Early Growth Response Protein 1 Exacerbates Murine Inflammatory Bowel Disease by Transcriptional Activation of Matrix Metalloproteinase 12.

Inflammatory bowel disease (IBD) is an inflammatory condition affecting the colon and small intestine, with Crohn's disease and ulcerative colitis being the major types. Individuals with long-term IBD are at an increased risk of developing colorectal cancer. Early growth response protein 1 (Egr1) is a nuclear protein that functions as a transcriptional regulator. Egr1 is known to control the expression of numerous genes and play a role in cell growth, proliferation, and differentiation. While IBD has been associated with severe inflammation, the precise mechanisms underlying its pathogenesis remain unclear. This study aimed to investigate the role of Egr1 in the development of IBD. High levels of Egr1 expression were observed in a mouse model of colitis induced by dextran sulfate sodium (DSS), as determined by immunohistochemical (IHC) staining. Chronic DSS treatment showed that Egr1 knockout (KO) mice exhibited resistance to the development of IBD, as determined by changes in their body weight and disease scores. Additionally, enzyme-linked immunosorbent assay (ELISA) and IHC staining demonstrated decreased expression levels of proinflammatory cytokines such as IL-1ß, IL-6, and TNF-α, as well as matrix metalloproteinase 12 (MMP12). Putative Egr1 binding sites were identified within the MMP12 promoter region. Through reporter assays and chromatin immunoprecipitation (ChIP) analysis, it was shown that Egr1 binds to the MMP12 promoter and regulates MMP12 expression. In conclusion, we found that Egr1 plays a role in the inflammation process of IBD through transcriptionally activating MMP12.

Problematic Use of Internet Associates with Poor Quality of Life via Psychological Distress in Invididuals with ADHD.

Background: Problematic use of internet (PUI) may have negative impacts on psychological distress and quality of life (QoL). This situation might be more profound in people with attention-deficit/hyperactivity disorder (ADHD) due to poorer behavioral control and regulatory capacity. However, there is little evidence regarding mediated effects in the associations between PUI, psychological distress, and QoL in people with ADHD. Aims: To investigate mediating effects of psychological distress in the associations of problematic smartphone use (PSPU), problematic use of social media (PUSM), and problematic gaming (PG) with QoL in individuals with ADHD. Methods and Procedures: PUI behaviors of participants with ADHD (n = 99) were assessed using the Smartphone Application-Based Addiction Scale, Bergen Social Media Addiction Scale, and Internet Gaming Disorder-Short Form. Psychological distress was assessed using the Depression, Anxiety, Stress Scale and QoL using the Kid-KINDL. Outcomes and Results: Psychological distress mediated the associations between PUI and different domains of QoL, except for self-esteem QoL. There were also positively direct effects between PG and physical QoL, PUSM and friends' QoL, and PSPU and physical QoL. Conclusions and Implications: PUI may associate with poor QoL in people with ADHD via psychological distress. Programs on reducing PUI for people with ADHD are needed.

Long-Term Usage of Proton Pump Inhibitors Associated with Prognosis in Patients with Colorectal Cancer.

The dose-response effect of proton pump inhibitors on colorectal cancer prognosis is still under exploration. This population-based study in Taiwan was designed to examine the effect of proton pump inhibitors on overall death, colorectal cancer-specific death, and recurrence in colorectal cancer patients with different cumulative proton pump inhibitor dose levels. This cohort study was based on the Taiwan Cancer Registry and Taiwan National Health Insurance Research Database from 2005 to 2020. After frequency matching with a 1:1 ratio, a total of 20,889 users with proton pump inhibitors and 20,889 without proton pump inhibitors were analyzed. The cumulative defined daily dose level of proton pump inhibitor was stratified to explore the dose-response relationship. A proton pump inhibitor exposure cumulative defined daily dose > 60 after colorectal cancer diagnosis had higher risk of all-cause death than non-proton pump inhibitor users with adjusted hazard ratios of 1.10 (95% CIs: 1.04-1.18). For recurrence, a proton pump inhibitor exposure cumulative defined daily dose > 60 had reduced recurrence risk with an adjusted hazard ratio of 0.84 (95% CIs: 0.76-0.93). This study demonstrated that the long-term use of proton pump inhibitors in patients with colorectal cancer was associated with an increased risk of death that related to the proton pump inhibitor exposure cumulative defined daily dose > 60 and had different dose-response effect in various dose level.

Family Communication as a Mediator between Family Resilience and Family Functioning under the Quarantine and COVID-19 Pandemic in Arabic Countries.

The coronavirus pandemic has become an unprecedented world crisis in which we have struggled against the most potent threat of the twenty-first century. This pandemic has had a profound impact on individuals and families. Therefore, the study aimed to examine family communication as a mediator of the relationship between family resilience and family functioning under the quarantine and coronavirus pandemic in Algeria and Iraq. This study was conducted among individuals in Iraq and Algeria (N = 361). The respondents completed the Family Communication Scale (FCS), Walsh Family Resilience Questionnaire (WFRQ), and Family Functioning Scale (FFS). Structural equation modeling (SEM) with the bootstrapping method was used to conduct the mediated effects of family communication. Using the bootstrapping method in SEM, family resilience and communication significantly affected family functioning (coefficient = 0.808). Moreover, the direct effect and indirect effect (via family functioning) of family resilience on family functioning were both significant, with coefficients of 0.682 and 0.126. In addition, numerous groups from Iraq and Algeria have been analyzed as a sample and have shown no differences in the relationships between family resilience, family communication, and family functioning. In conclusion, the results showed that family communication mediated the relationship between family resilience and family functioning. Moreover, the type of this mediation seemed to be partial because of the significant direct relationship between family resilience and family functioning. According to the findings, healthcare providers should consider improving family resilience and communication to achieve good family functioning.

The impact of intensity-modulated radiotherapy in conjunction with chemotherapy on proximal pT3N0 rectal cancer patients after total mesorectum excision.

BACKGROUND: This study aimed to ascertain if the incorporation of intensity-modulated radiotherapy (IMRT) with chemotherapy (CTx) offered any advantages for patients diagnosed with stage pT3N0 rectal cancer located in the proximal (upper) region following a complete total mesorectum excision (TME). METHODS: We retrospectively examined medical records of stage II/III rectal cancer patients who had undergone CTx or concurrent chemoradiation (CCRT) with IMRT after a successful TME. We juxtaposed a variety of survival outcomes across two patient cohorts. Each outcome was further classified according to Gunderson's risk stratification between proximal and distal (middle and low) rectal cancer patients, and we evaluated the factors associated with each outcome. RESULTS: The median follow-up duration was 4.9 years. Our research comprised 236 rectal adenocarcinoma patients treated at our institution between 2007 and 2019. They received either the CTx (n = 135) or the CCRT (n = 101) with 10-year locoregional recurrence-free survival (LRRFS) of 90.1% and 96.1%, respectively (p = 0.163). However, after performing multivariate adjustments, a pattern emerged hinting at a better LRRFS for the CCRT group (p = 0.052). Perforation had a strong correlation with locoregional recurrence. No significant differences were observed in other survival between the two treatment arms and their respective subgroups. The CCRT group witnessed significantly higher immediate and chronic complications with p = 0.007 and 0.009, respectively. The CCRT group had two secondary cancer-related fatalities (2%, one attributed to IMRT), and another reported by the CTx group (1%). The sole classified locoregional recurrence within the cohort of 37 individuals treated with CTx for proximal pT3N0 rectal cancer was, in fact, the development of sigmoid colon cancer. CONCLUSION: The results suggest that for patients with proximal pT3N0 rectal cancer post-TME, IMRT is better when not combined with CTx, except in highly perilous scenarios or those involving perforation.

Absorption and Metabolism of Urolithin A and Ellagic Acid in Mice and Their Cytotoxicity in Human Colorectal Cancer Cells.

Background: Ellagic acid is a natural polyphenol compound found in pomegranates, walnuts, and many berries. It is not easily absorbed, but it could be metabolized to urolithins by the gut microbiota. Urolithin A, one of the ellagic acid metabolites, has been proved to prolong the lifespan of C. elegans and increases muscle function of mice. The purpose of this current study was to analyze the absorption and metabolites of urolithin A and ellagic acid in mice and the anticancer effects of urolithin A, urolithin B, and ellagic acid in colorectal cancer cells. Methods: Urolithin A and urolithin B were synthesized and analyzed by HPLC and NMR. A pharmacokinetic study of urolithin A was performed in mice by analyzing urolithin A and its metabolites in urines. Absorption and biotransformation of ellagic acid were also studied in mice by analyzing the plasma, liver, and feces. The cytotoxicity of urolithin A, urolithin B, and ellagic acid was assayed in SW480, SW620, HCT 116, and HT-29 cells. Results: Urolithin A and urolithin B were synthesized and purified to reach 98.1% and 99% purity, respectively, and the structures were identified by NMR. In urolithin A intake analysis, urolithin A was only detectable at 3 h, not at 6-24 h; it suggested that urolithin A was rapidly metabolized to some unknown metabolites. Using UPLC-MS/MS analysis, the metabolites might be urolithin A 3-O-glucuronide, urolithin A 3-sulfate, and urolithin A-sulfate glucuronide. After feeding mice with ellagic acid for consecutive 14 days, ellagic acid contents could be detected in the fecal samples, but not in plasma and liver, and urolithin A was not detected in all samples. It suggests that ellagic acid is not easily absorbed and that the biotransformation of ellagic acid to urolithin A by intestinal flora might be very low. From the cytotoxicity assay, it was found that there was anticancer effect in urolithin A and urolithin B but not in ellagic acid. In contrast, ellagic acid promoted the proliferation of SW480 and SW620 cells.

Diet-mediated gut microbial community modulation and signature metabolites as potential biomarkers for early diagnosis, prognosis, prevention and stage-specific treatment of colorectal cancer.

BACKGROUND: Over the last decade, studies have shown an increased incidence of colorectal cancer (CRC), particularly early onset colorectal cancer (EOCRC). Researchers have demonstrated that dietary behavior, especially among young adults, influences alterations in the gut microbial community, leading to an increased accumulation of pathogenic gut microbiota and a decrease in beneficial ones. Unfortunately, CRC is likely to be diagnosed at a late stage, increasing CRC-related mortality. However, this alteration in the gut microbiota (gut dysbiosis) can be harnessed as a biomarker for non-invasive diagnosis, prognosis, prevention, and treatment of CRC in an effort to prevent late diagnosis and poor prognosis associated with CRC. AIM OF REVIEW: This review discusses identification of potential biomarkers by targeting diet-mediated gut dysbiosis for the stage-specific diagnosis, prognosis, treatment, and prevention of CRC. Our findings provide a comprehensive insight into the potential of protumorigenic bacteria (e.g.pathogenic Escherichia coli,enterotoxigenic Bacteroides fragilis and Fusobacterium nucleatum) and their metabolites (e.g., colibactin and B. fragilis toxin) from gut dysbiosis as biomarkers for the diagnosis of CRC. KEY SCIENTIFIC CONCEPTS OF REVIEW: Collectively, a detailed understanding of the available data from current studies suggests that, further research on quantification of metabolites and stage-specific pathogenic microbial abundance is required for the diagnosis and treatment of CRC based on microbial dysbiosis. Specifically, future studies on faecal samples, from patient with CRC, should be conducted for F. nucleatum among different opportunistic bacteria, given its repeated occurrence in faecal samples and CRC biopsies in numerous studies. Finally, we discuss the potential of faecal microbial transplantation (FMT) as an intervention to restore damaged gut microbiota during CRC treatment and management.

Unusually high incidence of polyomavirus JC infection in the higher grade of colorectal cancer tissues in Taiwan.

INTRODUCTION: The human JC polyomavirus (JCPyV) has been detected in colorectal cancer (CRC) tissues and is suggested to contribute to CRC tumorigenesis. The rearrangement of the JCPyV regulatory region is supposedly associated with CRC development. The progression of CRC involves the stepwise accumulation of mutations. The large tumor antigen (LT) of JCPyV can trigger uncontrolled cell cycle progression by targeting oncogenes, and tumor suppressor genes, and causing chromosome instability. Few studies have focused on the presence of JCPyV DNA in the higher grade of CRC tissues. METHODS: We collected 95 tissue blocks from samples of stages I, II, III, and IV CRC. Nested PCR targeting the regulatory region of the viral genome was performed to determine the presence of JCPyV DNA in the various stages of colorectal cancer tissues. RESULTS: The nested PCR results showed that the positive rate of JCPyV DNA increased with the progression of CRC stages. The archetypal-like, non-rearrangement genotype of JCPyV with subtle mutations was the major genotype found in CRC samples. CONCLUSIONS: This finding in our study suggests that there may be an association between JCPyV and CRC progression.

Colorectal Cancer Stage-Specific Fecal Bacterial Community Fingerprinting of the Taiwanese Population and Underpinning of Potential Taxonomic Biomarkers.

Despite advances in the characterization of colorectal cancer (CRC), it still faces a poor prognosis. There is growing evidence that gut microbiota and their metabolites potentially contribute to the development of CRC. Thus, microbial dysbiosis and their metabolites associated with CRC, based on stool samples, may be used to advantage to provide an excellent opportunity to find possible biomarkers for the screening, early detection, prevention, and treatment of CRC. Using 16S rRNA amplicon sequencing coupled with statistical analysis, this study analyzed the cause-effect shift of the microbial taxa and their metabolites that was associated with the fecal gut microbiota of 17 healthy controls, 21 polyps patients, and 21 cancer patients. The microbial taxonomic shift analysis revealed striking differences among the healthy control, polyps and cancer groups. At the phylum level, Synergistetes was reduced significantly in the polyps group compared to the healthy control and cancer group. Additionally, at the genus level and in association with the cancer group, a total of 12 genera were highly enriched in abundance. In contrast, only Oscillosprira was significantly higher in abundance in the healthy control group. Comparisons of the polyps and cancer groups showed a total of 18 significantly enriched genera. Among them, 78% of the genera associated with the cancer group were in higher abundance, whereas the remaining genera showed a higher abundance in the polyps group. Additionally, the comparison of healthy control and polyp groups showed six significantly abundant genera. More than 66% of these genera showed a reduced abundance in the polyps group than in healthy controls, whereas the remaining genera were highly abundant in the polyps group. Based on tumor presence and absence, the abundance of Olsenella and Lactobacillus at the genus level was significantly reduced in the patient group compared to healthy controls. The significant microbial function prediction revealed an increase in the abundance of metabolites in the polyps and cancer groups compared to healthy controls. A correlation analysis revealed a higher contribution of Dorea in the predicted functions. This study showed dysbiosis of gut microbiota at the taxonomic level and their metabolic functions among healthy subjects and in two stages of colorectal cancer, including adenoma and adenocarcinoma, which might serve as potential biomarkers for the early diagnosis and treatment of CRC.

The correlation of epithelial-mesenchymal transition-related gene expression and the clinicopathologic features of colorectal cancer patients in Taiwan.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the world. It has been the most prevalent malignancy in Taiwan for consecutive thirteen years. Despite the diversity of its etiologic and pathophysiologic factors, a biological process named as epithelial-mesenchymal transition (EMT) is indispensable in the progression of epithelial cancer. Our aim is to investigate the correlation between the expression of 8 EMT-related proteins (E-cadherin, ß-catenin, claudin-1, CD44, N-cadherin, fibronectin, vimentin, S100A4) and the clinicopathologic features of CRC in Taiwan, along with the DNA CpG epigenetic status of CD44 gene. In immunohistochemical assessment, decreased expression of E-cadherin is statistically associated with the progression of cancer stage, while decreased expression of claudin-1 as well as increased ß-catenin nuclear translocation and N-cadherin expression is statistically associated with the progression of histopathologic grade. E-cadherin, nuclear ß-catenin and claudin-1 are also associated with other important prognostic factors, including nodal metastasis, tumor deposits, and elevated serum CA 19-9 levels. In addition, the left-sided colon and rectal cancers show increased nuclear translocation of ß-catenin compared to the right-sided colon cancers, while the rectal cancers show increased fibronectin expression compared to the right-sided and left-sided colon cancers. Moreover, vimentin is aberrantly expressed in one case of signet-ring cell carcinoma. The DNA methylation levels of CD44 gene promoter between the tumoral and non-tumorous tissues by NGS comparison showed statistical difference on six CpG sites. However, such difference may not be sufficient because these DNA methylation proportions are too low to inactivate CD44 gene. Our results demonstrate the expression of E-cadherin, claudin-1, and nuclear ß-catenin is closely related to the clinicopathologic prognostic determinants of CRC in Taiwan. The DNA methylation level of CD44 gene and its protein expression, however, show no correlation with the clinicopathologic features in CRC.

Taiwan Society of Colon and Rectal Surgeons (TSCRS) Consensus for Cytoreduction Selection in Metastatic Colorectal Cancer.

BACKGROUND: Taiwan has witnessed a surge in the incidence of colorectal cancer (CRC), of which 40-60% metastasize. Continuous updating of cytoreductive strategies in metastatic CRC (mCRC) has contributed to median overall survival reaching 40 months. In this changing scenario, to standardize the approaches across Taiwan, a group of experts from the Taiwan Society of Colon and Rectal Surgeons (TSCRS) convened to establish evidence- and opinion-based recommendations for defining the criteria of "resectability" in mCRC. METHODS: Over the course of one-on-one consultations, lasting 30-40 min each, with 30 medical specialists (19 colorectal surgeons, 4 general surgeons, and 7 medical oncologists) from 16 hospitals in Taiwan followed by a 2-h meeting with 8 physician experts (3 general surgeons, 4 colorectal surgeons, and 1 thoracic surgeon), 12 key questions on cytoreduction were addressed. This was further contextualized based on published literature. RESULTS: The final consensus includes eight recommendations regarding the criteria for metastasis resection, role of local control treatment in liver potentially resectable patients, management of synchronous liver metastases, approach for peritoneal metastasis, place for resection in multiple-organ metastasis, and general criteria for resectability. CONCLUSIONS: mCRC patients undergoing R0 resection have the greatest survival advantage following surgery. Our role as a multidisciplinary team (MDT) should be to treat potentially resectable mCRC patients as rapidly and safely as possible, and achieve R0 resection as far as possible and for as long as possible (continuum of care). This TSCRS consensus statement aims to help build clinical capacity within the MDTs, while making better use of existing healthcare resources.

Improved patient survivals with colorectal cancer under multidisciplinary team care: A nationwide cohort study of 25,766 patients in Taiwan.

OBJECTIVES: The evidence of improved survival in patients of colorectal cancer (CRC) receiving multidisciplinary team (MDT) care remains inconclusive. METHODS: All patients with incident CRC but no prior cancer history in 2005-2008 were included and followed till 2010. A logistic regression model was used to predict the associated factors to participate in the MDT care model. The propensity score method was included under Cox proportional hazards model to reduce potential bias and to conduct survival analyses. RESULTS: In total, 25,766 patients were included; the mean follow-up period was 35.1 months. The factors associated with participating in MDT included receiving treatments at regional hospitals, at private hospitals, and stage III cancer (all p values <0.001). The favorable survival factors included participating in MDT (HR=0.91, p=0.001), age of 45-75, top-ranked income group, receiving treatments at district hospitals, or at hospitals or with doctors that had higher service volumes (all p values <0.05). Regarding individual stages, the risk of mortality was significantly lower at stage IV (HR=0.88, p=0.002). CONCLUSION: Colorectal cancer patients with participation in MDT have a lower mortality risk; the improvements of survival exist in all colorectal cancer patients, especially in those with stage IV disease.

Health-related quality of life and cost comparison of adjuvant capecitabine versus 5-fluorouracil/leucovorin in stage III colorectal cancer patients.

PURPOSE: The purpose of this study was to compare health-related quality of life (HRQoL) and costs associated with 2 adjuvant chemotherapy regimens [capecitabine-based therapy versus 5-fluorouracil/leucovorin (5-FU/LV)-based therapy] in stage III colorectal cancer patients. METHODS: We conducted a prospective, open-label, observational, multicenter study from July 2008 to July 2011. The European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires was used to assess HRQoL before, during, and after treatment. The direct and indirect costs of adjuvant treatment were estimated from a specially prepared questionnaire, the National Health Insurance Research Database, and other published sources. We used propensity scoring to match samples between groups and performed multivariate analyses to adjust for differences in patient demographics and clinical characteristics. RESULTS: A total of 497 patients were enrolled, and 356 completed the surveys. Following propensity score matching, 239 patients were included in the analysis (122 in the capecitabine-based group, 117 in the 5-FU/LV-based group). Global HRQoL scores did not differ significantly between the two groups. However, compared to patients in the 5-FU/LV-based group, patients in the capecitabine-based group had less nausea and vomiting (mid-term, P = 0.024; final, P = 0.013), appetite loss (mid-term, P < 0.0001; final, P = 0.001), and fewer side effects from chemotherapy (mid-term, P = 0.017). In addition, the monthly cost of capecitabine-based therapy was lower than those of 5-FU/LV-based therapy [NT$31,895.46 (US$1063.18) vs. NT$79,159.24 (US$2638.64) per patient]. CONCLUSIONS: Capecitabine is a reasonable alternative and cost-effective treatment option under current conditions for patients with stage III colorectal cancer.