Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β cells. To identify candidate genes contributing to T2D pathophysiology, we studied human pancreatic islets from ...approximately 300 individuals. We found 395 differentially expressed genes (DEGs) in islets from individuals with T2D, including, to our knowledge, novel (OPRD1, PAX5, TET1) and previously identified (CHL1, GLRA1, IAPP) candidates. A third of the identified expression changes in islets may predispose to diabetes, as expression of these genes associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β cells, based on single-cell RNA-Seq data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D SNPs. Mouse KO strains demonstrated that the identified T2D-associated candidate genes regulate glucose homeostasis and body composition in vivo. Functional validation showed that mimicking T2D-associated changes for OPRD1, PAX5, and SLC2A2 impaired insulin secretion. Impairments in Pax5-overexpressing β cells were due to severe mitochondrial dysfunction. Finally, we discovered PAX5 as a potential transcriptional regulator of many T2D-associated DEGs in human islets. Overall, we have identified molecular alterations in human pancreatic islets that contribute to β cell dysfunction in T2D pathophysiology.
The association between increasing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and risk of breast cancer is unique in cancer epidemiology in that a ...crossover effect exists, with risk reduction before and risk increase after menopause. The inverse association with premenopausal breast cancer risk is poorly characterized but might be important in the understanding of breast cancer causation.
To investigate the association of BMI with premenopausal breast cancer risk, in particular by age at BMI, attained age, risk factors for breast cancer, and tumor characteristics.
This multicenter analysis used pooled individual-level data from 758 592 premenopausal women from 19 prospective cohorts to estimate hazard ratios (HRs) of premenopausal breast cancer in association with BMI from ages 18 through 54 years using Cox proportional hazards regression analysis. Median follow-up was 9.3 years (interquartile range, 4.9-13.5 years) per participant, with 13 082 incident cases of breast cancer. Participants were recruited from January 1, 1963, through December 31, 2013, and data were analyzed from September 1, 2013, through December 31, 2017.
Body mass index at ages 18 to 24, 25 to 34, 35 to 44, and 45 to 54 years.
Invasive or in situ premenopausal breast cancer.
Among the 758 592 premenopausal women (median age, 40.6 years; interquartile range, 35.2-45.5 years) included in the analysis, inverse linear associations of BMI with breast cancer risk were found that were stronger for BMI at ages 18 to 24 years (HR per 5 kg/m2 5.0-U difference, 0.77; 95% CI, 0.73-0.80) than for BMI at ages 45 to 54 years (HR per 5.0-U difference, 0.88; 95% CI, 0.86-0.91). The inverse associations were observed even among nonoverweight women. There was a 4.2-fold risk gradient between the highest and lowest BMI categories (BMI≥35.0 vs <17.0) at ages 18 to 24 years (HR, 0.24; 95% CI, 0.14-0.40). Hazard ratios did not appreciably vary by attained age or between strata of other breast cancer risk factors. Associations were stronger for estrogen receptor-positive and/or progesterone receptor-positive than for hormone receptor-negative breast cancer for BMI at every age group (eg, for BMI at age 18 to 24 years: HR per 5.0-U difference for estrogen receptor-positive and progesterone receptor-positive tumors, 0.76 95% CI, 0.70-0.81 vs hormone receptor-negative tumors, 0.85 95% CI: 0.76-0.95); BMI at ages 25 to 54 years was not consistently associated with triple-negative or hormone receptor-negative breast cancer overall.
The results of this study suggest that increased adiposity is associated with a reduced risk of premenopausal breast cancer at a greater magnitude than previously shown and across the entire distribution of BMI. The strongest associations of risk were observed for BMI in early adulthood. Understanding the biological mechanisms underlying these associations could have important preventive potential.
To assess the relationship between radiation doses to the coronary arteries (CAs) and location of a coronary stenosis that required intervention after three-dimensional conformal radiotherapy (3DCRT) ...for breast cancer (BC).
The study population consisted of 182 women treated for BC in Sweden between 1992 and 2012. All women received 3DCRT and subsequently underwent coronary angiography due to a suspected coronary event. CA segments were delineated in the patient's original planning-CT and radiation doses were recalculated based on the dose distribution of the original radiotherapy (RT) plan. The location of the CA stenosis that required intervention was identified from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Logistic regression analysis was used to assess the relationship between CA radiation doses and risk of a later coronary intervention at this specific location.
The odds ratio (OR) varied by radiation dose to the mid left anterior descending artery (LAD) (p = 0.005). Women receiving mean doses of 1-5 Gray (Gy) to the mid LAD had an adjusted OR of 0.90 (95% CI 0.47-1.74) for a later coronary intervention compared to women receiving mean doses of 0-1 Gy to the mid LAD. In women receiving mean doses of 5-20 Gy to the mid LAD, an adjusted OR of 1.24 (95% CI 0.52-2.95) was observed, which increased to an OR of 5.23 (95% CI 2.01-13.6) for mean doses over 20 Gy, when compared to women receiving mean doses of 0-1 Gy to the mid LAD.
In women receiving conventional 3DCRT for BC between 1992 and 2012, radiation doses to the LAD remained high and were associated with an increased requirement of coronary intervention in mid LAD. The results support that the LAD radiation dose should be considered in RT treatment planning and that the dose should be kept as low as possible. Minimising the dose to LAD is expected to diminish the risk of later radiation-induced stenosis.
There are situations when we need to model multiple time-scales in survival analysis. A usual approach in this setting would involve fitting Cox or Poisson models to a time-split dataset. However, ...this leads to large datasets and can be computationally intensive when model fitting, especially if interest lies in displaying how the estimated hazard rate or survival change along multiple time-scales continuously.
We propose to use flexible parametric survival models on the log hazard scale as an alternative method when modelling data with multiple time-scales. By choosing one of the time-scales as reference, and rewriting other time-scales as a function of this reference time-scale, users can avoid time-splitting of the data.
Through case-studies we demonstrate the usefulness of this method and provide examples of graphical representations of estimated hazard rates and survival proportions. The model gives nearly identical results to using a Poisson model, without requiring time-splitting.
Flexible parametric survival models are a powerful tool for modelling multiple time-scales. This method does not require splitting the data into small time-intervals, and therefore saves time, helps avoid technological limitations and reduces room for error.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Among breast cancer patients, tamoxifen use is associated with reduced risk of disease relapse and death, but it is often difficult for women to sustain therapy during the 5 years ...required to obtain maximum benefit. Objectives: We sought to examine the influence of patient-centered care activities on ongoing tamoxifen use 4 years after initiation, we examined key components of patient-centered care and rates of ongoing tamoxifen. Methods: Using a prospective cohort study that included observational data from the National Initiative for Cancer Care Quality (NICCQ), we studied 881 patients with stage I-III breast cancer who were registered with an initial diagnosis in 1998 by an American College of Surgeons-approved hospital cancer registry in 1 of 5 metropolitan areas, who initiated tamoxifen treatment. A patient survey and medical record abstraction were used as measurements. Results: Among women who initiated tamoxifen, 79% were still taking it 4 years later. Other than older age and the severity of side effects, other demographic, clinical and cancer characteristics, and treatments did not predict ongoing tamoxifen use. In contrast, after adjusting for these factors, the proportion of patients with ongoing tamoxifen use was lower for patients reporting less support than needed (82% vs. 69%, P = 0.0051), less than wanted role in decision-making (80% vs. 70%, P = 0.0486), decision-making about tamoxifen without doctor input (79% vs. 64%, P = 0.0182), and for patients who weren't told about side effects in advance (82% vs. 72%, P = 0.0016). Conclusions: Although age and the severity of side-effects remain important, patient-centered care was a primary mediator of patient adherence to ongoing cancer treatment with tamoxifen.
INTRODUCTION
Cognitive reserve might mitigate the risk of Alzheimer's dementia among memory clinic patients. No study has examined the potential modifying role of stress on this relation.
METHODS
We ...examined cross‐sectional associations of the cognitive reserve index (CRI; education, occupational complexity, physical and leisure activities, and social health) with cognitive performance and AD‐related biomarkers among 113 memory clinic patients. The longitudinal association between CRI and cognition over a 3‐year follow‐up was assessed. We examined whether associations were influenced by perceived stress and five measures of diurnal salivary cortisol.
RESULTS
Higher CRI scores were associated with better cognition. Adjusting for cortisol measures reduced the beneficial association of CRI on cognition. A higher CRI score was associated with better working memory in individuals with higher (favorable) cortisol AM/PM ratio, but not among individuals with low cortisol AM/PM ratio. No association was found between CRI and AD‐related biomarkers.
DISCUSSION
Physiological stress reduces the neurocognitive benefits of cognitive reserve among memory clinic patients.
Highlights
Physiological stress may reduce the neurocognitive benefits accrued from cognitively stimulating and enriching life experiences (cognitive reserve CR) in memory clinic patients.
Cortisol awakening response modified the relation between CR and P‐tau181, a marker of Alzheimer's disease (AD).
Effective stress management techniques for AD and related dementia prevention are warranted.
Aim
We explored physicians’ experiences of communicating with families when their child had cancer and a cure was no longer an option, by focusing on barriers and facilitating factors.
Methods
...Physicians from the six cancer centres in Sweden took part in focus group discussions between December 2017 and May 2018, and the data were analysed using qualitative content analysis. Focus groups enabled us to gather individual and shared perspectives.
Results
The 35 physicians (20 male) had a mean age of 47 (range 31‐74) and a mean of 11 years’ experience in oncology, ranging from under one year to 43 years. They reported communication challenges when a cure was not possible, namely: emotional and mental drain, lack of mutual understanding and uncertainty about communication skills. They also reported facilitating factors: flexibility in complex conversations, the child’s position in the conversations, continuity and trusting relationships, support from colleagues and having discussed the potentially life‐threatening nature of cancer from the very start of treatment.
Conclusion
Training to overcome communication issues could support the early integration of palliative care.
The yeast Malassezia furfur, also known as Pityrosporum orbiculare (ovale), is part of the normal microflora of the human skin but has also been associated with different skin diseases including ...atopic dermatitis. More than 50% of atopic dermatitis patients have positive skin test and specific IgE to M. furfur extracts; however, the pathophysiologic role of these IgE-mediated reactions in the development of the disease remains unknown. The yeast is able to produce a wide panel of IgE-binding proteins, variably recognized by sera of individual patients. In order to assess the contribution of individual components to the disease, highly pure allergen preparations are required. We have cloned M. furfur allergens from a cDNA library displayed on the phage surface, sequenced the inserts and produced recombinant proteins in Escherichia coli. Phage displaying IgE-binding proteins were selectively enriched from the library using IgE from a M. furfur-sensitized atopic dermatitis patient as a ligand. We were able to identify five different inserts coding for IgE-binding polypeptides. Three of the sequenced cDNA encode incomplete gene products with molecular masses of 21.3 kDa (MF 7), 14.4 kDa (MF 8), and 9.7 kDa (MF 9), respectively, having no sequence similarity to known proteins. The other two cDNA encode allergens of 18.2 kDa (Mal f 5) and 17.2 kDa (Mal f 6). Mal f 5 shows significant homology to M. furfur allergens Mal f 2, Mal f 3 and an Aspergillus fumigatus allergen Asp f 3. Mal f 6 has significant homology with cyclophilin. All of the recombinant polypeptides were capable of binding serum IgE from atopic dermatitis patients in immunoblotting experiments. The availability of pure recombinant M. furfur allergens will allow the careful investigation of the role of IgE-binding proteins in atopic dermatitis.
Immunoglobulin A nephropathy (IgAN) is a leading cause of chronic kidney disease, frequently associated with hypertension and renal inflammation. ω-3 fatty acids eicosapentaenoic acid (EPA) and ...docosahexaenoic acid (DHA) in fish oil (FO) improve kidney function in animal models, but have inconsistent metabolic effects in humans. Oxylipin profiles in serum from IgAN patients supplemented with either FO or corn oil (CO) placebo were analyzed by liquid chromatography coupled to tandem mass spectrometry. EPA cyclooxygenase and lipoxygenase metabolites, and EPA and DHA epoxides and diols were increased in response to FO supplementation, as were total epoxides and epoxide/diol ratios. Several of these metabolites were drivers of separation as assessed by multivariate analysis of FO patients pre- versus post-supplementation, including 17,18-dihydroxyeicosatrienoic acid, prostaglandin D
3
, prostagalandin E
3
, Resolvin E1, 12-hydroxyeicosapentaenoic acid, and 10(11)-epoxydocosapentaenoic acid. In patients whose proteinuria improved, plasma total oxylipins as well as several hydroxyoctadecadienoic acids, hydroxyeicosatetraenoic acids, and leukotriene B
4
metabolites were among the metabolites that were significantly lower than in patients whose proteinuria either did not improve or worsened. These data support the involvement of oxylipins in the inflammatory component of IgAN as well as the potential use of oxylipin profiles as biomarkers and for assessing responsiveness to ω-3 fatty acid supplementation in IgAN patients.
PDF
