C-reactive protein binds to integrin α2 and Fcγ receptor I, leading to breast cell adhesion and breast cancer progression.

C-reactive protein (CRP) is an acute phase protein synthesized upon the inflammatory responses, associated with breast cancer. The process of tumor cell invasion and metastasis involves the adherence of cells to the extracellular matrix via integrin as a receptor for matrix molecules. The present study investigated the role of CRP in the adhesive phenotype of breast cells and the underlying mechanisms. Here, we first showed that CRP induces adhesion of MCF10A human breast epithelial cells through the activation of integrin α2 signaling. Expression of integrin α2 was induced by CRP in which transcription factors c-fos and SP1 may be involved. Binding of CRP with integrin α2 leads to the activation of focal adhesion kinase (FAK), paxillin and ERKs. CRP also binds to an Fcγ receptor Fcγ receptor I (FcγRI), and induces activation of paxillin, FAK and ERKs. Integrin α2 and FAK have crucial roles in the adhesive and invasive phenotypes as well as MMP-9 upregulation induced by CRP in MCF10A cells. Treatment with an inflammatory lipid sphingosine-1-phosphate induced CRP, which may be secreted and exert an autocrine effect by binding to FcγRI and integrin α2. Involvement of CRP in adhesion, invasion, anchorage-independent growth and upregulation of integrin α2, paxillin and FAK was observed in MDA-MB-231 triple-negative human breast cancer (TNBC) cells. Using an in vivo invasion model and an orthotopic mouse tumor model with MDA-MB-231 cells, we showed that CRP has an important role in intravasation and tumor growth in vivo, demonstrating the in vivo relevance of our in vitro results. The present study elucidates a critical molecular basis between CRP, integrin α2 and FcγRI pathways in MCF10A breast cells and MDA-MB-231 TNBC cells, thereby providing useful information on CRP-induced aggressiveness of breast cells in the inflammatory microenvironment.

Clinical benefit of nomogram for predicting positive resection margins in breast conserving surgery.

PURPOSE: Previously, we reported a nomogram for the prediction of positive resection margin (RM) after breast conserving surgery (BCS). This study was conducted to evaluate the clinical usefulness of the nomogram. METHODS: Prospective patients who underwent operations using the nomogram between July 2012 and August 2013 (nomogram group; N = 260) were compared with past control patients who underwent operations between July 2010 and October 2011 and underwent frozen section biopsy (FSB) without use of the nomogram (N = 266). In the nomogram group, an intraoperative assessment of RM using FSB was only performed when the nomogram score was higher than predefined cut-off (>80). In addition, we conducted retrospective analysis of additional 181 patients who received BCS in another institute (Kyoto University Hospital). These patients did not undergo FSBs for RMs. RESULTS: Of 260 patients, 161 (61.9%) presented low nomogram scores and avoided FSB. The surgical decision to use the nomogram did not significantly increase reoperation rate due to positive RM compared with the control FSB group (4.6% vs. 3.8%, p = 0.47). The surgery time was significantly reduced by 18.1% (mean 14.7 min) in nomogram group (p < 0.001). Of 99 nomogram high-score patients, 14 presented with positive RM on FSB and 11 of them avoided reoperation. In the Kyoto cohort, the reoperation rate was significantly lower in low-score patients than in high-score patients (2.7% vs. 11.4%, p < 0.001). CONCLUSIONS: We showed that our nomogram is useful to reduce FSBs without increasing reoperation rate for surgeons who perform routine FSBs. For most surgeons, it can give useful information about the possibility of tumor-positive RMs.

Efficacy and safety of certolizumab pegol for Crohn's disease in clinical practice.

BACKGROUND: Certolizumab pegol (CZP) is Food and Drug Administration (FDA)-approved to treat Crohn's disease (CD). However, the efficacy and safety of CZP outside clinical trials are not well established. AIM: To report the efficacy, safety and predictors of response to CZP in CD patients treated during a 6-year period since FDA-approval at a tertiary care centre. METHODS: All CD patients who received CZP at our institution between 2008 and 2013 were evaluated through retrospective medical record-based review of steroid-free complete response (SCR), loss of response and safety. RESULTS: A total of 358 patients were included. One hundred twelve patients (31.3%) and 189 (52.8%) received CZP as their second and third biological agent, respectively. The probability of SCR at 26 week was 19.9% (95% CI, 15.9-24.5). The probability of survival free of loss of response at 2 year was 45.7% (95% CI, 32.5-59.5). A predictor of SCR was age at CD diagnosis of >40 years old (hazard ratio, HR relative to those <17, 4.69; 95% CI, 1.75-12.61). Negative predictors included present perianal fistula (HR, 0.39; 95% CI, 0.16-0.98) and prior primary nonresponse to adalimumab (ADA; HR relative to secondary loss of response, 0.18; 95% CI, 0.04-0.76). Twenty-three patients (6.4%) experienced serious adverse events and 19 patients (5.3%) discontinued CZP due to adverse events. CONCLUSIONS: Certolizumab pegol was both effective and well tolerated for the treatment of Crohn's disease in this large tertiary care centre enriched with biologics-exposed patients. It may be more effective in patients without early-aged Crohn's disease diagnosis, prior primary nonresponse to adalimumab and present perianal fistula.

Role of second-look ultrasound examinations for MR-detected lesions in patients with breast cancer.

PURPOSE: To assess the clinical value of second-look ultrasound (US) examination for the evaluation of additional enhancing lesions detected on magnetic resonance (MR) imaging. MATERIALS AND METHODS: Between May 2008 and February 2011, 794 consecutive patients with histologically confirmed breast cancer underwent breast MR imaging. We included 101 patients with 132 additional enhancing breast lesions detected on MR imaging who underwent second-look US.  The imaging features and lesion category according to the Breast Imaging and Reporting and Data System (BI-RADS) were assessed with MR and US imaging, respectively. RESULTS: According to the BI-RADS system, 67 lesions (50.8 %) were classified as category 0, 33 lesions (25.0 %) as category 3, and 32 lesions (24.2 %) as category 4. Of the 67 indeterminate lesions on MR imaging, 34 (50.7 %) were demonstrated on second-look US. 11 of these 34 lesions showed suspicious sonographic features, including 1 lesion that showed malignancy (9.1 %, 1/11). Most of the suspicious lesions on MR imaging (26 of 32 BI-RADS category 4 lesions, 81.3 %) were demonstrated on second-look US, and 17 were malignant (65.4 %, 17/26). Of the 6 BI-RADS category 4 lesions without sonographic correlation, 1 was malignant (16.7 %, 1/6). CONCLUSION: Second-look US examination was useful for evaluating MR-detected lesions in patients with breast cancer.

Inhibition of monoamine oxidase isoforms modulates nicotine withdrawal syndrome in the rat.

AIMS: There have been many reports of monoamine oxidase (MAO) inhibition by non-nicotine ingredients in tobacco smoke, persisting for days after smoking cessation. This study determined the effect of inhibiting MAO and its isoforms on nicotine withdrawal syndrome. MAIN METHODS: Rats were rendered nicotine-dependent by seven days of subcutaneous (s.c.) 9 mg/kg/day infusion of nicotine bitartrate. Twenty-two hours after termination of infusion, they were observed over 20 min for somatically expressed nicotine withdrawal signs. Three hours before observation, rats were injected intraperitoneally (i.p.) with 4 mg/kg each of the MAO A antagonist clorgyline and the MAO B antagonist deprenyl, or with saline alone. A similar experiment was performed with non-dependent, saline-infused rats. Another experiment compared nicotine-dependent rats that received injections of either saline or 4 mg/kg clorgyline alone. A further experiment compared rats receiving either saline or 4 mg/kg deprenyl alone. KEY FINDINGS: Combined treatment with both MAO inhibitors markedly and significantly exacerbated somatically expressed nicotine withdrawal signs in nicotine infused rats, while having no significant effects in saline-infused rats. Rats injected s.c. with 4 mg/kg clorgyline alone had significantly more withdrawal signs than saline-injected rats, while deprenyl-injected rats had significantly fewer signs than saline controls. Assays confirmed that clorgyline thoroughly reduced MAO A enzymatic activity and deprenyl thoroughly reduced MAO B activity. SIGNIFICANCE: The results suggest that inhibition of MAO A may contribute to the intensity of withdrawal syndrome in smoking cessation.

Intracranial dermoid cyst ruptured into the membranous labyrinth causing sudden sensorineural hearing loss: CT and MR imaging findings.

A ruptured dermoid cyst is rare and can present with various symptoms. We report imaging findings of an intracranial dermoid cyst that ruptured into the endolymphatic sac, causing sudden sensorineural hearing loss.

Case report. Tuberculous cervical lymphadenitis mimicking metastatic lymph nodes from papillary thyroid carcinoma.

We report two unusual cases of tuberculous lymphadenitis mimicking metastatic lymph nodes from papillary thyroid carcinoma (PTC). Pre-operative ultrasonography of the cervical nodes suggested a metastasis with cystic necrosis and calcification in PTC patients, but permanent pathology revealed tuberculosis lymphadenitis after neck dissection. In cases suspicious for metastatic cervical nodes in patients with PTC, fine-needle aspiration cytology may be indicated for the differential diagnosis of tuberculosis lymphadenitis, especially in those who have experienced tuberculosis in the past.

Age and HER2 expression status affect MRI accuracy in predicting residual tumor extent after neo-adjuvant systemic treatment.

BACKGROUND: Although recent studies suggest high accuracy of breast magnetic resonance imaging (MRI) in predicting residual tumor extent after neo-adjuvant systemic treatment (NST), its use is still controversial. In this study, we aimed to identify predictive factors of MRI accuracy after NST to determine a subgroup of patients in whom the use of MRI provides best additional benefit. MATERIALS AND METHODS: Clinicopathologic and molecular profiles of breast cancer patients were investigated and their relationships with MRI accuracy were analyzed. RESULTS: From January 2006 to February 2008, 195 patients received NST and preoperative MRI. In overall, MRI predicted residual tumor extent with higher accuracy than ultrasonography. Triple-negative (TN) tumors showed highest correlation between MRI-measured and pathologic tumor size (r = 0.781) when compared with other subtypes. Multivariate analysis showed age and HER2 expression status as independent factors predicting MRI accuracy. When patients were classified based on their age and HER2 status, relatively older patients (>45) with HER2-negative tumors showed highest MRI accuracy. This finding was further validated using an independent cohort of 63 consecutive patients. CONCLUSION: Age and HER2 status independently affected MRI accuracy after NST. This observation may guide more tailored approach in using MRI in breast cancer patients undergoing NST.

Computer-aided diagnosis using morphological features for classifying breast lesions on ultrasound.

OBJECTIVES: To develop and evaluate a computer-aided diagnosis (CAD) system with automatic contouring and morphological analysis to aid in the classification of breast tumors using ultrasound. METHODS: We evaluated 118 breast lesions (34 malignant and 84 benign tumors). Each tumor contour was automatically extracted from the digitized ultrasound image. Nineteen practical morphological features from the extracted contour were calculated and principal component analysis (PCA) was applied to find independent features. A support vector machine (SVM) classifier utilized the selected principal vectors to identify the breast tumor as benign or malignant. In this study, all the cases were sampled with k-fold cross-validation (k = 10) to evaluate the performance by receiver-operating characteristics (ROC) curve analysis. RESULTS: The areas under the ROC curves for the proposed CAD systems using all morphological features and the lower-dimensional principal vector were 0.91 and 0.90, respectively. The classification ability for breast tumors using morphological information was good. CONCLUSIONS: This system differentiates benign from malignant breast tumors well and therefore provides a clinically useful second opinion. Moreover, the morphological features are nearly setting-independent and thus available to various ultrasound machines.

Optimal clustering of kinetic patterns on malignant breast lesions: comparison between K-means clustering and three-time-points method in dynamic contrast-enhanced MRI.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is useful for breast cancer diagnosis and treatment planning. Nevertheless, due to the multi-temporal nature of DCE-MRI data, the assessment of early stage breast cancer is a challenging task. In this study, we applied an unsupervised clustering approach and cluster validation technique to the analysis of malignant intral-tumoral kinetic curves in DCE-MRI. K-means cluster analysis was performed from real world malignant tumor cases and the data were transformed into an optimal number of reference patterns representative each cluster. The optimal number of clusters was estimated by a cluster validation index, which was calculated with the ratio of inter-class scatter to intra-class scatter. This technique then classifies tumor specific patterns from a given MRI data by measuring the vector distances from the reference pattern set, and compared the result from the k-means clustering with that from three-time-points (3TP) method, which represents a clinical standard protocol for analysis of tumor kinetics. The evaluation of twenty five cases indicates that optimal k-means clustering reflects partitioning intra-tumoral kinetic patterns better than the 3TP technique. This method will greatly enhance the capability of radiologists to identify and characterize internal kinetic heterogeneity and vascular change of a tumor in breast DCE-MRI.

Peripheral ossifying fibroma in the oral cavity: CT and MR findings.

We report a case of peripheral ossifying fibroma arising from the anterior oral cavity in a 12-year-old boy. CT and MR scans showed a large exophytic soft tissue mass overlying the anterior hard palate and maxillary alveolar ridge. The tumour revealed peripheral calcification without adjacent bone changes.

An extract of Polygonum multiflorum protects against free radical damage induced by ultraviolet B irradiation of the skin.

Over the last decades, the incidence of ultraviolet B (UVB)-related skin problems has been increasing. Damages induced by UVB radiation are related to mutations that occur as a result of direct DNA damage and/or the production of reactive oxygen species. We investigated the anti-oxidant effects of a Polygonum multiflorum thumb extract against skin damage induced by UVB irradiation. Female SKH-1 hairless mice were divided into three groups: control (N = 7), distilled water- (N = 10), and P. multiflorum extract-treated (PM, N = 10) groups. The PM (10 g) was extracted with 100 mL distilled water, cryo-dried and 9.8 g was obtained. The animals received a topical application of 500 microL distilled water or PM extract (1, 2, 4, 8, and 16%, w/v, dissolved in distilled water) for 30 min after UVB irradiation (wavelength 280-320 nm, 300 mJ/cm(2); 3 min) of the dorsal kin for 14 days, and skin immunohistochemistry and Cu,Zn-superoxide dismutase (SOD1) activity were determined. SOD1 immunoreactivity, its protein levels and activities in the skin were significantly reduced by 70% in the distilled water-treated group after UVB irradiation compared to control. However, in the PM extract-treated groups, SOD1 immunoreactivity and its protein and activity levels increased in a dose-dependent manner (1-16%, w/v, PM extract) compared to the distilled water-treated group. SOD1 protein levels and activities in the groups treated with 8 and 16%, w/v, PM extract recovered to 80-90% of the control group levels after UVB. These results suggest that PM extract strongly inhibits the destruction of SOD1 by UV radiation and probably contains anti-skin photoaging agents.

An extract of Polygonum multiflorum protects against free radical damage induced by ultraviolet B irradiation of the skin

Over the last decades, the incidence of ultraviolet B (UVB)-related skin problems has been increasing. Damages induced by UVB radiation are related to mutations that occur as a result of direct DNA damage and/or the production of reactive oxygen species. We investigated the anti-oxidant effects of a Polygonum multiflorum thumb extract against skin damage induced by UVB irradiation. Female SKH-1 hairless mice were divided into three groups: control (N = 7), distilled water- (N = 10), and P. multiflorum extract-treated (PM, N = 10) groups. The PM (10 g) was extracted with 100 mL distilled water, cryo-dried and 9.8 g was obtained. The animals received a topical application of 500 æL distilled water or PM extract (1, 2, 4, 8, and 16 percent, w/v, dissolved in distilled water) for 30 min after UVB irradiation (wavelength 280-320 nm, 300 mJ/cm²; 3 min) of the dorsal kin for 14 days, and skin immunohistochemistry and Cu,Zn-superoxide dismutase (SOD1) activity were determined. SOD1 immunoreactivity, its protein levels and activities in the skin were significantly reduced by 70 percent in the distilled water-treated group after UVB irradiation compared to control. However, in the PM extract-treated groups, SOD1 immunoreactivity and its protein and activity levels increased in a dose-dependent manner (1-16 percent, w/v, PM extract) compared to the distilled water-treated group. SOD1 protein levels and activities in the groups treated with 8 and 16 percent, w/v, PM extract recovered to 80-90 percent of the control group levels after UVB. These results suggest that PM extract strongly inhibits the destruction of SOD1 by UV radiation and probably contains anti-skin photoaging agents.

Non-surgical management of microperforation induced by EMR of the stomach.

BACKGROUND: Perforation and bleeding are major complications associated with gastric endoscopic mucosal resection. Evident perforation during endoscopic mucosal resection can be managed by endoscopic clipping. However, management of microperforation is not well established. PATIENT AND METHOD: From January 2002 to June 2004, 109 early gastric cancers and 300 adenomas were treated with endoscopic mucosal resection. Iatrogenic perforations occurred in 4.16% (n=17) patients. Following exclusion of four evident perforations, microperforation was observed in 3.18% (n=13) patients. The clinical features of microperforation in patients were retrospectively reviewed. RESULTS: In a total of 13 microperforation cases, 2 patients were managed surgically. The remaining patients successfully recovered without surgical management. In the case of 11 patients without surgery, 7 experienced abdominal pain, which required analgesics, 2 patients experienced mild discomfort and 2 patients experienced no symptoms. A body temperature above 37.5 degrees C was observed in 9.1% (n=1) patients and leucocytosis above 9000 microL-1 was in 72.7% (n=8) patients. The mean duration of nasogastric tube drainage was 2.36+/-1.03 days, of fasting 4.18+/-1.17 days, of intravenous antibiotics 5.55+/-1.44 days and of hospitalisation 7.45+/-1.04 days. CONCLUSION: Microperforation induced by gastric endoscopic mucosal resection can be managed successfully using a non-surgical approach including fasting, nasogastric tube drainage and intravenous antibiotics.

Effects of supplementation of beta-glucan on the growth performance and immunity in broilers.

Two experiments were conducted to evaluate the efficacy of beta-glucan on commercial broilers. In experiment 1, one hundred and forty-four broiler chicks were employed in a 2x3 factorial design with cage and open floor housing with three levels of beta-glucan viz. 0%, 0.02% and 0.04%. In experiment 2, ninety-six broilers were used with 4 treatments: No beta-glucan and antibiotic (T1), beta-glucan 0.03% (T2), antibiotic (T3), and beta-glucan 0.03% + antibiotic (T4) for 34 d with 3 replicates of 8 chicks each in both studies. During experiment 1 there was no significant effect of the feeding system or the beta-glucan levels on the performance from 0 to 17 d but during 18-34 days birds housed on the open floor had significantly (p<0.0001) higher weight gain compared with those in cages. In experiment 2, no significant effect was noticed on the weight gains when the effect of beta-glucan, antibiotic or their interaction were tested. The retention of dry matter increased in both experiments with beta-glucan supplementation. The CD8 and TCR 1 cells were significantly higher in the 0.04% beta-glucan group at 42 days as compared with the control. It could be concluded that beta-glucan supplementation was beneficial for broilers.