To elucidate the molecular mechanisms contributing to the unique clinicopathologic characteristics of mucinous ovarian carcinoma, global gene expression profiling of mucinous ovarian tumors was ...carried out.
Gene expression profiling was completed for 25 microdissected mucinous tumors 6 cystadenomas, 10 low malignant potential (LMP) tumors, and 9 adenocarcinomas using Affymetrix U133 Plus 2.0 oligonucleotide microarrays. Hierarchical clustering and binary tree prediction analysis were used to determine the relationships among mucinous specimens and a series of previously profiled microdissected serous tumors and normal ovarian surface epithelium. PathwayAssist software was used to identify putative signaling pathways involved in the development of mucinous LMP tumors and adenocarcinomas.
Comparison of the gene profiles between mucinous tumors and normal ovarian epithelial cells identified 1,599, 2,916, and 1,765 differentially expressed in genes in the cystadenomas, LMP tumors, and adenocarcinomas, respectively. Hierarchical clustering showed that mucinous and serous LMP tumors are distinct. In addition, there was a close association of mucinous LMP tumors and adenocarcinomas with serous adenocarcinomas. Binary tree prediction revealed increased heterogeneity among mucinous tumors compared with their serous counterparts. Furthermore, the cystadenomas coexpressed a subset of genes that were differentially regulated in LMP and adenocarcinoma specimens compared with normal ovarian surface epithelium. PathwayAssist highlighted pathways with expression of genes involved in drug resistance in both LMP and adenocarcinoma samples. In addition, genes involved in cytoskeletal regulation were specifically up-regulated in the mucinous adenocarcinomas.
These data provide a useful basis for understanding the molecular events leading to the development and progression of mucinous ovarian cancer.
We examined the association for rates of age- and sex-standardized body mass index (zBMI) gain between 0-3, 3-18, and 18-36 months with BP in children at 36-72 months of age.
We collected repeated ...measures of zBMI and BP in 2502 children. zBMI was calculated using the World Health Organization standards. Each child's zBMI at birth and rates of zBMI gain in each period from birth to 36 months were estimated using linear spline multilevel models. Generalized estimating equations were used to determine whether zBMI at birth and zBMI gain between 0-3, 3-18, and 18-36 months were each associated with repeated measures of BP at 36-72 months of age. We sequentially conditioned on zBMI at birth and zBMI gain in each period prior to each period tested, as covariates, and adjusted for important socio-demographic, familial, and study design covariates. We examined whether these associations were modified by birthweight or maternal obesity, by including interaction terms.
After adjusting for all covariates and conditioning on prior zBMI gains, a 1 standard deviation unit faster rate of zBMI gain during 0-3 months, (β = 0.59 mmHg; 95% CI 0.31, 0.86) and 3-18 months (β = 0.74 mmHg; 95% CI 0.46, 1.03) were each associated with higher systolic BP at 36-72 months. No significant associations were observed, however, for zBMI at birth or zBMI gain in the 18-36 month growth period. zBMI gains from 0-3 and 3-18 months were also associated with diastolic BP. Birthweight significantly modified the relationship during the 3-18 month period (p = 0.02), with the low birthweight group exhibiting the strongest association for faster rate of zBMI gain with higher systolic BP (β = 1.31 mmHg; 95% CI 0.14, 2.48).
Given that long-term exposure to small elevations in BP are associated with subclinical cardiovascular disease, promoting interventions targeting healthy growth in infancy may be important.
The misfolding and aggregation of proteins to form amyloid fibrils is a characteristic feature of several common age-related diseases. Agents that directly inhibit formation of amyloid fibrils ...represent one approach to combating these diseases. We have investigated the potential of a cyclic peptide to inhibit fibril formation by fibrillogenic peptides from human apolipoprotein C-II (apoC-II). Cyc60–70 was formed by disulfide cross-linking of cysteine residues added to the termini of the fibrillogenic peptide comprising apoC-II residues 60–70. This cyclic peptide did not self-associate into fibrils. However, substoichiometric concentrations of cyc60–70 significantly delayed fibril formation by the fibrillogenic, linear peptides apoC-II60–70 and apoC-II56–76. Reduction of the disulfide bond or scrambling the amino acid sequence within cyc60–70 significantly impaired its inhibitory activity. The solution structure of cyc60–70 was solved using NMR spectroscopy, revealing a well-defined structure comprising a hydrophilic face and a more hydrophobic face containing the Met60, Tyr63, Ile66 and Phe67 side chains. Molecular dynamics (MD) studies identified a flexible central region within cyc60–70, while MD simulations of “scrambled” cyc60–70 indicated an increased formation of intramolecular hydrogen bonds and a reduction in the overall flexibility of the peptide. Our structural studies suggest that the inhibitory activity of cyc60–70 is mediated by an elongated structure with inherent flexibility and distinct hydrophobic and hydrophilic faces, enabling cyc60–70 to interact transiently with fibrillogenic peptides and inhibit fibril assembly. These results suggest that cyclic peptides based on amyloidogenic core peptides could be useful as specific inhibitors of amyloid fibril formation.
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► A cyclic derivative of a linear fibrillogenic peptide from apoC-II was studied. ► The cyclic peptide inhibited fibril formation by the linear parent peptides. ► The structure of the cyclic peptide comprises hydrophilic and hydrophobic faces. ► MD simulations of the cyclic peptide indicate a flexible, dynamic structure. ► Cyclic core peptides could be useful inhibitors of amyloid fibril formation.
A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed ...interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted.
Patients with mild asthma represent a substantial proportion of the population with asthma, yet there are limited data on their true burden of disease. We aimed to describe the clinical and ...healthcare resource utilisation (HCRU) burden of physician-assessed mild asthma.
Patients with mild asthma were included from the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329), a global, 3-year, real-world prospective study of patients with asthma and/or chronic obstructive pulmonary disease from community practice (specialised and primary care). Diagnosis and severity were based on physician discretion. Clinical burden included physician-reported exacerbations and patient-reported measures. HCRU included inpatient and outpatient visits.
Overall, 2004 patients with mild asthma were included; 22.8% experienced ≥1 exacerbation in the previous 12 months, of whom 72.3% experienced ≥1 severe exacerbation. Of 625 exacerbations reported, 48.0% lasted >1 week, 27.7% were preceded by symptomatic worsening lasting >3 days, and 50.1% required oral corticosteroid treatment. Health status was moderately impacted (St George's Respiratory Questionnaire score: 23.5 standard deviation ± 17.9). At baseline, 29.7% of patients had asthma symptoms that were not well controlled or very poorly controlled (Asthma Control Test score <20), increasing to 55.6% for those with ≥2 exacerbations in the previous year. In terms of HCRU, at least one unscheduled ambulatory visit for exacerbations was required by 9.5% of patients, including 9.2% requiring ≥1 emergency department visit and 1.1% requiring ≥1 hospital admission.
In this global sample representing community practice, a significant proportion of patients with physician-assessed mild asthma had considerable clinical burden and HCRU.
•Patients with physician-assessed mild asthma still have significant disease burden.•Over 20% of patients experienced any exacerbation in the previous 12 months.•Almost 10% of patients had one or more hospital or clinic visit for an exacerbation.•Nearly 30% of patients had not well or very poorly controlled asthma symptoms.•Many patients were prescribed medication consistent with more severe disease.
The adverse effects of depression on patients' life have been reported but information about its effects on the sequential organization of the information processing stages remains poorly understood ...as previous studies focused only on distinct stages. This study adds to existing knowledge by examining the effect of major depressive disorder (MDD) on the sequential organization of information processing, executive and community functioning. Fifty-seven participants with 19 participants each for first episode depression (FMDD), recurrent episodes depression (RMDD), and healthy controls (HCs) participated in this study. They completed assessments on executive and community functioning measures, and choice reaction time task (CRTT) for the event-related potential (ERP) data. Findings revealed no significant between-group difference in executive functioning but participants with depression (FMDD and RMDD) were found to be more depressed, with FMDD participants having worse community functioning skills compared with HCs. There was no significant between-group main effect on behavioral data. ERP data showed significantly less positive-going P3b among RMDD participants compared with HCs. FMDD participants used a different information processing strategy at P1, while HCs and RMDD participants used a different processing strategy at N2b compared with the other group(s), respectively. The results suggest the use of multifaceted assessment to get a holistic view of the health status of people with MDD in order to inform clinicians on the appropriate interventional strategies needed for the patient.
To evaluate the diagnostic utility of publicly funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases.
We prospectively enrolled 297 probands who met eligibility ...criteria and received ES across 5 sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests.
Laboratories reported 105 molecular diagnoses and 165 uncertain results in known and novel genes. Of these, clinicians interpreted 102 of 105 (97%) molecular diagnoses and 6 of 165 (4%) uncertain results as clinical-molecular diagnoses. The 108 clinical-molecular diagnoses were in 104 families (35% diagnostic yield). Each eligibility criteria resulted in diagnostic yields of 30% to 40%, and higher yields were achieved when >2 eligibility criteria were met (up to 45%). Hypothetical tests would have identified 61% of clinical-molecular diagnoses.
We demonstrate robustness in eligibility criteria and high clinical validity of laboratory results from ES testing. The importance of ES was highlighted by the potential 40% of patients that would have gone undiagnosed without this test.
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