Summary
Background
Actinic keratosis (AK) is a common sun‐induced skin disorder that can progress to invasive squamous cell carcinoma. However, there is still no reliable method to predict high‐risk ...AK.
Aim
To identify markers that reflect the biological behaviour of AK and to understand the pathogenesis of AK.
Methods
In total, 52 patients with AK and 17 site‐matched healthy controls (HCs) were enrolled. We evaluated solar elastosis and immunohistochemical features using antibodies to p53, vitamin D receptor (VDR), claudin‐1 and Langerin (CD207). Comparisons between AK and HC skin were performed and analyses carried out according to the pathological grade of AK.
Results
We found that in both patients and HCs, solar elastosis increased and Langerhans cell (LC) density decreased with ageing. Solar elastosis and p53 expression were higher and VDR expression was lower in patients than in HCs; however, there was no statistical difference between them in relation to the pathological grade of AK. Claudin‐1 expression gradually decreased from HC skin to severe AK, and particularly decreased in areas with epidermal atypia. LC density in severe AK was significantly lower than in HC skin and mild AK, while there was no difference in LC density between HC skin, mild AK and moderate AK.
Conclusions
Claudin‐1 could be a useful marker of the pathological severity of AK. In addition, p53 increases and VDR decreases in AK, not in a gradual manner but in the early steps of carcinogenesis. LC density is relatively maintained in AK until it reaches severe dysplasia.
An expansion of a CTG repeat at the DM1 locus causes myotonic dystrophy (DM) by altering the expression of the two adjacent genes, DMPK and SIX5, and through a toxic effect of the repeat-containing ...RNA. Here we identify two CTCF-binding sites that flank the CTG repeat and form an insulator element between DMPK and SIX5. Methylation of these sites prevents binding of CTCF, indicating that the DM1 locus methylation in congenital DM would disrupt insulator function. Furthermore, CTCF-binding sites are associated with CTG/CAG repeats at several other loci. We suggest a general role for CTG/CAG repeats as components of insulator elements at multiple sites in the human genome.
Advances in the field of bioactivation have significantly contributed to our understanding and prediction of drug-induced liver injury (DILI). It has been established that many adverse drug ...reactions, including DILI, are associated with the formation and reactivity of metabolites. Modern methods allow us to detect and characterize these reactive metabolites in earlier stages of drug development, which helps anticipate and circumvent the potential for DILI. Improved in silico models and experimental techniques that better reflect in vivo environments are enhancing predictive capabilities for DILI risk. Further, studies on the mechanisms of bioactivation, including enzyme interactions and the role of individual genetic differences, have provided valuable insights for drug optimizations. Cumulatively, this progress is continually refining our approaches to drug safety evaluation and personalized medicine.Shuai Wang and Cyrus Khojasteh, on behalf of the authors.Advances in the field of bioactivation have significantly contributed to our understanding and prediction of drug-induced liver injury (DILI). It has been established that many adverse drug reactions, including DILI, are associated with the formation and reactivity of metabolites. Modern methods allow us to detect and characterize these reactive metabolites in earlier stages of drug development, which helps anticipate and circumvent the potential for DILI. Improved in silico models and experimental techniques that better reflect in vivo environments are enhancing predictive capabilities for DILI risk. Further, studies on the mechanisms of bioactivation, including enzyme interactions and the role of individual genetic differences, have provided valuable insights for drug optimizations. Cumulatively, this progress is continually refining our approaches to drug safety evaluation and personalized medicine.Shuai Wang and Cyrus Khojasteh, on behalf of the authors.
Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on ...cardiovascular outcomes remain uncertain.
We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.
A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients 11.7% vs. 927 13.3%; hazard ratio, 0.87; 95% confidence interval CI, 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 8.2% vs. 663 9.5%; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 3.7% vs. 334 4.8%; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 6.2% vs. 529 7.6%; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels.
Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).
In the pyrochemical process of used nuclear fuel, the purification of waste salts containing radioactive nuclides can greatly contribute to a radioactive waste reduction. For this reason, the ...purification of LiCl–KCl eutectic salt containing rare earth chlorides was performed using a series of the phosphorylation process and the distillation process. LiCl–KCl eutectic salt recovered from the purification had a very low concentration (<1 ppm) for the rare earth chlorides. The recycling feasibility of the recovered salt was verified through a uranium electro-deposition test using LiCl–KCl eutectic salt as the electrolyte. Based on these results, one body type of reactive distillation equipment with two top covers was designed.
Despite intensive studies of microbial-community diversity, the questions of which kinds of microbial populations are associated with changes in community diversity have not yet been fully solved by ...molecular approaches. In this study, to investigate the impact of livestock wastewater on changes in the bacterial communities in groundwater, bacterial communities in subsurface aquifers were analyzed by characterizing their 16S rDNA sequences. The similarity coefficients of restriction fragment length polymorphism (RFLP) patterns of the cloned 16S ribosomal DNAs showed that the bacterial communities in livestock wastewater samples were more closely related to those in contaminated aquifer samples. In addition, calculations of community diversity clearly showed that bacterial communities in the livestock wastewater and the contaminated aquifer were much more diverse than those in the uncontaminated aquifer. Thus, the increase in bacterial-community diversity in the contaminated aquifer was assumed to be due to the infiltration of livestock wastewater, containing high concentrations of diverse microbial flora, into the aquifer. Phylogenetic analysis of the sequences from a subset of the RFLP patterns showed that the Cytophaga-Flexibacter-Bacteroides and low-G+C gram-positive groups originating from livestock wastewater were responsible for the change in the bacterial community in groundwater. This was evidenced by the occurrence of rumen-related sequences not only in the livestock wastewater samples but also in the contaminated-groundwater samples. Rumen-related sequences, therefore, can be used as indicator sequences for fecal contamination of groundwater, particularly from livestock.
New Findings
What is the central question of this study?
To what extent cardiorespiratory fitness is impaired in patients with abdominal aortic aneurysmal (AAA) disease and corresponding implications ...for postoperative survival requires further investigation.
What is the main finding and its importance?
Cardiorespiratory fitness is impaired in patients with AAA disease. Patients with peak oxygen uptake of <13.1 ml O2 kg−1 min−1 and ventilatory equivalent for carbon dioxide at anaerobic threshold ≥34 are associated with increased risk of postoperative mortality at 2 years. These findings demonstrate that cardiorespiratory fitness can predict mid‐term postoperative survival in AAA patients, which may help to direct care provision.
Preoperative cardiopulmonary exercise testing is a standard assessment of cardiorespiratory fitness (CRF) and risk stratification. However, to what extent CRF is impaired in patients undergoing surgical repair of abdominal aortic aneurysm (AAA) disease and the corresponding implications for postoperative outcome requires further investigation. We measured CRF during an incremental exercise test to exhaustion using online respiratory gas analysis in patients with AAA disease (n = 124, aged 72 ± 7 years) and healthy sedentary control subjects (n = 104, aged 70 ± 7 years). Postoperative survival was examined for association with CRF, and threshold values were calculated for independent predictors of mortality. Patients who underwent preoperative cardiopulmonary exercise testing before surgical repair had lower CRF age‐adjusted mean difference of 12.5 ml O2 kg−1 min−1 for peak oxygen uptake (V̇O2 peak ), P < 0.001 versus control subjects. After multivariable analysis, both V̇O2 peak and the ventilatory equivalent for carbon dioxide at anaerobic threshold (V̇E/V̇CO2− AT ) were independent predictors of mid‐term postoperative survival (2 years). Hazard ratios of 5.27 (95% confidence interval 1.62–17.14, P = 0.006) and 3.26 (95% confidence interval 1.00–10.59, P = 0.049) were observed for V̇O2 peak < 13.1 ml O2 kg−1 min−1 and V̇E/V̇CO2− AT ≥ 34, respectively. Thus, CRF is lower in patients with AAA, and those with a V̇O2 peak < 13.1 ml O2 kg−1 min−1 and V̇E/V̇CO2− AT ≥ 34 are associated with a markedly increased risk of postoperative mortality. Collectively, our findings demonstrate that CRF can predict mid‐term postoperative survival in AAA patients, which may help to direct care provision.
10nm logic technology using Si FinFET is developed for low power and high performance applications. Power-speed gain of 27% compared to 14nm technology node was obtained using four key developments: ...1) advanced gate stack engineering enabling 4 multi-Vt devices, 2) 3 rd generation Fin technology, 3) highly doped source/drain (S/D), and 4) contact resistance optimization. CVD liner for BEOL process was also applied for better metal fill capability. Finally yield of the smallest ever SRAM with 0.04um 2 SRAM bit-cell size was demonstrated.
PDF
