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Background Interleukin-17 (IL-17) is a proinflammatory cytokine that plays a vital role in the promotion of tumorigenesis in various cancers, including colorectal cancer (CRC). Based on current evidence, IL-17 binds to interleukin-17 receptor A (IL-17RA); however, the role of IL-17RA has not been elucidated in previous studies on CRC. In this study, we explored the role of IL-17RA in human CRC tissues and the progression of CRC in humans and mice. Methods The expressions of IL-17RA and epithelial-mesenchymal transition (EMT)-related genes were examined in CRC cells and tissue samples by quantitative real-time polymerase chain reaction. The role of IL-17RA in pathogenesis and prognosis was evaluated using a Chi-square test, Kaplan-Meier analysis, univariate and multivariate Cox regression analysis in 133 CRC patients. Murine stable IL-17RA knockdown CT-26 CRC cells were used to examine the functions of IL-17RA on cells proliferation, migration and invasion. In addition, A tumor-bearing mice model was executed to evaluate the role of IL-17RA in tumor growth, vascularity and population of infiltrating immune cells. Results IL-17RA expression was found to be significantly higher in CRC tissues than in adjacent normal tissues. The expression of IL-17RA in stage IV patients was significantly higher than that in stages I and II patients. Patients with high IL-17RA expression exhibited significantly worse overall and CRC-specific survival than those with low IL-17RA expression. Functional assessment suggested that the knockdown of IL-17RA expression distinctly suppressed cellular proliferation, migration, invasion, and EMT-related gene expression. In a tumor-bearing mouse model, decreased IL-17RA expression significantly repressed tumor growth and vascularity and reduced the population of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Reduced IL-17RA expression also suppressed cellular proliferation, migration, and invasion, and the expression of EMT genes. Knockdown of IL-17RA inhibited tumor growth and vascularity and decreased the population of Tregs and MDSCs in mouse tumors. Conclusion Our results suggest that decrease IL-17RA expression impairs cellular proliferation, migration and invasion ability, as well as EMT gene expression. Furthermore, knockdown IL-17RA suppressed the tumor vascularity, growth and reduced the population of Tregs and MDSCs in mice tumors. In addition, IL-17RA expression was identified to be independently associated with the prognosis of patients with CRC.

Simple Summary Metastasis of tumor cells is the leading cause of death in cancer patients. Concurrent therapy with surgical removal of primary and metastatic lesions is the main approach for cancer therapy. Currently, therapeutic resistant properties of cancer stem cells (CSCs) are known to drive malignant cancer progression, including metastasis. Our study aimed to identify molecular tools dedicated to the detection and treatment of CSCs. We confirmed that microRNA-210-3p (miR-210) was upregulated in colorectal stem-like cancer cells, which targeted stathmin1 (STMN1), to decrease cell elasticity for increasing mobility. We envision that strategies for softening cellular elasticity will reduce the onset of CSC-orientated metastasis. Abstract Cell migration is critical for regional dissemination and distal metastasis of cancer cells, which remain the major causes of poor prognosis and death in patients with colorectal cancer (CRC). Although cytoskeletal dynamics and cellular deformability contribute to the migration of cancer cells and metastasis, the mechanisms governing the migratory ability of cancer stem cells (CSCs), a nongenetic source of tumor heterogeneity, are unclear. Here, we expanded colorectal CSCs (CRCSCs) as colonospheres and showed that CRCSCs exhibited higher cell motility in transwell migration assays and 3D invasion assays and greater deformability in particle tracking microrheology than did their parental CRC cells. Mechanistically, in CRCSCs, microRNA-210-3p (miR-210) targeted stathmin1 (STMN1), which is known for inducing microtubule destabilization, to decrease cell elasticity in order to facilitate cell motility without affecting the epithelial–mesenchymal transition (EMT) status. Clinically, the miR-210-STMN1 axis was activated in CRC patients with liver metastasis and correlated with a worse clinical outcome. This study elucidates a miRNA-oriented mechanism regulating the deformability of CRCSCs beyond the EMT process.

Magnetic silica core/shell nanovehicles presenting atherosclerotic plaque-specific peptide-1 (AP-1) as a targeting ligand (MPVA-AP1 nanovehicles) have been prepared through a double-emulsion method and surface modification. Amphiphilic poly(vinyl alcohol) was introduced as a polymer binder to encapsulate various drug molecules (hydrophobic, hydrophilic, polymeric) and magnetic iron oxide (Fe3O4) nanoparticles. Under a high-frequency magnetic field, magnetic carriers (diameter: ca. 50 nm) incorporating the anti-cancer drug doxorubicin collapsed, releasing approximately 80% of the drug payload, due to the heat generated by the rapidly rotating Fe3O4 nanoparticles, thereby realizing rapid and accurate controlled drug release. Simultaneously, the magnetic Fe3O4 themselves could also kill the tumor cells through a hyperthermia effect (inductive heating). Unlike their ungrafted congeners (MPVA nanovehicles), the AP1-grafted nanovehicles bound efficiently to colorectal cancer cells (CT26-IL4Rα), thereby displaying tumor-cell selectivity. The combination of remote control, targeted dosing, drug-loading flexibility, and thermotherapy and chemotherapy suggests that magnetic nanovehicles such as MPVA-AP1 have great potential for application in cancer therapy.

Few diagnostic biomarkers for sepsis after emergency peritonitis surgery are available to clinicians, and, thus, it is important to develop new biomarkers for patients undergoing this procedure. We investigated whether serum glutamine and selenium levels could be diagnostic biomarkers of sepsis in individuals recovering from emergency peritonitis surgery. From February 2012 to March 2013, patients who had peritonitis diagnosed at the emergency department and underwent emergency surgery were screened for eligibility. Serum glutamine and selenium levels were obtained at pre-operative, post-operative and recovery time points. The average level of pre-operation serum glutamine was significantly different from that on the recovery day (0.317 ± 0.168 vs. 0.532 ± 0.155 mM, P < 0.001); moreover, serum glutamine levels were unaffected by surgery. Selenium levels were significantly lower on the day of surgery than they were at recovery (106.6 ± 36.39 vs. 130.68 ± 56.98 ng/mL, P = 0.013); no significant difference was found between pre-operation and recovery selenium levels. Unlike selenium, glutamine could be a sepsis biomarker for individuals with peritonitis. We recommend including glutamine as a biomarker for sepsis severity assessment in addition to the commonly used clinical indicators.

Pulmonary aspergilloma and pulmonary actinomycosis are rare pulmonary infectious diseases. Clinical manifestations of pulmonary aspergilloma and pulmonary actinomycosis include chronic cough, fever, chest pain, haemoptysis and other pathologies, but some patients may be asymptomatic. We report a case of a healthy 33-year-old woman without any underlying diseases, who was admitted to Zhongxing Branch of Taipei City Hospital, Taiwan, for intermittent haemoptysis and right upper chest pain, which had persisted for several months. A chest radiograph revealed a focal consolidation in the right upper lobe (RUL) of the lung, which grew in size over time. A sputum study and bronchoscopy revealed no positive findings, although malignancy could not be ruled out. Thus, the patient received a wedge resection of the RUL lesion. Subsequent, pathological examination demonstrated the presence of pulmonary aspergilloma and pulmonary actinomycosis. The patient's symptoms resolved after resection of the RUL lesion.

Background Diagnosing acute appendicitis clinically is still difficult. We developed random forests, support vector machines, and artificial neural network models to diagnose acute appendicitis. Methods Between January 2006 and December 2008, patients who had a consultation session with surgeons for suspected acute appendicitis were enrolled. Seventy-five percent of the data set was used to construct models including random forest, support vector machines, artificial neural networks, and logistic regression. Twenty-five percent of the data set was withheld to evaluate model performance. The area under the receiver operating characteristic curve (AUC) was used to evaluate performance, which was compared with that of the Alvarado score. Results Data from a total of 180 patients were collected, 135 used for training and 45 for testing. The mean age of patients was 39.4 years (range, 16–85). Final diagnosis revealed 115 patients with and 65 without appendicitis. The AUC of random forest, support vector machines, artificial neural networks, logistic regression, and Alvarado was 0.98, 0.96, 0.91, 0.87, and 0.77, respectively. The sensitivity, specificity, positive, and negative predictive values of random forest were 94%, 100%, 100%, and 87%, respectively. Random forest performed better than artificial neural networks, logistic regression, and Alvarado. Conclusion We demonstrated that random forest can predict acute appendicitis with good accuracy and, deployed appropriately, can be an effective tool in clinical decision making.

Our previous studies showed that colorectal tumor has high interleukin-4 receptor α (IL-4Rα) expression, whereas adjacent normal tissue has low or no IL-4Rα expression. We also observed that human atherosclerotic plaque-specific peptide-1 (AP1) can specifically target to IL-4Rα. In this study, we investigated the therapeutic efficacy and systemic toxicity of AP1-conjuagted liposomal doxorubicin. AP1 bound more strongly to and was more efficiently internalized into IL-4Rα-overexpressing CT26 cells than CT26 control cells. Selective cytotoxicity experiment revealed that AP1-conjugated liposomal doxorubicin preferentially killed IL-4Rα-overexpressing CT26 cells. AP1-conjugated liposomal doxorubicin administered intravenously into mice produced significant inhibition of tumor growth and showed decreased cardiotoxicity of doxorubicin. These results indicated that AP1-conjugated liposomal doxorubicin has a potent and selective anticancer potential against IL-4Rα-overexpressing colorectal cancer cells, thus providing a model for targeted anticancer therapy.

Background Traditional Chinese Medicine (TCM) has been used increasingly as complementary medicine in cancer care. Kuan-Sin-Yin (KSY) is a TCM decoction containing seven herbs known to cause immunomodulation or anticancer activity, and which are associated with the TCM concept of Qi and energy supply. Kuan-Sin-Yin has cytostatic effects on cancer cells in animal models. Objective The aim of this study is to evaluate the level of improvement in meridian energy and heart-rate variability (HRV) and to assess whether these observations are compatible with TCM theory. Method A non-randomized controlled trial was designed with monitoring of the meridian electro-conductivity and heart-rate variability (HRV) to compare the efficacy of Kuan-Sin-Yin in the control and experimental groups. 52 patients were enrolled in this study. We also measured cancer-related symptoms and quality of life as secondary outcomes. Results We found that colon cancer patients who received KSY as complementary therapy benefitted with enhancement of meridian energy (Yin meridian: 27.90:35.45μA; p =0.014; Yang meridian: 27.09:33.55μA; p =0.024) and increases in HRV activity (78.40:129.04ms; SDNN: p =0.001) and parasympathetic tone(HF:1644.80:3217.92 ms 2 ; p =0.003; RMMSD:99.76:164.52ms; p =0.002). Cancer-related symptoms decreased (ECOG>1:46.2:7.7%; p =0.0001), and quality of life (KSY group: PCS 35.46:42.12, p =0.0001; MCS: 44.50:47.55, p =0.209) was improved with statistical significance. Conclusions The correlation of positive results reflected in meridian energy and HRV activity confirms the positive role of complementary medicine of Kuan-Sin-Yin in cancer care.

Background. Exposure of the abdominal region to ionizing radiation is associated with serious untoward symptoms of intestinal dysfunction and some reports indicate that nutrient supplements may reduce these adverse effects. This study was designed to investigate the possible beneficial effects of oral arginine or glutamine supplementation on the radiation-induced tissue injury. Materials and methods. Rats were given one of three feeding regimens: standard diet and water (control group), diet and water containing 2% arginine (arginine group), diet and water containing 2% glutamine (glutamine group) for 3 days prior to radiation. All rats were then subjected to a single does of 1100 cGy to the abdomen. Several serum biochemical parameters and the histologic alterations in different segments of gastrointestinal tract and liver were measured 4 days after irradiation. Results. All the arginine-fed rats developed diarrhea on Day 4 postirradiation, compared to 71% incidence in control rats and 86% in glutamine-fed rats. Serum levels of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in the arginine group were markedly higher than those in other groups. On histological examination, radiation caused more serious damage to various segments of intestine in the arginine-fed rats compared to rats on other feeding regimens. Conclusion. These observations seriously question the beneficial effects of arginine and glutamine supplementations on radiation-induced tissue injury.

Given the significant racial and ethnic diversity in genetic variation, we are intrigued to find out whether the single nucleotide polymorphisms (SNPs) identified in genome-wide association studies of colorectal cancer (CRC) susceptibility in East Asian populations are also relevant to the population of Taiwan. Moreover, loss of heterozygosity (LOH) may provide insight into how variants alter CRC risk and how regulatory elements control gene expression. To investigate the racial and ethnic diversity of CRC-susceptibility genetic variants and their relevance to the Taiwanese population, we genotyped 705 CRC cases and 1,802 healthy controls (Taiwan Biobank) for fifteen previously reported East Asian CRC-susceptibility SNPs and four novel genetic variants identified by whole-exome sequencing. We found that rs10795668 in FLJ3802842 and rs4631962 in CCND2 were significantly associated with CRC risk in the Taiwanese population. The previously unreported rs1338565 was associated with a significant increased risk of CRC. In addition, we also genotyped tumor tissue and paired adjacent normal tissues of these 705 CRC cases to search for LOH, as well as risk-associated and protective alleles. LOH analysis revealed preferential retention of three SNPs, rs12657484, rs3802842, and rs4444235, in tumor tissues. rs4444235 has been recently reported to be a cis-acting regulator of BMP4 gene; in this study, the C allele was preferentially retained in tumor tissues (p = 0.0023). rs4631962 and rs10795668 contribute to CRC risk in the Taiwanese and East Asian populations, and the newly identified rs1338565 was specifically associated with CRC, supporting the ethnic diversity of CRC-susceptibility SNPs. LOH analysis suggested that the three CRC risk variants, rs12657484, rs3802842, and rs4444235, exhibited somatic allele-specific imbalance and might be critical during neoplastic progression.

According to previous reports, the prevalence of hepatitis B virus (HBV) infection in patients with systemic lupus erythematosus (SLE) is varied. There has been no report on Taiwan, a hyperendemic area for HBV infection. Furthermore, impaired production of interferon (IFN) in peripheral blood mononuclear cells (PBMC) has been reported to be potentially pathogenic to both chronic HBV infection and SLE. However, the production of IFN in patients with both diseases coexisting is unknown. The aims of this study were to evaluate the prevalence of HBV infection in lupus patients in Taiwan and to measure the production of IFN in patients with both diseases coexisting. One hundred and seventy-three consecutive lupus patients and a control group of 692 age- and sex-matched healthy subjects were included for evaluation of the prevalence of HBsAg. Four groups of subjects (patients with SLE and HbsAg, SLE, chronic hepatitis B and normal controls) were selected for evaluation of the in vitro production of IFN-alpha and -gamma. Six (3.5%) of the 173 SLE patients were positive for HBsAg, which was significantly lower than that of controls (14.7%; P < 0.0001). Patients with coexistent SLE and chronic HBV infection had less lupus activity, including less proteinuria (P = 0.02) and a lower serum titre of anti-double stranded DNA antibodies (anti-dsDNA; P = 0.04), than HBsAg-negative lupus patients. The in vitro production of IFN-alpha in patients with chronic hepatitis B was significantly lower than in those patients with SLE or in the normal control group (P < 0.01). The yields of IFN-alpha and -gamma in patients with coexistent SLE and chronic HBV infection were significantly different from those patients with SLE alone (P < 0.05), but close to those of patients with chronic HBV infection. In conclusion, the prevalence of HBsAg carriers is significantly lower in lupus patients in Taiwan. Patients with coexistent SLE and chronic HBV infection had less lupus activity. Interferon-alpha and -gamma may play a role in the above phenomenon.

Recently, with an available serological hepatitis E virus diagnostic kit, the prevalence of IgG antibody to hepatitis E virus among Chinese subjects in Taiwan was evaluated by means of a solid-phase enzyme-linked immunoassay based on two recombinant hepatitis E virus antigens. The overall prevalence of hepatitis E virus antibody was 10.7% among 384 healthy subjects older than 20 yr but only 0.3% among 600 schoolchildren and young adolescents younger than 20 yr (p

Background Taurine has chemical structure similar to an inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Previous studies on GABA in the stomach suggest GABAergic neuron is involved in acid secretion, but the effects of taurine are poor understood. Methods The effects of taurine on acid secretion, signal transduction, and localization of taurinergic neurons were determined in the rat stomach using everted whole stomach, RIA kit and immunohistochemical methods. Results We used antibodies against taurine-synthesizing enzyme, cysteine sulfuric acid decarboxylase (CSAD), and taurine. CSAD- and taurine-positive cells were found in the muscle and mucosal layers. Distributions of CSAD- and taurine-positive cells in both mucosal and muscle layers were heterogeneous in the stomach. Taurine at 10-9~10-4 M induced acid secretion, and the maximum secretion was at 10-5 M, 1.6-fold higher than the spontaneous secretion. Taurine-induced acid secretion was completely inhibited by bicuculline and atropine but not by cimetidine, proglumide, or strychnine. Atropine and tetrodotoxin (TTX) completely inhibited the acid secretion induced by low concentrations of taurine and partially inhibited induced by high concentrations. Verapamil, a calcium blocker agent, inhibited acid output elicited by taurine. We assumed all Ca2+ channels involved in the response to these secretagogues were equally affected by verapamil. Intracellular cAMP (adenosine 3', 5'-monophosphat) in the stomach significantly increased with taurine treatment in a dose-dependent manner. High correlation (r=0.859, p < 0.001) of taurine concentrations with cAMP was observed. Conclusions Our results demonstrated for the first time in taurine-induced acid secretion due to increase intracellular calcium may act through the A type of GABA receptors, which are mainly located on cholinergic neurons though cAMP pathway and partially on nonneuronal cells in the rat stomach.

Background Mechanism underlying the pathogenesis of mechanical intestinal obstruction has been suggested to be closely associated with bowel inflammatory response in which reactive oxygen metabolites might play an important role. This study was designed to examine the involvement of superoxide anion in the obstruction-induced intestinal injury. Materials and methods Rats were randomly assigned to four groups: sham, obstruction, obstruction with polyethylene glycol (PEG), and obstruction with polyethylene glycol-superoxide dismutase (PEG-SOD) groups. A ligation at the ileum 20 cm proximal to the cecum was created under anesthesia. The superoxide anion production and the pathological manifestations in the obstructed intestine were measured after 24 h of ligation. Results There were significant intestinal shortening, distension, fluid accumulation and mucosal damage in the segment proximal to the ligation site. Pronounced generation of superoxide anion was found in the obstructed intestinal segment. Supplement of SOD, a superoxide free radicals scavenger, ameliorated obstruction-induced bowel distension, fluid accumulation and mucosal damage. Conclusion These data suggest superoxide anion is one of the important mediators in the pathophysiologic changes of simple mechanical intestinal obstruction.

Background. Glutamine has been shown to be an important dietary component for the maintenance of gut integrity. Although considered a nonessential amino acid in normal circumstances, glutamine may become conditionally essential for the bowel during episodes of severe illness and malnutrition. In this study, we employed an animal model simulating mechanical intestinal obstruction to explore the beneficial effects of glutamine on the intestine in response to obstruction-induced injury. Materials and methods. Rats were on three feeding regimens—standard diet and water (control group), diet and water containing 2% glutamine (glutamine group), or diet and water containing 2% arginine (arginine group)—for 3 days prior to surgical preparation of intestinal obstruction. The bowel distension, fluid accumulation, and histological alterations in the intestinal mucosa were measured 40 h after ileal ligation. Results. After 3 days of drinking water intervention, the plasma glutamine levels in the glutamine group (677 ± 12 μM) were higher than those in the control (451 ± 27 μM) and arginine (379 ± 25 μM) groups. The distension ratio measured 40 h after ileal ligation was significantly lower in the glutamine group (30.9 ± 4.2%) than in the control and arginine groups (45.9 ± 1.7 and 46.1 ± 3.4%, respectively). Also, glutamine markedly decreased the fluid accumulation in the obstructed bowel segment (control group, 178.41 ± 18.60 mg/cm; glutamine group, 104.97 ± 13.17 mg/cm; arginine group, 141.4 ± 12.85 mg/cm). Furthermore, the obstruction-induced mucosal injury was substantially improved in glutamine-fed rats. Conclusions. Our findings indicate that glutamine can significantly reduce the degree of those physiological derangements induced by mechanical intestinal obstruction.