No abstract available.
Tobacco Smoke Pollution*

Nanomedicine usually refers to nanoparticles that deliver the functional drugs and siRNAs to treat cancer. Recent research has suggested that cancer cells can also make nanoparticles that also deliver functional molecules in promoting cancer metastasis, which is the leading cause of various cancer mortalities. This nanoparticle is called tumor-derived vesicles, or better-known as tumor-derived exosomes (TEXs). TEXs are nanoscale membrane vesicles (30-140 nm) that are released continuously by various types of cancer cells and contain tumor-derived functional biomolecules, including lipids, proteins, and genetic molecules. These endogenous TEXs can interact with host immune cells and epithelial cells locally and systemically. More importantly, they can reprogram the recipient cells in favor of promoting metastasis through facilitating tumor cell local invasion, intravasation, immune evasion, extravasation, and survival and growth in distant organs. Growing evidence suggests that TEXs play a key role in cancer metastasis. Here, we will review the most recent findings of how cancer cells harness TEXs to promote cancer metastasis through modulating vascular permeability, suppressing systemic immune surveillance, and creating metastatic niches. We will also summarize recent research in targeting TEXs to treat cancer metastasis.

PURPOSE: Accurate clinical diagnosis of acute appendicitis is more difficult in children since they may not be able to communicate their complaints adequately, and findings on physical examination may be nonspecific.The uncertainty in diagnosis may lead to a delay of surgery or to unnecessary laparotomy. Prompt diagnosis is important due to their complications such as perforation, abscess formation, and peritonitis. The authors conducted this study in order to find out usefulness of ultrasonography in diagnosis of acute appendicitis in children. METHODS: The authors was performed ultrasonographical examination to 290 children with abdominal pain under the age of 15 during a recent 16-months period from January 1994 to April 1995. High-resolution ultrasonography was used according to the graded compression method. The ultrasonographic findings were correlated with pathologic outcome in 87 cases. RESULTS: 1) Among 290 patients with abdominal pain, acute appendicitis was 81 cases (27.9%), and there were mesenteric lymphadenitis, terminal ileitis, intussusception, acute gastroenteritis, and nonspecific findings. 2) Sex ratio of acute appendicitis was 1.53:1. The acute appendicitis was occurred 13.6% in under the age of 5 and 86.4% in over the age of 6. Mean age was 10.6 3) The most frequent symptom was abdominal pain followed by vomiting, fever, nausea, and diarrhea. 4) Leukocytosis (>10,000/cu.mm) was occurred in 71 of 81 (87.7%) cases of acute appendicitis and 24 of 28 (85.7%) cases of acute appendicitis with perforation. 5) The perforation rate was higher in delayed diagnosis and in younger children. 6) Ultrasonography had a sensitivity of 97.5%, specificity of 96.2%, positive predictive value of 90.8%, and negative predictive value of 99.0% on diagnosis in acute appendicitis. CONCLUSIONS: Upon the above results, the authors were able to conclude that graded compression ultrasonography had high sensitivity and specificity and was useful for the diagnosis of acute appendicitis in children. And the ultrasonography can be applied as rapid, noninvasive, and well-tolerated investigation. So, it has diagnostic value as screening test in children whose chief complaint is abdominal pain.
Abdominal Pain ; Abscess ; Appendicitis* ; Child* ; Crohn Disease ; Delayed Diagnosis ; Diagnosis* ; Diarrhea ; Fever ; Gastroenteritis ; Humans ; Intussusception ; Laparotomy ; Leukocytosis ; Mass Screening ; Mesenteric Lymphadenitis ; Nausea ; Peritonitis ; Physical Examination ; Sensitivity and Specificity ; Sex Ratio ; Ultrasonography* ; Uncertainty ; Vomiting

Ninety percent of clinical drug development fails despite implementation of many successful strategies, which raised the question whether certain aspects in target validation and drug optimization are overlooked? Current drug optimization overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity in disease/normal tissues using structure‒tissue exposure/selectivity-relationship (STR), which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity. We propose structure‒tissue exposure/selectivity-activity relationship (STAR) to improve drug optimization, which classifies drug candidates based on drug's potency/selectivity, tissue exposure/selectivity, and required dose for balancing clinical efficacy/toxicity. Class I drugs have high specificity/potency and high tissue exposure/selectivity, which needs low dose to achieve superior clinical efficacy/safety with high success rate. Class II drugs have high specificity/potency and low tissue exposure/selectivity, which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated. Class III drugs have relatively low (adequate) specificity/potency but high tissue exposure/selectivity, which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked. Class IV drugs have low specificity/potency and low tissue exposure/selectivity, which achieves inadequate efficacy/safety, and should be terminated early. STAR may improve drug optimization and clinical studies for the success of clinical drug development.

BACKGROUND/AIMS: High-resolution methods have advanced esophageal and anorectal manometry interpretation but are incompletely established for intestinal manometry. We characterized normal fasting duodeno-jejunal manometry parameters not measurable by standard techniques using clustered closely-spaced recordings. METHODS: Ten fasting recordings were performed in 8 healthy controls using catheters with 3–4 gastrointestinal manometry clusters with 1–2 cm channel spacing. Migrating motor complex phase III characteristics were quantified. Spatial-temporal contour plots measured propagation direction and velocity of individual contractions. Coupling was defined by pressure peak continuity within clusters. RESULTS: Twenty-three phase III complexes (11 antral, 12 intestinal origin) with 157 (95% CI, 104–211) minute periodicities, 6.99 (6.25–7.74) minute durations, 10.92 (10.68–11.16) cycle/minute frequencies, 73.6 (67.7–79.5) mmHg maximal amplitudes, and 4.20 (3.18–5.22) cm/minute propagation velocities were recorded. Coupling of individual contractions was 39.1% (32.1–46.1); 63.0% (54.4–71.6) of contractions were antegrade and 32.8% (24.1–41.5) were retrograde. Individual phase III contractions propagated > 35 fold faster (2.48 cm/sec; 95% CI, 2.25–2.71) than complexes themselves. Phase III complexes beyond the proximal jejunum were longer in duration (P = 0.025) and had poorer contractile coupling (P = 0.025) than proximal complexes. Coupling was greater with 1 cm channel spacing vs 2 cm (P < 0.001). CONCLUSIONS: Intestinal manometry using clustered closely-spaced pressure ports characterizes novel antegrade and retrograde propagation and coupling properties which degrade in more distal jejunal segments. Coupling is greater with more closely-spaced recordings. Applying similar methods to dysmotility syndromes will define the relevance of these methods.
Catheters ; Fasting ; Intestines ; Jejunum ; Manometry ; Muscle Contraction ; Myoelectric Complex, Migrating ; Periodicity

BACKGROUND: It is known that hyperglycemia increase oxidative stress. Korean type 2 diabetic patients usually appear to be insulin deficient and insulin resistant. The blood glucose control can be normalized by the intensive insulin therapy. It has been reported that hyperinsulinemia have harmful effects on oxidative stress. The purpose of this study was to determine whether continuous subcutaneous insulin infusion (CSII) therapy by insulin pump affects the defense mechanism of oxidative stress in Korean type 2 diabetic patients. METHODS: Fasting blood from eighty three subjects was collected prior to starting CSII therapy using portable insulin pump and after hospitalization for 2 weeks. Serum and red blood cell lipid peroxide concentrations were analyzed by Yagi's methods. Serum tocopherol and vitamin C concentrations were measured by HPLC. Red blood cell glutathione peroxidase, superoxide dismutase and catalase activities were also measured. RESULTS: The mean age of subjects were 50.0+/-10.9 years, and they had diabetes for 8.4+/-5.8 years. Their average body mass index was 23.4+2.7 kg/m2. Their blood glucose levels were not controlled by oral hypoglycemic agents, diet and exercise treatment. Patients were divided into two categories according to blood glucose levels prior to CSII treatment. One category consists of patients with less than 11.1 mmol/L of average daily blood glucose levels prior to CSII treatment (the controlled group). The other category consists of patients with more than 11.1 mmol/L of average daily blood glucose levels (the uncontrolled group). Patients in the uncontrolled group had higher serum lipid peroxide levels than those in the controlled group before CSII therapy. After 2 weeks of CSII therapy, oxidative stress was not changed in controlled and uncontrolled groups. Serum insulin levels of all patients were increased after CSII treatment, but the levels before and after treatments were in the normal range, not hyperinsulinemic. Also, serum insulin levels did not correlate with serum lipid peroxide levels regardless of CSII treatment. Average serum vitamin C levels were remarkably increased after the therapy in all patients, but average serum total tocopherol levels was not altered. Also, activities of antioxidant enzymes such as glutathione peroxidase, superoxide dismutase, and catalase were not significantly changed. CONCLUSION: The blood glucose levels were normalized with the normal ranges of serum insulin levels after two weeks of CSII treatment. However, serum lipid peroxide levels were not changed even though serum vitamin C levels were increased. It is concluded that the oxidative stress of Korean type 2 diabetic patients are not changed after two weeks of CSII treatment, but there may be possibility the longer duation of CSII therapy may gradually improve oxidative stress.
Antioxidants ; Ascorbic Acid ; Blood Glucose ; Body Mass Index ; Catalase ; Chromatography, High Pressure Liquid ; Diet ; Erythrocytes ; Fasting ; Glutathione Peroxidase ; Hospitalization ; Humans ; Hyperglycemia ; Hyperinsulinism ; Hypoglycemic Agents ; Insulin* ; Oxidative Stress* ; Reference Values ; Superoxide Dismutase ; Tocopherols

OBJECTIVE: Our purpose was to investigate urinary malondialdehyde (MDA), manganese superoxide dismutase (Mn-SOD) activity and polymorphism in placental tissues of women with preeclampsia and to evaluate oxidative stress in the pathophysiology of preeclampsia. METHODS: Urins and placental tissues were obtained from 20 normal and 20 preeclamptic women at 3rd trimester. Urinary MDA was assayed by an high performanance liquid chromatography (HPLC). The placental Mn-SOD activity was assayed by westen blotting and The placental Mn-SOD genotyping was assayed by PCR-RFLP. Data were analyzed statistically using Student's t-test and Chi-square test. RESULTS: 1) Urinary concentration of MDA was not significantly different in preeclampsia (4.43+/-2.37 ug/g) as compared with normotensive pregnancy (4.39+/-1.17 ug/g). 2) Preeclamptic women had similar Mn-SOD activity in placenta (1.04+/-0.04U/mL protein) as compared with normotensive pregnancy (1.44+/-0.34 U/mL protein). 3) No significant difference in the polymorphismthe of Mn-SOD genotype in placenta was observed between preeclampsia and normotensive pregnancy (X2=0.06, p>0.05) CONCLUSION: The findings in this study do not show that oxidative stress might be a pathogenetically relevent process causally contributing to the disease, and polymorphism in the Mn-SOD genotype in placenta do not seem to be risk factors for preeclampsia.
Chromatography, Liquid ; Female ; Genotype ; Humans ; Malondialdehyde ; Oxidative Stress ; Placenta ; Polymorphism, Genetic* ; Pre-Eclampsia* ; Pregnancy* ; Risk Factors ; Superoxide Dismutase* ; Superoxides*

It is well known that malnutrition is a predictor of mortality in hemodialysis patients. The number of diabetic nephropathy patients is increasing rapidly. This study aimed to investigate nutritional status and nutrient intake according to the presence of diabetes among hemodialysis patients. The nutritional intake and general characteristics of outpatients at Ajou University Hospital (24 with diabetes and 30 without diabetes) were investigated between July and September 2015. Patients' general data were collected, and nutritional status by Patient-Generated Subjective Global Assessment (PG-SGA) was evaluated. Nutrient intakes were assessed according to 3-day food records. There was no significant difference regarding body weight between the two groups. However, the non-diabetic group showed a better nutritional status by Patient-Generated Subjective Global Assessment (PG-SGA) (5.2±4.4 vs. 8.0±4.3 score, non-diabetics vs. diabetics, P<0.05). There was no difference in daily calorie intake (1,473.9±370.5 vs. 1,503.8±397.5 kcal) and protein intake (60.3±19.7 vs. 65.6±20.5 g) in those with diabetes. Intakes of vegetables protein, sodium, potassium, vitamin C, folic acid and fiber were significantly higher in the diabetic group compared to those of the non-diabetic group. There was no difference in daily nutrient intake between the hemodialysis weekday and weekend groups. The non-diabetic group had higher calorie and sodium intakes per meal in the hemodialysis weekday group, but the difference was not significant. Based on these results, intervention should be performed to improve nutritional status in consideration of diabetes and dietary patterns.
Ascorbic Acid ; Body Weight ; Diabetes Mellitus ; Diabetic Nephropathies ; Folic Acid ; Humans ; Malnutrition ; Meals ; Mortality ; Nutritional Status* ; Outpatients ; Potassium ; Prospective Studies* ; Renal Dialysis* ; Sodium ; Vegetables

SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. When acting alone, SAG scavenges oxygen radicals by forming inter- and intra-molecular disulfide bonds, whereas by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. Specifically, SAG protects cells from apoptosis, confers radioresistance, and plays an essential and non-redundant role in mouse embryogenesis and vasculogenesis. Furthermore, stress-inducible SAG is overexpressed in a number of human cancers and SAG overexpression correlates with poor patient prognosis. Finally, SAG transgenic expression in epidermis causes an early stage inhibition, but later stage promotion, of skin tumorigenesis triggered by DMBA/TPA. Given its major role in promoting targeted degradation of tumor suppressive proteins, leading to apoptosis suppression and accelerated tumorigenesis, SAG E3 ligase appears to be an attractive anticancer target.
Animals ; Antioxidants ; metabolism ; Apoptosis ; Carrier Proteins ; chemistry ; genetics ; metabolism ; Cell Transformation, Neoplastic ; Humans ; RING Finger Domains ; Substrate Specificity ; Ubiquitin-Protein Ligases ; chemistry ; metabolism ; Ubiquitination

Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.