48 research outputs found
Differential effects of organic nitrates on arterial diameter among healthy Japanese participants with different mitochondrial aldehyde dehydrogenase 2 genotypes: randomised crossover trial
Role of ER Stress in Ventricular Contractile Dysfunction in Type 2 Diabetes
BACKGROUND: Diabetes mellitus (DM) is associated with an increased risk of ischemic heart disease and of adverse outcomes following myocardial infarction (MI). Here we assessed the role of endoplasmic reticulum (ER) stress in ventricular dysfunction and outcomes after MI in type 2 DM (T2DM). METHODOLOGY AND PRINCIPAL FINDINGS: In hearts of OLETF, a rat model of T2DM, at 25∼30 weeks of age, GRP78 and GRP94, markers of ER stress, were increased and sarcoplasmic reticulum calcium ATPase (SERCA)2a protein was reduced by 35% compared with those in LETO, a non-diabetic control. SERCA2a mRNA levels were similar, but SERCA2a protein was more ubiquitinated in OLETF than in LETO. Left ventricular (LV) end-diastolic elastance (Eed) was higher in OLETF than in LETO (53.9±5.2 vs. 20.2±5.6 mmHg/µl), whereas LV end-systolic elastance and positive inotropic responses to β-adrenergic stimulation were similar in OLETF and LETO. 4-Phenylbutyric acid (4-PBA), an ER stress modulator, suppressed both GRP up-regulation and SERCA2a ubiquitination and normalized SERCA2a protein level and Eed in OLETF. Sodium tauroursodeoxycholic acid, a structurally different ER stress modulator, also restored SERCA2a protein level in OLETF. Though LV dysfunction was modest, mortality within 48 h after coronary occlusion was markedly higher in OLETF than in LETO (61.3% vs. 7.7%). Telemetric recording showed that rapid progression of heart failure was responsible for the high mortality rate in OLETF. ER stress modulators failed to reduce the mortality rate after MI in OLETF. CONCLUSIONS: ER stress reduces SERCA2a protein via its augmented ubiquitination and degradation, leading to LV diastolic dysfunction in T2DM. Even at a stage without systolic LV dysfunction, susceptibility to lethal heart failure after infarction is markedly increased, which cannot be explained by ER stress or change in myocardial response to sympathetic nerve activation
KLC1-ALK: A Novel Fusion in Lung Cancer Identified Using a Formalin-Fixed Paraffin-Embedded Tissue Only
The promising results of anaplastic lymphoma kinase (ALK) inhibitors have changed the significance of ALK fusions in several types of cancer. These fusions are no longer mere research targets or diagnostic markers, but they are now directly linked to the therapeutic benefit of patients. However, most available tumor tissues in clinical settings are formalin-fixed and paraffin-embedded (FFPE), and this significantly limits detailed genetic studies in many clinical cases. Although recent technical improvements have allowed the analysis of some known mutations in FFPE tissues, identifying unknown fusion genes by using only FFPE tissues remains difficult. We developed a 5′-rapid amplification of cDNA ends-based system optimized for FFPE tissues and evaluated this system on a lung cancer tissue with ALK rearrangement and without the 2 known ALK fusions EML4-ALK and KIF5B-ALK. With this system, we successfully identified a novel ALK fusion, KLC1-ALK. The result was confirmed by reverse transcription-polymerase chain reaction and fluorescence in situ hybridization. Then, we synthesized the putative full-length cDNA of KLC1-ALK and demonstrated the transforming potential of the fusion kinase with assays using mouse 3T3 cells. To the best of our knowledge, KLC1-ALK is the first novel oncogenic fusion identified using only FFPE tissues. This finding will broaden the potential value of archival FFPE tissues and provide further biological and clinical insights into ALK-positive lung cancer
Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults
Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We
estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from
1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories.
Methods We used data from 3663 population-based studies with 222 million participants that measured height and
weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate
trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children
and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the
individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference)
and obesity (BMI >2 SD above the median).
Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in
11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed
changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and
140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of
underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and
countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior
probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse
was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of
thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a
posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%)
with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and
obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for
both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such
as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged
children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls
in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and
42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents,
the increases in double burden were driven by increases in obesity, and decreases in double burden by declining
underweight or thinness.
Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an
increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy
nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of
underweight while curbing and reversing the increase in obesit
Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.
BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking.
METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality.
RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6).
Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.)
30-minute postload plasma glucose levels during an oral glucose tolerance test predict the risk of future type 2 diabetes: the Hisayama Study
Introduction To investigate the associations of 30 min postload plasma glucose (30 mPG) levels during an oral glucose tolerance test (OGTT) with the risk of future diabetes in a general Japanese population.Research design and methods A total of 2957 Japanese community-dwelling residents without diabetes, aged 40–79 years, participated in the examinations in 2007 and 2008 (participation rate, 77.1%). Among them, 2162 subjects who received 75 g OGTT in a fasting state with measurements of plasma glucose level at 0, 30, and 120 min were followed up for 7 years (2007–2014). Cox’s proportional hazards model was used to estimate HRs and their 95% CIs of each index for the development of type 2 diabetes using continuous variables and quartiles with adjustment for traditional risk factors. The influence of 30 mPG on the predictive ability was estimated with Harrell’s C-statistics, integrated discrimination improvement (IDI), and the continuous net reclassification index (cNRI).Results During follow-up, 275 subjects experienced type 2 diabetes. Elevated 30 mPG levels were significantly associated with increased risk of developing diabetes (p<0.01 for trend): the multivariable-adjusted HR was 8.41 (95% CI 4.97 to 14.24) for the highest versus the lowest quartile, and 2.26 (2.04 to 2.52) per 1 SD increase. This association was attenuated but remained significant after further adjustment for fasting and 2-hour postload plasma glucose levels. Incorporation of 30 mPG into the model including traditional risk factors with fasting and 2-hour postload plasma glucose levels for diabetes improved the predictive ability of type 2 diabetes (improvement in Harrell’s C-statistics values: from 0.828 to 0.839, p<0.01; IDI: 0.016, p<0.01; cNRI: 0.103, p=0.37).Conclusions Elevated 30 mPG levels were associated with increased risk of diabetes, and inclusion of 30 mPG levels significantly improved the predictive ability for future diabetes, suggesting that 30 mPG may be useful for identifying high-risk populations for type 2 diabetes
TERT Promoter Mutation and Extent of Thyroidectomy in Patients with 1–4 cm Intrathyroidal Papillary Carcinoma
There are concerns regarding overtreatment in papillary thyroid carcinoma (PTC). BRAF V600E and TERT promoter mutations play important roles in the development of PTC. However, initial surgical approaches for PTC based on genetic characteristics remain unclear. The present study aimed to identify genetic mutations as predictors of prognosis and to establish proper indications for lobectomy (LT) in patients with 1–4 cm intrathyroidal PTC. Prospectively accumulated data from 685 consecutive patients with PTC who underwent primary thyroid surgery at the Cancer Institute Hospital, Tokyo, Japan, between 2001 and 2012 were retrospectively reviewed. Of the 685 patients examined, 538 (78.5%) had BRAF V600E mutation and 133 (19.4%) had TERT promoter mutations. Patients with TERT promoter mutations displayed significantly worse outcomes than those without mutations (10-year cause-specific survival (CSS): 73.7% vs. 98.1%, p < 0.001; 10-year disease-free survival (DFS): 53.7% vs. 93.3%, p < 0.001). As for extent of thyroidectomy among TERT mutation-negative patients with 1–4 cm intrathyroidal PTC, patients who underwent LT showed no significant differences in 10-year CSS and 10-year DFS compared to patients who had total thyroidectomy (TT) under propensity score-matching. Avoiding TT for those patients indicates a possible pathway to prevent overtreatment and reduce postoperative complications