Relationship between the type of hormone replacement therapy and incidence of breast cancer in Korea.

OBJECTIVE: This study aimed to investigate the relationship between hormone replacement therapy (HRT) types and breast cancer (BC) incidence in postmenopausal women in Korea. METHODS: The nested case-control study used data from the National Health Insurance Service database. Among the women aged ≥50 years who menopaused between 2004 and 2007, BC incidence up to 2017 was analyzed in 36,446 women using or having used HRT for >1 year and in 36,446 women who did not use any HRT for more than 1 year. HRT types and duration were classified into three categories. RESULTS: BC risk (BCR) decreased with tibolone use for all ages. With HRT initiation in women aged ≥50 years, BCR was lower with tibolone and estrogen-progestogen therapy. HRT for <3 years showed lower BCR with tibolone, while higher BCR was observed with estrogen-only therapy. BCR was lower in women of all ages on HRT for >5 years than in the control group. CONCLUSIONS: For women in their 50s, tibolone use lowers BCR; for all ages, the use of any HRT for >5 years showed lower BCR in Korea. These divergent results from western countries could be associated with the specific characteristics of BC in Korea.

Endoscopically assisted malarplasty: L-rotation technique.

INTRODUCTION: Endoscopically assisted malarplasty with a greenstick fracture is a method for preserving the body eminence and improving arch protrusion. However, this technique is inadequate when malar body reduction is required. To compensate for these limitations, we developed a new surgical technique using the endoscope to reduce body protrusion. MATERIAL AND METHODS: We enrolled 261 patients who visited our clinic for zygoma reduction from January 2017 to December 2018. Their mean age was 31 (range 17-63) years. After a scalp incision, an incomplete osteotomy was created from the most prominent portion of the zygoma body to the zygomaticomaxillary suture line. A complete osteotomy was performed on the arch. These osteotomies resulted in an L-shaped zygoma segment after tapping the bone with a mallet. RESULTS: Of the 261 patients who underwent our L-rotation technique, 242 also received a corticotomy. Of those patients, 15 underwent a different degree of zygoma reduction on both sides. A floating zygomatic segment occurred in four cases, although no further surgery was required. One patient's zygomatic segment dropped on one side, requiring rigid fixation through the intraoral approach. Most patients were satisfied and there were no specific complications. CONCLUSIONS: Endoscopically assisted malarplasty using an L-rotation technique enables the protrusion of both the arch and body to be reduced. The zygoma reduction can be modified based on the location of the incomplete osteotomoy line and the number of corticotomies required.

Flexion decreases the ventilation quality of the Ambu® AuraGain™ laryngeal mask in paralysed children: A prospective randomised crossover study.

BACKGROUND: The influence of different head and neck positions on ventilation with the Ambu® AuraGain™ remains unevaluated in children. This study assessed the influence of different head and neck positions on ventilation with the AuraGain™ in paediatric patients. METHODS: In this prospective, randomised crossover study, children ≤7 years of age who were scheduled for elective surgery under general anaesthesia were enrolled. An AuraGain™ was placed in all patients; mechanical ventilation was performed using a volume-controlled mode with a tidal volume of 10 mL/kg. Respiratory rate was adjusted to maintain a ET CO2 of 35-40 mm Hg. The oropharyngeal leak pressure, expiratory tidal volume, peak inspiratory pressure, ventilation score and fibreoptic bronchoscopic view score were assessed for the neutral head and neck position, and then for the flexed, extended and rotated head and neck positions in a random order. RESULTS: Compared with the neutral position, the oropharyngeal leak pressure increased in the flexed position (P < .001), and decreased in the extended (P = .014) and rotated position (P = .002). The expiratory tidal volume and ventilation score were significantly reduced during flexion (all P < .005), and were comparable among the neutral, extended and rotated positions. The fibreoptic score improved in the extended and rotated position (all P < .001). Only the flexion ventilation score was lower compared with the neutral position (P = .014). CONCLUSIONS: Clinically, the flexed head and neck positions negatively affected ventilation due to obstruction of the airway. Ventilation with AuraGain™ can be effectively performed with the head and neck in the neutral, extended and rotated position in paediatric patients.

Whole-Tumor Histogram and Texture Analyses of DTI for Evaluation of IDH1-Mutation and 1p/19q-Codeletion Status in World Health Organization Grade II Gliomas.

BACKGROUND AND PURPOSE: Prediction of the isocitrate dehydrogenase 1 (IDH1)-mutation and 1p/19q-codeletion status of World Health Organization grade ll gliomas preoperatively may assist in predicting prognosis and planning treatment strategies. Our aim was to characterize the histogram and texture analyses of apparent diffusion coefficient and fractional anisotropy maps to determine IDH1-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas. MATERIALS AND METHODS: Ninety-three patients with World Health Organization grade II gliomas with known IDH1-mutation and 1p/19q-codeletion status (18 IDH1 wild-type, 45 IDH1 mutant and no 1p/19q codeletion, 30 IDH1-mutant and 1p/19q codeleted tumors) underwent DTI. ROIs were drawn on every section of the T2-weighted images and transferred to the ADC and the fractional anisotropy maps to derive volume-based data of the entire tumor. Histogram and texture analyses were correlated with the IDH1-mutation and 1p/19q-codeletion status. The predictive powers of imaging features for IDH1 wild-type tumors and 1p/19q-codeletion status in IDH1-mutant subgroups were evaluated using the least absolute shrinkage and selection operator. RESULTS: Various histogram and texture parameters differed significantly according to IDH1-mutation and 1p/19q-codeletion status. The skewness and energy of ADC, 10th and 25th percentiles, and correlation of fractional anisotropy were independent predictors of an IDH1 wild-type in the least absolute shrinkage and selection operator. The area under the receiver operating curve for the prediction model was 0.853. The skewness and cluster shade of ADC, energy, and correlation of fractional anisotropy were independent predictors of a 1p/19q codeletion in IDH1-mutant tumors in the least absolute shrinkage and selection operator. The area under the receiver operating curve was 0.807. CONCLUSIONS: Whole-tumor histogram and texture features of the ADC and fractional anisotropy maps are useful for predicting the IDH1-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas.

The effect of 6% hydroxyethyl starch (130/0.4) on acute kidney injury in paediatric cardiac surgery: a prospective, randomised trial.

We have evaluated the effect of a colloid solution on acute kidney injury in paediatric cardiac surgery. A total of 195 patients were ramdomly divided into an hydroxyethyl starch group and a control group. In the starch group, 6% hydroxyethyl starch 130/0.4 (Volulyte® ) was used as the primary fluid for volume resuscitation but was limited to 30 ml.kg-1 . In the control group, only crystalloid fluid was used during the peri-operative period. The incidence of acute kidney injury, peri-operative transfusion, clinical outcomes and laboratory data were compared. The incidence of acute kidney injury determined by Paediatric Risk, Injury, Failure, Loss, End-stage renal disease (pRIFLE) and Acute Kidney Injury Network (AKIN) criteria were no different between the two groups (starch group 40.8% vs. control group 30.0%; p = 0.150 using pRIFLE; 19.6% vs. 21.1% respectively, p = 0.602 using AKIN). There were no differences in clinical outcomes such as mortality, major adverse events, intensive care unit stay or duration of mechanical ventilation. Clotting time as measured using rotational thromboelastometry (ROTEM) was prolonged, and clot firmness after 10 min and maximal clot firmness were shorter in the starch group compared with the control group after sternal closure. There was no difference in transfusion between the two groups. Patients with acute kidney injury had worse clinical courses than those without acute kidney injury. We conclude that intra-operative use of 6% hydroxyethyl starch 130/0.4 up to 30 ml.kg-1 was not associated with postoperative acute kidney injury in paediatric cardiac patients.

Assessment of dynamic variables of fluid responsiveness to predict desufflation-induced hypotension during paediatric laparoscopic surgery.

BACKGROUND: During laparoscopic surgery in paediatric patients, sudden hypotension may occur following peritoneal desufflation due to hypovolaemia or an acute increase in gastrointestinal venous capacitance by the release of intra-abdominal pressure. This study examined whether dynamic variables of fluid responsiveness during pneumoperitoneum can predict the occurrence of hypotension following desufflation. METHODS: A total of 120 paediatric subjects were prospectively enrolled. A predictor was derived from the initial 83 subjects and validated thereafter in 37 high-risk subjects. The pleth variability index, respiratory variation in the pulse oximetry plethysmographic waveform (ΔPOP), systolic pressure variation and pulse pressure variation during pneumoperitoneum were obtained 1 min before desufflation. Predictors of desufflation-induced hypotension were investigated using the multivariable logistic regression analysis. Predictability was assessed using the area under the receiver-operating characteristic curve (AUC). RESULTS: In the derivation cohort, 27% (n=23) of subjects developed hypotension. Only ΔPOP was found to be a predictor, and showed high predictability of desufflation-induced hypotension [AUC 0.87, P<0.0001, 95% confidence interval (CI): 0.78-0.93]. A ΔPOP cut-off point of 38% predicted hypotension with a sensitivity of 83% and a specificity of 90%. In the validation cohort, 43% (n=16) of subjects developed hypotension, and ΔPOP was verified to be highly predictive of the occurrence of hypotension (AUC 0.90, P<0.0001, 95% CI: 0.76-0.98). The sensitivity and specificity of a ΔPOP cut-off point of 38% to predict hypotension was 88% and 90%, respectively. CONCLUSIONS: The ΔPOP during pneumoperitoneum is useful in predicting desufflation-induced hypotension during paediatric laparoscopic surgery. CLINICAL TRIAL REGISTRATION: NCT02536521.

The Initial Area Under the Curve Derived from Dynamic Contrast-Enhanced MRI Improves Prognosis Prediction in Glioblastoma with Unmethylated MGMT Promoter.

BACKGROUND AND PURPOSE: Although perfusion and permeability MR parameters have known to have prognostic value, they have reproducibility issues. Our aim was to evaluate whether the initial area under the time-to-signal intensity curve (IAUC) derived from dynamic contrast-enhanced MR imaging can improve prognosis prediction in patients with glioblastoma with known MGMT status. MATERIALS AND METHODS: We retrospectively examined 88 patients with glioblastoma who underwent preoperative dynamic contrast-enhanced MR imaging. The means of IAUC values at 30 and 60 seconds (IAUC30mean and IAUC60mean) were extracted from enhancing tumors. The prognostic values of IAUC parameters for overall survival and progression-free survival were assessed with log-rank tests, according to the MGMT status. Multivariate overall survival and progression-free survival models before and after adding the IAUC parameters as covariates were explored by net reclassification improvement after receiver operating characteristic analysis for 1.5-year overall survival and 1-year progression-free survival and by random survival forest. RESULTS: High IAUC parameters were associated with worse overall survival and progression-free survival in the unmethylated MGMT group, but not in the methylated group. In the unmethylated MGMT group, 1.5-year overall survival and 1-year progression-free survival prediction improved significantly after adding IAUC parameters (overall survival area under the receiver operating characteristic curve, 0.86; progression-free survival area under the receiver operating characteristic curve, 0.74-0.76) to the model with other prognostic factors (overall survival area under the receiver operating characteristic curve, 0.81; progression-free survival area under the receiver operating characteristic curve, 0.69; P < .05 for all) except in the case of IAUC60mean for 1-year progression-free survival prediction (P = .059). Random survival forest models indicated that the IAUC parameters were the second or most important predictors in the unmethylated MGMT group, except in the case of the IAUC60mean for progression-free survival. CONCLUSIONS: IAUC can be a useful prognostic imaging biomarker in patients with glioblastoma with known MGMT status, improving prediction of glioblastoma prognosis with the unmethylated MGMT promoter status.

Effects of an alveolar recruitment manoeuvre guided by lung ultrasound on anaesthesia-induced atelectasis in infants: a randomised, controlled trial.

Atelectasis occurs in the majority of children undergoing general anaesthesia. Lung ultrasound has shown reliable sensitivity and specificity for diagnosing anaesthesia-induced atelectasis. We assessed the effects of a recruitment manoeuvre on atelectasis using lung ultrasound in infants undergoing general anaesthesia. Forty infants, randomly allocated to either a recruitment manoeuvre group or a control group, received volume-controlled ventilation with 5 cmH2 O positive end-expiratory pressure. Lung ultrasound examination was performed twice in each patient, the first a minute after starting mechanical ventilation of the lungs and the second at the end of surgery. Patients in the recruitment manoeuvre group received ultrasound-guided recruitment manoeuvres after each lung ultrasound examination. The incidence of significant anaesthesia-induced atelectasis at the second lung ultrasound examination was less in the recruitment manoeuvre group compared with the control group (25% vs. 80%; p = 0.001; odds ratio (OR) 0.083; 95% confidence interval (CI): 0.019-0.370). The median (IQR [range]) lung ultrasound scores for consolidation and B-lines on the second examination were lower in the recruitment manoeuvre group compared with the control group; 6.0 (3.0-9.3 [0.0-14.0]) vs. 13.5 (11.0-16.5 [8.0-23.0]); p < 0.001 and 6.5 (3.0-12.0 [0.0-28.0]) vs. 15.0 (10.8-20.5 [7.0-28.0]); p < 0.001, respectively. The lung ultrasound scores for consolidation on the first and second examinations showed a negative correlation with age (r = -0.340, p = 0.008; r = -0.380, p = 0.003). We conclude that ultrasound-guided recruitment manoeuvres with positive end-expiratory pressure proved useful in reducing the incidence of anaesthesia-induced atelectasis in infants, although 5 cmH2 O positive end-expiratory pressure alone was not sufficient to eliminate it. In addition, the younger the patient, the more susceptible they were to atelectasis.

Development of a nomogram for predicting the probability of postoperative delirium in patients undergoing free flap reconstruction for head and neck cancer.

PURPOSE: To develop nomogram for prediction of postoperative delirium (POD) in patients undergoing ablative and reconstruction surgery for head and neck cancer. METHODS: Total 341 patients were retrospectively analyzed, and clinical variables in preoperative, intraoperative and postoperative periods were compared between delirium group (n = 89) and non-delirium group (n = 252). Multivariate logistic regression, receiver operating characteristics curve, and area under the curve (AUC) were used to generate and test a nomogram, which performance was evaluated by 10-fold cross validation (CV) procedure. RESULTS: In univariate and multivariate analysis, age, history of psychiatric disorder, marital status, preoperative numeric rating scale for pain, ASA classification, and ICU stay period were identified as significant risk factors. Using these factors, nomogram for predicting the POD was developed and it showed sensitivity of 61.8%, specificity of 75.4%, PPV of 47.0%, and NPV of 84.8% (Youden's index of 0.372). In 10-fold cross validation set, corresponding values were 44.9%, 84.1%, 50.0% and 81.2% (Youden's index of 0.337). AUC was comparable between two sets (0.7407 and 0.6898). CONCLUSIONS: Proposed nomogram showed fair discriminative power for POD risk in head and neck cancer patients undergoing major surgery.

Ultrasound assessment of gastric volume in children after drinking carbohydrate-containing fluids.

BACKGROUND: Gastric ultrasound is a valid tool for non-invasive assessment of the nature and volume of gastric contents in adults and children. Perioperative fasting guidelines recommend oral carbohydrates up to 2 h before elective surgery. We evaluated gastric volume in children using ultrasound before and after drinking carbohydrate fluids before surgery. METHODS: Paediatric patients younger than 18 yr old undergoing elective surgery were enrolled. Initial ultrasound assessment of gastric volume was performed after fasting for 8 h. Two hours before surgery, patients were given carbohydrate drinks: 15 ml kg(-1) for patients younger than 3 yr old and 10 ml kg(-1) for those more than 3 yr old. Before induction of general anaesthesia, the gastric volume was reassessed. Parental satisfaction scores (0=totally satisfied, 10=totally dissatisfied) and complications were recorded. RESULTS: Of the 86 enrolled patients, 79 completed the study; three refused to ingest the requested volume, and surgery was delayed for more than 2 h in four patients. The mean (sd) of the initial and second ultrasound measurements were 2.09 (0.97) and 1.85 (0.94) cm(2), respectively (P=0.01; mean difference 0.24 cm(2), 95% confidence interval 0.06-0.43). The median (interquartile range) satisfaction score was 2.4 (0-6). Two instances of postoperative vomiting and one instance of postoperative nausea occurred. CONCLUSIONS: Carbohydrate fluids ingested 2 h before surgery reduced the gastric volume and did not cause serious complications in paediatric patients. Parents were satisfied with the preoperative carbohydrate drink. Children may benefit from drinking carbohydrate fluids up to 2 h before elective surgery. CLINICAL TRIAL REGISTRATION: cris.nih.go.kr (KCT0001546).

Development of operational immunologic tolerance with neonatal gene transfer in nonhuman primates: preliminary studies.

Achieving persistent expression is a prerequisite for effective genetic therapies for inherited disorders. These proof-of-concept studies focused on adeno-associated virus (AAV) administration to newborn monkeys. Serotype rh10 AAV expressing ovalbumin and green fluorescent protein (GFP) was administered intravenously at birth and compared with vehicle controls. At 4 months postnatal age, a second injection was administered intramuscularly, followed by vaccination at 1 year of age with ovalbumin and GFP. Ovalbumin was highest 2 weeks post administration in the treated monkey, which declined but remained detectable thereafter; controls demonstrated no expression. Long-term AAV genome copies were present in myocytes. At 4 weeks, neutralizing antibodies to rh10 were present in the experimental animal only. With AAV9 administration at 4 months, controls showed transient ovalbumin expression that disappeared with the development of strong anti-ovalbumin and anti-GFP antibodies. In contrast, increased and maintained ovalbumin expression was noted in the monkey administered AAV at birth, without antibody development. After vaccination, the experimental monkey maintained levels of ovalbumin without antibodies, whereas controls demonstrated high levels of antibodies. These preliminary studies suggest that newborn AAV administration expressing secreted and intracellular xenogenic proteins may result in persistent expression in muscle, and subsequent vector administration can result in augmented expression without humoral immune responses.

The Added Prognostic Value of Preoperative Dynamic Contrast-Enhanced MRI Histogram Analysis in Patients with Glioblastoma: Analysis of Overall and Progression-Free Survival.

BACKGROUND AND PURPOSE: The prognostic value of dynamic contrast-enhanced MR imaging in patients with glioblastoma is controversial. We investigated the added prognostic value of dynamic contrast-enhanced MR imaging to clinical parameters and molecular biomarkers in patients with glioblastoma by using histogram analysis. MATERIALS AND METHODS: This retrospective study consisted of 61 patients who underwent preoperative dynamic contrast-enhanced MR imaging for glioblastoma. The histogram parameters of dynamic contrast-enhanced MR imaging, including volume transfer constant, extravascular extracellular volume fraction, and plasma volume fraction, were calculated from entire enhancing tumors. Univariate analyses for overall survival and progression-free survival were performed with preoperative clinical and dynamic contrast-enhanced MR imaging parameters and postoperative molecular biomarkers. Multivariate Cox regression was performed to build pre- and postoperative models for overall survival and progression-free survival. The performance of models was assessed by calculating the Harrell concordance index. RESULTS: In univariate analysis, patients with higher volume transfer constant and extravascular extracellular volume fraction values showed worse overall survival and progression-free survival, whereas plasma volume fraction showed no significant correlation. In multivariate analyses for overall survival, the fifth percentile value of volume transfer constant and kurtosis of extravascular extracellular volume fraction were independently prognostic in the preoperative model, and kurtosis of volume transfer constant and extravascular extracellular volume fraction were independently prognostic in the postoperative model. For progression-free survival, independent prognostic factors were minimum and fifth percentile values of volume transfer constant and kurtosis of extravascular extracellular volume fraction in the preoperative model and kurtosis of extravascular extracellular volume fraction in the postoperative model. The performance of preoperative models for progression-free survival was significantly improved when minimum or fifth percentile values of volume transfer constant and kurtosis of extravascular extracellular volume fraction were added. CONCLUSIONS: Higher volume transfer constant and extravascular extracellular volume fraction values are associated with worse prognosis, and dynamic contrast-enhanced MR imaging may have added prognostic value in combination with preoperative clinical parameters, especially in predicting progression-free survival.

Association between changes in body composition and risk of developing Type 2 diabetes in Koreans.

AIMS: To examine the effects of longitudinal changes in fat mass or lean body mass on risk of Type 2 diabetes in Korean adults. METHODS: Participants included 18 687 Korean adults (aged 20-79 years) who underwent routine medical check-ups in 2007-2008 and again in 2011-2012 with a mean (range) of 4.3 (3.0-5.7) years interval. Total fat, fat-free, and soft fat-free masses were determined using bioelectrical impedance. RESULTS: A total of 692 subjects (3.7%) developed Type 2 diabetes during follow-up. Those who developed diabetes had a greater increase in percent body fat (2.9 ± 3.0 vs 2.6 ± 3.2 percentage points, P = 0.043), as well as greater decreases in percent fat-free mass (-3.0 ± 3.3 vs -2.7 ± 3.3 percentage points, P = 0.008) and percent soft fat-free mass (-2.8 ± 3.1 vs -2.4 ± 3.1 percentage points, P = 0.003) compared with those who did not develop diabetes. In multiple logistic regression analysis, an increase in total fat mass of > 10% was associated with an increased odds ratio for diabetes (1.29, 1.05-1.60), and a decreased total fat mass was associated with lower odds ratio (0.75, 0.58-0.96). A loss of total fat-free mass of > 5% (odds ratio 1.08, 0.90-1.30) or an increase in total fat-free mass (odds ratio 0.96, 0.71-1.28) was not significantly associated with the risk of diabetes after adjustments for baseline waist circumference and glucose levels. CONCLUSIONS: These results show that changes in total body fat mass, but not lean body mass, are associated with development of Type 2 diabetes, independently of baseline measures of general or central obesity.

Whole-genome analysis of a patient with early-stage small-cell lung cancer.

We performed whole-genome sequencing (WGS) of a case of early-stage small-cell lung cancer (SCLC) to analyze the genomic features. WGS revealed a lot of single-nucleotide variations (SNVs), small insertion/deletions and chromosomal abnormality. Chromosomes 4p, 5q, 13q, 15q, 17p and 22q contained many block deletions. Especially, copy loss was observed in tumor suppressor genes RB1 and TP53, and copy gain in oncogene hTERT. Somatic mutations were found in TP53 and CREBBP. Novel nonsynonymous (ns) SNVs in C6ORF103 and SLC5A4 genes were also found. Sanger sequencing of the SLC5A4 gene in 23 independent SCLC samples showed another nsSNV in the SLC5A4 gene, indicating that nsSNVs in the SLC5A4 gene are recurrent in SCLC. WGS of an early-stage SCLC identified novel recurrent mutations and validated known variations, including copy number variations. These findings provide insight into the genomic landscape contributing to SCLC development.

15-deoxy-Δ12,14-prostaglandin J2 induces p53 expression through Nrf2-mediated upregulation of heme oxygenase-1 in human breast cancer cells.

Heme oxygenase-1 (HO-1) is a stress-responsive enzyme that has antioxidant and cytoprotective functions. However, HO-1 has oncogenic functions in cancerous or transformed cells. In the present work, we investigated the effects of HO-1 on the expression of p53 induced by 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) in human breast cancer (MCF-7) cells. Treatment of MCF-7 cells with 15d-PGJ2 led to time-dependent increases in the expression of p53 as well as HO-1. Upregulation of p53 expression by 15d-PGJ2 was abrogated by si-RNA knock-down of HO-1. In MCF-7 cells transfected with HO-1 si-RNA, 15d-PGJ2 failed to induce expression of p53 as well as HO-1. In addition, HO-1 inducers enhanced the p53 expression. We speculated that iron, a by-product of HO-1-catalyzed reactions, could mediate 15d-PGJ2-induced p53 expression. Upregulation of p53 expression by 15d-PGJ2 was abrogated by the iron chelator desferrioxamine in MCF-7 cells. Iron released from heme by HO-1 activity is mostly in the Fe(2+) form. When MCF-7 cells were treated with the Fe(2+)-specific chelator phenanthroline, 15d-PGJ2-induced p53 expression was attenuated. In addition, levels of the Fe-sequestering protein H-ferritin were elevated in 15d-PGJ2-treated MCF-7 cells. In conclusion, upregulation of p53 and p21 via HO-1 induction and subsequent release of iron with accumulation of H-ferritin may confer resistance to oxidative damage in cancer cells frequently challenged by redox-cycling anticancer drugs.

The Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin increases cisplatin antitumor activity by inducing p53-mediated apoptosis in head and neck cancer.

The tumor suppressor p53 is often inactivated in head and neck cancer (HNC) through TP53 mutations or overexpression of mouse double minute 2 or mouse double minute X. Restoration of p53 function by counteracting these p53 repressors is a promising strategy for cancer treatment. The present study assessed the ability of a heat shock protein 90 (Hsp90) inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), to induce apoptosis in HNC by restoring p53 function. The effect of 17AAG, alone or in combination with Nutlin-3a or cisplatin, was assessed in HNC cells using growth and apoptosis, immunoblotting, quantitative reverse transcription-polymerase chain reaction, and preclinical tumor xenograft models. 17AAG activated and stabilized p53 in HNC cells bearing wild-type TP53 by disrupting the p53-MDMX interaction. 17AAG upregulated p21 and proapoptotic gene expression, and promoted apoptosis in a concentration-dependent manner. Growth inhibition by 17AAG was highest in tumor cells with MDMX overexpression. The apoptotic response was blocked by inhibition of p53 expression, demonstrating that the effect of 17AAG depended on p53 and MDMX. 17AAG synergized in vitro with Nutlin-3a and in vitro and in vivo with cisplatin to induce p53-mediated apoptosis. 17AAG effectively induced p53-mediated apoptosis in HNC cells through MDMX inhibition and increased the antitumor activity of cisplatin synergistically, suggesting a promising strategy for treating HNC.

Gastrin promotes intestinal polyposis through cholecystokinin-B receptor-mediated proliferative signaling and fostering tumor microenvironment.

Increased serum gastrin concentrations in patients with colorectal cancer suggested the tumorigenic trophic effect of gastrin. Detailed and global molecular mechanisms explaining trophic effect of gastrin had not been revealed. In the current study, intestinal polyposis of APC(Min/⁺) mice was compared between phosphate buffered saline (PBS) injected and gastrin (10 µg/kg, thrice per week) injected group. Total number of intestinal polyposis was counted and immunohistochemical staining with F4/80 and CD3 was done. MTT assay, cell cycle analysis, and Western blot for cyclin D1, CDK4, and ß-catenin were performed in Raw 264.7 and HCT116 cells before and after gastrin administration. Experiments were repeated with YM022 or transfection with si-cholecystokinin-B receptor (CCK-B-R). Intraperitoneal gastrin significantly increased intestinal polyposis in APC(Min/⁺) mice (P<0.005), in which significant increases in macrophage were noted on F4/80 immunohistochemical staining (Plt;0.05) as well as Ki-67 staining (Plt;0.05) after gastrin. On comparative cytokine array, gastrin increased interleukin-1ß (IL-1ß), interleukin 3Rß (IL-3Rß), stromal cell-derived factor-1α (SDF-1α), thymus and activation-regulated chemokine (TARC), and thymus-derived chemotactic agent 3 (TCA-3) in macrophage cells, which was further confirmed with real time polymerase chain reaction (RT-PCR) analysis (P<0.05). In addition to increased inflammatory cytokines, gastrin increased macrophage proliferation accompanied with increased cyclin D1 and CDK4. Targeted for HCT116 cells, gastrin significantly increased proliferation as well as increases in synthetic phase of cell cycle. YM022 as gastrin antagonist significantly abolished the trophic actions of gastrin (P<0.05). HCT116 cells transfected with siCCK-B-R, gastrin did not increase either cell cycle or ß-catenin in spite of gastrin administration. Conclusively, gastrin promoted intestinal polyposis through either direct gastrin receptor-mediated proliferative signaling or fostering tumor microenvironment such as macrophage activation.

Nonsteroidal anti-inflammatory drugs (NSAID) sparing effects of glucosamine hydrochloride through N-glycosylation inhibition; strategy to rescue stomach from NSAID damage.

Gastrointestinal or cardiovascular complications limit nonsteroidal anti-inflammatory drugs (NSAID) prescription. Glucosamine hydrochloride (GS-HCl) alternatively chosen, but debates still exist in its clinical efficiency. COX-2 instability through inhibiting COX-2 N-glycosylation of GS-HCl raised the possibility of NSAID sparing effect. Study was done to determine whether combination treatment of glucosamine and NSAID contributes to gastric safety through NSAID sparing effect. IEC-6 cells were stimulated with TNF-α and compared the expressions of inflammatory mediators after indomethacin alone or combination of indomethacin and GS-HCl by Western blotting and RT-PCR. C57BL/6 mice injected with type II collagen to induce arthritis were treated with indomethacin alone or combination of reduced dose of indomethacin and GS-HCl after 3 weeks. TNF-α increased the expression of COX-2, iNOS and inflammatory cytokines, but GS-HCl significantly attenuated TNF-α-induced COX-2 expression. Decreased COX-2 after GS-HCl was caused by N-glycosylation inhibition as much as tunicamycin. Combination of reduced dose of indomethacin and GS-HCl significantly reduced the expressions of ICAM-1, VCAM-1, IL-8, IL-1ß, MMP-2, MMP-7, MMP-9, and MMP-11 mRNA as well as NF-κB activation better than high dose indomethacin alone. These NSAID sparing effect of GS-HCl was further proven in collagen-induced arthritis model. Combination of GS-HCl and 2.5 mg/kg indomethacin showed significant protection from gastric damages as well as efficacious anti-arthritic effect. Taken together, COX-2 N-glycosylation inhibition by GS-HCl led to indomethacin sparing effects, based on which combination of GS-HCl and reduced dose of NSAID can provide the strategy to secure stomach from NSAID-induced gastric damage as well as excellent anti-arthritic effects.

Higher serum uric acid is associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in healthy postmenopausal women.

UNLABELLED: Higher serum uric acid (UA) was associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in postmenopausal women. Furthermore, UA suppressed osteoclastogenesis and decreased production of reactive oxygen species in osteoclast precursors, indicating UA may have beneficial effects on bone metabolism as an antioxidant. INTRODUCTION: UA is known to play a physiological role as an antioxidant, and oxidative stress has detrimental effects on bone metabolism. In the present study, we investigated the association of serum UA level with the osteoporosis-related phenotypes and its direct effect on bone-resorbing osteoclasts using in vitro systems. METHODS: This is a large cross-sectional study, including 7,502 healthy postmenopausal women. Bone mineral density (BMD) and serum UA concentrations were obtained from all subjects. Data on bone turnover markers and lateral thoracolumbar radiographs were available for 1,023 and 6,918 subjects, respectively. An in vitro study investigated osteoclastogenesis and reactive oxygen species (ROS) levels according to UA treatment. RESULTS: After adjusting for multiple confounders, serum UA levels were positively associated with BMD at all sites (all p < 0.001). Compared with the participants in the highest UA quartile, the odds for osteoporosis were 40 % higher in those in the lowest quartile. The serum UA levels were inversely related to both serum C-terminal telopeptide of type I collagen and osteocalcin levels (p < 0.001 and p = 0.004, respectively). Consistently, subjects with vertebral fracture had lower serum UA levels, compared with those without it (p = 0.009). An in vitro study showed that UA decreased osteoclastogenesis in a dose-dependent manner and reduced the production of ROS in osteoclast precursors. CONCLUSION: These results provide epidemiological and experimental evidence that serum UA may have a beneficial effect on bone metabolism as an antioxidant in postmenopausal women.

Neural transdifferentiation of human bone marrow mesenchymal stem cells on hydrophobic polymer-modified surface and therapeutic effects in an animal model of ischemic stroke.

Human bone marrow-derived mesenchymal stem cells (MSCs) have multi-lineage differentiation potential and can become cells of mesodermal and neural lineages. These stem cells thus hold considerable clinical promise for the treatment of neurodegenerative diseases. For successful regeneration of damaged neural tissues, directed differentiation of neural or neuronal precursor cells from MSCs and integration of transplanted cells are pivotal factors. We induced MSCs into neurogenesis using a modified protocol. The therapeutic potency of the resulting neural progenitor cells in a rat model of ischemic stroke was analyzed. Using a highly hydrophobic diphenylamino-s-triazine-bridged p-phenylene (DTOPV)-coated surface and adopting a procedure for propagation of neural stem cells, we efficiently converted MSCs into neurosphere-like cellular aggregates (NS-MSCs). The spherical cells were subsequently induced to differentiate into neural cells expressing neuroectodermal markers. To determine whether these cells had neuronal fates and induced neuro-protective effects in vivo, NS-MSCs were intra-cerebrally administered to rats 48h after permanent middle cerebral artery occlusion (pMCAo). The results showed a remarkable attenuation of ischemic damage with significant functional recovery, although the cells were not fully incorporated into the damaged tissues on post-operative day 26. Improvement in the NS-MSC-transplanted rats was faster than in the MSC group and suppression of inflammation was likely the key factor. Thus, our culture system using the hydrophobic surface of a biocompatible DTOPV coating efficiently supported neural cell differentiation from MSCs. Neural-primed MSCs exhibited stronger therapeutic effects than MSCs in rat brains with pMCAo.