The prognostic significance of ataxia‐telangiectasia‐mutated (ATM) expression in gastric cancer remains unclear. The functional loss of ATM gene exhibits a biologic correlation with microsatellite ...instability (MSI). In this study, we investigated the significance of ATM expression with MSI by evaluating gastric cancer patients who had underwent curative resection. ATM expression was classified into low ATM expression (−, ±, +) and high ATM expression (++, +++) using immunohistochemistry analysis. MSI status was classified as MSI‐negative (MSS, MSI‐low) and MSI‐positive (MSI‐high). Of 321 patients, 205 (63.9%) exhibited low ATM expression and 116 (36.1%) exhibited high ATM expression. Low ATM expression was more frequently identified in patients of older age, more advanced stage and with MSI‐positive tumor (p = 0.025, p = 0.001 and p = 0.014, respectively). The probability of 5‐year disease‐free survival (DFS) and overall survival (OS) was lower in low ATM expression group compared with the high ATM expression group (DFS: 62.5%, 76.4%, p = 0.017, OS: 65.9%, 78.5%, p = 0.027, respectively). According to MSI status, a subgroup of MSI‐negative and low ATM expression cases exhibited the worst prognosis for DFS and OS; this subgroup also exhibited poorer DFS according to multivariable analysis (hazard radio = 1.8, 95% confidence interval, 1.2–2.8, p = 0.010), although prognostic value of ATM expression alone did not remain in the multivariable analysis. Taken together, these findings indicate that ATM expression with MSI status is an independent factor for gastric cancer prognosis in gastric cancer patients who received curative surgery.
What's new?
ATM is a protein kinase that controls the repair of double‐stranded breaks in DNA. Defective ATM has been reported in several types of tumors. Defects in a different type of DNA‐repair, mismatch repair, have been associated with microsatellite instability (MSI). In this study, however, the authors confirmed that MSI can also be associated with defective ATM function. In addition, they found that ATM expression plus MSI status may be a useful prognostic biomarker in gastric cancer. These results may be beneficial for further studies of agents that target the DNA‐repair pathways controlled by ATM.
We assessed the safety and immunogenicity of two recombinant DNA vaccines for COVID-19: GX-19 containing plasmid DNA encoding the SARS-CoV-2 spike protein, and GX-19N containing plasmid DNA encoding ...the SARS-CoV-2 receptor-binding domain (RBD) foldon, nucleocapsid protein, and plasmid DNA encoding the spike protein.
Two open-label non-randomised phase 1 trials, one of GX-19 and the other of GX-19N were done at two hospitals in South Korea. We enrolled healthy adults aged 19–49 years for the GX-19 trial and healthy adults aged 19–54 years for the GX-19N trial. Participants who tested positive by serological testing for SARS-CoV-2 were excluded. At 4-week intervals, the GX-19 trial participants received two vaccine doses (either 1·5 mg or 3·0 mg), and the GX-19N trial participants received two 3·0 mg doses. The vaccines were delivered intramuscularly using an electroporator. The participants were followed up for 52 weeks after first vaccination. Data collected up to day 57 after first vaccination were analysed in this interim analysis. The primary outcome was safety within 28 days after each vaccination measured in the intention-to-treat population. The secondary outcome was vaccine immunogenicity using blood samples collected on day 43 or 57 after first vaccination measured in the intention-to-treat population. The GX-19 (NCT044445389) and GX-19N (NCT04715997) trials are registered with ClinicalTrials.gov.
Between June 17 and July 30, 2020, we screened 97 individuals, of whom 40 (41%) participants were enrolled in the GX-19 trial (20 50% in the 1·5 mg group and 20 50% in the 3·0 mg group). Between Dec 28 and 31, 2020, we screened 23 participants, of whom 21 (91%) participants were enrolled on the GX-19N trial. 32 (52%) of 61 participants reported 80 treatment-emergent adverse events after vaccination. All solicited adverse events were mild except one (2%) case of moderate fatigue in the 1·5 mg GX-19 group; no serious vaccine-related adverse events were detected. Binding antibody responses increased after second dose of vaccination in all groups (p=0·0002 in the 1·5 mg GX-19 group; p<0·0001 in the 3·0 mg GX-19; and p=0·0004 for the spike protein and p=0·0001 for the RBD in the 3·0 mg GX-19N group).
GX-19 and GX-19N are safe and well tolerated. GX-19N induces humoral and broad SARS-CoV-2-specific T-cell responses. GX-19N shows lower neutralising antibody responses and needs improvement to enhance immunogenicity.
The Korea Drug Development Fund, funded by the Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare.
To evaluate the efficacy of a medical emergency team activated using 24-hour monitoring by electronic medical record-based screening criteria followed by immediate intervention by a skilled team.
...Retrospective cohort study.
Academic tertiary care hospital with approximately 2,700 beds.
A total of 3,030 events activated by a medical emergency team from March 1, 2008, to February 28, 2010.
None.
We collected data for all medical emergency team activations: patient characteristics, trigger type for medical emergency team (electronic medical record-based screening vs calling criteria), interventions during each event, outcomes of the medical emergency team intervention, and 28-day mortality after medical emergency team activation. We analyzed data for 2009, when the medical emergency team functioned 24 hours a day, 7 days a week (period 2), compared with that for 2008, when the medical emergency team functioned 12 hours a day, 7 days a week (period 1). The commonest cause of medical emergency team activation was respiratory distress (43.6%), and the medical emergency team performed early goal-directed therapy (21.3%), respiratory care (19.9%), and difficult airway management (12.3%). For patients on general wards, 51.3% (period 1) and 38.4% (period 2) of medical emergency team activations were triggered by the electronic medical record-based screening system (electronic medical record-triggered group). In 23.4%, activation occurred because of an abnormality in laboratory screening criteria. The commonest activation criterion from electronic medical record-based screening was respiratory rate (39.4%). Over half the patients were treated in the general ward, and one third of the patients were transferred to the ICU. The electronic medical record-triggered group had lower ICU admission with an odds ratio of 0.35 (95% CI, 0.22-0.55). In surgical patients, the electronic medical record-triggered group showed the lower 28-day mortality (10.5%) compared with the call-triggered group (26.7%) or the double-triggered group (33.3%) (odds ratio 0.365 with 95% CI, 0.154-0.867, p = 0.022).
We successful managed the medical emergency team with electronic medical record-based screening criteria and a skilled intervention team. The electronic medical record-triggered group had lower ICU admission than the call-triggered group or the double-triggered group. In surgical patients, the electronic medical record-triggered group showed better outcome than other groups.
The ferric uptake regulator (Fur) family proteins include sensors of Fe (Fur), Zn (Zur), and peroxide (PerR). Among Fur family proteins, Fur and Zur are ubiquitous in most prokaryotic organisms, ...whereas PerR exists mainly in Gram positive bacteria as a functional homologue of OxyR. Gram positive bacteria such as Bacillus subtilis, Listeria monocytogenes and Staphylococcus aureus encode three Fur family proteins: Fur, Zur, and PerR. In this study, we identified five Fur family proteins from B. licheniformis: two novel PerR-like proteins (BL00690 and BL00950) in addition to Fur (BL05249), Zur (BL03703), and PerR (BL00075) homologues. Our data indicate that all of the five B. licheniformis Fur homologues contain a structural Zn2+ site composed of four cysteine residues like many other Fur family proteins. Furthermore, we provide evidence that the PerR-like proteins (BL00690 and BL00950) as well as PerRBL (BL00075), but not FurBL (BL05249) and ZurBL (BL03703), can sense H2O2 by histidine oxidation with different sensitivity. We also show that PerR2 (BL00690) has a PerR-like repressor activity for PerR-regulated genes in vivo. Taken together, our results suggest that B. licheniformis contains three PerR subfamily proteins which can sense H2O2 by histidine oxidation not by cysteine oxidation, in addition to Fur and Zur.
Background:
Skeletal muscle depletion is prevalent in elderly patients and is associated with unfavorable outcomes in patients with chronic diseases. However, the relationship between skeletal muscle ...mass and neurological outcomes following in-hospital cardiac arrest (IHCA) has not been evaluated. The aim of this study was to investigate whether skeletal muscle status before cardiac arrest is an independent factor affecting neurological outcomes in patients with IHCA.
Methods:
We reviewed a prospectively enrolled registry of IHCA patients. Consecutive adult patients (>18 years) admitted to a tertiary care hospital from 2013 to 2019 were included in the study. Of these, 421 patients who underwent abdominopelvic computed tomography within 3 months of cardiac arrest were included. Skeletal muscle index (SMI) was measured at the third lumbar vertebra, and skeletal muscle depletion was defined using sex- and body mass index-specific cutoffs of SMI. The primary outcome was a Cerebral Performance Category score of 1 or 2 at 6 months after cardiac arrest, which was considered a good neurological outcome.
Results:
Of the 421 patients, 248 (58.9%) had skeletal muscle depletion before IHCA. The patients without skeletal muscle depletion showed significantly better neurological outcomes at 6 months after cardiac arrest than those with pre-arrest muscle depletion (20.8 vs. 10.9%,
p
= 0.004). The absence of skeletal muscle depletion was significantly associated with good neurological outcomes in a multivariable logistic analysis (OR = 3.49, 95% confidence intervals: 1.83–6.65,
p
< 0.001), along with the absence of diabetes, presence of active cancer, shockable rhythm, and short resuscitation duration.
Conclusion:
Pre-arrest skeletal muscle depletion was associated with long-term mortality and poor neurological outcomes after IHCA. Skeletal muscle depletion may be used as a tool to identify at-risk patients who may benefit from aggressive treatments.
Hair loss remains a significant problem that is difficult to treat; therefore, there is a need to identify safe natural materials that can help patients with hair loss. We evaluated the hair anagen ...activation effects of limonin, which is abundant in immature citrus fruits. Limonin increased the proliferation of rat dermal papilla cells (rDPC) by changing the levels of cyclin D1 and p27, and increasing the number of BrdU-positive cells. Limonin increased autophagy by decreasing phosphorylated mammalian target of rapamycin levels and increasing the phospho-Raptor, ATG7 and LC3B. Limonin also activated the Wnt/β-catenin pathway by increasing phospho-β-catenin levels. XAV939, a Wnt/β-catenin inhibitor, inhibited these limonin-induced changes, including induced autophagy, BrdU-positive cells, and cell proliferation. Limonin increased the phosphorylated AKT levels in both two-dimensional cultured rDPC and three-dimensional spheroids. Treatment with the PI3K inhibitor wortmannin inhibited limonin-induced proliferation, and disrupted other limonin-mediated changes, including decreased p27, increased BrdU-positive cells, induced autophagy, and increased ATG7 and LC3B levels. Wortmannin also inhibited limonin-induced cyclin D1 and LC3 expression in spheroids. Collectively, these results indicate that limonin can enhance anagen signaling by activating autophagy via targeting the Wnt/β-catenin and/or PI3K/AKT pathways in rDPC, highlighting a candidate nutrient for hair loss treatment.
Introduction
We aimed to investigate the risk factors associated with attention‐deficit hyperactivity disorder (ADHD) in children and adolescents using a nationally representative sample of the ...Korean population.
Methods
Data from children and adolescents aged less than 18 years (n = 23 561) were obtained from the Korean National Health and Nutrition Examination Survey, 2005 to 2014. ADHD was assessed using a self‐reported diagnosis of ADHD. We estimated the annual prevalence and number of Korean children and adolescents with physician‐diagnosed ADHD from 2005 to 2014. We considered various risk factors including demographics, obesity, and family environment (household income, parental age, depression in adults in the household, and exposure to environmental smoke at home). The relationship between ADHD and the considered risk factors was evaluated using multiple logistic regression.
Results
The annual prevalence of physician‐diagnosed ADHD showed a 4‐fold increase (0.35% in 2005 and 1.36% 2014) over the study period. Among ADHD patients, boys and girls constituted 78% and 22%, respectively. Total smoking amounts and depression in adults in the household were significantly associated with children's ADHD. When the analysis was limited to parental effects, only the father's smoking amount and depression were associated with the children's ADHD.
Discussion
This study identified adults' smoking and depression as family environmental factors associated with children's ADHD. From a public health care perspective, this result illuminates the need for awareness programs emphasizing a parent's conditions that may influence the development of ADHD in children.
The use of fluoroscopically-guided interventional (FGI) procedures by orthopedic surgeons has been increasing. This study aimed to investigate the occupational radiation exposure among orthopedic ...surgeons in South Korea.
A nationwide survey of orthopedic surgeons was conducted in South Korea in October 2017. The dosimetry data of the participants were obtained from the National Dosimetry Registry. The orthopedic surgeons were categorized by job specialty spine or trauma specialists, other orthopedic specialists, and residents, and descriptive statistics for the demographics and work-related characteristics were presented. Multivariable logistic regression analysis was used to evaluate the risk factors for the orthopedic surgeons who were not linked with the dosimetry data.
Among the total participants (
= 513), 40.5% of the orthopedic surgeons spent more than 50% of their time working with the FGI procedures when compared with their overall work. The average frequency of the FGI procedures among the orthopedic surgeons was 12.3 days per month. Less than 30% of the participants were regularly provided with radiation monitoring badges. The proportion of subjects who always wore lead aprons and thyroid shields were 52 and 29%, respectively. The residents group experienced more unfavorable working conditions of radiation exposure than the other specialists. The dosimetry data were not significantly linked among the residents (odds ratio OR 2.10, 95% confidence interval CI 1.11-3.95) and orthopedic surgeons working at small hospitals (OR 4.76, 95% CI 1.05-21.51).
Although orthopedic surgeons often performed FGI procedures, they wore protective gear less frequently, and a large proportion of orthopedic surgeons were not monitored by the national radiation dosimetry system. As the number of radiation procedures performed by the orthopedic surgeons increases, more intensive approaches are needed to reduce radiation exposure, especially for spine and trauma surgeons.
Peroxisome proliferator‐activated receptor (PPAR) δ is a promising therapeutic target in metabolic and inflammatory disorders. However, its role in oncogenesis is controversial, and its therapeutic ...potential remains to be determined. In our study, we show that ligand‐activated PPARδ forms a complex with the proto‐oncogene product c‐Myc. The interaction of PPARδ with c‐Myc affected the transcriptional activity of c‐Myc and the expression of its target genes. The PPARδ‐dependent regulation of c‐Myc activity was associated with decreased tumorigenicity in breast cancer cells. Administration of the PPARδ ligand GW501516 inhibited tumor growth in xenograft model mice bearing MDA‐MB‐231 cells stably expressing wild‐type PPARδ, but not those expressing dominant‐negative PPARδ, by interfering with c‐Myc function through protein–protein interaction. Our results indicating that PPARδ forms an antitumorigenic complex with c‐Myc in the presence of ligand suggest a potential role of PPARδ in breast cancer development.
What's new?
Peroxisome proliferator‐activated receptor (PPAR) δ is a promising therapeutic target in metabolic and inflammatory disorders. However, its role in oncogenesis is controversial, and its therapeutic potential remains to be determined. This study shows that ligand‐activated PPARδ forms a complex with the proto‐oncogene product c‐Myc. The interaction of PPARδ with c‐Myc represses the transcriptional activity of c‐Myc and expression of its target genes. The PPARδ‐dependent regulation of c‐Myc activity is associated with decreased tumorigenicity in breast cancer cells and xenograft model mice bearing MDA‐MB‐231 cells, providing a strong mechanistic rationale for therapeutic activation of PPARδ via its non‐genomic and genomic actions.
Background
Dacomitinib, an irreversible panHER inhibitor, shows significant preclinical antitumor activity in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). The aim of ...this study was to evaluate the clinical activity of dacomitinib and discover potential biomarkers in HER2-positive GC patients.
Methods
We enrolled previously treated advanced HER2-positive GC HER2 FISH (+) or HER2 IHC 3+ patients. The patients received dacomitinib 45 mg once daily.
Results
A total of 27 patients were enrolled. The number of prior chemotherapy regimens was 1 in 7 patients (26 %), 2 in 9 patients (33 %), and more than 2 in 11 patients (41 %). Seven patients had received prior anti-HER2 therapy. The 4-month progression-free survival (PFS) rate was 22.2 % and median PFS was 2.1 months (95 % CI, 2.3–3.4) There were 2 partial response (PRs) and 9 stable disease (SDs), resulting in 7.4 % (95 % CI, 0–17.5 %) of response rate (RR) and 40.7 % (95 % CI, 21.9–59.6 %) of disease control rate (DCR). Eleven patients (41 %) showed some degree of tumor shrinkage. Overall survival was 7.1 months (95 % CI, 4.4–9.8). The most common toxicities were skin rash, diarrhea, and fatigue, most of which were grade 1 or 2. The C
trough
of dacomitinib was lower in gastrectomy patients than nongastrectomy patients. Higher serum levels of HER2 extracellular domain (ECD) and lower levels of soluble E-cadherin (sECAD) correlated with higher dacomitinib activity.
Conclusions
Dacomitinib functions as a single agent in HER2-positive GC patients with a tolerable safety profile. HER2 ECD and sECAD have the potential to be biomarkers for patient selection in a panHER inhibition strategy for HER2-positive GC. (ClinicalTrials.gov: NCT01152853).
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