Comparison of the prevalence of osteoporosis in people with spinal cord injury according to bone mineral density reference values for the diagnosis of osteoporosis: a retrospective, cross-sectional study.

BACKGROUND: Spinal cord injury (SCI) is a complex cause of rapid low bone mass that easily predisposes the affected individuals to osteoporosis-induced fractures. Several studies have investigated osteoporosis pathophysiology in SCI; however, those associated with its diagnosis in SCI are limited. Additionally, errors in osteoporosis diagnosis and its prevalence vary based on the bone mineral density (BMD) reference values (BMDRV), and no studies have reported BMDRV application for osteoporosis diagnosis in individuals with SCI. Therefore, this study aimed to compare the prevalence of osteoporosis among Korean adults aged ≥ 50 years with SCI according to BMDRV for diagnosing osteoporosis. METHODS: Overall, 855 patients with SCI who underwent BMD tests of the lumbar spine, femoral neck, and total hip at the National Rehabilitation Center (NRC) in Korea between 2010 and 2020 were included in this retrospective cross-sectional study. Osteoporosis was diagnosed in patients with SCI by comparing the differences in prevalence, diagnostic consistency, and risk factors according to the region-based BMDRV of the dual-energy x-ray absorptiometry (DXA) manufacturer and international BMDRV based on the Third National Health and Nutrition Examination Survey (NHANES III) data of females aged 20-29 years. RESULTS: The prevalence of osteoporosis according to the T-score provided by a single reference population of the NHANES III (TNHA) (PONHA) (males: 26.69%; females: 69.35%) was significantly higher in females and males than that according to the T-scores provided by the DXA manufacturer (TDXA) (PODXA) (males: 15.32%; females: 43.15%). The lumbar spine and femoral neck were major osteoporosis diagnosis sites for the PODXA and PONHA, respectively. Risk factors for osteoporosis differed based on the probability of osteoporosis (also known as the OZ ratio) according to the BMD criteria; however, the risk factors were similar according to old age, female sex, low body mass index (BMI), and long SCI period. No significant relationship was noted between the different SCI-related clinical factors (p > 0.05). CONCLUSIONS: The osteoporosis diagnostic site and prevalence in SCI differed according to the regional-based TDXA and international standards of the TNHA. Therefore, further studies on BMDRV are warranted to establish accurate diagnostic criteria for osteoporosis prevention in patients with SCI.

Mycorrhizal Fungal Diversity Associated with Six Understudied Ectomycorrhizal Trees in the Republic of Korea.

Mycorrhizal fungi are key components of forest ecosystems and play essential roles in host health. The host specificity of mycorrhizal fungi is variable and the mycorrhizal fungi composition for the dominant tree species is largely known but remains unknown for the less common tree species. In this study, we collected soil samples from the roots of six understudied ectomycorrhizal tree species from a preserved natural park in the Republic of Korea over four seasons to investigate the host specificity of mycorrhizal fungi in multiple tree species, considering the abiotic factors. We evaluated the mycorrhizal fungal composition in each tree species using a metabarcoding approach. Our results revealed that each host tree species harbored unique mycorrhizal communities, despite close localization. Most mycorrhizal taxa belonged to ectomycorrhizal fungi, but a small proportion of ericoid mycorrhizal fungi and arbuscular mycorrhizal fungi were also detected. While common mycorrhizal fungi were shared between the plant species at the genus or higher taxonomic level, we found high host specificity at the species/OTU (operational taxonomic unit) level. Moreover, the effects of the seasons and soil properties on the mycorrhizal communities differed by tree species. Our results indicate that mycorrhizal fungi feature host-specificity at lower taxonomic levels.

XAF1 drives apoptotic switch of endoplasmic reticulum stress response through destabilization of GRP78 and CHIP.

X-linked inhibitor of apoptosis-associated factor-1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in many human cancers. Despite accumulating evidence for the pro-apoptotic role for XAF1 under various stressful conditions, its involvement in endoplasmic reticulum (ER) stress response remains undefined. Here, we report that XAF1 increases cell sensitivity to ER stress and acts as a molecular switch in unfolded protein response (UPR)-mediated cell-fate decisions favoring apoptosis over adaptive autophagy. Mechanistically, XAF1 interacts with and destabilizes ER stress sensor GRP78 through the assembly of zinc finger protein 313 (ZNF313)-mediated destruction complex. Moreover, XAF1 expression is activated through PERK-Nrf2 signaling and destabilizes C-terminus of Hsc70-interacting protein (CHIP) ubiquitin E3 ligase, thereby blocking CHIP-mediated K63-linked ubiquitination and subsequent phosphorylation of inositol-required enzyme-1α (IRE1α) that is involved in in the adaptive ER stress response. In tumor xenograft assays, XAF1-/- tumors display substantially lower regression compared to XAF1+/+ tumors in response to cytotoxic dose of ER stress inducer. XAF1 and GRP78 expression show an inverse correlation in human cancer cell lines and primary breast carcinomas. Collectively this study uncovers an important role for XAF1 as a linchpin to govern the sensitivity to ER stress and the outcomes of UPR signaling, illuminating the mechanistic consequence of XAF1 inactivation in tumorigenesis.

The CDK1/TFCP2L1/ID2 cascade offers a novel combination therapy strategy in a preclinical model of bladder cancer.

Aberrant activation of embryogenesis-related molecular programs in urothelial bladder cancer (BC) is associated with stemness features related to oncogenic dedifferentiation and tumor metastasis. Recently, we reported that overexpression of transcription factor CP2-like protein-1 (TFCP2L1) and its phosphorylation at Thr177 by cyclin-dependent kinase-1 (CDK1) play key roles in regulating bladder carcinogenesis. However, the clinical relevance and therapeutic potential of this novel CDK1-TFCP2L1 molecular network remain elusive. Here, we demonstrated that inhibitor of DNA binding-2 (ID2) functions as a crucial mediator by acting as a direct repressive target of TFCP2L1 to modulate the stemness features and survival of BC cells. Low ID2 and high CDK1 expression were significantly associated with unfavorable clinical characteristics. TFCP2L1 downregulated ID2 by directly binding to its promoter region. Consistent with these findings, ectopic expression of ID2 or treatment with apigenin, a chemical activator of ID2, triggered apoptosis and impaired the proliferation, suppressed the stemness features, and reduced the invasive capacity of BC cells. Combination treatment with the specific CDK1 inhibitor RO-3306 and apigenin significantly suppressed tumor growth in an orthotopic BC xenograft animal model. This study demonstrates the biological role and clinical utility of ID2 as a direct target of the CDK1-TFCP2L1 pathway for modulating the stemness features of BC cells.

Trends in the high blood glucose and non-alcoholic fatty liver disease among Korean adolescents.

High blood glucose level and non-alcoholic fatty liver disease (NAFLD) in adolescents are long-term risk factors for cardiovascular diseases and poor prognosis. We investigated recent trends of high blood glucose levels and NAFLD among Korean adolescents aged 12-18 years. We conducted a cross-sectional analysis using data of 5,685 adolescents aged 12-18 years from the Korea National Health and Nutrition Examination Surveys (KNHANES), from 2007-2009 to 2016-2018. Linear trends in the prevalence of high blood glucose level, NAFLD, and associated factors were assessed using multivariable logistic regression analyses. During the study period, the odds ratios for high blood glucose level and NAFLD increased significantly in both sexes and in girls, respectively (p for trend <0.05). Over-consumption of total calories in boys and fat intake in boys and girls increased significantly (p for trend <0.05). In Korean adolescents, the prevalence of high blood glucose level and NAFLD has increased recently. Efforts to modify the associated factors and further research to determine the public health measures are warranted to prevent these metabolic abnormalities in adolescents.

XAF1 destabilizes estrogen receptor α through the assembly of a BRCA1-mediated destruction complex and promotes estrogen-induced apoptosis.

X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a pro-apoptotic tumor suppressor that is frequently inactivated in multiple human cancers. However, its candidacy as a suppressor in the pathogenesis of breast cancer remains undefined. Here, we report that XAF1 acts as a molecular switch in estrogen (E2)-mediated cell-fate decisions favoring apoptosis over cell proliferation. XAF1 promoter hypermethylation is observed predominantly in estrogen receptor α (ERα)-positive versus ERα-negative tumor cells and associated with attenuated apoptotic response to E2. XAF1 is activated by E2 through a G protein-coupled estrogen receptor-mediated non-genomic pathway and induces ERα degradation and apoptosis while it is repressed by ERα for E2 stimulation of cell proliferation. The XAF1-ERα mutual antagonism dictates the outcomes of E2 signaling and its alteration is linked to the development of E2-resistant tumors. Mechanistically, XAF1 destabilizes ERα through the assembly of breast cancer-associated gene 1 (BRCA1)-mediated destruction complex. XAF1 interacts with ERα and BRCA1 via the zinc finger (ZF) domains 5/6 and 4, respectively, and the mutants lacking either of these domains fail to drive ERα ubiquitination and apoptosis. E2-induced regression of XAF1+/+ tumors is abolished by XAF1 depletion while XAF1-/- tumors recover E2 response by XAF1 restoration. XAF1 and ERα expression show an inverse correlation in primary breast tumors, and XAF1 expression is associated with the overall survival of patients with ERα-positive but not ERα-negative cancer. Together, this study uncovers an important role for the XAF1-ERα antagonism as a linchpin to govern E2-mediated cell-fate decisions, illuminating the mechanistic consequence of XAF1 alteration in breast tumorigenesis.

XAF1 directs glioma response to temozolomide through apoptotic transition of autophagy by activation of ATM-AMPK signaling.

Background: X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a tumor suppressor that is commonly inactivated in multiple human cancers. However, its role in the pathogenesis and therapeutic response of glioma is poorly characterized. Methods: XAF1 activation by temozolomide (TMZ) and its effect on TMZ cytotoxicity were defined using luciferase reporter, flow cytometry, and immunofluorescence assays. Signaling mechanism was analyzed using genetic and pharmacologic experiments. In vivo studies were performed in mice to validate the role of XAF1 in TMZ therapy. Results: Epigenetic alteration of XAF1 is frequent in cell lines and primary tumors and contributes to cancer cell growth. XAF1 transcription is activated by TMZ via JNK-IRF-1 signaling to promote apoptosis while it is impaired by promoter hypermethylation. In tumor cells expressing high O 6-methylguanine-DNA methyltransferase (MGMT), XAF1 response to TMZ is debilitated. XAF1 facilitates TMZ-mediated autophagic flux to direct an apoptotic transition of protective autophagy. Mechanistically, XAF1 is translocated into the mitochondria to stimulate reactive oxygen species (ROS) production and ataxia telangiectasia mutated (ATM)-AMP-activated protein kinase (AMPK) signaling. A mutant XAF1 lacking the zinc finger 6 domain fails to localize in the mitochondria and activate ROS-ATM-AMPK signaling and autophagy-mediated apoptosis. XAF1-restored xenograft tumors display a reduced growth rate and enhanced therapeutic response to TMZ, which is accompanied with activation of ATM-AMPK signaling. XAF1 expression is associated with overall survival of TMZ treatment patients, particularly with low MGMT cancer. Conclusions: This study uncovers an important role for the XAF1-ATM-AMPK axis as a linchpin to govern glioma response to TMZ therapy.

Intravital imaging and single cell transcriptomic analysis for engraftment of mesenchymal stem cells in an animal model of interstitial cystitis/bladder pain syndrome.

Mesenchymal stem cell (MSC) therapy is a promising treatment for various intractable disorders including interstitial cystitis/bladder pain syndrome (IC/BPS). However, an analysis of fundamental characteristics driving in vivo behaviors of transplanted cells has not been performed, causing debates about rational use and efficacy of MSC therapy. Here, we implemented two-photon intravital imaging and single cell transcriptome analysis to evaluate the in vivo behaviors of engrafted multipotent MSCs (M-MSCs) derived from human embryonic stem cells (hESCs) in an acute IC/BPS animal model. Two-photon imaging analysis was performed to visualize the dynamic association between engrafted M-MSCs and bladder vasculature within live animals until 28 days after transplantation, demonstrating the progressive integration of transplanted M-MSCs into a perivascular-like structure. Single cell transcriptome analysis was performed in highly purified engrafted cells after a dual MACS-FACS sorting procedure and revealed expression changes in various pathways relating to pericyte cell adhesion and cellular stress. Particularly, FOS and cyclin dependent kinase-1 (CDK1) played a key role in modulating the migration, engraftment, and anti-inflammatory functions of M-MSCs, which determined their in vivo therapeutic potency. Collectively, this approach provides an overview of engrafted M-MSC behavior in vivo, which will advance our understanding of MSC therapeutic applications, efficacy, and safety.

Gene Expression Profiles of Multiple Synchronous Lesions in Lung Adenocarcinoma.

Many studies support a stepwise continuum of morphologic changes between atypical adenomatous hyperplasia (AAH) and lung adenocarcinoma (ADC). Here we characterized gene expression patterns and the association of differentially expressed genes and immune tumor microenvironment behaviors in AAH to ADC during ADC development. Tumor tissues from nine patients with ADC and synchronous multiple ground glass nodules/lesions (GGN/Ls) were analyzed using RNA sequencing. Using clustering, we identified genes differentially and sequentially expressed in AAH and ADC compared to normal tissues. Functional enrichment analysis using gene ontology terms was performed, and the fraction of immune cell types was estimated. We identified up-regulated genes (ACSL5 and SERINC2) with a stepwise change of expression from AAH to ADC and validated those expressions by quantitative PCR and immunohistochemistry. The immune cell profiles revealed increased B cell activities and decreased natural killer cell activities in AAH and ADC. A stepwise change of differential expression during ADC development revealed potential effects on immune function in synchronous precursors and in tumor lesions in patients with lung cancer.

Body Shape Indices in Adolescents Based on the 2009-2012 Korea National Health and Nutrition Examination Survey.

A Body Shape Index (ABSI) is a recently proposed index for standardizing waist circumference (WC) for body mass index (BMI) and height in adults, using 2/3 and 1/2 as scaling exponents, respectively. However, ABSI has limited applicability to children and adolescents, as the relationship between height and weight changes with age and varies according to sex. This study aimed to investigate whether ABSI can be applied to adolescents and to analyze the relationships among BMI, WC, height, weight, and body shape index (BSI) in Korean adolescents. The data of 1023 adolescents aged 10-19 years from the 2009-2012 Korea National Health and Nutrition Examination Survey were collected. Body measurements (height, weight, WC, and BMI) were analyzed to estimate the BSI using log-linear regression. The scaling exponents for standardizing WC for weight and height were estimated according to age (per year) and sex. The scaling exponents for standardizing WC for weight and height were 0.698 and -1.090 for boys and 0.646 and -0.855 for girls, respectively. The exponents also differed according to age. BSI was negatively correlated with height, weight, and BMI in boys and girls, and these correlations differed in direction from those in adults. ABSI cannot be applied to adolescents. In adolescents, the BSI is dependent on age and sex and is associated with growth and puberty. Further studies are required to evaluate the association between BSI and other biomarkers, to improve its applicability as a parameter for predicting the risk of chronic diseases in adolescents.

Effects of government policies on the spread of COVID-19 worldwide.

The outbreak of novel COVID-19 disease elicited a wide range of anti-contagion and economic policies like school closure, income support, contact tracing, and so forth, in the mitigation and suppression of the spread of the SARS-CoV-2 virus. However, a systematic evaluation of these policies has not been made. Here, 17 implemented policies from the Oxford COVID-19 Government Response Tracker dataset employed in 90 countries from December 31, 2019, to August 31, 2020, were analyzed. A Poisson regression model was applied to analyze the relationship between policies and daily confirmed cases using a generalized estimating equations approach. A lag is a fixed time displacement in time series data. With that, lagging (0, 3, 7, 10, and 14 days) was also considered during the analysis since the effects of policies implemented on a given day may affect the number of confirmed cases several days after implementation. The countries were divided into three groups depending on the number of waves of the pandemic observed in each country. Through subgroup analysis, we showed that with and without lagging, contact tracing and containment policies were significant for countries with two waves, while closing, economic, and health policies were significant for countries with three waves. Wave-specific analysis for each wave showed that significant health, economic, and containment policies varied across waves of the pandemic. Emergency investment in healthcare was consistently significant among the three groups of countries, while the Stringency index was significant among all waves of the pandemic. These findings may help in making informed decisions regarding whether, which, or when these policies should be intensified or lifted.

Which National Factors Are Most Influential in the Spread of COVID-19?

The outbreak of the novel COVID-19, declared a global pandemic by WHO, is the most serious public health threat seen in terms of respiratory viruses since the 1918 H1N1 influenza pandemic. It is surprising that the total number of COVID-19 confirmed cases and the number of deaths has varied greatly across countries. Such great variations are caused by age population, health conditions, travel, economy, and environmental factors. Here, we investigated which national factors (life expectancy, aging index, human development index, percentage of malnourished people in the population, extreme poverty, economic ability, health policy, population, age distributions, etc.) influenced the spread of COVID-19 through systematic statistical analysis. First, we employed segmented growth curve models (GCMs) to model the cumulative confirmed cases for 134 countries from 1 January to 31 August 2020 (logistic and Gompertz). Thus, each country's COVID-19 spread pattern was summarized into three growth-curve model parameters. Secondly, we investigated the relationship of selected 31 national factors (from KOSIS and Our World in Data) to these GCM parameters. Our analysis showed that with time, the parameters were influenced by different factors; for example, the parameter related to the maximum number of predicted cumulative confirmed cases was greatly influenced by the total population size, as expected. The other parameter related to the rate of spread of COVID-19 was influenced by aging index, cardiovascular death rate, extreme poverty, median age, percentage of population aged 65 or 70 and older, and so forth. We hope that with their consideration of a country's resources and population dynamics that our results will help in making informed decisions with the most impact against similar infectious diseases.

A Preclinical Study of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells for Treating Detrusor Underactivity by Chronic Bladder Ischemia.

BACKGROUND: The therapeutic effects of human embryonic stem cell-derived multipotent mesenchymal stem cells (M-MSCs) were evaluated for detrusor underactivity (DUA) in a rat model with atherosclerosis-induced chronic bladder ischemia (CBI) and associated mechanisms. METHODS: Sixteen-week-old male Sprague-Dawley rats were divided into five groups (n = 10). The DUA groups underwent 30 bilateral repetitions of endothelial injury to the iliac arteries to induce CBI, while the sham control group underwent a sham operation. All rats used in this study received a 1.25% cholesterol diet for 8 weeks. M-MSCs at a density of 2.5, 5.0, or 10.0 × 105 cells (250 K, 500 K, or 1000 K; K = a thousand) were injected directly into the bladder 7 weeks post-injury, while the sham and DUA group were treated only with vehicle (phosphate buffer solution). One week after M-MSC injection, awake cystometry was performed on the rats. Then, the bladders were harvested, studied in an organ bath, and prepared for histological and gene expression analyses. RESULTS: CBI by iliac artery injury reproduced voiding defects characteristic of DUA with decreased micturition pressure, increased micturition interval, and a larger residual volume. The pathological DUA properties were improved by M-MSC treatment in a dose-dependent manner, with the 1000 K group producing the best efficacy. Histological analysis revealed that M-MSC therapy reduced CBI-induced injuries including bladder fibrosis, muscular loss, and apoptosis. Transplanted M-MSCs mainly engrafted as vimentin and NG2 positive pericytes rather than myocytes, leading to increased angiogenesis in the CBI bladder. Transcriptomes of the CBI-injured bladders were characterized by the complement system, inflammatory, and ion transport-related pathways, which were restored by M-MSC therapy. CONCLUSIONS: Single injection of M-MSCs directly into the bladder of a CBI-induced DUA rat model improved voiding profiles and repaired the bladder muscle atrophy in a dose-dependent manner.

Relationship of domain-specific quality of life with body mass index and waist circumference in a Korean elderly population.

BACKGROUND: Obesity affects health-related quality of life (QoL); however, their relationship among elderly Asians is not well known. AIMS: Relationship of domain-specific QoL with body mass index (BMI) and waist circumference and the sex differences were investigated using a nationally representative sample of elderly Korean population. METHODS: In the Korea National Health and Nutrition Examination Survey phase VII (2016-2018), 3659 adults aged ≥ 65 years (1551 men and 2108 women) participated. BMI and waist circumference were classified according to Asian- and Korean-specific criteria. QoL was evaluated using the European Quality of Life Scale-Five Dimensions (EQ-5D). Multivariable logistic regressions were used to examine the relationship of QoL with BMI and waist circumference. RESULTS: Men with BMI < 18.5 kg/m2 and ≥ 25.0 kg/m2 had a significant association with poor QoL in mobility and self-care, but no relationship was found with the other domains. Women with BMI ≥ 25.0 kg/m2 had poor QoL in mobility and self-care, and those with BMI ≥ 30.0 kg/m2 had poor QoL in usual activities and pain/discomfort. There was no significant association with anxiety/depression. Both elderly men and women with abdominal obesity had a significant association with poor QoL in mobility, self-care, usual activities, and pain/discomfort; however, there was no significant relationship with waist circumference and anxiety/depression. CONCLUSIONS: The association between QoL and BMI was different according to sex and the domains of QoL. Domain-specific QoL should be considered in the management of body weight of the elderly.

Correlation between Serum Lipid Parameters and Interleukin-10 Concentration in Obese Individuals.

Background: The role of interleukin-10 (IL-10) in humans is controversial because IL-10 has been proposed to exhibit both pro- and anti-inflammatory effects. We aimed to determine the relationships between the changes in these parameters in obese individuals participating in a weight-reduction program. Methods: We measured cardiometabolic parameters including lipid profile and serum IL-10 concentration before and after completion of a 12-week weight-reduction program in 63 non-diabetic obese subjects with a body mass index ≥27 kg/m2 who had comorbid hypertension or dyslipidemia. All the participants were provided with individual intervention sessions designed to implement lifestyle modifications and administered 120 mg orlistat three times daily for 12 weeks. The relationships between changes in serum IL-10 concentration and changes in cardiometabolic risk factors were analyzed. Results: Changes in serum IL-10 concentration were significantly negatively correlated with changes in total cholesterol (r=-0.377), high-density lipoprotein cholesterol (HDL-C; r=-0.377), and low-density lipoprotein cholesterol (LDL-C; r=-0.278) concentrations. However, there were no correlations between changes in serum IL-10 concentration and changes in other cardiometabolic parameters. Conclusion: Serum IL-10 concentration can increase as serum total cholesterol decreases. Additional studies are needed to explore the mechanisms linking changes in serum IL-10 with serum LDL-C and HDL-C concentrations.

Forecasting of the COVID-19 pandemic situation of Korea.

For the novel coronavirus disease 2019 (COVID-19), predictive modeling, in the literature, uses broadly susceptible exposed infected recoverd (SEIR)/SIR, agent-based, curve-fitting models. Governments and legislative bodies rely on insights from prediction models to suggest new policies and to assess the effectiveness of enforced policies. Therefore, access to accurate outbreak prediction models is essential to obtain insights into the likely spread and consequences of infectious diseases. The objective of this study is to predict the future COVID-19 situation of Korea. Here, we employed 5 models for this analysis; SEIR, local linear regression (LLR), negative binomial (NB) regression, segment Poisson, deep-learning based long short-term memory models (LSTM) and tree based gradient boosting machine (GBM). After prediction, model performance comparison was evelauated using relative mean squared errors (RMSE) for two sets of train (January 20, 2020‒December 31, 2020 and January 20, 2020‒January 31, 2021) and testing data (January 1, 2021‒February 28, 2021 and February 1, 2021‒February 28, 2021) . Except for segmented Poisson model, the other models predicted a decline in the daily confirmed cases in the country for the coming future. RMSE values' comparison showed that LLR, GBM, SEIR, NB, and LSTM respectively, performed well in the forecasting of the pandemic situation of the country. A good understanding of the epidemic dynamics would greatly enhance the control and prevention of COVID-19 and other infectious diseases. Therefore, with increasing daily confirmed cases since this year, these results could help in the pandemic response by informing decisions about planning, resource allocation, and decision concerning social distancing policies.

Statistical Estimation of Effects of Implemented Government Policies on COVID-19 Situation in South Korea.

Since the outbreak of novel SARS-COV-2, each country has implemented diverse policies to mitigate and suppress the spread of the virus. However, no systematic evaluation of these policies in their alleviation of the pandemic has been done. We investigate the impact of five indices derived from 12 policies in the Oxford COVID-19 Government Response Tracker dataset and the Korean government's index, which is the social distancing level implemented by the Korean government in response to the changing pandemic situation. We employed segmented Poisson model for this analysis. In conclusion, health and the Korean government indices are most consistently effective (with negative coefficients), while the restriction and stringency indexes are mainly effective with lagging (1~10 days), as intuitively daily confirmed cases of a given day is affected by the policies implemented days before, which shows that a period of time is required before the impact of some policies can be observed. The health index demonstrates the importance of public information campaign, testing policy and contact tracing, while the government index shows the importance of social distancing guidelines in mitigating the spread of the virus. These results imply the important roles of these polices in mitigation of the spread of COVID-19 disease.

Genetic Alterations in Preinvasive Lung Synchronous Lesions.

PURPOSE: Despite advances in treatment, lung cancer remains the leading cause of cancer mortality. This study aimed to characterise genome-wide tumorigenesis events and to understand the hypothesis of the multistep carcinogenesis of lung adenocarcinoma (LUAD). MATERIALS AND METHODS: We conducted multiregion whole-exome sequencing of LUAD with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, or minimally invasive adenocarcinoma of 19 samples from three patients to characterize genome-wide tumorigenesis events and validate the hypothesis of the multistep carcinogenesis of LUAD. We identified potential pathogenic mutations preserved in preinvasive lesions and supplemented the finding by allelic variant level from RNA sequencing. RESULTS: Overall, independent mutational profiles were observed per patient and between patients. Some shared mutations including epidermal growth factor receptor (EGFR , p.L858R) were present across synchronous lesions. CONCLUSION: Here, we show that there are driver gene mutations in AAH, and they may exacerbate as a sequence in a histological continuum, supporting the Darwinian evolution model of cancer genome. The intertumoral and intratumoral heterogeneity of synchronous LUAD implies that multi-biomarker strategies might be necessary for appropriate treatment.

NORE1A directs apoptotic switch of TNF signaling through reciprocal modulation of ITCH-mediated destruction of TNFRI and BAX.

NORE1A (RASSF5) is a tumor suppressor of the Ras-association domain family (RASSF) that is commonly inactivated in multiple human cancers. However, the molecular mechanism underlying its growth inhibition function remains largely undefined. Here we report that NORE1A antagonizes tumor necrosis factor receptor I (TNFRI) through the assembly of ITCH-mediated destruction complex to suppress TNF-NF-κB signaling and tumorigenesis. Moreover, NORE1A is identified as a transcription target of NF-κB, which directs an apoptotic switch of TNF effect by blocking ITCH interaction with and ubiquitination of BAX. Mechanistically, NORE1A binds directly to TNFRI and ITCH via the C1 and PPXY domains, respectively to facilitate the formation of ITCH-mediated destruction complex followed by ubiquitination-mediated lysosomal degradation of TNFRI. Through this function, NORE1A suppresses TNF-induced NF-κB-mediated transcription of pro-inflammatory and tumor-promoting genes, epithelial-to-mesenchymal transition, invasion and migration of tumor cells, and also debilitates tumor cell activation of macrophage and fibroblast. While NORE1A suppresses TNF receptor-mediated apoptosis, it activates TNF-induced apoptosis through BAX activation by protecting BAX from ITCH binding and ubiquitination. Cytotoxic response to TNF is substantially attenuated in NORE1A-depleted cells and tumors, and NORE1A-induced tumor regression is highly impeded in BAX-depleted tumors. An inverse correlation is shown between NORE1A and TNFRI expression in both cancer cell lines and primary tumors, and NORE1A effect on survival of cancer patients is strongly associated with expression status of ITCH. Collectively, this study uncovers that NORE1A directs a substrate switch of ITCH favoring TNFRI over BAX to terminate TNF signaling and accelerate apoptosis, illuminating the mechanistic consequence of NORE1A inactivation in tumorigenesis.