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Background Since colon cancer stem cells (CSCs) play an important role in chemoresistance and in tumor recurrence and metastasis, targeting of CSCs has emerged as a sophisticated strategy for cancer therapy. α-mangostin (αM) has been confirmed to have antiproliferative and apoptotic effects on cancer cells. This study aimed to evaluate the selective inhibition of αM on CSCs in colorectal cancer (CRC) and the suppressive effect on 5-fluorouracil (5-FU)-induced CSCs. Methods The cell viability assay was performed to determine the optimal concentration of αM. A sphere forming assay and flow cytometry with CSC markers were carried out to evaluate the αM-mediated inhibition of CSCs. Western blot analysis and quantitative real-time PCR were performed to investigate the effects of αM on the Notch signaling pathway and colon CSCs. The in vivo anticancer efficacy of αM in combination with 5-FU was investigated using a xenograft mouse model. Results αM inhibited the cell viability and reduced the number of spheres in HT29 and SW620 cells. αM treatment decreased CSCs and suppressed the 5-FU-induced an increase in CSCs on flow cytometry. αM markedly suppressed Notch1, NICD1, and Hes1 in the Notch signaling pathway in a time- and dose-dependent manner. Moreover, αM attenuated CSC markers CD44 and CD133, in a manner similar to that upon DAPT treatment, in HT29 cells. In xenograft mice, the tumor and CSC makers were suppressed in the αM group and in the αM group with 5-FU treatment. Conclusion This study shows that low-dose αM inhibits CSCs in CRC and suppresses 5-FU–induced augmentation of CSCs via the Notch signaling pathway.

Fabrics are widely used in hospitals and many other settings for bedding, clothing, and face masks; however, microbial pathogens can survive on surfaces for a long time, leading to microbial transmission. Coatings of metallic particles on fabrics have been widely used to eradicate pathogens. However, current metal particle coating technologies encounter numerous issues such as nonuniformity, processing complexity, and poor adhesion. To overcome these issues, an easy-to-control and straightforward method is reported to coat a wide range of fabrics by using gallium liquid metal (LM) particles to facilitate the deposition of liquid metal copper alloy (LMCu) particles. Gallium particles coated on the fabric provide nucleation sites for forming LMCu particles at room temperature via galvanic replacement of Cu2+ ions. The LM helps promote strong adhesion of the particles to the fabric. The presence of the LMCu particles can eradicate over 99% of pathogens (including bacteria, fungi, and viruses) within 5 min, which is significantly more effective than control samples coated with only Cu. The coating remains effective over multiple usages and against contaminated droplets and aerosols, such as those encountered in facemasks. This facile coating method is promising for generating robust antibacterial, antifungal, and antiviral fabrics and surfaces.

This study examined the association between physical activity (PA) and quality of life (QOL) in Korean patients with inflammatory bowel disease (IBD). We enrolled 158 patients with IBD (81 men and 47 women). PA levels were assessed using the International PA questionnaire. Using self-reported frequency (day) and duration (h) of physical activities, the patients were categorized into 3 groups based on their total metabolic equivalent (MET-h/wk) values: least, moderate, and most active. The QOL of patients with IBD was assessed using the inflammatory bowel disease questionnaire (IBDQ), the Medical Outcomes Study 36-Item Short Form Version 2 (SF36v2), the EuroQOL five dimensions questionnaire (EQ5D), and the EuroQOL visual analog scale (EQ-VAS). Of 158 patients, 62, 73, and 23 patients with Crohn disease, ulcerative colitis, and intestinal Behçet disease, respectively, were included. The mean age was 45.96 ± 17.58 years, and 97 (61.4%) patients were men. Higher PA levels correlated with higher EQ5D and EQ-VAS scores (P

meso-Carboxyl-BODIPY responds to small electronic changes resulting from acyl substitution reactions with a marked change in fluorescence. Herein, the minute changes that accompany the thioester to amide conversion encountered in native chemical ligation (NCL) are exploited in the construction of fluorescent "turn-on" probes. Two fluorogenic probes, 1 a and 4, derived from a meso-thioester-BODIPY scaffold, were designed for the selective detection of cysteine (1 a) and aminopeptidase N (4), respectively. The aromatic (1 a) and aliphatic (4) thioesters of meso-carboxyl-BODIPY are nonfluorescent. However, specific analyte-induced conversion to the meso-amide derivative caused significant spectral changes and a dramatic fluorescence enhancement. Probe 1 a exhibited a large fluorescence "turn-on" response with high selectivity toward cysteine via a tandem NCL reaction. Probe 4 was successfully applied to the monitoring and imaging of endogenous aminopeptidase N in live cancer cells.

Background/Aims: The optimal tools for monitoring Crohn’s disease (CD) are controversial. We compared radiology plus ileocolonoscopy and radiology alone in terms of prognosis prediction and evaluated the agreement between radiologic and ileocolonoscopic findings in patients with CD.Methods: Patients with CD who were followed up with computed tomography enterography (CTE) or magnetic resonance enterography (MRE) alone or CTE or MRE plus ileocolonoscopy were retrospectively recruited. Time to relapse was investigated to evaluate the difference in prognosis using the log-rank and Cox regression tests, and the agreement between radiologic and ileocolonoscopic findings was determined using a kappa value.Results: A total of 501 patients with CD in clinical remission who underwent CTE or MRE and/or ileocolonoscopy were analyzed. Of these, 372 (74.3%) patients underwent CTE or MRE alone and 129 (25.7%) patients underwent CTE or MRE plus ileocolonoscopy. The cumulative maintenance rate of clinical remission between the two groups was not significantly different (p = 0.526, log-rank test). In multivariate analysis, age

Since the first successful establishment of organoids from adult intestinal stem cells, organoid technology has rapidly developed. With advances in normal organoid technology, intestinal disorders, such as colorectal tumors and inflammatory bowel disease, have been major target diseases for patient-derived organoid (PDO) development. PDO biobanking for colorectal cancer has subsequently been developed, and some reports have shown the possibility of using PDO models to predict anticancer drug responses. However, to apply these models to real-world practice, we need more long-term clinical follow-up data from further large-scale PDO biobanks, as well as advanced technology for more rapid and efficient PDO establishment. In addition, in the field of regenerative medicine, the implantation of healthy intestinal PDOs to refractory tissue defects could be a new treatment strategy to accelerate the healing and repair of mucosal defects. This PDO technology could also be applied to inflammatory bowel diseases and serve as a very useful model for drug development via high-throughput screening of useful candidate drugs.

Phototherapy has recently emerged as a promising solution for cancer treatment due to its multifunctionality and minimal invasiveness. Notwithstanding the limited penetration depth of light through skin, the ability of photopharmaceutical device systems to deliver light to desired lesions is important. The device system deploys advanced biocompatible materials and fabrication technologies for electronics, and eventually enables more efficient phototherapy. In this review, we focus on diverse optical electronics to illuminate the lesion site with light. Then, moving on to the phototherapy, we highlight photo-thermal therapy with light absorbing materials, photo-activated chemotherapy with light sensitive materials, and photo-dynamic therapy using photosensitizers. Furthermore, we introduce a drug delivery system that can deliver these photopharmaceutical agents spatiotemporally to the tumor site. To this end, we provide a general overview of materials and devices for phototherapy and discuss critical issues and pending limitations of such phototherapy.

Redox-active metal ions are pivotal for rapid metabolism, proliferation, and aggression across cancer types, and this presents metal chelation as an attractive cancer cell-targeting strategy. Here, we identify a metal chelator, KS10076, as a potent anti-cancer drug candidate. A metal-bound KS10076 complex with redox potential for generating hydrogen peroxide and superoxide anions induces intracellular reactive oxygen species (ROS). The elevation of ROS by KS10076 promotes the destabilization of signal transducer and activator of transcription 3, removes aldehyde dehydrogenase isoform 1-positive cancer stem cells, and subsequently induces autophagic cell death. Bioinformatic analysis of KS10076 susceptibility in pan-cancer cells shows that KS10076 potentially targets cancer cells with increased mitochondrial function. Furthermore, patient-derived organoid models demonstrate that KS10076 efficiently represses cancer cells with active KRAS, and fluorouracil resistance, which suggests clinical advantages.

Triggering receptor expressed on myeloid cell-1 (TREM-1) signaling is expressed on neutrophils and monocytes that is necessary for the successful antimicrobial response and resolution of inflammation in the gut. In this study, we determined the effect of an anti-TREM-1 agonistic antibody (α-TREM-1) on colitis and identify its underlying mechanism of action. Administration of α-TREM-1 alleviated colitis in mice and resolved dysbiosis, which required TLR4/Myd88 signaling. α-TREM-1 increased the production of neutrophil extracellular traps and interleukin-22 by CD177+ neutrophils, which led to pathogen clearance and protection of the intestinal barrier. TREM-1 activation using an α-TREM-1 antibody protects against colitis by rebalancing the microbiota and protecting the epithelium against the immune response as well as modulates the function of neutrophils and macrophages. These results highlight the importance of the TREM-1 pathway in intestinal homeostasis and suggest that α-TREM-1 treatment may be an effective therapeutic strategy for inflammatory bowel disease.

Background/Aims Many patients with Crohn's disease (CD) undergo intestinal resection during the disease course. Despite surgery, postoperative recurrence (POR) commonly occurs. Although postoperative use of tumor necrosis factor α (TNF-α) inhibitors is known to be effective in preventing POR, few studies have evaluated the effectiveness of continuing the same TNF-α inhibitors postoperatively in patients who received TNF-ɑ inhibitors before surgery. Methods This retrospective observational study was performed in a single tertiary medical center. We retrospectively reviewed patients who had undergone the first intestinal resection due to CD and divided them into two groups: TNF-α inhibitor users in both the preoperative and postoperative periods, and TNF-α inhibitor users in only the preoperative period. We compared the clinical outcomes between these two groups. Results In total, 45 patients who used TNF-α inhibitors preoperatively were recruited. Among them, TNF-α inhibitors were used postoperatively in 20 patients (44.4%). The baseline characteristics except age at diagnosis were similar in both groups. The rates of surgical and endoscopic recurrence were not different between the two groups, but the cumulative clinical recurrence rate was significantly lower in the postoperative TNF-α inhibitors group (log-rank p=0.003). In multivariate Cox regression analysis, postoperative TNF-α inhibitors use was significantly associated with a decreased risk of clinical recurrence (adjusted hazard ratio, 0.204; 95% confidence interval, 0.060 to 0.691; p=0.011). Conclusions Continuing TNF-α inhibitors postoperatively in patients who were receiving TNF-α inhibitors before surgery significantly reduced the rate of clinical recurrence. For patients with CD who received TNF-α inhibitors preoperatively, continuing their use after surgery could be recommended.

Graphene oxide (GO) is considered a comparatively recent biomaterial with enormous potential because of its nontoxicity, high dispersity, and enhanced interaction with biomolecules. These characteristics of GO can promote the interactions between the substrates and cell surfaces. In this study, we incorporated GO in a cryogel-based scaffold system to observe their influence on the osteogenic responses of human tonsil-derived mesenchymal stem cells (hTMSCs). Compared to polyethylene glycol (PEG)-based cryogel scaffold, GO-embedded PEG-based (PEGDA-GO) cryogels not only showed improved cell attachment and focal adhesion kinase (FAK) signaling activation but also enhanced cell viability. Taken together, we demonstrated that PEGDA-GO cryogels can stimulate osteogenic differentiation under an osteoinductive condition and enhance osteogenic phenotypes compared to the control group. In summary, we demonstrate that GO embedded in cryogels system is an effective biofunctionalizing scaffold to control osteogenic commitment of stem cells.

In this work, highly osmotic oxidized sucrose-crosslinked polyethylenimine (SP2K) polymers were developed for gene delivery systems, and the transfection mechanism is examined. First, periodate-oxidized sucrose and polyethylenimine 2K (PEI2K) were crosslinked with various feed ratios via reductive amination. The synthesis was confirmed by 1H NMR and FTIR. The synthesized SP2K polymers could form positively charged (~40 mV zeta-potential) and nano-sized (150&ndash, 200 nm) spherical polyplexes with plasmid DNA (pDNA). They showed lower cytotoxicity than PEI25K but concentration-dependent cytotoxicity. Among them, SP2K7 and SP2K10 showed higher transfection efficiency than PEI25K in both serum and serum-free conditions, revealing the good serum stability. It was found that SP2K polymers possessed high osmolality and endosome buffering capacity. The transfection experiments with cellular uptake inhibitors suggest that the transfection of SP2K polymers would progress by multiple pathways, including caveolae-mediated endocytosis. It was also thought that caveolae-mediated endocytosis of SP2K polyplexes would be facilitated through cyclooxygenase-2 (COX-2) expression induced by high osmotic pressure of SP2K polymers. Confocal microscopy results also supported that SP2K polyplexes would be internalized into cells via multiple pathways and escape endosomes efficiently via high osmolality and endosome buffering capacity. These results demonstrate the potential of SP2K polymers for gene delivery systems.

BackgroundAlthough the current standard preoperative chemoradiotherapy (PCRT) for stage II/III rectal cancer decreases the risk of local recurrence, it does not improve survival and increases the likelihood of preoperative overtreatment, especially in patients without circumferential resection margin (CRM) involvement.MethodsStage II/III rectal cancer without CRM involvement and lateral lymph node metastasis was radiologically defined by preoperative magnetic resonance imaging (MRI). Patients who received PCRT followed by total mesorectal excision (TME) (PCRT group) and upfront surgery (US) with TME (US group) between 2010 and 2016 were analyzed. We derived cohorts of PCRT group versus US group using propensity-score matching for stage, age, and distance from the anal verge. Three-year relapse-free survival rate, disease-free survival (DFS), and overall survival (OS) were compared between the two groups.ResultsA total of 202 patients were analyzed after propensity score matching. There were no differences in baseline characteristics. The median follow-up duration was 62 months (interquartile range, 46–87). There was no difference in the 3-year disease-free survival rate between the PCRT and US groups (83 vs. 88%, respectively; p=0.326). Likewise, there was no significant difference in the 3-year OS (89 vs. 91%, respectively; p=0.466). The 3-year locoregional recurrence rates (3 vs. 2% with US, p=0.667) and distant metastasis rates (16 vs. 11%, p=0.428) were not significantly different between the two groups. Time to completion of curative treatment was significantly shorter in the US group (132 days) than in the PCRT group (225 days) (pConclusionUsing MRI-guided selection for better risk stratification, US without neoadjuvant therapy can be considered in early stage patients with good prognosis. PCRT may not be required for all stage II/III rectal cancer patients, especially for the MRI-proven intermediate-risk group (cT1-2/N1, cT3N0) without CRM involvement and lateral lymph node metastasis. Further prospective studies are warranted.

Successful applications of photodynamic therapy (PDT) in cancer treatment require the development of effective photosensitizers with controllable singlet oxygen generation. Here we report a ubiquinone-BODIPY photosensitizer that self-assembles into nanoparticles (PS-Q-NPs) and undergoes selective activation and deaggregation within the highly reductive intracellular environment of tumor cells. PS-Q-NPs are highly stable in aqueous buffer solution, and exhibit minimal fluorescence and photosensitization due to a rapid non-radiative relaxation process. Upon endocytosis by cancer cells, reduction of the ubiquinone moiety by intracellular glutathione (GSH) triggers the conversion of the aggregated hydrophobic precursor into the active hydrophilic carboxylate derivative PS-A. The conversion results in enhanced fluorescence and therapeutic singlet oxygen generation, portending to its application as an activatable photosensitizer for fluorescence imaging-guided photodynamic cancer therapy.

Familial adenomatous polyposis (FAP) is a hereditary disease characterized by the development of numerous colorectal adenomas in young adults. Metformin, an oral diabetic drug, has been shown to have antineoplastic effects and a favorable safety profile. We performed a randomized, double-blind, controlled trial to evaluate the efficacy of metformin on the regression of colorectal and duodenal adenoma in patients with FAP. Thirty-four FAP patients were randomly assigned in a 1:2:2 ratio to receive placebo, 500 mg metformin, or 1,500 mg metformin per day orally for 7 months. The number and size of polyps and the global polyp burden were evaluated before and after the intervention. This study was terminated early based on the results of the interim analysis. No significant differences were determined in the percentage change of colorectal and duodenal polyp number over the course of treatment among the three treatment arms (P = 0.627 and P = 1.000, respectively). We found no significant differences in the percentage change of colorectal or duodenal polyp size among the three groups (P = 0.214 and P = 0.803, respectively). The overall polyp burdens of the colorectum and duodenum were not significantly changed by metformin treatment at either dosage. Colon polyps removed from the metformin-treated patients showed significantly lower mTOR signal (p-S6) expression than those from patients in the placebo arm. In conclusion, 7 months of treatment with 500 mg or 1,500 mg metformin did not reduce the mean number or size of polyps in the colorectum or duodenum in FAP patients (ClinicalTrials.gov ID: NCT01725490). Prevention Relevance: A 7-month metformin treatment (500 mg or 1,500 mg) did not reduce the number or size of polyps in the colorectum or duodenum of FAP patients as compared to placebo. These results do not support the use of metformin to promote regression of intestinal adenomas in FAP patients.

5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/β-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients., The relative enrichment of cancer stem cells after treatment results in tumour recurrence. Here, the authors show a mechanism where p53 induces WNT3, which increases the number of colorectal cancer stem cells following treatment of 5-fluorouracil.

BackgroundPatients with inflammatory bowel disease (IBD) and intestinal Behçet’s disease (BD) are vulnerable to micronutrient deficiencies due to diarrhea-related gastrointestinal loss and poor dietary intake caused by disease-related anorexia. However, few studies have investigated the incidence and risk factors for micronutrient deficiency.MethodsWe retrospectively analyzed 205 patients with IBD who underwent micronutrient examination, including folate, vitamin B12, 25-OH-vitamin D, and/or ferritin level quantification, with follow-up blood tests conducted 6 months later.ResultsEighty patients (39.0%), who were deficient in any of the four micronutrients, were classified as the deficiency group, and the remaining 125 (61.0%) were classified as the non-deficient group. Compared to those in the non-deficiency group, patients in the deficiency group were much younger, had more Crohn's disease (CD) patients, more patients with a history of bowel operation, and significantly less 5-amino salicylic acid usage. Multivariate analysis revealed that CD and bowel operation were significant independent factors associated with micronutrient deficiency.ConclusionsThe incidence of micronutrient deficiency was high (39.0%). Factors including CD, bowel operation, and younger ages were found to be associated with higher risks of deficiency. Therefore, patients with IBD, especially young patients with CD who have undergone bowel resection surgery, need more attention paid to micronutrition.

Interaction between a tumor and its microenvironment is important for tumor initiation and progression. Cancer stem cells (CSCs) within the tumor interact with a microenvironmental niche that controls their maintenance and differentiation. We investigated the CSC-promoting effect of factors released from myofibroblasts into the microenvironment of early colorectal cancer tumors and its molecular mechanism. By messenger RNA microarray analysis, expression of HES1, a Notch signaling target, significantly increased in Caco-2 cells cocultured with 18Co cells (pericryptal myofibroblasts), compared to its expression in Caco-2 cells cultured alone. Caco-2 cells cultured in 18Co-conditioned media (CM) showed a significant increase in CD133+CD44+ cells and HES1 expression compared to that in Caco-2 cells cultured in regular media. Significant amounts of interleukin-6 (IL-6) and IL-8 were detected in 18Co-CM compared to levels in regular media. The 18Co-CM-induced increase in CD133+CD44+ cells was attenuated by IL-6- and IL-8-neutralizing antibodies. Furthermore, these neutralizing antibodies and inhibitors of STAT3 and gamma-secretase reduced the expression of HES1 induced in Caco-2 cells cultured in 18Co-CM. Immunohistochemical analysis of human tissues revealed that IL-6, IL-8, and HES1 expression increased from normal to adenoma, and from adenoma to cancer tissues. In addition, IL-6 and HES1 expression was positively correlated in early colorectal cancer tissues. In conclusion, the increase of CSCs by myofibroblasts could be mediated by IL-6/IL-8-induced HES1 activation in the tumor microenvironment. Based on these data, the IL-6/IL-8-mediated Notch/HES1 and STAT3 pathway, through which CSCs interact with their microenvironment, might be a potential target for the prevention and treatment of colorectal tumors.

Background The National Lung Screening Trial (NLST) and NELSON trial showed that low-dose chest computed tomography (LDCT) screening significantly reduced the mortality form lung cancer. Although cancer survivors are known to have high risk for second malignant neoplasm (SMN), the usefulness of LDCT screening for lung cancer in cancer survivors is not clear. Methods Between August 2016 and August 2017, 633 long-term colorectal cancer (CRC) survivors visited the survivorship clinic in Cancer Prevention Center, Yonsei Cancer Center, Seoul, Republic of Korea. We surveyed the smoking status and recommended LDCT screening to ever-smoking CRC survivors aged 55–80 years. The participants were classified into three risk groups: risk group 1 (RG1) who met the NLST criteria (Age 55–74 years, ≥ 30 pack-years of smoking, smoking cessation < 15 years); risk group 2 (RG2) who would not meet the NLST criteria but were at increased 6-year risk of lung cancer (PLCOM2012 ≥ 0.0151); risk group 3 (RG3) who did not meet any of the criteria above. Results Among 176 ever-smoking CRC survivors, 173 (98.3%) were male, 32 (18.2%) were current-smoker, and median age was 66 years (range, 55–79 years). We found 38 positive findings (non-calcified nodule ≥ 4 mm), 8 clinically significant findings, 66 minor abnormalities, and 64 negative findings on LDCT. Positive findings were identified in 15 of 79 (19.0%) of RG1, in 9 of 36 (25%) of RG2, and in 14 of 61 (23.0%) of RG3. Second primary lung cancers were found in 2 patients of RG2, and in 1 patient of RG3. SMN was most frequently found in RG2 (11 of 36 patients, 30.6%), compared with RG1 (12.7%) or RG3 (9.8%) (P = 0.016). Conclusions LDCT screening for lung cancer in Korean CRC survivors is feasible. Well-designed clinical trial for defining high risk patients for lung cancer among CRC survivors is needed.

Background The influence of family history (FH) on cancer recurrence and survival among patients with established colorectal cancer (CRC) remains uncertain. This study aimed to evaluate the association of FH with cancer recurrence, survival, and the incidence of colorectal adenomas in patients with CRC. Methods Consecutive patients with stage III CRC diagnosed between 2004 and 2009 and followed-up in Severance Hospital were retrospectively enrolled and followed until December 2014. Overall survival (OS) and disease-free survival (DFS) according to FH of CRC or colorectal neoplasm were evaluated using Cox proportional hazards regression and Kaplan-Meier curve. Results Among analyzed 979 patients, 69 (7.0%) was identified as having a FH of CRC in a first-degree relative. During a median follow-up of 9.6 years, mortality occurred in 14 of 69 patients (20.3%) with a FH of CRC and 348 of 910 patients (38.2%) without a FH. Compared with patients without a FH, a first-degree FH of CRC, first or second-degree FH of CRC, and first-degree FH of colorectal neoplasm (CRC or polyps) were associated with a significant reduction in the risk of overall mortality, with adjusted hazard ratios (HRs) of 0.52 (95% CI, 0.29-0.92), 0.51 (95% CI, 0.30-0.88), and 0.48 (95% CI, 0.28-0.82), respectively. However, DFS improvement was significant only when the definition of FH was FH of colorectal neoplasm (adjusted HR 0.57; 95% CI, 0.36-0.89). The incidence of adenoma and advanced adenoma was not different according to the FH. Conclusions Among patients with stage III CRC receiving curative surgery, a FH of colorectal neoplasm was associated with a reduction in cancer recurrence and mortality. The larger scaled studies are needed.

We report the design of an enhanced PeT-based fluorogenic phosgene probe 1-CN comprising a BODIPY fluorescence reporter, and a catechol quencher at the meso-position acting as the phosgene reaction site. The fluorescent catechol-derived probe 1-CN specifically reacts with phosgene to result in a cyclic carbonate ester. The fast (

Metformin is a well-known AMPK (AMP-activated protein kinase) activator that suppresses cancer stem cells (CSCs) in some cancers. However, the mechanisms of the CSC-suppressing effects of metformin are not yet well understood. In this study, we investigated the CSC-suppressive effect of metformin via the mevalonate (MVA) pathway in colorectal cancer (CRC). Two colorectal cancer cell lines, HT29 and DLD-1 cells, were treated with metformin, mevalonate, or a combination of the two. We measured CSC populations by flow cytometric analysis (CD44+/CD133+) and by tumor spheroid growth. The expression of p-AMPK, mTORC1 (pS6), and key enzymes (HMGCR, FDPS, GGPS1, and SQLE) of the MVA pathway was also analyzed. We investigated the effects of metformin and/or mevalonate in xenograft mice using HT29 cells, immunohistochemical staining for CSC markers and key enzymes of the MVA pathway in tumor xenografts was performed. In both HT29 and DLD-1 cells, the CSC population was significantly decreased following treatment with metformin, AMPK activator (AICAR), HMG-CoA reductase inhibitor (simvastatin), or mTOR inhibitor (rapamycin), and was increased by mevalonate. The CSC-suppressing effect of these drugs was attenuated by mevalonate. The results of tumor spheroid growth matched those of the CSC population experiments. Metformin treatment increased p-AMPK and decreased mTOR (pS6) expression, these effects were reversed by addition of mevalonate. The expression of key MVA pathway enzymes was significantly increased in tumor spheroid culture, and by addition of mevalonate, and decreased upon treatment with metformin, AICAR, or rapamycin. In xenograft experiments, tumor growth and CSC populations were significantly reduced by metformin, and this inhibitory effect of metformin was abrogated by combined treatment with mevalonate. Furthermore, in the MVA pathway, CSC populations were reduced by inhibition of protein prenylation with a farnesyl transferase inhibitor (FTI-277) or a geranylgeranyl transferase inhibitor (GGTI-298), but not by inhibition of cholesterol synthesis with a squalene synthase inhibitor (YM-53601). In conclusion, the CSC-suppressive effect of metformin was associated with AMPK activation and repression of protein prenylation through MVA pathway suppression in colorectal cancer.

The roles of individual bacteria and their relationship in the development of colorectal cancer (CRC) remain unclear. We aimed to determine the prevalence of CRC-associated bacteria using quantitative real-time PCR (qPCR) or 16S rRNA analysis and the statistical correlations of patient demographics and clinical characteristics comprising alcohol consumption with CRC-associated bacteria. We determined the prevalence of five CRC-associated bacterial species in 38 CRC patients (39 samples) and 21 normal individuals using qPCR, and the relative abundance of bacterial taxa in the gut microbiome was assessed using 16S rRNA analysis. Fusobacterium nucleatum was the only bacterium that was significantly (P Fusobacterium, Peptostreptococcus, Collinsella, Prevotella, Parvimonas, and Gemella, in patients with CRC. An integrated analysis using 16S rRNA data and epidemiological characteristics showed that alcohol consumption was significantly correlated with the abundance of Fusobacterium OTUs. The correlation of alcohol consumption with the abundance of Fusobacterium OTUs in cancer tissue discovered using 16S rRNA analysis suggests a possible link between alcohol metabolism and subsequent tumorigenesis caused by F. nucleatum.

Objective Dairy cattle nutrient requirement systems acknowledge amino acid (AAs) requirements in aggregate as metabolizable protein (MP) and assume fixed efficiencies of MP used for milk protein. Regulation of mammary protein synthesis may be associated with AA input and milk protein output. The aim of this study was to evaluate the effect of nanoemulsified methionine and cysteine on the in-vitro expression of milk protein (casein) in bovine mammary epithelial cells (MAC-T cells). Methods Methionine and cysteine were nonionized using Lipoid S 75 by high-speed homogenizer. The nanoemulsified AA particle size and polydispersity index were determined by dynamic light scattering correlation spectroscopy using a high-performance particle sizer instrument. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to determine the cytotoxicity effect of AAs with and without nanoionization at various concentrations (100 to 500 μg/mL) in mammary epithelial cells. MAC-T cells were subjected to 100% of free AA and nanoemulsified AA concentration in Dulbecco’s modified Eagle medium/nutrient mixture F-12 (DMEM/F12) for the analysis of milk protein (casein) expression by the quantitative reverse transcription polymerase chain reaction method. Results The AA-treated cells showed that cell viability tended to decrease (80%) in proportion to the concentration before nanogenesis, but cell viability increased as much as 90% after nanogenesis. The analysis of the expression of genetic markers related to milk protein indicated that; αs2-casein increased 2-fold, κ-casein increased 5-fold, and the amount of unchanged β-casein expression was nearly doubled in the nanoemulsified methionine-treated group when compared with the free-nanoemulsified methionine-supplemented group. On the contrary, the non-emulsified cysteine-administered group showed higher expression of genetic markers related to milk protein αs2-casein, κ-casein, and β-casein, but all the genetic markers related to milk protein decreased significantly after nanoemulsification. Conclusion Detailed knowledge of factors, such nanogenesis of methionine, associated with increasing cysteine and decreasing production of genetic markers related to milk protein (casein) will help guide future recommendations to producers for maximizing milk yield with a high level of milk protein casein.

This paper presents an effective performance shaping methodology of discrete-time sliding mode control (DSMC) with disturbance observer (DOB) based on the analysis of error dynamics. DSMC with DOB exhibits excellent tracking performance and robustness subject to external disturbances and unknowns including uncertain parameters and unmodelled dynamics. In addition, DSMC with DOB can be easily implemented in various control applications attributed to its simple structure and discrete-domain representation. However, the performance cannot be easily predicted by the controller parameters of DSMC with DOB, and much tuning effort is required to achieve the desired performance. This paper derives a relationship between the performance and the controller parameters of DSMC with DOB using a disturbance-to-error transfer function. In addition, a tuning methodology for shaping the performance of DSMC with DOB is also suggested. Finally, the developed analysis is demonstrated experimentally in a commercial linear motor system.

Summary Energy storage devices are limited by the trade-off between the transport properties and charge storage ability of materials. Electrolytic capacitors are kinetically fast, operating at kilohertz frequency, but limited by low capacitance. Electrochemical capacitors (ECs) provide high capacitance, yet their sluggish kinetics limit frequency response to a few hertz. Here, we devise strongly interacting, porous MXene/conducting polymer hybrids for large-scale flexible alternating current filtering symmetric ECs with high areal and volumetric capacitances of 0.56 mF cm−2 and 24.2 F cm−3 at 120 Hz, respectively. The high capacitance was maintained up to 1,000 V s−1 and originates from synergy of MXene/polymer hybrids. The operation of tandem ECs that filter a pulsating voltage from 60 to 10,000 Hz is demonstrated with device flexibility and durability over 30,000 cycles. These MXene hybrid-based ECs are expected to bridge the performance gap between high capacitance and the high-frequency response toward the form-factor-free miniature and scalable devices.

Fluorescence-based amine-reactive dyes are highly valuable for the sensing of amines and the labeling of biomolecules. Although it would be highly desirable, large changes in emission spectra and intensity seldom accompany the conjugation of known amine-reactive dyes to their target molecules. On the contrary, amide bond formation between amines and the pentafluorophenyl (

Hydroponic strawberry culture system is increasing annually. Most of strawberry farmers use mulched bed in hydroponic culture and strawberry plants were transplanted in early September. After transplanting, Fusarium wilt caused by Fusarium oxysporum f. sp. fragariae and twospotted spider mite (TSSM), Tetranychus urticae, can increase their occurrence under high temperature condition. Therefore, we conducted for comparison occurrence of Fusarium wilt and TSSM on mulched with green polyethylene film and non-mulched bed. Occurrence of Fusarium wilt on mulched bed was started from early October and more increase than non-mulched bed. Damage rate of TSSM on mulched bed was shown higher than non-mulched bed. Temperature of substrate in mulched bed increased than non-mulched bed, but relative humidity near plants was decreased. As a result, use of non-mulched bed should be effective for reducing of Fusarium wilt and TSSM on strawberry plants.

Background Analysis of high microsatellite instability (MSI-H) phenotype in colorectal carcinoma (CRC) is important for evaluating prognosis and choosing a proper adjuvant therapy. Although the conventional MSI analysis methods such as polymerase chain reaction (PCR) fragment analysis and immunohistochemistry (IHC) show high specificity and sensitivity, there are substantial barriers to their use. Methods In this study, we analyzed the MSI detection performance of three molecular tests and IHC. For the molecular tests, we included a recently developed peptide nucleic acid probe (PNA)-mediated real-time PCR-based method using five quasi-monomorphic mononucleotide repeat markers (PNA method) and two conventional PCR fragment analysis methods using NCI markers (NCI method) or five quasi-monomorphic mononucleotide repeat markers (MNR method). IHC analysis was performed with four mismatch repair proteins. The performance of each method was validated in 166 CRC patient samples, which consisted of 76 MSI-H and 90 microsatellite stable (MSS) CRCs previously diagnosed by NCI method. Results Of the 166 CRCs, 76 MSI-H and 90 MSS CRCs were determined by PNA method. On the other hand, 75 MSI-H and 91 MSS CRCs were commonly determined by IHC and MNR methods. Based on the originally diagnosed MSI status, PNA showed 100% sensitivity and 100% specificity while IHC and MNR showed 98.68% sensitivity and 100% specificity. When we analyzed the maximum sensitivity of MNR and PNA method, which used the same five markers, PNA method could detect alterations in all five mononucleotide repeat markers in samples containing down to 5% MSI-H DNAs, whereas MNR required at least 20% MSI-H DNAs to achieve the same performance. Conclusions Based on these findings, we suggest that PNA method can be used as a practical laboratory test for the diagnosis of MSI. Electronic supplementary material The online version of this article (10.1186/s12885-018-5127-6) contains supplementary material, which is available to authorized users.

Background This experimental study aims to evaluate the effect of hyaluronic acid on healing of infected extraction sockets compared with recombinant human bone morphogenetic protein-2 (rhBMP-2). Methods Both third and fourth mandibular premolars of six beagle dogs were hemisected, and the distal roots were extracted at baseline. Subsequently, combined endodontic-periodontic lesions were induced at the remaining mesial roots. After 4 months, the mesial roots on both sides of the mandible were removed. Four sockets per dog were randomly allocated to four groups: Group 1, Control; Group 2, only absorbable collagen sponge (ACS: carrier); Group 3, 1% hyaluronic acid (HA) gel + ACS; and Group 4, rhBMP-2 + ACS. After 3 months of healing, the dogs were euthanized for microcomputed tomography and histologic analysis. Results After the lesion induction period (4 months), communication between the periodontal lesion and endodontic periapical lesion was observed at all remaining mesial roots. Alveolar bone overgrowth was observed in groups 3 and 4, but bone volume density was not significantly different among all groups. At the crestal portion, mineralization, and osteocalcin expression were higher in groups 3 and 4 than in groups 1 and 2. Conclusion Treatment with HA can promote bone formation and improve the wound healing rate comparable to rhBMP-2 in infected extraction sockets.

Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of β-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both β-catenin and Ras via GSK3β activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both β-catenin and RAS as well as EGFR via targeting the Wnt/β-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the Wnt/β-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations., Colorectal cancer: Potential treatment for drug-resistant cases A recently identified small molecule shows promise for tackling resistance to a leading colorectal cancer drug. Three proteins that are over-expressed in colorectal cancer are epidermal growth factor receptor (EGFR), RAS and β-catenin. These proteins and their interconnected signaling pathways are therefore important therapeutic targets. EGFR is the target of the drug cetuximab, but many patients are resistant to this drug attributed to mutations in a gene that influences the signaling pathways of the three key proteins. Kang-Yell Choi at Yonsei University in Seoul, South Korea, and co-workers trialed a novel molecular drug on human colorectal cancer tissues and on mice. They confirmed that the new drug leads to reduced EGFR levels by degrading RAS and β-catenin and therefore suppresses the growth of colorectal cancer cells in samples with or without the resistant mutations.

Purpose Wide-neck aneurysms (WNAs) associated with a dilated parent artery (PA) are not uncommon morphological abnormalities and usually cause inappropriate wall apposition and incomplete neck coverage of a tubular stent in stent-assisted coiling of aneurysms. We aimed to introduce a fusiform-shaped stent (FSS) and test its effectiveness in treating intracranial WNAs associated with a dilated PA using a three-dimensional (3D) model. Materials and methods Two FSS types were designed with the middle one-third segment dilated by 10% (FSS10) and 20% (FSS20) and were compared with the tubular-shaped stent (TSS). A patient-specific 3D WNA model was prototyped and produced, and in vitro stent placement was performed. Angiographic images of the three stent types were analyzed and compared using predetermined parameters. Results The stent lumens were significantly larger in FSS10 and FSS20 than in TSS in the middle segments (P=0.046), particularly FSS20 (P=0.018). The non-covered area at the ostium tended to be smaller in FSS10 and FSS20 than in TSS, but the difference was not significant (P>0.05). The stent length was significantly longer in FSS10 and FSS20 than in TSS. The stent cell size was significantly larger in FSS than in TSS. Conclusion Better vessel wall apposition and aneurysmal neck coverage was observed for FSS than for TSS. No significant difference was observed between FSS10 and FSS20.

The objective of this study was to evaluate the effect of treating dairy cattle with exogenous human chorionic gonadotrophin (hCG), five (5) days post artificial insemination (AI) on serum progesterone (P4) concentration and pregnancy rate. In this experiment, five days after AI, cows were assigned randomly to two groups namely: a) treated group (67) which were administrered with 1500 IU hCG (Chorulon) and b) control group (61), which received no treatment. On day 5, 10, 15 and 20 after the artificial insemination, blood samples from a total of 8 cows (4 from each group) were collected and were analyzed for serum P4 concentration. Cows were detected for estrus according to standing heat by visual observation. Cows that were detected still in estrus after days 18-24 were re-inseminated and recorded as not pregnant (open). Pregnancy diagnosis was conducted by ultrasonographic examination and transrectal palpation of the uterus on approximately 60 days in cows that observed to be not in estrus. The conception rate in hCG treated and control groups were 52.5 and 36.1%, respectively. The results proved that there were no significant differences in conception rate between two groups (p=0.0568). However, pregnancy rates were reduced by hCG treatment. Average serum P4 concentrations did not differ between Hcg-treated and control groups on day 5 (0.377 versus 0.375 ng/ml). On day 20 serum P4 concentrations were greater in the treated group compared with the control group (3.085 versus 2.010 ng/ml). The treatment with hCG seemed to increase P4 level compared with the control. In conclusion, the results of this study showed that 1500 IU of hCG administered on 5 day post AI increased conception rate in dairy cows. This was supported by the results on serum P4 concentration which was greater in hCG treated group.

Background Peritoneal carcinomatosis can influence clinical outcomes of patients receiving self-expandable metal stents (SEMS) for malignant colorectal obstruction, but data regarding this issue are sparse. We analyzed the clinical outcomes of post-SEMS insertion for malignant colorectal obstruction based on carcinomatosis status. Methods Stent- and patient-related clinical outcomes were compared for carcinomatosis status in a retrospective review involving 323 consecutive patients (colorectal cancer 198 patients; extracolonic malignancy 125 patients) who underwent palliative SEMS placement for malignant colorectal obstruction from January 2005 to March 2012. Severity of carcinomatosis was classified as mild, moderate, or severe. Results Carcinomatosis was observed in 190 patients (58.8 %). The rates of technical (84.7 vs. 94.7 %; P = 0.005) and clinical (73.2 vs. 83.5 %; P = 0.03) success were lower in patients with vs. without carcinomatosis. Rates of early (2.1 % vs. 3.0 %; P = 0.72) and delayed (1.6 % vs. 6.0 %; P = 0.08) perforation and stent failure (27.9 % vs. 26.3 %; P = 0.75) showed no difference. Technical and clinical success rates were significantly different based on the severity of carcinomatosis (technical success rate: mild 90.7 %, moderate 97.4 %, severe 76.3 %, P = 0.003; clinical success rate: mild 83.3 %, moderate 82.1 %, severe 63.9 %, P = 0.01). In multivariate analysis, severe carcinomatosis was identified as an independent factor related to technical (odds ratio [OR] 0.18, 95 % confidence interval [CI] 0.06 – 0.56) and clinical (OR 0.33, 95 %CI 0.15 – 0.74) success. Conclusions Peritoneal carcinomatosis was associated with decreased technical and clinical success rates in patients receiving SEMS for malignant colorectal obstruction. Moreover, the presence of severe carcinomatosis was an independent factor determining these clinical outcomes.