Prediction of Inflammatory Breast Cancer Survival Outcomes Using Computed Tomography-Based Texture Analysis

Background: Although inflammatory breast cancer (IBC) has poor overall survival (OS), there is little information about using imaging features for predicting the prognosis. Computed tomography (CT)-based texture analysis, a non-invasive technique to quantify tumor heterogeneity, could be a potentially useful imaging biomarker. The aim of the article was to investigate the usefulness of chest CT-based texture analysis to predict OS in IBC patients. Methods: Of the 3,130 patients with primary breast cancers between 2006 and 2016, 104 patients (3.3%) with IBC were identified. Among them, 98 patients who underwent pre-treatment contrast-enhanced chest CT scans, got treatment in our institution, and had a follow-up period of more than 2 years were finally included for CT-based texture analysis. Texture analysis was performed on CT images of 98 patients, using commercially available software by two breast radiologists. Histogram-based textural features, such as quantification of variation in CT attenuation (mean, standard deviation, mean of positive pixels [MPP], entropy, skewness, and kurtosis), were recorded. To dichotomize textural features for survival analysis, receiver operating characteristic curve analysis was used to determine cutoff points. Clinicopathologic variables, such as age, node stage, metastasis stage at the time of diagnosis, hormonal receptor positivity, human epidermal growth factor receptor 2 positivity, and molecular subtype, were assessed. A Cox proportional hazards model was used to determine the association of textural features and clinicopathologic variables with OS. Results: During a mean follow-up period of 47.9 months, 41 of 98 patients (41.8%) died, with a median OS of 20.0 months. The textural features of lower mean attenuation, standard deviation, MPP, and entropy on CT images were significantly associated with worse OS, as was the M1 stage among clinicopathologic variables (all P-values < 0.05). In multivariate analysis, lower mean attenuation (hazard ratio [HR], 3.26; P = 0.003), lower MPP (HR, 3.03; P = 0.002), and lower entropy (HR, 2.70; P = 0.009) on chest CT images were significant factors independent from the M1 stage for predicting worse OS. Conclusions: Lower mean attenuation, MPP, and entropy on chest CT images predicted worse OS in patients with IBC, suggesting that CT-based texture analysis provides additional predictors for OS

Disrupted-in-schizophrenia 1 (DISC1) and Syntaphilin collaborate to modulate axonal mitochondrial anchoring

In neuronal axons, the ratio of motile-to-stationary mitochondria is tightly regulated by neuronal activation, thereby meeting the need for local calcium buffering and maintaining the ATP supply. However, the molecular players and detailed regulatory mechanisms behind neuronal mitochondrial movement are not completely understood. Here, we found that neuronal activation-induced mitochondrial anchoring is regulated by Disrupted-in-schizophrenia 1 (DISC1), which is accomplished by functional association with Syntaphilin (SNPH). DISC1 deficiency resulted in reduced axonal mitochondrial movement, which was partially reversed by concomitant SNPH depletion. In addition, a SNPH deletion mutant lacking the sequence for interaction with DISC1 exhibited an enhanced mitochondrial anchoring effect than wild-type SNPH. Moreover, upon neuronal activation, mitochondrial movement was preserved by DISC1 overexpression, not showing immobilized response of mitochondria. Taken together, we propose that DISC1 in association with SNPH is a component of a modulatory complex that determines mitochondrial anchoring in response to neuronal activation.117Ysciescopu

Regulation of the actin cytoskeleton by the Ndel1-Tara complex is critical for cell migration

Nuclear distribution element-like 1 (Ndel1) plays pivotal roles in diverse biological processes and is implicated in the pathogenesis of multiple neurodevelopmental disorders. Ndel1 function by regulating microtubules and intermediate filaments; however, its functional link with the actin cytoskeleton is largely unknown. Here, we show that Ndel1 interacts with TRIO-associated repeat on actin (Tara), an actin-bundling protein, to regulate cell movement. In vitro wound healing and Boyden chamber assays revealed that Ndel1- or Tara-deficient cells were defective in cell migration. Moreover, Tara overexpression induced the accumulation of Ndel1 at the cell periphery and resulted in prominent co-localization with F-actin. This redistribution of Ndel1 was abolished by deletion of the Ndel1-interacting domain of Tara, suggesting that the altered peripheral localization of Ndel1 requires a physical interaction with Tara. Furthermore, co-expression of Ndel1 and Tara in SH-SY5Y cells caused a synergistic increase in F-actin levels and filopodia formation, suggesting that Tara facilitates cell movement by sequestering Ndel1 at peripheral structures to regulate actin remodeling. Thus, we demonstrated that Ndel1 interacts with Tara to regulate cell movement. These findings reveal a novel role of the Ndel1-Tara complex in actin reorganization during cell movement.1142Ysciescopu

The elderly in the psychiatric emergency service (PES); a descriptive study

<p>Abstract</p> <p>Background</p> <p>The impact of an aging population on the psychiatric emergency service (PES) has not been fully ascertained. Cognitive dysfunctions aside, many DSM-IV disorders may have a lower prevalence in the elderly, who appear to be underrepresented in the PES. We therefore attempted to more precisely assess their patterns of PES use and their clinical and demographic characteristics.</p> <p>Methods</p> <p>Close to 30,000 visits to a general hospital PES (Montreal, Quebec, Canada) were acquired between 1990 and 2004 and pooled with over 17,000 visits acquired using the same methodology at three other services in Quebec between 2002 and 2004.</p> <p>Results</p> <p>The median age of PES patients increased over time. However, the proportion of yearly visits attributable to the elderly (compared to those under 65) showed no consistent increase during the observation period. The pattern of return visits (two to three, four to ten, eleven or more) did not differ from that of patients under 65, although the latter made a greater number of total return visits per patient. The elderly were more often women (62%), widowed (28%), came to the PES accompanied (42%) and reported « illness » as an important stressor (29%). About 39% were referred for depression or anxiety. They were less violent (10%) upon their arrival. Affective disorders predominated in the diagnostic profile, they were less co-morbid and more likely admitted than patients under 65.</p> <p>Conclusion</p> <p>Although no proportional increase in PES use over time was found the elderly do possess distinct characteristics potentially useful in PES resource planning so as to better serve this increasingly important segment of the general population.</p

Evaluation of Microwave Steam Bags for the Decontamination of Filtering Facepiece Respirators

Reusing filtering facepiece respirators (FFRs) has been suggested as a strategy to conserve available supplies for home and healthcare environments during an influenza pandemic. For reuse to be possible, used FFRs must be decontaminated before redonning to reduce the risk of virus transmission; however, there are no approved methods for FFR decontamination. An effective method must reduce the microbial threat, maintain the function of the FFR, and present no residual chemical hazard. The method should be readily available, inexpensive and easily implemented by healthcare workers and the general public. Many of the general decontamination protocols used in healthcare and home settings are unable to address all of the desired qualities of an efficient FFR decontamination protocol. The goal of this study is to evaluate the use of two commercially available steam bags, marketed to the public for disinfecting infant feeding equipment, for FFR decontamination. The FFRs were decontaminated with microwave generated steam following the manufacturers' instructions then evaluated for water absorption and filtration efficiency for up to three steam exposures. Water absorption of the FFR was found to be model specific as FFRs constructed with hydrophilic materials absorbed more water. The steam had little effect on FFR performance as filtration efficiency of the treated FFRs remained above 95%. The decontamination efficacy of the steam bag was assessed using bacteriophage MS2 as a surrogate for a pathogenic virus. The tested steam bags were found to be 99.9% effective for inactivating MS2 on FFRs; however, more research is required to determine the effectiveness against respiratory pathogens

Immunotherapy with MVA-BN®-HER2 induces HER-2-specific Th1 immunity and alters the intratumoral balance of effector and regulatory T cells

MVA-BN®-HER2 is a new candidate immunotherapy designed for the treatment of HER-2-positive breast cancer. Here, we demonstrate that a single treatment with MVA-BN®-HER2 exerts potent anti-tumor efficacy in a murine model of experimental pulmonary metastasis. This anti-tumor efficacy occurred despite a strong tumor-mediated immunosuppressive environment characterized by a high frequency of regulatory T cells (Treg) in the lungs of tumor-bearing mice. Immunogenicity studies showed that treatment with MVA-BN®-HER2 induced strongly Th1-dominated HER-2-specific antibody and T-cell responses. MVA-BN®-HER2-induced anti-tumor activity was characterized by an increased infiltration of lungs with highly activated, HER-2-specific, CD8+CD11c+ T cells accompanied by a decrease in the frequency of Treg cells in the lung, resulting in a significantly increased ratio of effector T cells to Treg cells. In contrast, administration of HER2 protein formulated in Complete Freund’s Adjuvant (CFA) induced a strongly Th2-biased immune response to HER-2. However, this did not lead to significant infiltration of the tumor-bearing lungs by CD8+ T cells or the decrease in the frequency of Treg cells nor did it result in anti-tumor efficacy. In vivo depletion of CD8+ cells confirmed that CD8 T cells were required for the anti-tumor activity of MVA-BN®-HER2. Furthermore, depletion of CD4+ or CD25+ cells demonstrated that tumor-induced Treg cells promoted tumor growth and that CD4 effector cells also contribute to MVA-BN®-HER2-mediated anti-tumor efficacy. Taken together, our data demonstrate that treatment with MVA-BN®-HER2 controls tumor growth through mechanisms including the induction of Th1-biased HER-2-specific immune responses and the control of tumor-mediated immunosuppression

Cell Free DNA of Tumor Origin Induces a 'Metastatic' Expression Profile in HT-29 Cancer Cell Line

BACKGROUND: Epithelial cells in malignant conditions release DNA into the extracellular compartment. Cell free DNA of tumor origin may act as a ligand of DNA sensing mechanisms and mediate changes in epithelial-stromal interactions. AIMS: To evaluate and compare the potential autocrine and paracrine regulatory effect of normal and malignant epithelial cell-related DNA on TLR9 and STING mediated pathways in HT-29 human colorectal adenocarcinoma cells and normal fibroblasts. MATERIALS AND METHODS: DNA isolated from normal and tumorous colonic epithelia of fresh frozen surgically removed tissue samples was used for 24 and 6 hour treatment of HT-29 colon carcinoma and HDF-alpha fibroblast cells. Whole genome mRNA expression analysis and qRT-PCR was performed for the elements/members of TLR9 signaling pathway. Immunocytochemistry was performed for epithelial markers (i.e. CK20 and E-cadherin), DNA methyltransferase 3a (DNMT3a) and NFkappaB (for treated HDFalpha cells). RESULTS: Administration of tumor derived DNA on HT29 cells resulted in significant (p/=1, p/=1, p</=0.05), including increased expression of key adaptor molecules of TLR9 pathway (e.g. MYD88, IRAK2, NFkappaB, IL8, IL-1beta), STING pathway (ADAR, IRF7, CXCL10, CASP1) and the FGF2 gene. CONCLUSIONS: DNA from tumorous colon epithelium, but not from the normal epithelial cells acts as a pro-metastatic factor to HT-29 cells through the overexpression of pro-metastatic genes through TLR9/MYD88 independent pathway. In contrast, DNA derived from healthy colonic epithelium induced TLR9 and STING signaling pathway in normal fibroblasts

Combined Use of Serum Adiponectin and Tumor Necrosis Factor-Alpha Receptor 2 Levels Was Comparable to 2-Hour Post-Load Glucose in Diabetes Prediction

Background: Adipose tissue inflammation and dysregulated adipokine secretion are implicated in obesity-related insulin resistance and type 2 diabetes. We evaluated the use of serum adiponectin, an anti-inflammatory adipokine, and several proinflammatory adipokines, as biomarkers of diabetes risk and whether they add to traditional risk factors in diabetes prediction. Methods: We studied 1300 non-diabetic subjects from the prospective Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). Serum adiponectin, tumor necrosis factor-alpha receptor 2 (TNF-α R2), interleukin-6 (IL-6), adipocyte-fatty acid binding protein (A-FABP) and high-sensitivity C-reactive protein (hsCRP) were measured in baseline samples. Results: Seventy-six participants developed diabetes over 5.3 years (median). All five biomarkers significantly improved the log-likelihood of diabetes in a clinical diabetes prediction (CDP) model including age, sex, family history of diabetes, smoking, physical activity, hypertension, waist circumference, fasting glucose and dyslipidaemia. In ROC curve analysis, "adiponectin + TNF-α R2" improved the area under ROC curve (AUC) of the CDP model from 0.802 to 0.830 (P = 0.03), rendering its performance comparable to the "CDP + 2-hour post-OGTT glucose" model (AUC = 0.852, P = 0.30). A biomarker risk score, derived from the number of biomarkers predictive of diabetes (low adiponectin, high TNF-α R2), had similar performance when added to the CDP model (AUC = 0.829 [95% CI: 0.808-0.849]). Conclusions: The combined use of serum adiponectin and TNF-α R2 as biomarkers provided added value over traditional risk factors for diabetes prediction in Chinese and could be considered as an alternative to the OGTT. © 2012 Woo et al.published_or_final_versio

Caspase Dependent Programmed Cell Death in Developing Embryos: A Potential Target for Therapeutic Intervention against Pathogenic Nematodes

Pathogenic nematodes currently infect billions of people around the world and pose serious challenges to the economic welfare and public health in most developing countries. At present, limitations of existing therapies warrant identification of new anti-parasitic drugs/drug targets to effectively treat and control neglected tropical diseases [NTD] caused by nematode pathogens. The current gold standard for measuring/screening drug effectiveness against most helminth parasites is in-vitro assessment of motility of parasites/larvae and larval development assays which fails to provide any conclusive idea about the precise mechanism of death of parasitic worms or their larval stages. Given the huge load of parasites or their larval stages in an infected host, a compound which shows promise in in-vitro/motility screening assays but induces necrotic death in parasites/larvae will be of limited use, as it may elicit severe inflammatory response in infected hosts. In this context, the present study, which demonstrates induction of apoptotic death in developing embryos of a pathogenic nematode as a potential drug target for the first time, and provides scope for high throughput screening of pharmacological agents for their apoptogenicity against nematode embryos, is a step forward to develop novel anti-parasitic measures to challenge NTD caused by nematode pathogens

A Model of Salmonella Colitis with Features of Diarrhea in SLC11A1 Wild-Type Mice

Background: Mice do not get diarrhea when orally infected with S. enterica, but pre-treatment with oral aminoglycosides makes them susceptible to Salmonella colitis. However, genetically susceptible ItyS mice (Nramp1 G169D allele) die from systemic infection before they develop diarrhea, so a new model is needed to study the pathogenesis of diarrhea. We pretreated ItyR mice (Nramp1 G169) with oral kanamycin prior to infecting them with virulent S. Typhimurium strain 14028s in order to study Salmonella-induced diarrhea. We used both a visual scoring system and the measurement of fecal water content to measure diarrhea. BALB/c.D2 Nramp1 congenic started losing weight 5 days post-infection and they began to die from colitis 10–14 days after infection. A SPI-1 (invA) mutant caused cecal, but not colonic inflammation and did not cause diarrhea. A phoP- mutant did not cause manifestations of diarrhea in either normal or NADPHdeficient (gp91 phox) mice. However, strain 14028s caused severe colitis and diarrhea in gp91 phox-deficient mice on an ItyR background. pmr A and F mutants, which are less virulent in orally infected BALB/c mice, were fully virulent in this model of colitis. Conclusions: S. enterica must be able to invade the colonic epithelium and to persist in the colon in order to cause colitis with manifestations of diarrhea. The NADPH oxidase is not required for diarrhea in Salmonella colitis. Furthermore,