Sphingosine kinase1 (SphK1) is an acetyl-CoA dependent acetyltransferase which acts on cyclooxygenase2 (COX2) in neurons in a model of Alzheimer's disease (AD). However, the mechanism underlying this ...activity was unexplored. Here we show that N-acetyl sphingosine (N-AS) is first generated by acetyl-CoA and sphingosine through SphK1. N-AS then acetylates serine 565 (S565) of COX2, and the N-AS-acetylated COX2 induces the production of specialized pro-resolving mediators (SPMs). In a mouse model of AD, microglia show a reduction in N-AS generation, leading to decreased acetyl-S565 COX2 and SPM production. Treatment with N-AS increases acetylated COX2 and N-AS-triggered SPMs in microglia of AD mice, leading to resolution of neuroinflammation, an increase in microglial phagocytosis, and improved memory. Taken together, these results identify a role of N-AS in the dysfunction of microglia in AD.
PurposeThe National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) is a cohort of participants who participated in health screening programmes provided by the NHIS in the Republic of ...Korea. The NHIS constructed the NHIS-HEALS cohort database in 2015. The purpose of this cohort is to offer relevant and useful data for health researchers, especially in the field of non-communicable diseases and health risk factors, and policy-maker.ParticipantsTo construct the NHIS-HEALS database, a sample cohort was first selected from the 2002 and 2003 health screening participants, who were aged between 40 and 79 in 2002 and followed up through 2013. This cohort included 514 866 health screening participants who comprised a random selection of 10% of all health screening participants in 2002 and 2003.Findings to dateThe age-standardised prevalence of anaemia, diabetes mellitus, hypertension, obesity, hypercholesterolaemia and abnormal urine protein were 9.8%, 8.2%, 35.6%, 2.7%, 14.2% and 2.0%, respectively. The age-standardised mortality rate for the first 2 years (through 2004) was 442.0 per 100 000 person-years, while the rate for 10 years (through 2012) was 865.9 per 100 000 person-years. The most common cause of death was malignant neoplasm in both sexes (364.1 per 100 000 person-years for men, 128.3 per 100 000 person-years for women).Future plansThis database can be used to study the risk factors of non-communicable diseases and dental health problems, which are important health issues that have not yet been fully investigated. The cohort will be maintained and continuously updated by the NHIS.
Tg2576 transgenic mice for Alzheimer's disease (AD) exhibited significant phenotypes for neuropathological constipation, but no research has been conducted on the association of the fecal microbiota ...with dysbiosis. The correlation between fecal microbiota composition and neuropathological constipation in Tg2576 mice was investigated by examining the profile of fecal microbiota and fecal microbiota transplantation (FMT) in 9-10-month-old Tg2576 mice with the AD phenotypes and constipation. Several constipation phenotypes, including stool parameters, colon length, and histopathological structures, were observed prominently in Tg2576 mice compared to the wild-type (WT) mice. The fecal microbiota of Tg2576 mice showed decreases in Bacteroidetes and increases in the Firmicutes and Proteobacteria populations at the phylum level. The FMT study showed that stool parameters, including weight, water content, and morphology, decreased remarkably in the FMT group transplanted with a fecal suspension of Tg2576 mice (TgFMT) compared to the FMT group transplanted with a fecal suspension of WT mice (WFMT). The distribution of myenteric neurons and the interstitial cells of Cajal (ICC), as well as the enteric nervous system (ENS) function, remained lower in the TgFMT group. These results suggest that the neuropathological constipation phenotypes of Tg2576 mice may be tightly linked to the dysbiosis of the fecal microbiota.
•Epidemiologic features of the second and third waves of the coronavirus disease 2019 (COVID-19) pandemic in South Korea were compared.•Strengthening of social distancing policies was delayed in the ...third wave compared with the second wave.•The third wave persisted longer than the second wave, and had a higher case fatality rate.•Early public health intervention is important to control the COVID-19 pandemic.
To compare epidemiologic features of the second and third waves of the coronavirus disease 2019 (COVID-19) pandemic in South Korea.
Nationwide COVID-19 data were collected between 6 May and 30 December 2020. The degree of social activity was estimated using an Internet search trend analysis program for leisure-related keywords, including ‘eating-out’, ‘trip’ and ‘get directions’ (transportation). Demographics, transmission chains, case fatality rates, social activity levels and public health responses were compared between the second (13 August–18 September 2020) and third (4 November 2020–present) waves.
In comparison with the second wave, the third wave was characterized by delayed strengthening of social distancing policies (3 vs. 15 days), longer duration (36 vs. >56 days) and a higher case fatality rate (0.91% vs. 1.26%). There were significant differences in transmission chains between the second and third waves (P < 0.01). In comparison with the second wave, the proportion of local clusters (24.8% vs. 45.7%) was lower in the third wave, and personal contact transmission (38.5% vs. 25.9%) and unknown routes of transmission (23.5% vs. 20.8%) were higher in the third wave.
Early and timely interventions with strengthened social distancing policies should be implemented to suppress and control the COVID-19 pandemic effectively.
Background
Although recent advances in high-throughput technology have provided many insights into gastric cancer (GC), few reliable biomarkers for diffuse-type GC have been identified. Here, we aim ...to identify a prognostic and predictive signature of diffuse-type GC heterogeneity.
Methods
We analyzed RNA-seq-based transcriptome data to identify a molecular signature in 150 gastric tissue samples including 107 diffuse-type GCs. The predictive value of the signature was verified using other diffuse-type GC samples in three independent cohorts (
n
= 466). Log-rank and Cox regression analyses were used to estimate the association between the signature and prognosis. The signature was also characterized by somatic variant analyses and tissue microarray analysis between diffuse-type GC subtypes.
Results
Transcriptomic profiling of RNA-seq data identified a signature which revealed distinct subtypes of diffuse-type GC: the intestinal-like (INT) and core diffuse-type (COD) subtypes. The signature showed high predictability and independent clinical utility in diffuse-type GC prognosis in other patient cohorts (HR 2.058, 95% CI 1.53–2.77,
P
= 1.76 × 10
–6
). Integrative mutational and gene expression analyses demonstrated that the COD subtype was responsive to chemotherapy, whereas the INT subtype was responsive to immunotherapy with an immune checkpoint inhibitor (ICI). Tissue microarray analysis showed the practical utility of IGF1 and NXPE2 for predicting diffuse-type GC heterogeneity.
Conclusions
We present a molecular signature that can identify diffuse-type GC patients who display different clinical behaviors as well as responses to chemotherapy or ICI treatment.
Objectives:
Tumor-infiltrating lymphocytes (TILs) have prognostic significance in breast cancer. The tertiary lymphoid structure (TLS) is related to the influx of TILs, and expression of major ...histocompatibility complex (MHC) I in tumor cells is necessary for the effective action of TILs.
Methods:
We retrospectively evaluated the relationship of TILs and TLS and the expression of MHC I in 447 HER2-positive breast cancers treated with chemotherapy and 1 year of trastuzumab.
Results:
TILs were more abundant in hormone receptor (HR)−/HER2+ tumors than in HR+/HER2+ tumors. HR−/HER2+ breast cancers with abundant TILs showed a higher histologic grade, the absence of lymphovascular invasion, the presence of peritumoral lymphocytic infiltration, moderate to abundant TLSs in adjacent tissue, and stronger HLA-ABC and HLA-A expression. Abundant TILs and the absence of lymphovascular invasion were found to be good, independent prognostic factors for disease-free survival in patients with HR−/HER2+ breast cancer. The level of TILs was not associated with the patients’ prognosis in HR+ tumors.
Conclusions:
Abundant TILs are an independent prognostic factor in HR−/HER2+ breast cancers. Evaluation of TILs in HR−/HER2+ breast cancers may provide valuable information regarding the prognosis of patients treated using adjuvant chemotherapy and trastuzumab.
The prognostic significance of tumor-infiltrating lymphocytes and immune signals has been described previously in triple-negative breast cancer (TNBC). Furthermore, recent studies have shown that ...immunologic parameters are relevant for the response to neoadjuvant chemotherapy (NAC) in breast cancer as well as for outcomes after adjuvant chemotherapy. However, immune signals are variable, and which signals are important is largely unknown. We, therefore, evaluated the expression of immune-related genes in TNBC treated with NAC. We retrospectively evaluated biopsy tissue from 55 patients with primary TNBC treated with NAC (anthracycline, cyclophosphamide, and docetaxel) against the NanoString nCounter GX Human Immunology Panel (579 immune-related genes). Higher expression of cytotoxic molecules, T cell receptor signaling pathway components, cytokines related to T helper cell type 1 (Th1), and B cell markers was associated with a pathologic complete response (pCR). Higher expression of
NFKB1, MAPK1, TRAF1, CXCL13, GZMK,
and
IL7R
was significantly associated with pCR, higher Miller-Payne grade, and lower residual cancer burden class. Expression of
NFKB1, TRAF1,
and
CXCL13
genes, in particular, was significantly correlated with a longer disease-free survival rate. Conversely, patients those who failed to achieve a pCR showed increased expression of genes related to neutrophils. Higher expression of cytotoxic molecules, T cell receptor signaling pathway components, Th1-related cytokines, and B cell markers is correlated with pCR and survival in TNBC patients treated with NAC. Our results suggest that the activation status of neutrophils may provide additional predictive information for TNBC patients treated with NAC.
The source apportionment of volatile organic compounds (VOCs) was examined using receptor models (positive matrix factorization and chemical mass balance) and a chemical transport model (CTM). The ...receptor model-based analysis was performed using the datasets collected from four different sites from the megacity of Seoul during the years 2013–2015. The contributions of VOC emission sources to ozone (O3) and PM2.5 concentrations and the subsequent health effects in the study area were also assessed during a photochemically active period (June 2015) using a three-dimensional CTM, Community Multi-scale Air Quality (CMAQ), and the Environmental Benefits Mapping and Analysis Program (BenMAP). The solvent use and the on-road mobile emission sources were found to exert dominant controls on the VOC levels observed in the target city. VOCs transported from regions outside of Seoul accounted for a significant proportion (up to approximately 35%) of ambient VOC levels during the study period. The solvent use accounted for 3.4% of the ambient O3 concentrations during the day (daily mean of 2.6%) and made insignificant contributions to PM2.5 (<1%) during the simulation period. Biogenic VOC made insignificant contributions to O3 (<1%) and a small contribution to PM2.5 during the day (5.6% with a daily mean of 2.4%). The number of premature deaths attributed indirectly (O3 and PM2.5 formations via the oxidation of VOCs) to solvent use is expected to be significant.
Display omitted
•The solvent use and the on-road mobile emission sources exert dominant controls on the VOC levels.•VOCs transported from regions outside of Seoul accounted for a significant proportion of ambient VOC levels.•Biogenic VOC made insignificant contributions to O3 and PM2.5•The number of premature deaths attributed indirectly to solvent use is expected to be significant.
PDF
