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Many unexpected problems have resulted from the unprecedented coronavirus disease 2019 (COVID-19) pandemic. The optimal management of patients with inflammatory bowel disease (IBD) during the COVID-19 pandemic has also been a challenge. Therefore, the Korean Association for the Study of Intestinal Diseases (KASID) developed a consensus statement of experts regarding the management of IBD during the COVID-19 pandemic. This consensus statement made recommendations regarding the risk and treatment of COVID-19 in IBD patients. This statement emphasizes that IBD is not a risk factor for COVID-19, and care should be taken not to exacerbate IBD in patients in remission state by maintaining their medications, except for corticosteroids.

In order to identify new cancer-associated metabolites that may be useful for early detection of lung cancer, we performed a global metabolite profiling of a non–small cell lung cancer (NSCLC) line and immortalized normal lung epithelial cells from the same patient. Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N-acetylaspartate (NAA), in cancer cells—undetectable in normal lung epithelium. NAA's cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues. NAA's cancer specificity was further supported in our analysis of NAA synthetase (gene symbol: NAT8L) gene expression levels in The Cancer Genome Atlas: elevated NAT8L expression in approximately 40% of adenocarcinoma and squamous cell carcinoma cases (N = 577), with minimal expression in all nonmalignant lung tissues (N = 74). We then showed that NAT8L is functionally involved in NAA production of NSCLC cells through siRNA-mediated suppression of NAT8L, which caused selective reduction of intracellular and secreted NAA. Our cell culture experiments also indicated that NAA biosynthesis in NSCLC cells depends on glutamine availability. For preliminary evaluation of NAA's clinical potential as a circulating biomarker, we developed a sensitive NAA blood assay and found that NAA blood levels were elevated in 46% of NSCLC patients (N = 13) in comparison with age-matched healthy controls (N = 21) among individuals aged 55 years or younger. Taken together, these results indicate that NAA is produced specifically in NSCLC tumors through NAT8L overexpression, and its extracellular secretion can be detected in blood. Cancer Prev Res; 9(1); 43–52. ©2015 AACR.

Supplementary Figure S1. Identical exact masses of MMG and MMG-L from HCC4017. Supplementary Figure S2. Confirmation of MMG-L as NAA with LC-MS/MS. Supplementary Figure S3. Confirmation of MMG-L as NAA by comparing its GC MS data (top panel) with that of standard NAA (bottom panel). Supplementary Figure S4. Gene expression levels of NAT8L, the key enzyme for NAA biosynthesis, in 16 squamous cell carcinoma (SC) lung tumors as compared with patient-matched non-malignant lung tissues. Supplementary Figure S5. Gene expression levels of NAT8L in tumors and non-tumor regions of lung cancer patients. Supplementary Figure S6. Western Blot analysis of NAT8L in NSCLC cell lines. Supplementary Figure S7. Dependence of NAA biosynthesis on NAT8L enzyme in HCC4017 lung cancer cells. Supplementary Figure S8. Comparison of intracellular levels of NAA with those of glutamine, glucose, or NAT8L proteins in NSCLC cell lines. Supplementary Figure S9. Comparison of NAAG and NAA levels in HCC4017 cells using LC-MS. Supplementary Figure S10. Standard curve for NAA blood concentrations vs normalized NAA intensities. Supplementary Figure S11. Age-dependent variation of NAA blood levels in control human samples.

Clinical information of blood plasma samples from lung cancer patients and control individuals.

Chemical identification of MMG-L as N-acetylaspartate (NAA). Supplementary Methods Supplementary Figure Legends

Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

Supplementary Figure S1 - PDF file 84K, Supplementary Figure S1. Verification of specific detection of ACTA2 in lung ADC primary tumors Immunohistochmical staining patterns by two different antibodies against ACTA2 purchased from Dako and Thermo Scientific Pierce were compared in primary lung tumors from ACTA2-High and Low group

PDF file - 61K, Primers for RT-qPCR.

PDF file - 58 KB, Association of T stage with recurrence (N=328)

Supplementary Figure Legends - PDF file 75K, Supplementary figure legends

Purpose: Metastatic relapse of primary lung cancer leads to therapeutic resistance and unfavorable clinical prognosis; therefore, identification of key molecules associated with metastatic conversion has significant clinical implications. We previously identified a link between early brain metastasis of lung adenocarcinoma and amplification of the α-smooth muscle actin (ACTA2) gene. The aim of present study was to investigate the prognostic and functional significance of ACTA2 expression in cancer cells for the metastatic potential of lung adenocarcinomas.Experimental Design:ACTA2 expression was analyzed in tumor cells from 263 patients with primary lung adenocarcinomas by immunohistochemistry, and was correlated with clinicopathologic parameters. The expression of ACTA2 in human lung adenocarcinoma cells was modulated with short hairpin RNAs (shRNA) and siRNAs specifically targeting ACTA2.Results: The patients with lung adenocarcinomas with high ACTA2 expression in tumor cells showed significantly enhanced distant metastasis and unfavorable prognosis. ACTA2 downregulation remarkably impaired in vitro migration, invasion, clonogenicity, and transendothelial penetration of lung adenocarcinoma cells without affecting proliferation. Consistent with the in vitro results, depletion of ACTA2 in human lung adenocarcinoma PC14PE6 cells significantly reduced their metastatic potential without altering their tumorigenic potential. Expression of c-MET and FAK in lung adenocarcinoma cells was also reduced by ACTA2-targeting siRNAs and shRNAs, and was accompanied by a loss of mesenchymal characteristics.Conclusions: These findings indicate that ACTA2 regulates c-MET and FAK expression in lung adenocarcinoma cells, which positively and selectively influence metastatic potential. Therefore, ACTA2 could be a promising prognostic biomarker and/or therapeutic target for metastatic lung adenocarcinoma. Clin Cancer Res; 19(21); 5879–89. ©2013 AACR.

PDF file - 140 KB, Primer sequences used for MSP

β-arrestin 2 (ARRB2) is functionally implicated in cancer progression via various signaling pathways. However, its role in lung cancer remains unclear. To obtain clinical insight on its function in lung cancer, microarray data from lung tumor tissues (LTTs) and matched lung normal tissues (LNTs) of primary non-small cell lung cancer (NSCLC) patients (n = 37) were utilized. ARRB2 expression levels were markedly decreased in all 37 LTTs compared to those in matched LNTs of NSCLC patients. They were significantly co-related to enrichment gene sets associated with oncogenic and cancer genes. Importantly, Gene Set Enrichment Analysis (GSEA) between three LTTs with highly down-regulated ARRB2 and three LTTs with lowly down-regulated ARRB2 revealed significant enrichments related to toll-like receptor (TLR) signaling and autophagy genes in three LTTs with highly down-regulated ARRB2, suggesting that ARRB2 was negatively involved in TLR-mediated signals for autophagy induction in lung cancer. Biochemical studies for elucidating the molecular mechanism revealed that ARRB2 interacted with TNF receptor-associated factor 6 (TRAF6) and Beclin 1 (BECN1), thereby inhibiting the ubiquitination of TRAF6-TAB2 to activate NF-κB and TRAF6-BECN1 for autophagy stimulated by TLR3 and TLR4, suggesting that ARRB2 could inhibit the TRAF6-TAB2 signaling axis for NF-κB activation and TRAF6-BECN1 signaling axis for autophagy in response to TLR3 and TLR4. Notably, ARRB2-knockout (ARRB2KO) lung cancer cells exhibited marked enhancements of cancer migration, invasion, colony formation, and proliferation in response to TLR3 and TLR4 stimulation. Altogether, our current data suggest that ARRB2 can negatively regulate lung cancer progression by inhibiting TLR3- and TLR4-induced autophagy.

The coronavirus disease 2019 (COVID-19) pandemic has reduced the ability to prevent or control chronic disease due to the concerns about safety in accessing health care. Inflammatory bowel disease (IBD) is a chronic condition requiring long- term sustained treatment, which is difficult in the current panedemic situation. The Korean Association for the Study of Intestinal Diseases (KASID) has developed an expert consensus statement on the clinical practice management of adult inflammatory bowel disease during the COVID-19 pandemic. This expert consensus statement is based on guidelines and clinical reports from several countries around the world. It provides recommendations to deal with the risk of COVID-19 and medication use in IBD patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and emphasizes the importance of right treatment approach to avoid worsening of the disease condition in IBD patients.

With the advent of checkpoint inhibitors, it has opened up opportunities for numerous cancer patients. However, as is the case with every treatment, complications need to be weighed. Gastrointestinal adverse effects, such as diarrhea and colitis are well-known complications for checkpoint inhibitors. In severe cases, colitis-induced colonic perforation may occur with an estimation of 1.0% to 1.5% in anti-CTLA-4 antibodies. However, only a handful of cases of such devastating complications have been reported in anti-PD-1 antibodies such as pembrolizumab and nivolumab. We here report a case of intestinal perforation in a patient treated with nivolumab.

This study aimed to understand aberrant methylation of SLITs genes as a biomarker for the early detection and prognosis prediction of non-small cell lung cancer (NSCLC). Methylation levels of SLITs were determined using the Infinium HumanMethylation450 BeadChip or pyrosequencing. Five CpGs at the CpG island of SLIT1, SLIT2 or SLIT3 genes were significantly (Bonferroni corrected p < 0.05) hypermethylated in tumor tissues obtained from 42 NSCLC patients than in matched normal tissues. Methylation levels of these CpGs did not differ significantly between bronchial washings obtained from 76 NSCLC patients and 60 cancer-free patients. However, methylation levels of SLIT2 gene were significantly higher in plasma cell-free DNA of 72 NSCLC patients than in that of 61 cancer-free patients (p = 0.001, Wilcoxon rank sum test). Prediction of NSCLC using SLIT2 methylation was achieved with a sensitivity of 73.7% and a specificity of 61.9% in a plasma test dataset (N = 40). A Cox proportional hazards model showed that SLIT2 hypermethylation in plasma cell-free DNA was significantly associated with poor recurrence-free survival (hazards ratio = 2.19, 95% confidence interval = 1.21–4.36, p = 0.01). The present study suggests that aberrant methylation of SLIT2 in plasma cell-free DNA is a valuable biomarker for the early detection of NSCLC and prediction of recurrence-free survival. However, further research is needed with larger sample size to confirm results.

Simple Summary Despite significant advances in the detection, prevention, and treatment of lung cancer, the prognosis of the patients is still very poor due in part to micrometastasis of cancer cells to surrounding tissues at the time of diagnosis. Therefore, identifying biomarkers for early detection of lung cancer is very important for prolonging the lifespan of patients with lung cancer. The methylation statuses of SLIT1, SLIT2, SLIT3 genes were analyzed in bronchial washing, bronchial biopsy, sputum, tumor and matched normal tissues, or plasma samples obtained from a total of 208 non-small cell lung cancer (NSCLC) patients and 121 cancer-free patients to understand the feasibility of the genes as biomarkers for early detection and survival prediction of NSCLC. The present study suggests that aberrant methylation of SLIT2 in plasma cell-free DNA might be a potential biomarker for the early detection and prognosis prediction of NSCLC patient. Abstract This study aimed to understand aberrant methylation of SLITs genes as a biomarker for the early detection and prognosis prediction of non-small cell lung cancer (NSCLC). Methylation levels of SLITs were determined using the Infinium HumanMethylation450 BeadChip or pyrosequencing. Five CpGs at the CpG island of SLIT1, SLIT2 or SLIT3 genes were significantly (Bonferroni corrected p < 0.05) hypermethylated in tumor tissues obtained from 42 NSCLC patients than in matched normal tissues. Methylation levels of these CpGs did not differ significantly between bronchial washings obtained from 76 NSCLC patients and 60 cancer-free patients. However, methylation levels of SLIT2 gene were significantly higher in plasma cell-free DNA of 72 NSCLC patients than in that of 61 cancer-free patients (p = 0.001, Wilcoxon rank sum test). Prediction of NSCLC using SLIT2 methylation was achieved with a sensitivity of 73.7% and a specificity of 61.9% in a plasma test dataset (N = 40). A Cox proportional hazards model showed that SLIT2 hypermethylation in plasma cell-free DNA was significantly associated with poor recurrence-free survival (hazards ratio = 2.19, 95% confidence interval = 1.21–4.36, p = 0.01). The present study suggests that aberrant methylation of SLIT2 in plasma cell-free DNA is a valuable biomarker for the early detection of NSCLC and prediction of recurrence-free survival. However, further research is needed with larger sample size to confirm results.

Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, is threatening global health worldwide with unprecedented contagiousness and severity. The best strategy to overcome COVID-19 is a vaccine. Various vaccines are currently being developed, and mass vaccination is in progress. Despite the very encouraging clinical trial results of these vaccines, there is insufficient information on the safety and efficacy of vaccines for inflammatory bowel disease (IBD) patients facing various issues. After reviewing current evidence and international guidelines, the Korean Association for the Study of Intestinal Diseases (KASID) developed an expert consensus statement on COVID-19 vaccination issues for Korean IBD patients. This expert consensus statement emphasizes that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination be strongly recommended for IBD patients, and it is safe for IBD patients receiving immunomodulatory therapy.

Background and Objectives: There is currently no consensus on the criteria for admitting older adults to the intensive care unit. Methods: This single-center retrospective study evaluated the baseline and clinical characteristics of older adults admitted to the intensive care unit between January 2017 and June 2017; patients were analyzed according to their age group. Factors associated with in-hospital mortality were specifically determined using logistic regression analysis. Results: Among 582 patients included in the present study, 34.2%, 46.6%, and 19.2% were aged 65–74, 75–84, and over 84 years, respectively. In terms of clinical outcomes, although there were no significant differences in the length of intensive care unit and hospital stay and intensive care unit mortality, significant differences were observed in terms of in-hospital mortality, hospital discharge disposition, and neurologic outcomes at discharge ( p = 0.039, p = 0.005, and p = 0.032, respectively). Predictive factors for in-hospital mortality were age (⩾85 years), initial mental status (stupor to coma), a Korean Triage and Acuity Scale level of 1, underlying diagnosis of cancer, abdominal pain or discomfort, apnea, and a chief compliant of dyspnea. Conclusion: Compared to those aged 65–84 years, in-hospital mortality was 1.96-fold higher in those aged over 84 years. However, the overall mortality in our cohort was not considerably different from that of the younger population. Intensive care unit admission should be considered in selected older adults after evaluating the risk factors for mortality.

Cancer is a catabolic inflammatory disease that causes patients to often experience weight loss, or even cachexia in severe cases. Undernourishment in patients with cancer impairs the quality of life and therapeutic response, further leading to poor prognosis. Active and frequent nutritional screening and assessment using valid tools are important for fast and appropriate nutritional intervention. Additionally, a suitable individualized nutritional intervention strategy should be established based on the nutritional assessment result. In general, nutritional intervention begins with nutritional counseling of patients diagnosed with cancer, and a well-planned nutritional counseling improves the treatment adherence and nutritional status. When planning nutritional supplementation for cancer patients, specific nutrients, including amino acids and fatty acids, should be considered. However, there has been no consistent result showing that any particular nutrient significantly improves the prognosis of cancer patients. Hence, continuous attention from clinical physicians is needed to plan nutritional improvement in patients with cancer.

Sirtuin 1 (SIRT1) is known to play a role in a variety of tumorigenesis processes by deacetylating histone and non‐histone proteins; however, antitumour effects by suppressing SIRT1 activity in non‐small cell lung cancer (NSCLC) remain unclear. This study was designed to scrutinize clinicopathological significance of SIRT1 in NSCLC and investigate effects of metformin on SIRT1 inhibition. This study also evaluated new possibilities of drug combination using a SIRT1 inhibitor, tenovin‐6, in NSCLC cell lines. It was found that SIRT1 was overexpressed in 300 (62%) of 485 formalin‐fixed paraffin‐embedded NSCLC tissues. Its overexpression was significantly associated with reduced overall survival and poor recurrence‐free survival after adjusted for histology and pathologic stage. Thus, suppression of SIRT1 expression may be a reasonable therapeutic strategy for NSCLC. Metformin in combination with tenovin‐6 was found to be more effective in inhibiting cell growth than either agent alone in NSCLC cell lines with different liver kinase B1 (LKB1) status. In addition, metformin and tenovin‐6 synergistically suppressed SIRT1 expression in NSCLC cells regardless of LKB1 status. The marked reduction in SIRT1 expression by combination of metformin and tenovin‐6 increased acetylation of p53 at lysine 382 and enhanced p53 stability in LKB1‐deficient A549 cells. The combination suppressed SIRT1 promoter activity more effectively than either agent alone by up‐regulating hypermethylation in cancer 1 (HIC1) binding at SIRT1 promoter. Also, suppressed SIRT1 expression by the combination synergistically induced caspase‐3‐dependent apoptosis. The study concluded that metformin with tenovin‐6 may enhance antitumour effects through LKB1‐independent SIRT1 down‐regulation in NSCLC cells.

Cancer cachexia is a syndrome accompanying weight loss, skeletal muscle atrophy, and loss of adipose tissue in patients with advanced cancer. Since interleukin-6 (IL-6) is one of core mediators causing cancer cachexia and kimchi can modulate IL-6 response, we hypothesized dietary intake of kimchi can ameliorate cancer cachexia. In this study, we studied preemptive administration of kimchi can ameliorate mouse colon carcinoma cells colon (C26) adenocarcinoma-induced cancer cachexia and explored anti-cachexic mechanisms of kimchi focused on the changes of muscle atrophy, cachexic inflammation, and catabolic catastrophe. As results, dietary intake of kimchi significantly attenuated the development of cancer cachexia, presented with lesser weight loss, higher muscle preservation as well as higher survival from cancer cachexia in mice. Starting from significant inhibition of IL-6 and its signaling, kimchi afforded significant inhibition of muscle specific ubiquitin-proteasome system including inhibition of atrogin-1 and muscle ring finger protein-1 (MuRF-1) with other muscle related genes including mitofusin-2 (Mfn-2) and PGC-1α. Significant inhibition of lipolysis gene such as adipose triglyceride lipase (ATGL) and hormone-sensitive ligase (HSL) accompanied with significant induction of fatty acid synthase (FAS) and sterol response element binding protein 1 (SREBP1) was achieved with kimchi. As gene regulation, IL-6 and their receptor as well as Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were significantly attenuated with kimchi. In conclusion, dietary intake of cancer preventive kimchi can be an anticipating option to ameliorate cancer cachexia via suppressive action of IL-6 accompanied with decreased muscle atrophy and lipolysis.

BackgroundThis study aimed at understanding the effect of metformin on histone H3 modifications at the promoters of cell cycle regulatory genes in lung cancer cells. MethodsHistone H3 modifications were analyzed using ChIP-seq, and changes in DNA methylation and chromatin accessibility were evaluated using the SureSelect Methyl-Seq Target Enrichment System and ATAC-seq, respectively. MLL2 overexpression was analyzed in tumor and matched normal tissues from 42 non-small cell lung cancer (NSCLC) patients. ResultsMetformin showed little effect on DNA methylation or chromatin accessibility at the promoter regions of cell cycle regulatory genes in lung cancer cells but significantly downregulated histone H3K4 methyltransferase MLL2 and reduced H3K4me3 levels at the promoters of positive cell cycle regulatory genes such as CDK1, CDK6, and E2F8. Eighty-eight genes involved in cell cycle showed reduced H3K4me3 levels in response to metformin, and 27% of them showed mRNA downregulation. The siRNA-mediated knockdown of MLL2 significantly reduced the H3K4me3 levels at the promoters of positive cell cycle regulatory genes. MLL2 overexpression was found in 14 (33%) of 42 NSCLC patients, with a higher prevalence in females (P = 0.04). A Cox proportional hazards analysis showed that recurrence-free survival of adenocarcinoma patients with MLL2 overexpression was approximately 1.32 (95% CI = 1.08–4.72; p = 0.02) times poorer than in those without it after adjusting for sex and pathologic stage. ConclusionsThe present study suggests that metformin might reduce H3K4me3 levels at the promoters of positive cell cycle regulatory genes through MLL2 downregulation in lung cancer cells. And, MLL2 may be a potential therapeutic target for reducing the recurrence of lung adenocarcinoma.

TRAF6-BECN1 signaling axis is critical for autophagy induction and functionally implicated in cancer progression. Here, we report that AMP-activated protein kinase alpha 1 (AMPK&alpha, 1, PRKAA1) is positively involved in autophagy induction and cancer progression by regulating TRAF6-BECN1 signaling axis. Mechanistically, AMPK&alpha, 1 interacted with TRAF6 and BECN1. It also enhanced ubiquitination of BECN1 and autophagy induction. AMPK&alpha, 1-knockout (AMPK&alpha, 1KO) HEK293T or AMPK&alpha, 1-knockdown (AMPK&alpha, 1KD) THP-1 cells showed impaired autophagy induced by serum starvation or TLR4 (Toll-like receptor 4) stimulation. Additionally, AMPK&alpha, 1KD THP-1 cells showed decreases of autophagy-related and autophagosome-related genes induced by TLR4. AMPK&alpha, 1KO A549 cells exhibited attenuation of cancer migration and invasion induced by TLR4. Moreover, primary non-small cell lung cancers (NSCLCs, n = 6) with low AMPK&alpha, l levels showed markedly decreased expression of genes related to autophagy, cell migration and adhesion/metastasis, inflammation, and TLRs whereas these genes were significantly upregulated in NSCLCs (n = 5) with high AMPK&alpha, l levels. Consistently, attenuation of cancer migration and invasion could be observed in AMPK&alpha, 1KO MDA-MB-231 and AMPK&alpha, 1KO MCF-7 human breast cancer cells. These results suggest that AMPK&alpha, 1 plays a pivotal role in cancer progression by regulating the TRAF6-BECN1 signaling axis for autophagy induction.

The impact of adherence to follow-up examination after a fecal occult blood test (FOBT) remains ill-defined.To evaluate the impact of adherence to the follow-up examination on clinical outcomes in individuals with positive FOBT results.This was a retrospective cohort study involving Korean individuals aged 50 years or older who participated in the National Cancer Screening Program for CRC from 2009 to 2010. Individuals who underwent a confirmative examination within a year after positive FOBT results were included in compliant group, and those who did not were included in non-compliant group. The incidence and stage of CRC, and 5-year survival were compared between two groups.5,914 were diagnosed with CRC in the compliant group and 2,973 in the non-compliant group. The proportion of advanced-stage CRC was significantly higher in the non-compliant group (localized CRC 44.6% vs. 36.7% and distant CRC 8.7% vs. 12.5%, p0.0001). The survival probability within 5 years was 71.0% in the non-compliant group and 85.9% in the compliant group (hazard ratio 1.70, 95% CI, 1.52-1.90, p0.001).Individuals who underwent follow-up examination 1 year or more after positive FOBT had a lower survival rate compared with that in those who underwent examination within 1 year.

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

This study aimed to understand whether the effect of non-metastatic cells 1 (NME1) on recurrence-free survival (RFS) in early stage non-small cell lung cancer (NSCLC) can be modified by &beta, catenin overexpression and cisplatin-based adjuvant chemotherapy. Expression levels of NME1 and &beta, catenin were analyzed using immunohistochemistry in formalin-fixed paraffin-embedded tissues from 425 early stage NSCLC patients. Reduced NME1 expression was found in 39% of samples. The median duration of follow-up was 56 months, and recurrence was found in 186 (44%) of 425 patients. The negative effect of reduced NME1 expression on RFS was worsened by cisplatin-based adjuvant chemotherapy (adjusted hazard ratio = 3.26, 95% CI = 1.16&ndash, 9.17, p = 0.03). &beta, catenin overexpression exacerbated the effect of reduced NME1 expression on RFS and the negative effect was greater when receiving cisplatin-based adjuvant chemotherapy: among patients treated with cisplatin-based adjuvant chemotherapy, hazard ratios of patients with reduced NME1 expression increased from 5.59 (95% confidence interval (CI) = 0.62&ndash, 50.91, p = 0.13) to 15.52 (95% CI = 2.94&ndash, 82.38, p = 0.001) by &beta, catenin overexpression, after adjusting for confounding factors. In conclusion, the present study suggests that cisplatin-based adjuvant chemotherapy needs to be carefully applied to early stage NSCLC patients with overexpressed &beta, catenin in combination with reduced NME1 expression.

This study aimed to understand the clinicopathological significance of runt-related transcription factor 1 (RUNX1) in non-small cell lung cancer (NSCLC). The methylation and mRNA levels of RUNX1 in NSCLC were determined using the Infinium HumanMethylation450 BeadChip and the HumanHT-12 expression BeadChip. RUNX1 protein levels were analyzed using immunohistochemistry of formalin-fixed paraffin-embedded tissues from 409 NSCLC patients. Three CpGs (cg04228935, cg11498607, and cg05000748) in the CpG island of RUNX1 showed significantly different methylation levels (Bonferroni corrected p &lt, 0.05) between tumor and matched normal tissues obtained from 42 NSCLC patients. Methylation levels of the CpGs in the tumor tissues were inversely related to mRNA levels of RUNX1. A logistic regression model based on cg04228935 showed the best performance in predicting NSCLCs in a test dataset (N = 28) with the area under the receiver operating characteristic (ROC) curve (AUC) of 0.96 (95% confidence interval (CI) = 0.81&ndash, 0.99). The expression of RUNX1 was reduced in 125 (31%) of 409 patients. Adenocarcinoma patients with reduced RUNX1 expression showed 1.97-fold (95% confidence interval = 1.16&ndash, 3.44, p = 0.01) higher hazard ratio for death than those without. In conclusion, the present study suggests that abnormal methylation of RUNX1 may be a valuable biomarker for detection of NSCLC regardless of race. And, reduced RUNX1 expression may be a prognostic indicator of poor overall survival in lung adenocarcinoma.

Background: The compliance with the follow-up examination after a positive fecal occult blood test (FOBT) is lower than expected. We aimed to evaluate the adherence rate to the follow-up examination in patients with a positive FOBT and to identify the clinical factors associated with this adherence. Methods: The study population comprised adults aged &ge, 50 years who participated in the National Cancer Screening Program for colorectal cancer (CRC) in 2013. Compliance was defined as undergoing follow-up examination within 1 year of a positive FOBT. Results: From 214,131 individuals with a positive FOBT, 120,911 (56.5%) were in the compliance group and 93,220 (43.5%) were in the non-compliance group. On multivariate analysis, good compliance was associated with men (odds ratio (OR) = 1.12, 95% confidence interval (CI) (1.09&ndash, 1.15)), younger ages (70&ndash, 79 years, OR = 2.19 (2.09&ndash, 2.31), 60&ndash, 69 years, OR = 3.29 (3.13&ndash, 3.46), 50&ndash, 59 years, OR = 3.57 (3.39&ndash, 3.75) vs. &gt, 80 years), previous experience of CRC screening (a negative FOBT, OR = 1.18 (1.15&ndash, 1.21), a positive FOBT, OR = 2.42 (2.31&ndash, 2.54)), absent previous experience of colonoscopy or barium enema (OR = 2.06 (1.99&ndash, 2.13)), higher economic income (quartile, 75%, OR = 1.14 (1.11&ndash, 1.17), 100%, OR = 1.22 (1.19&ndash, 1.25)), current smokers (OR = 1.12 (1.09&ndash, 1.15)), alcohol intake (OR = 1.03 (1.01&ndash, 1.05)), active physical activity (&ge, 3 times/week, OR = 1.13 (1.11&ndash, 1.15)), depression (OR = 1.11 (1.08&ndash, 1.14)), and present comorbidities (Charlson Comorbidity Index, &ge, 1). Conclusion: This study identified clinical factors, namely, male, younger ages, prior experience of fecal test, absent history of colonoscopy or double-contrast barium enema (DCBE) within 5 years, and high socioeconomic status to be associated with good adherence to the follow-up examination after a positive FOBT.