Fas-associated protein with death domain (FADD) is a pivotal component of death receptor-mediated extrinsic apoptosis and necroptosis. Here we show that FADD is regulated by Makorin Ring Finger ...Protein 1 (MKRN1) E3 ligase-mediated ubiquitination and proteasomal degradation. MKRN1 knockdown results in FADD protein stabilization and formation of the rapid death-inducing signalling complex, which causes hypersensitivity to extrinsic apoptosis by facilitating caspase-8 and caspase-3 cleavage in response to death signals. We also show that MKRN1 and FADD are involved in the regulation of necrosome formation and necroptosis upon caspase inhibition. Downregulation of MKRN1 results in severe defects of tumour growth upon tumour necrosis factor-related apoptosis-inducing ligand treatment in a xenograft model using MDA-MB-231 breast cancer cells. Suppression of tumour growth by MKRN1 depletion is relieved by simultaneous FADD knockdown. Our data reveal a novel mechanism by which fas-associated protein with death domain is regulated via an ubiquitination-induced degradation pathway.
Myostatin (MSTN) is a well-reported negative regulator of muscle growth and a member of the transforming growth factor (TGF) family. MSTN has important functions in skeletal muscle (SM), and its ...crucial involvement in several disorders has made it an important therapeutic target. Several strategies based on the use of natural compounds to inhibitory peptides are being used to inhibit the activity of MSTN. This review delivers an overview of the current state of knowledge about SM and myogenesis with particular emphasis on the structural characteristics and regulatory functions of MSTN during myogenesis and its involvements in various muscle related disorders. In addition, we review the diverse approaches used to inhibit the activity of MSTN, especially
in silico
approaches to the screening of natural compounds and the design of novel short peptides derived from proteins that typically interact with MSTN.
Low-dose aspirin use for chemoprevention of lung cancer risk remains controversial.
To investigate the association between low-dose aspirin use and lung cancer risk, and to identify specific ...subgroups that may derive the most benefit from low-dose aspirin use.
This nationwide, retrospective, cohort study used data from the Korean National Health Information Database from 2002 to 2015. Data analyses were performed from October 2016 to December 2018. Eligible participants (n = 12 969 400) were people aged 40 to 84 years who had undergone national health screening between 2009 and 2010 and had no history of lung cancer between 2006 and 2010 and no standard-dose aspirin use for 6 months between 2002 and 2010.
The duration of low-dose aspirin use between January 2002 and December 2010 was calculated for each participant. Lung cancer was defined as the first recorded diagnosis of lung cancer-using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and expanding benefit coverage-between January 2011 and December 2015.
A total of 63 040 participants with a mean (SD) age of 66.4 (9.3) years received a diagnosis of lung cancer. Of these, 45 156 (71.6%) were men. The incidence rate of lung cancer was 98.8 per 100 000 person-years. The duration of low-dose aspirin use was none for 10 987 417 participants (84.7%), 1 to 2 years for 750 992 participants (5.8%), 3 to 4 years for 506 945 participants (3.9%), 5 to 6 years for 371 062 participants (2.9%), 7 to 8 years for 240 528 participants (1.9%), and 9 years for 112 456 participants (0.9%). Compared with no aspirin use, 5 to 6 years (adjusted hazard ratio, 0.96 95% CI, 0.92-0.99), 7 to 8 years (adjusted hazard ratio, 0.94 95% CI, 0.90-0.99), and 9 years (adjusted hazard ratio, 0.89 95% CI, 0.84-0.94) of aspirin use were significantly associated with reduced lung cancer risk. After stratified analysis, a significant reduction of lung cancer risk was observed among people aged 65 years or older and among people without diabetes.
Although the use of low-dose aspirin for more than 5 years was associated with decreased risk of lung cancer, particularly among elderly participants and among people without diabetes, the observed effect size was quite modest. Future prospective studies are needed to determine whether there is a causal association.
From 2002 through 2015, hundreds of people died of fatal lung injuries associated with the use of humidifier disinfectants (HDs) in Korea. Several chemical disinfectants used for household ...humidifiers were later clinically confirmed to cause HD-associated lung injury (HDLI). The aim of this study is to evaluate the registered lung disease cases and to compare the distribution of HDLI patients, including deaths, by HD use characteristics including types of HD and HD brands categorized by age group. A total of 530 registered were clinically examined through two rounds of investigations conducted from July 2013 until April 2015. Information on HD use was obtained from a structured questionnaire and home investigations. Approximately one-half of the patients (n=221) were clinically confirmed to be associated with the use of HDs. Pregnant women (n=35, 16%) and pre-school children≤6years old (n=128, 58%) accounted for most of the HD-associated lung injury patients (n=163, 74%). Sixty-seven percent of HDLI patients developed HDLI after less than one year of HD use. HD products containing polyhexamethylene guanidine phosphate (PHMG) were the most frequently used among confirmed HDLI patients (n=123, 55.7%), followed by oligo (2-(2-ethoxy) ethoxyethyl guanidinium (PGH) (n=24, 10.9%) and a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) (n=3, 1.4%). Other HDs did not appear to be linked to HDLI. The majority of the HDLI patients (n=85, 38.5%) was found to use only Oxy Saksak® products containing PHMG. The development of HDLI was clinically found to be associated with the use of several HD products containing PHMG and PGH, and to lesser extent, CMIT/MIT.
Display omitted
•221 fatal lung injury (LI) patients were confirmed to be clinically associated with the use of HD.•67% of HD-associated LI patients developed HDLI after less than one year of HD use.•Pregnant women (n=35) and pre-school children (n=128) accounted for 74% of HDLI.•HDLI patients (n=221) responded to use HD brands containing PHMG (n=123) and PGH (n=24).
Abstract
Objective
AS is a rheumatic disease characterized by chronic inflammation and bony ankylosis. This study was to evaluate whether a signal transducer and activator of transcription 3 ...phosphorylation inhibitor (stat3-p Inh) could treat both chronic inflammation and bone formation in AS.
Methods
Primary AS osteoprogenitor cells and spinal entheseal cells were examined for osteogenic differentiation. SF mononuclear cells (SFMCs) and lamina propria mononuclear cells (LPMCs) were obtained from AS patients. Inflammatory cytokine-producing cells were analysed using flow cytometry and ELISA. Female SKG mice were treated with stat3-p Inh, IL-17A blocker or vehicle. Inflammation and new bone formation were evaluated using immunohistochemistry, PET and micro-CT.
Results
In the SKG mouse model, stat3-p Inh significantly suppressed arthritis, enthesitis, spondylitis and ileitis. In experiments culturing SFMCs and LPMCs, the frequencies of IFN-γ-, IL-17A- and TNF-α-producing cells were significantly decreased after stat3-p Inh treatment. When comparing current treatments for AS, stat3-p Inh showed a comparable suppression effect on osteogenesis to Janus kinase inhibitor or IL-17A blocker in AS-osteoprogenitor cells. Stat3-p Inh suppressed differentiation and mineralization of AS-osteoprogenitor cells and entheseal cells toward osteoblasts. Micro-CT analysis of hind paws revealed less new bone formation in stat3-p Inh-treated mice than vehicle-treated mice (P = 0.005). Hind paw and spinal new bone formation were similar between stat3-p Inh- and anti-IL-17A-treated SKG mice (P = 0.874 and P = 0.117, respectively).
Conclusion
Stat-3p inhibition is a promising treatment for both inflammation and new bone formation in AS.
Alzheimer's disease (AD) is the most common dementia, and no disease-modifying therapeutic agents are currently available. BDNF/TrkB signaling is impaired in AD and is associated with prominent ...delta-secretase (δ-secretase, also known as asparaginyl endopeptidase or legumain) activation, which simultaneously cleaves both APP and Tau and promotes Aβ production and neurofibrillary tangles (NFT) pathologies. Here we show that the optimized δ-secretase inhibitor (#11a) or TrkB receptor agonist (CF3CN) robustly blocks δ-secretase activity separately, and their combination synergistically blunts δ-secretase, exhibiting promising therapeutic efficacy in 3xTg AD mouse model. The optimal δ-secretase inhibitor reveals demonstrable brain exposure and oral bioavailability, suppressing APP N585 and Tau N368 cleavage by δ-secretase. Strikingly, CF3CN treatment evidently escalates BDNF levels. Both #11a and CF3CN display strong in vivo PK/PD properties and ability to suppress δ-secretase activity in the brain. Orally administrated CF3CN strongly activates TrkB that triggers active Akt to phosphorylate δ-secretase T322, preventing its proteolytic activation and mitigating AD pathologies. #11a or CF3CN significantly diminishes AD pathogenesis and improves cognitive functions with the combination exhibiting the maximal effect. Thus, our data support that these derivatives are strong pharmaceutical candidates for the treatment of AD.
Display omitted
∙Optimized δ-secretase inhibitor (#11a) and TrkB receptor agonist (CF3CN) combination synergistically blunts δ-secretase.∙CF3CN strongly activates p-TrkB that triggers active Akt to phosphorylate δ-secretase T322, preventing its proteolytic activation and mitigating AD pathologies.∙#11a or CF3CN significantly diminishes AD pathogenesis and improves cognitive functions with the combination exhibiting the maximal effect.
The number of lower extremity amputations in diabetic foot patients in Korea is increasing annually. In this nationwide population-based retrospective study, we investigated the data of 420,096 ...diabetes mellitus patients aged ≥18 years using the Korean Health Insurance Review and Assessment Service claim database. We aimed to study the seasonal and monthly trends in diabetic foot amputations in Korea. After applying the inclusion criteria, 8156 amputation cases were included. The analysis showed an increasing trend in monthly amputation cases. In terms of seasonality, the monthly frequency of amputation was commonly observed to be lower in February and September every year. Diabetic foot amputations frequently occurred in March, July, and November. There was no difference between the amputation frequency and mean temperature/humidity. This study is meaningful as it is the first nationwide study in Korea to analyze the seasonal and monthly trends in diabetic foot amputation in relation to climatic factors. In conclusion, we recognize an increased frequency of amputation in March, July, and November and recommend intensive educational program on foot care for all diabetes patients and their caregivers. This could improve wound management and amputation prevention guidelines for diabetic foot patients in the Far East with information on dealing with various seasonal changes.
ABSTRACT
Background
Epistasis and gene‐environment interactions are known to contribute significantly to variation of complex phenotypes in model organisms. However, their identification in human ...association studies remains challenging for myriad reasons. In the case of epistatic interactions, the large number of potential interacting sets of genes presents computational, multiple hypothesis correction, and other statistical power issues. In the case of gene‐environment interactions, the lack of consistently measured environmental covariates in most disease studies precludes searching for interactions and creates difficulties for replicating studies.
Results
In this work, we develop a new statistical approach to address these issues that leverages genetic ancestry, defined as the proportion of ancestry derived from each ancestral population (e.g., the fraction of European/African ancestry in African Americans), in admixed populations. We applied our method to gene expression and methylation data from African American and Latino admixed individuals, respectively, identifying nine interactions that were significant at P<5×10−8. We show that two of the interactions in methylation data replicate, and the remaining six are significantly enriched for low P‐values (P<1.8×10−6).
Conclusion
We show that genetic ancestry can be a useful proxy for unknown and unmeasured covariates in the search for interaction effects. These results have important implications for our understanding of the genetic architecture of complex traits.
Radiation exposure to the patient has become a concern for the radiologist in the multidetector computed tomography (CT) era. With the introduction of faster multidetector CT scanners, various ...techniques have been developed to reduce the radiation dose to the patient; one method is automatic exposure control (AEC). AEC systems make use of different types of control, including patient-size AEC, z-axis AEC, rotational or angular AEC, or a combination of two or more of these types. AEC systems operate on the basis of several methods: standard deviation, noise index, reference milliamperage, and reference image. A clear understanding of how to use different AEC systems on different multidetector CT scanners will allow users to modulate radiation dose, reduce photon starvation artifacts, and maintain image quality throughout the body. Further development of AEC systems and their successful introduction into clinical practice will require user education and good communication between users and manufacturers.
PDF
