brain structure and functional connectivity. Three cognitive subgroups were identified (intact, language/memory/executive function impairment, generalized impairment) which differed significantly, in a systematic fashion, across multiple features. The generalized impairment group was characterized by an earlier age at medication initiation (P < 0.05), fewer patient (P < 0.001) and parental years of education (P < 0.05), greater racial diversity (P < 0.05), and greater number of lifetime generalized seizures (P < 0.001). The three groups also differed in an orderly manner across total intracranial (P < 0.001) and bilateral cerebellar cortex volumes (P < 0.01), and rate of bilateral hippocampal atrophy (P < 0.014), but minimally in regional measures of cortical volume or thickness. In contrast, large-scale patterns of cortical-subcortical covariance networks revealed significant differences across groups in global and local measures of community structure and distribution of hubs. Resting-state fMRI revealed stepwise anomalies as a function of cluster membership, with the most abnormal patterns of connectivity evident in the generalized impairment group and no significant differences from controls in the cognitively intact group. Overall, the distinct underlying cognitive phenotypes of temporal lobe epilepsy harbor systematic relationships with clinical, sociodemographic and neuroimaging correlates. Cognitive phenotype variations in patient and familial education and ethnicity, with linked variations in total intracranial volume, raise the question of an early and persisting socioeconomic-status related neurodevelopmental impact, with additional contributions of clinical epilepsy factors (e.g., lifetime generalized seizures). The neuroimaging features of cognitive phenotype membership are most notable for disrupted large scale cortical-subcortical networks and patterns of functional connectivity with bilateral hippocampal and cerebellar atrophy. The cognitive taxonomy of temporal lobe epilepsy appears influenced by features that reflect the combined influence of socioeconomic, neurodevelopmental and neurobiological risk factors.
The neuropsychological complications of temporal lobe epilepsy are characterized by a spectrum of reproducible cognitive phenotypes that vary in the presence, type and degree of impairment. The ...nature of the disruptions to the neuropsychological networks that underlie these phenotypes remain to be characterized and represent the subject of this investigation.
Participants included 30 healthy controls and 104 patients with temporal lobe epilepsy who fell into three cognitive phenotypes (intact, focal impairment, generalized impairment). Eighteen neuropsychological measures representing multiple cognitive domains (language, memory, executive function, visuoperception, motor speed) were examined by graph theory techniques within the control and each epilepsy cognitive phenotype group to characterize their global and local network properties.
Across the control and epilepsy cognitive phenotype groups (intact to focal to generalized impairment), there was: 1) an orderly breakdown in the positive manifold reflected by a stepwise reduction of positive associations among the neuropsychological tests, 2) stepwise abnormal increases in global measures including the normalized clustering coefficient and modularity index, 3) stepwise abnormal decreases in normalized global efficiency, 4) a community structure demonstrating well organized modules within the control group while each epilepsy group showed deviations from controls, and 5) lower strength, compared to controls, across 8 nodes in the focal and generalized impairment groups compared to only 3 nodes in the no-impairment epilepsy group, pointing to the superior integration of local connections in controls.
The cognitive phenotypes of temporal lobe epilepsy are characterized by orderly abnormalities in their underlying neuropsychological networks. These findings inform the network perturbations that underlie the taxonomy of cognitive abnormality in temporal lobe epilepsy and provide a model for examination of similar issues in other focal and generalized epilepsies.
Complexity and risk adjustment are two strategies employed to understand chronic disease and healthcare cost within patient populations. There is a general assumption that the data applied to risk ...adjustment models, such as the clinical risk groups (CRG) is sufficient to infer patient complexity. Our aim in this study was to compare the calculated complexity of a patient population using the 3 M™ CRG software to complexity data extracted from community-based primary care electronic medical records (EMR). We found that the distribution of the 3 M™ CRG health status was significantly different from the primary care EMR health status distribution, and that the number and type of chronic conditions identified differed between the two methods. We calculated a new variable that combined the information from the 3 M™ CRG software with the primary care EMR data. The distribution of the Combined-CRG distribution was significantly different from the 3 M™ CRG software; specifically, we saw many patients originally classified as being healthy or having minor chronic condition(s) re-categorized into having significant chronic condition(s). The CRG health statuses alone may be sufficient to predict future health expenditures, but caution is warranted if CRGs are to be used to infer complexity of the patient population.
PDF
