Eosinophil-derived TGFß1 controls the new bone formation in chronic rhinosinusitis with nasal polyps

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by chronic eosinophilic inflammation and new bone formation (NBF). These processes may be associated with each other in the pathogenesis and influence the severity and prognosis of the disease. However, it is still unclear how eosinophilic inflammation is involved in the NBF. METHODOLOGY: Sinus bone cells were isolated from ethmoid bone tissues of patients with CRSwNP and controls. Transforming growth factor beta 1 (TGFß1) and alkaline phosphatase (ALP) expression in sinus bone cells was determined using quantitative RT-PCR, immunoblotting, and immunohistochemistry. The co-localization of TGFß1 with eosinophils was assessed by immunofluorescence staining. Sinus bone cells were co-cultured with eosinophils (Eol-1 cell line), which were differentiated with butyrate, to measure the osteoblast differentiation activity of sinus bone cells. RESULTS: TGFß1 expression was increased in sinus bone tissues and correlated with CT scores in CRSwNP. TGFß1 was also increased in the submucosa of CRSwNP and co-localized predominantly with eosinophils compared with neutrophils Differentiated Eol-1 cells-derived TGFß1 increased ALP expression in sinus bone cells. Treatment with a TGFß inhibitor attenuated TGFß1-induced ALP expression and staining in sinus bone cells of CRSwNP, leading to loss of bone formation. CONCLUSIONS: Eosinophil-derived TGFß1 was enriched in the submucosa of CRSwNP, which induced ALP expression in sinus bone cells and NBF. Therefore, eosinophil-derived TGFß1 may mediate aberrant bone remodeling in CRSwNP.

Clinical Feasibility of Ultrafast Contrast-Enhanced T1-Weighted 3D-EPI for Evaluating Intracranial Enhancing Lesions in Oncology Patients: Comparison with Standard 3D MPRAGE Sequence.

BACKGROUND AND PURPOSE: Contrast-enhanced 3D T1WI is a preferred sequence for brain tumor imaging despite the long scan time. This study investigated the clinical feasibility of ultrafast contrast-enhanced T1WI by 3D echo-planar imaging compared with a standard contrast-enhanced 3D MPRAGE sequence for evaluating intracranial enhancing lesions in oncology patients. MATERIALS AND METHODS: Sixty-one patients in oncology underwent brain MR imaging including both contrast-enhanced T1WI, 3D-EPI and 3D MPRAGE, in a single examination session for evaluating intracranial tumors. Two neuroradiologists evaluated image quality, lesion conspicuity, diagnostic confidence, number and size of the lesions, and contrast-to-noise ratio measurements from the 2 different sequences. RESULTS: Ultrafast 3D-EPI T1WI did not reveal significant differences in diagnostic confidence, contrast-to-noise ratiolesion/parenchyma, and the number of enhancing lesions compared with MPRAGE (P > .05). However, ultrafast 3D-EPI T1WI revealed inferior image quality, inferior anatomic delineation and greater susceptibility artifacts with fewer motion artifacts than images obtained with MPRAGE. The mean contrast-to-noise ratioWM/GM and visual conspicuity of the lesion on ultrafast 3D-EPI T1WI were lower than those of MPRAGE (P < .001). CONCLUSIONS: Ultrafast 3D-EPI T1WI showed comparable diagnostic performance with sufficient image quality and a 7-fold reduction in scan time for evaluating intracranial enhancing lesions compared with standard MPRAGE, even though it was limited by an inferior image quality and frequent susceptibility artifacts. Therefore, we believe that ultrafast 3D-EPI T1WI may be a viable option in oncology patients prone to movement during imaging studies.

The effects of hidden female smokers on the association between smoking and chronic obstructive pulmonary disease in Korean adults.

OBJECTIVE: Smoking is an important causative factor of chronic obstructive pulmonary disease (COPD), and females are considered more susceptible to the effects of smoking than males. However, in previous Korean studies, the effects of sex differences on the association between smoking and COPD have been controversial. In this study, the effects of sex differences on the association between smoking and COPD and the effects of female hidden smokers on that association in Korean adults were investigated. METHODS: Data were acquired from the Korea National Health and Nutrition Examination Surveys (KNHANES). RESULTS: The multivariate logistic regression analysis showed that self-reported smoking status for ex-smoker and current smoker correlated with COPD (odds ratio, OR: 1.67 and OR: 2.41, respectively). Self-reported smoking status for ex-smoker and current smoker correlated with COPD in men (OR: 1.61, OR: 2.43, respectively). Female self-reported current smoking status correlated with COPD (OR: 2.52), but female ex-smoker status was not significantly correlated with COPD. The ratios of cotinine-verified to self-reported smoking rates were 1.95 for women and 1.07 for men. CONCLUSION: The results of this study were that sex differences might affect the association between COPD and smoking and that female hidden smoking might affect the association between smoking and COPD in Korean adults.

Percentage volume of delayed kinetics in computer-aided diagnosis of MRI of the breast to reduce false-positive results and unnecessary biopsies.

AIM: To investigate the best cut-off percentage volume of delayed kinetics using magnetic resonance imaging (MRI) with computer-aided diagnosis (CAD) to reduce unnecessary biopsies in patients with newly diagnosed breast cancer. MATERIALS AND METHODS: Between January 2017 and December 2018, 94 malignant and 56 benign masses were analysed using MRI CAD. All malignant and benign masses measured <2 cm and were confirmed histopathologically. The optimal cut-off values for washout, plateau, and persistent components were determined using the maximum Youden Index. The positive predictive value (PPV) was analysed using morphological descriptors and combining the percentage volume of delayed kinetics. RESULTS: The area under the curve (AUC) was highest at ≤73% persistent component (AUC=0.759). In the subgroup analyses of masses <1 cm, the AUC was highest a plateau of >26% (AUC=0.697). When the persistent ≤73% criterion was applied to the lesions of C4a, the positive predictive value (PPV) increased from 61.9% to 72.44% with reduced false-negative cases and when applied to the lesions of C4a and C4b, the PPV increased from 61.9% to 78.1% with slightly increased false-negative cases. For subcentimetre lesions, the PPV increased from 46.77% to 54.72% with the same number of false-negative cases, when a plateau of >26% was applied to C4a, and the PPV increased from 46.77% to 61.36% with five false-negative cases when applied to C4a and C4b. CONCLUSION: The percentage volume of delayed kinetics has the potential to improve the PPV of breast MRI. When suspicious masses <2 cm do not show ≤73% persistence, follow-up rather than biopsy could be considered; however, to avoid increasing false-negative cases, delayed kinetic information should be used with caution and accurate margin assessment is essential.

Evaluation of the Biofire FilmArray meningitis/encephalitis assay for the detection of Cryptococcus neoformans/gattii.

OBJECTIVES: Cryptococcal meningitis (CM) remains an important cause of morbidity and mortality among immunocompromised patients. Laboratory diagnostics for CM includes antigen detection, staining and culture. Data on the performance of the Biofire® FilmArray® meningitis/encephalitis (ME) panel for detecting Cryptococcus neoformans/gattii is limited, with several reports describing false negativity for this target. METHODS: A retrospective analysis of 1384 physician-ordered ME panel tests ordered between January 2017 to October 2018 was performed. ME panel results were compared to cerebrospinal fluid (CSF) cryptococcal antigen (CrAg) and CSF culture testing and clinical significance of cryptococcal detection was determined. RESULTS: There were 34 patients positive for cryptococcal detection by either ME panel, CSF CrAg or CSF culture in 2.7% of CSF specimens tested (38/1384). Of the 34 patients positive for cryptococcal detection, 85.3% were human immunodeficiency virus positive (29/34). The ME panel detected 32/38 (84.2%) cryptococcal-positive specimens, culture detected 28/38 (73.7%) and CSF CrAg was positive in 37/38 specimens (97.4%). The ME panel had a sensitivity and specificity of 96.4% (95% CI 81.7-99.9%) and 99.6% (95% CI 99.2-99.9%) compared with culture, and 83.8% (95% CI 68.0-93.8%) and 99.9% (95% CI 99.6-100.0%) compared to CSF CrAg testing, respectively. CrAg titres were lower among ME panel-negative, culture-negative specimens compared with ME panel-positive, culture-negative specimens (reciprocal median end-point titres of 128 ± 60 vs. 1920 ± 1730, p 0.04). All five CrAg-positive, ME panel- and culture-negative specimens were obtained from previously treated CM patients. DISCUSSION: The ME panel had high correlation with CSF culture and a somewhat lower correlation with CSF CrAg testing. The potential utility of using negative ME panel test results to predict culture sterility among patients undergoing treatment for CM warrants further study.

Efficacy and clinical significance of omitting blue dye injection during sentinel lymph node biopsy before Mohs micrographic surgery for malignant melanoma of the lower extremities.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is usually performed using a triple technique that includes lymphoscintigraphy (LSG), which involves the injection of a radiolabelled tracer, blue dye injection, and detection of the radioisotope with a gamma probe. However, blue dye injection may cause pathological misinterpretation and obscure clinical margins, especially when combined with Mohs micrographic surgery (MMS) for cutaneous melanoma. OBJECTIVES: To assess the efficacy of SLNB without blue dye injection in patients who subsequently underwent MMS for melanomas of the lower extremities. METHODS: We evaluated patients who underwent MMS with or without SLNB using preoperative localization of the primary melanoma via LSG and intraoperative confirmation using a gamma probe between 2010 and 2016. RESULTS: Seventy-two patients with melanoma of mean Breslow thickness 3·03 ± 1·44 mm were evaluated. Sixty-five of the 72 patients underwent SLNB, the success rate of which was 98%. The 5-year overall and disease-free survival rates were 78% and 76%, respectively. CONCLUSIONS: Blue dye injection can be omitted without compromising the accuracy of standard SLNB. Omitting blue dye injection also has marked advantages in MMS for melanoma. What's already known about this topic? Sentinel lymph node biopsy (SLNB) is usually performed using a triple technique including lymphoscintigraphy, which involves the injection of a radiolabelled tracer, blue dye injection, and radioisotope detection using a gamma probe. Blue dye injection may cause pathological misinterpretation and obscure clinical margins. What does this study add? Omitting the dye does not decrease diagnostic accuracy and is particularly advantageous for Mohs micrographic surgery (MMS) in melanomas with clinically indistinct tumour borders. SLNB without blue dye injection is feasible in MMS for melanoma.

Comparison of the diagnostic performance of abbreviated MRI and full diagnostic MRI using a computer-aided diagnosis (CAD) system in patients with a personal history of breast cancer: the effect of CAD-generated kinetic features on reader performance.

AIM: To compare the diagnostic performance of abbreviated magnetic resonance imaging (MRI) and full diagnostic MRI with computer-aided diagnosis (CAD) system in patients with a personal history of breast cancer and to evaluate how the kinetic features affect the performance of two radiologists. MATERIALS AND METHODS: Between 1 January 2014 and 31 December 2017, 3,834 breast MRI examinations in 2,310 patients with a history of breast cancer comprised the study population. MRI images were reviewed retrospectively by two radiologists. First, two radiologists independently reviewed T1-weighted images scanned at 90 seconds after the contrast medium injection and T2-weighted images. After 6 months, the two readers reviewed contrast-enhanced T1-weighted images with five consecutive delayed images using CAD. The diagnostic performance of the abbreviated-sequence and full-sequence MRI were compared. RESULTS: Fifty-one intramammary recurrences were detected with breast MRI in 47 patients. Of the 51 tumour recurrences, 36 (70.6%) lesions occurred >3 years after initial cancer surgery and seven (13.7%) lesions at <2 years after initial surgery. The sensitivity and specificity were 92.2-94.1% and 97.6-98.6% on the abbreviated sequence and 94.1-96.1% and 97.9-98.3% on the full diagnostic MRI. Of 51 malignant lesions, six showed delayed persistent pattern, of which three lesions were non-mass enhancement and three lesions were small enhancing masses <1 cm. CONCLUSION: Overall diagnostic performances of abbreviated MRI and full diagnostic MRI were similar in both readers. The CAD-generated kinetic features could affect reader performance and the sensitivity could be improved or the specificity improved according to the reader.

The outcome following spinal instrumentation in haemodialyzed patients with pyogenic spondylodiscitis.

AIMS: The aim of this study was to evaluate the outcome of spinal instrumentation in haemodialyzed patients with native pyogenic spondylodiscitis. Spinal instrumentation in these patients can be dangerous due to rates of complications and mortality, and biofilm formation on the instrumentation. PATIENTS AND METHODS: A total of 134 haemodialyzed patients aged more than 50 years who underwent surgical treatment for pyogenic spondylodiscitis were included in the study. Their mean age was 66.4 years (50 to 83); 66 were male (49.3%) and 68 were female (50.7%). They were divided into two groups according to whether spinal instrumentation was used or not. Propensity score matching was used to attenuate the potential selection bias. The outcome of treatment was compared between these two groups. RESULTS: A total of 89 patients (66.4%) underwent non-instrumented surgery and 45 (33.5%) underwent instrumented surgery. There were no significant differences in the rates of postoperative complications, except for an increased rate of wound problems in the instrumented group, which was found in the unmatched cohorts (p = 0.034). There were no significant differences in the rate of recurrent infections (p = 0.328 for the unmatched cohort; p = 0.269 for the matched cohort) and mortality rate, including in-hospital (p = 0.713 for the unmatched cohort; p = 0.738 for the matched cohort) and one-year rates (p = 0.363 for the unmatched cohort; p = 0.787 for the matched cohort), between the groups. However, the interval between the initial diagnosis and the first recurrence was significantly longer in the instrumented group (p = 0.008 for the unmatched cohort; p = 0.032 for the matched cohort). CONCLUSION: Instrumented surgery for haemodialyzed patients with pyogenic spondylodiscitis showed similar outcomes, including recurrence and mortality, to non-instrumented surgery, despite the instrumented group having more severe neurological deficit, a larger number of involved levels, and increased kyphotic angle.

Risk Factors for Dropout From the Liver Transplant Waiting List of Hepatocellular Carcinoma Patients Under Locoregional Treatment.

BACKGROUND: In new organ allocation policy, patients with hepatocellular carcinoma (HCC) experience a 6-month delay in being granted Model for End-Stage Liver Disease exception points. However, it may not be fair for patients at risk of early progression of HCC. METHODS: All patients who were diagnosed as United Network for Organ Sharing (UNOS) stage 1 or 2 of HCC between January 2004 and December 2012 were included. Patients who received surgical resection or liver transplant (LT) as a primary treatment and who did not receive any treatment for HCC were excluded. Patients with baseline Model for End-Stage Liver Disease score ≥22 were also excluded because they have a higher chance of receiving LT. Patients who developed extrahepatic progression within 1 year were considered as high-risk for early recurrence after LT. RESULTS: A total of 586 patients were included. Mean (SD) age was 59.9 (10.3) years and 409 patients (69.8%) were men. The cumulative incidence of estimated dropout was 8.9% at 6 months; size of the maximum nodule (≥3 cm) and nonachievement of complete response were independent factors. Extrahepatic progression developed in 16 patients (2.7%) within 1 year; size of the maximum nodule (4 cm) and alpha-fetoprotein level (>100 ng/mL) were independent predictors. CONCLUSIONS: The estimated dropout rate from the waiting list within 6 months was 8.9%. Advantage points might be needed for patients with maximum nodule size ≥3 cm or those with noncomplete response. However, in patients with maximum nodule size ≥4 cm or alpha-fetoprotein level >100 ng/mL, caution is needed.

Comparison of Perioperative Renal Function Between Epidural and Intravenous Patient-Controlled Analgesia After Living-Donor Hepatectomy: A Retrospective Study.

BACKGROUND: Sympathetic blockade associated with epidural analgesia was reported to be a risk factor for acute kidney injury (AKI) following liver resection. The purpose of this study was to compare the incidence of AKI after living-donor hepatectomies according to the type of patient-controlled analgesia (PCA). METHODS: A total of 316 patients after living-donor hepatectomy were retrospectively analyzed; 148 patients in the epidural PCA group and 168 patients in the intravenous (IV) PCA group were evaluated. AKI was defined as an increase in serum creatinine ≥0.3 mg/dL, ie, 1.5-fold from the baseline, or a reduction in the urine output in the first 48 hours after surgery, based on the Acute Kidney Injury Network criteria. Logistic regression analysis was performed to identify the independent risk factors for AKI after living-donor hepatectomy. RESULTS: Baseline characteristics were similar between the 2 groups except the age. Volumes of fluids and colloids administered intraoperatively were greater in the epidural PCA group (P < .001 and P = .006, respectively). The incidence of AKI did not show significant differences between the 2 groups (8.1% vs 7.1%; P = .747). In multivariate analysis, preoperative serum alanine transaminase level ≥50 U/L was identified as a risk factor for postoperative AKI. However, epidural PCA failed to be a risk factor for postoperative AKI. CONCLUSIONS: The type of PCA did not affect the incidence of postoperative AKI after living-donor hepatectomy. Despite significant differences in the postoperative hemodynamics, the incidence of AKI was similar between 2 groups.

Prognostic significance of gross extrathyroidal extension invading only strap muscles in differentiated thyroid carcinoma.

BACKGROUND: In the eighth edition of the AJCC staging system for differentiated thyroid carcinoma (DTC), minimal extrathyroidal extension (ETE) is no longer a determinant of T3 category. Instead, gross ETE invading only strap muscles has been designated as a new T3b category. The long-term prognosis of patients with DTC and gross ETE invading only strap muscles was investigated. METHODS: This was a retrospective analysis of patients who underwent thyroidectomy between 1996 and 2005. Differences in cancer-specific and recurrence-free survival according to extent of ETE were assessed. RESULTS: A total of 3174 patients with DTC were included. No significant differences were observed in 10-year cancer-specific survival among patients with no ETE (98·6 per cent), microscopic ETE (98·3 per cent) and gross ETE invading only strap muscles (98·9 per cent) (P = 0·375). The 10-year recurrence-free survival rate for patients with gross ETE invading only strap muscles (89·2 per cent) was shorter than that for patients with no ETE (93·7 per cent; P = 0·016), but similar to that of patients with microscopic ETE (90·3 per cent). In univariable analysis, patients with gross ETE invading only strap muscles had a significantly higher risk of recurrence than those with no ETE (hazard ratio (HR) 1·67, 95 per cent c.i. 1·10 to 2·55; P = 0·017). In multivariable analysis, gross ETE invading only strap muscles was not an independent predictor of recurrence (HR 1·09, 0·71 to 1·69; P = 0·685). CONCLUSION: Although gross ETE invading only strap muscles may provide prognostic information about long-term recurrence, it does not affect mortality. The actual impact of gross ETE invading only strap muscles will be important in revising the staging system in the future.

Surgeon volume and prognosis of patients with advanced papillary thyroid cancer and lateral nodal metastasis.

BACKGROUND: Surgery is the most important treatment modality for papillary thyroid cancer (PTC). However, the relationship between surgeon volume and long-term oncological outcomes has not been explored. METHODS: Patients diagnosed with N1b PTC after initial thyroid surgery between 1 July 1994 and 31 December 2011 were eligible for inclusion in the study. Surgeons were categorized into high (at least 100 operations per year) and low (fewer than 100 operations per year) volume groups. Kaplan-Meier survival analysis according to surgeon volume was performed, and Cox proportional hazard modelling was used to estimate hazard ratios (HRs) with 95 per cent confidence intervals according to patient, tumour and surgeon factors. RESULTS: A total of 1103 patients with a median follow-up of 81 (i.q.r. 62-108) months were included in the study. During follow-up, 200 patients (18·1 per cent) developed structural recurrence. A high surgeon volume was associated with low structural recurrence (P = 0·006). After adjustment for age, sex and conventional risk factors for recurrence (histology, tumour size, gross extrathyroidal extension, margin status, more than 5 positive lymph nodes, radioactive iodine therapy), the adjusted HR for structural recurrence for low-volume surgeons was 1·46 (95 per cent c.i. 1·08 to 1·96), compared with high-volume surgeons. Distant metastasis (P = 0·242) and disease-specific mortality (P = 0·288) were not affected by surgeon volume. CONCLUSION: Surgeon volume is associated with structural recurrence, but not distant metastasis or cancer-specific death in patients with N1b PTC. Surgeon volume is important in initial surgery for advanced PTC with extensive nodal metastasis in order to ensure curative outcome and reduce treatment-related morbidity.

Annual prevalence and economic burden of genital warts in Korea: Health Insurance Review and Assessment (HIRA) service data from 2007 to 2015.

This study evaluated the annual prevalence of anogenital warts (AGW) caused by human papillomavirus (HPV) and analysed the trend in annual per cent changes (APC) by using national claims data from the Health Insurance Review and Assessment of Korea, 2007-2015. We also estimated the socio-economic burden and co-morbidities of AGW. All analyses were performed based on data for primary A63.0, the specific diagnosis code for AGW. The socio-economic cost of AGW was calculated based on the direct medical cost, direct non-medical cost and indirect cost. The overall AGW prevalence and socio-economic burden has increased during the last 9 years. However, the prevalence of AGW differed significantly by sex. The female prevalence increased until 2012, and decreased thereafter (APC + 3·6%). It would fall after the introduction of routine HPV vaccination, principally for females, in Korea. The male prevalence increased continuously over time (APC + 11·6%), especially in those aged 20-49 years. Referring to the increasing AGW prevalence and its disease burden, active HPV infection control surveillance and prevention in males are worth consideration.

MIG-6 negatively regulates STAT3 phosphorylation in uterine epithelial cells.

Endometrial cancer is the most common malignancy of the female genital tract. Progesterone (P4) has been used for several decades in endometrial cancer treatment, especially in women who wish to retain fertility. However, it is unpredictable which patients will respond to P4 treatment and which may have a P4-resistant cancer. Therefore, identifying the mechanism of P4 resistance is essential to improve the therapies for endometrial cancer. Mitogen-inducible gene 6 (Mig-6) is a critical mediator of progesterone receptor (PGR) action in the uterus. In order to study the function of Mig-6 in P4 resistance, we generated a mouse model in which we specifically ablated Mig-6 in uterine epithelial cells using Sprr2f-cre mice (Sprr2fcre+Mig-6f/f). Female mutant mice develop endometrial hyperplasia due to aberrant phosphorylation of signal transducers and activators of transcription 3 (STAT3) and proliferation of the endometrial epithelial cells. The results from our immunoprecipitation and cell culture experiments showed that MIG-6 inhibited phosphorylation of STAT3 via protein interactions. Our previous study showed P4 resistance in mice with Mig-6 ablation in Pgr-positive cells (Pgrcre/+Mig-6f/f). However, Sprr2fcre+Mig-6f/f mice were P4-responsive. P4 treatment significantly decreased STAT3 phosphorylation and epithelial proliferation in the uterus of mutant mice. We showed that Mig-6 has an important function of tumor suppressor via inhibition of STAT3 phosphorylation in uterine epithelial cells, and the antitumor effects of P4 are mediated by the endometrial stroma. These data help to develop a new signaling pathway in the regulation of steroid hormones in the uterus, and to overcome P4 resistance in human reproductive diseases, such as endometrial cancer.

Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer's disease neuropathological deficits.

Extensive evidence has indicated that a high rate of cholesterol biogenesis and abnormal neuronal energy metabolism play key roles in Alzheimer's disease (AD) pathogenesis. Here, for we believe the first time, we used osmotin, a plant protein homolog of mammalian adiponectin, to determine its therapeutic efficacy in different AD models. Our results reveal that osmotin treatment modulated adiponectin receptor 1 (AdipoR1), significantly induced AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) activation and reduced SREBP2 (sterol regulatory element-binding protein 2) expression in both in vitro and in vivo AD models and in Adipo-/- mice. Via the AdipoR1/AMPK/SIRT1/SREBP2 signaling pathway, osmotin significantly diminished amyloidogenic Aß production, abundance and aggregation, accompanied by improved pre- and post-synaptic dysfunction, cognitive impairment, memory deficits and, most importantly, reversed the suppression of long-term potentiation in AD mice. Interestingly, AdipoR1, AMPK and SIRT1 silencing not only abolished osmotin capability but also further enhanced AD pathology by increasing SREBP2, amyloid precursor protein (APP) and ß-secretase (BACE1) expression and the levels of toxic Aß production. However, the opposite was true for SREBP2 when silenced using small interfering RNA in APPswe/ind-transfected SH-SY5Y cells. Similarly, osmotin treatment also enhanced the non-amyloidogenic pathway by activating the α-secretase gene that is, ADAM10, in an AMPK/SIRT1-dependent manner. These results suggest that osmotin or osmotin-based therapeutic agents might be potential candidates for AD treatment.

Characterization of MUDENG, a novel anti-apoptotic protein.

MUDENG (Mu-2-related death-inducing gene, MuD) is revealed to be involved in cell death signaling. Astrocytes, the major glial cell type in the central nervous system, are a source of brain tumors. In this study, we examined MuD expression and function in human astroglioma cells. Stimulation of U251-MG cells with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in a 40% decrease in cell viability and a 33% decrease in MuD protein levels, although not in MuD mRNA levels. To study the functional relevance of MuD expression, stable transfectants expressing high levels of MuD were generated. Stimulation of these transfectants with TRAIL resulted in enhanced cell survival (77% for stable and 46% for control transfectants). Depletion of MuD led to a marked reduction upon TRAIL stimulation in cell viability (22% in MuD-depleted cells and 54% in control cells). In addition, we observed that MuD depletion increased the susceptibility of the cells to TRAIL by enhancing the cleavage of caspase-3/-9 and BH3-interacting domain death agonist (Bid). A unique 25-kDa fragment of B-cell lymphoma 2 (Bcl-2) lacking BH4 was observed 60-180 min post TRAIL treatment in MuD-depleted cells, suggesting that Bcl-2 is converted from its anti-apoptotic form to the truncated pro-apoptotic form. Importantly, the TRAIL-mediated decrease in cell viability in MuD-depleted cells was abrogated upon Bid depletion, indicating that the role of MuD in apoptotic signaling takes place at the Bid and Bcl-2 junction. MuD localizes predominantly in the endoplasmic reticulum and partly in the mitochondria and its amounts are reduced 6 h post TRAIL stimulation, presumably via caspase-3-mediated MuD cleavage. Collectively, these results suggest that MuD, a novel signaling protein, not only possesses an anti-apoptotic function but may also constitute an important target for the design of ideal candidates for combinatorial treatment strategies for glioma cells.

Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells.

The expression of immediate early response 3 (IER3), a protein with a short half-life, is rapidly induced by various cellular stimuli. We recently reported that IER3 induces the apoptosis of cervical cancer cells and that its expression is downregulated in patients with cervical cancer. However, the molecular mechanism involved in the rapid degradation of IER3 remains unknown. Here, we demonstrate that MDM2 is an E3 ligase that interacts with IER3 and promotes its ubiquitination, followed by proteasomal degradation. Polyubiquitination of the conserved lysine 60 of IER3 is essential for its degradation. In addition, four and a half LIM domains protein 2 (FHL2) binds to both IER3 and MDM2, allowing for efficient MDM2-mediated IER3 degradation by facilitating an association between MDM2 and IER3. Moreover, IER3 induces cell cycle arrest in cervical cancer cells and its activity is further enhanced in cells in which FHL2 or MDM2 was silenced, thereby preventing IER3 degradation. The E6 and E7 oncoproteins of human papilloma virus 18 regulated IER3 expression. FHL2 expression was significantly higher in the squamous epithelium of cervical carcinoma tissues than in non-cancerous cervical tissues, whereas cervical carcinoma expression of IER3 was downregulated in this region. Thus, we determined the molecular mechanism responsible for IER3 degradation, involving a ternary complex of IER3, MDM2 and FHL2, which may contribute to cervical tumor growth. Furthermore, we demonstrated that FHL2 serves as a scaffold for E3 ligase and its substrate during the ubiquitination reaction, a function that has not been previously reported for this protein.

Five-year decreased incidence of surgical site infections following gastrectomy and prosthetic joint replacement surgery through active surveillance by the Korean Nosocomial Infection Surveillance System.

BACKGROUND: Surveillance of healthcare-associated infection has been associated with a reduction in surgical site infection (SSI). AIM: To evaluate the Korean Nosocomial Infection Surveillance System (KONIS) in order to assess its effects on SSI since it was introduced. METHODS: SSI data after gastrectomy, total hip arthroplasty (THA), and total knee arthroplasty (TKA) between 2008 and 2012 were analysed. The pooled incidence of SSI was calculated for each year; the same analyses were also conducted from hospitals that had participated in KONIS for at least three consecutive years. Standardized SSI rates for each year were calculated by adjusting for SSI risk factors. SSI trends were analysed using the Cochran-Armitage test. FINDINGS: The SSI rate following gastrectomy was 3.12% (522/16,918). There was a significant trend of decreased crude SSI rates over five years. This trend was also evident in analysis of hospitals that had participated for more than three years. The SSI rate for THA was 2.05% (157/7656), which decreased significantly from 2008 to 2012. The risk factors for SSI after THA included the National Nosocomial Infections Surveillance risk index, trauma, reoperation, and age (60-69 years). The SSI rate for TKA was 1.90% (152/7648), which also decreased significantly during a period of five years. However, the risk-adjusted analysis of SSI did not show a significant decrease for all surgical procedures. CONCLUSION: The SSI incidence of gastrectomy and prosthetic joint replacement declined over five years as a result of active surveillance by KONIS.

cAMP-Response Element-Binding 3-Like Protein 1 (CREB3L1) is Required for Decidualization and its Expression is Decreased in Women with Endometriosis.

Endometriosis is a major cause of infertility and pelvic pain, affecting more than 10% of reproductive-aged women. Progesterone resistance has been observed in the endometrium of women with this disease, as evidenced by alterations in progesterone-responsive gene and protein expression. cAMPResponse Element-Binding 3-like protein 1 (Creb3l1) has previously been identified as a progesterone receptor (PR) target gene in mouse uterus via high density DNA microarray analysis. However, CREB3L1 function has not been studied in the context of endometriosis and uterine biology. In this study, we validated progesterone (P4) regulation of Creb3l1 in the uteri of wild-type and progesterone receptor knockout (PRKO) mice. Furthermore, we observed that CREB3L1 expression was significantly higher in secretory phase human endometrium compared to proliferative phase and that CREB3L1 expression was significantly decreased in the endometrium of women with endometriosis. Lastly, by transfecting CREB3L1 siRNA into cultured human endometrial stromal cells (hESCs) prior to hormonal induction of in vitro decidualization, we showed that CREB3L1 is required for the decidualization process. Interestingly, phosphorylation of ERK1/2, critical factor for decidualization, was also significantly reduced in CREB3L1-silenced hESCs. It is known that hESCs from patients with endometriosis show impaired decidualization and that dysregulation of the P4-PR signaling axis is linked to a variety of endometrial diseases including infertility and endometriosis. Therefore, these results suggest that CREB3L1 is required for decidualization in mice and humans and may be linked to the pathogenesis of endometriosis in a P4-dependent manner.