Critical Care Nurses' Perspectives of Caring for Patients With Cancer.

BACKGROUND: Critical care nurses are expected to work with patients who present with a wide range of health problems, but may lack sufficient education, skill development, and resources needed for providing psychosocial cancer care. OBJECTIVE: The purpose of this study was to gain a deeper understanding of nononcologic critical care nurses' experience working with patients and their families affected by cancer. METHOD: A phenomenological qualitative study using semistructured interviews was conducted with 15 nononcologic critical care nurses. Colaizzi's 7-step methodology was followed for data analysis and interpretation of findings. Audio recordings were transcribed verbatim, the narrative data were analyzed and coded, and themes were identified that were confirmed by participants. RESULTS: Four themes emerged from the nurses' narratives: lack of professional preparation refers to the perceived lack of education, skill development, and resources; collaboration and teamwork pertain to the importance of communication and moral support; being present expresses their perceived role in providing compassionate care; and nurtured empathy reflects the impact of cancer care on the nurses. DISCUSSION: The narratives provide insight into the experience and perceptions of the nononcologic critical care nurses caring for patients with cancer. Information from the themes and narratives can be used to inform the development of knowledge and skills for nononcologic nurses who provide care to patients with cancer.

Isogenic Mammary Models of Intraductal Carcinoma Reveal Progression to Invasiveness in the Absence of a Non-Obligatory In Situ Stage.

In breast cancer, progression to invasive ductal carcinoma (IDC) involves interactions between immune, myoepithelial, and tumor cells. Development of IDC can proceed through ductal carcinoma in situ (DCIS), a non-obligate, non-invasive stage, or IDC can develop without evidence of DCIS and these cases associate with poorer prognosis. Tractable, immune-competent mouse models are needed to help delineate distinct mechanisms of local tumor cell invasion and prognostic implications. To address these gaps, we delivered murine mammary carcinoma cell lines directly into the main mammary lactiferous duct of immune-competent mice. Using two strains of immune-competent mice (BALB/c, C57BL/6), one immune-compromised (severe combined immunodeficiency; SCID) C57BL/6 strain, and six different murine mammary cancer cell lines (D2.OR, D2A1, 4T1, EMT6, EO771, Py230), we found early loss of ductal myoepithelial cell differentiation markers p63, α-smooth muscle actin, and calponin, and rapid formation of IDC in the absence of DCIS. Rapid IDC formation also occurred in the absence of adaptive immunity. Combined, these studies demonstrate that loss of myoepithelial barrier function does not require an intact immune system, and suggest that these isogenic murine models may prove a useful tool to study IDC in the absence of a non-obligatory DCIS stage-an under-investigated subset of poor prognostic human breast cancer.

Phylogenetic diversity of two common Trypanosoma cruzi lineages in the Southwestern United States.

Trypanosoma cruzi is the causative agent of Chagas disease, a devastating parasitic disease endemic to Central and South America, Mexico, and the USA. We characterized the genetic diversity of Trypanosoma cruzi circulating in five triatomine species (Triatoma gerstaeckeri, T. lecticularia, T.indictiva, T. sanguisuga and T. recurva) collected in Texas and Southern Arizona using multilocus sequence typing (MLST) with four single-copy loci (cytochrome oxidase subunit II- NADH dehydrogensase subunit 1 region (COII-ND1), mismatch-repair class 2 (MSH2), dihydrofolate reductase-thymidylate synthase (DHFR-TS) and a nuclear gene with ID TcCLB.506529.310). All T. cruzi variants fall in two main genetic lineages: 75% of the samples corresponded to T. cruzi Discrete Typing Unit (DTU) I (TcI), and 25% to a North American specific lineage previously labelled TcIV-USA. Phylogenetic and sequence divergence analyses of our new data plus all previously published sequence data from those four loci collected in the USA, show that TcIV-USA is significantly different from any other previously defined T. cruzi DTUs. The significant level of genetic divergence between TcIV-USA and other T. cruzi DTUs should lead to an increased focus on understanding the epidemiological importance of this DTU, as well as its geographical range and pathogenicity in humans and domestic animals. Our findings further corroborate the fact that there is a high genetic diversity of the parasite in North America and emphasize the need for appropriate surveillance and vector control programs for Chagas disease in southern USA and Mexico.

Barriers and facilitators to accessing and utilising post-treatment psychosocial support by Black men treated for prostate cancer-a systematic review and qualitative synthesis.

PURPOSE: To synthesise findings from published studies on barriers and facilitators to Black men accessing and utilising post-treatment psychosocial support after prostate cancer (CaP) treatment. METHODS: Searches of Medline, Embase, PsycInfo, Cochrane Database of Systematic Reviews and Central, CINAHL plus and Scopus were undertaken from inception to May 2021. English language studies involving Black men aged ≥18 and reporting experiences of, or suggestions for, psychosocial support after CaP treatment were included. Low or moderate quality studies were excluded. Searches identified 4,453 articles and following deduplication, 2,325 were screened for eligibility. Two independent reviewers carried out screening, quality appraisal and data extraction. Data were analysed using thematic synthesis. RESULTS: Ten qualitative studies involving 139 Black men were included. Data analysis identified four analytical constructs: experience of psychosocial support for dealing with treatment side effects (including impact on self-esteem and fear of recurrence); barriers to use of psychosocial support (such as perceptions of masculinity and stigma around sexual dysfunction); facilitators to use of psychosocial support (including the influence of others and self-motivation); and practical solutions for designing and delivering post-treatment psychosocial support (the need for trusted healthcare and cultural channels). CONCLUSIONS: Few intervention studies have focused on behaviours among Black CaP survivors, with existing research predominantly involving Caucasian men. There is a need for a collaborative approach to CaP care that recognises not only medical expertise but also the autonomy of Black men as experts of their illness experience, and the influence of cultural and social networks.

Mammary collagen is under reproductive control with implications for breast cancer.

Mammographically-detected breast density impacts breast cancer risk and progression, and fibrillar collagen is a key component of breast density. However, physiologic factors influencing collagen production in the breast are poorly understood. In female rats, we analyzed gene expression of the most abundantly expressed mammary collagens and collagen-associated proteins across a pregnancy, lactation, and weaning cycle. We identified a triphasic pattern of collagen gene regulation and evidence for reproductive state-dependent composition. An initial phase of collagen deposition occurred during pregnancy, followed by an active phase of collagen suppression during lactation. The third phase of collagen regulation occurred during weaning-induced mammary gland involution, which was characterized by increased collagen deposition. Concomitant changes in collagen protein abundance were confirmed by Masson's trichrome staining, second harmonic generation (SHG) imaging, and mass spectrometry. We observed similar reproductive-state dependent collagen patterns in human breast tissue obtained from premenopausal women. SHG analysis also revealed structural variation in collagen across a reproductive cycle, with higher packing density and more collagen fibers arranged perpendicular to the mammary epithelium in the involuting rat mammary gland compared to nulliparous and lactating glands. Involution was also characterized by high expression of the collagen cross-linking enzyme lysyl oxidase, which was associated with increased levels of cross-linked collagen. Breast cancer relevance is suggested, as we found that breast cancer diagnosed in recently postpartum women displayed gene expression signatures consistent with increased collagen deposition and crosslinking compared to breast cancers diagnosed in age-matched nulliparous women. Using publicly available data sets, we found this involution-like, collagen gene signature correlated with poor progression-free survival in breast cancer patients overall and in younger women. In sum, these findings of physiologic collagen regulation in the normal mammary gland may provide insight into normal breast function, the etiology of breast density, and inform breast cancer risk and outcomes.

Efficacy of a novel topical combination of esafoxolaner, eprinomectin and praziquantel against Ixodes ricinus and Ixodes scapularis in cats.

Esafoxolaner is a purified enantiomer of afoxolaner with insecticidal and acaricidal properties. It is combined with eprinomectin and praziquantel in a novel topical endectoparasiticide formulation for cats. The efficacy of this novel formulation was evaluated in three Ixodes ricinus and two Ixodes scapularis experimental studies, with comparable designs. In each study, cats were randomly allocated, based on a pre-treatment tick infestation and count, to a placebo control group or a group treated with the minimum recommended dose of the novel formulation. Cats were infested two days before treatment and weekly thereafter. Immediate efficacy was evaluated 48 h after treatment; persistent efficacy was evaluated 48 h after new weekly infestations for at least one month after the treatment (in one of the studies, the first two weeks of persistent efficacy against I. ricinus were not tested). Efficacy was calculated at each timepoint by comparison of arithmetic means of live ticks found in the control and the treated groups. In the three studies targeting I. ricinus, immediate and persistent efficacies ranged between 91% and 100% for five weeks. In the two studies targeting I. scapularis, immediate and persistent efficacies ranged between 95% and 100%, and 98% and 100% for one month, respectively. These studies provide robust evidence of efficacy of the novel topical formulation of esafoxolaner, eprinomectin and praziquantel against experimental I. ricinus and I. scapularis infestations for at least one month in cats.

TITLE: Efficacité d'une nouvelle association topique d'esafoxolaner, d'éprinomectine et de praziquantel contre Ixodes ricinus et Ixodes scapularis chez le chat. ABSTRACT: L'esafoxolaner est un énantiomère purifié de l'afoxolaner aux propriétés insecticides et acaricides. Il est associé à l'éprinomectine et au praziquantel dans une nouvelle formulation d'endectoparasiticide topique pour chats. L'efficacité de cette nouvelle formulation a été évaluée dans trois études expérimentales sur Ixodes ricinus et deux sur Ixodes scapularis, avec des conceptions comparables. Dans chaque étude, les chats ont été répartis au hasard, sur la base d'une infestation et d'un nombre de tiques avant le traitement, dans un groupe témoin placebo ou dans un groupe traité avec la dose minimale recommandée de la nouvelle formulation. Les chats ont été infestés deux jours avant le traitement et une fois par semaine par la suite. L'efficacité immédiate a été évaluée 48 heures après le traitement et l'efficacité persistante a été évaluée 48 heures après les nouvelles infestations hebdomadaires pendant au moins un mois après le traitement (dans l'une des études, les deux premières semaines d'efficacité persistante contre I. ricinus n'ont pas été testées). L'efficacité a été calculée à chaque temps d'évaluation par comparaison des moyennes arithmétiques des tiques vivantes trouvées dans les groupes témoins et traités. Dans les trois études ciblant I. ricinus, les efficacités immédiates et persistantes variaient entre 91 % et 100 % pendant cinq semaines. Dans les deux études ciblant I. scapularis, les efficacités immédiates et persistantes variaient respectivement entre 95 % et 100 % et 98 % et 100 % pendant un mois. Ces études fournissent des preuves solides de l'efficacité de la nouvelle formulation topique d'esafoxolaner, d'éprinomectine et de praziquantel contre les infestations expérimentales par I. ricinus et I. scapularis pendant au moins un mois chez le chat.

Efficacy of a novel topical combination of esafoxolaner, eprinomectin and praziquantel in cats against Toxocara cati and Dipylidium caninum.

NexGard® Combo, a novel topical antiparasitic product for cats, combines the insecticide/acaricide esafoxolaner with the nematocide eprinomectin and cestodicide praziquantel. The efficacy of this combination product was evaluated against two common endoparasites of global occurrence in cats, the nematode Toxocara cati and the cestode Dipylidium caninum, in five controlled studies using naturally or experimentally infected cats with parasites of North American, South African or European origin. Cats evaluated in these studies harbored patent infection of the target parasite confirmed through a pre-treatment fecal examination. In each study, cats were allocated randomly to two groups of equal size (8 or 10 cats per group per study), one group treated with a placebo (mineral oil) and the other with NexGard® Combo. Both treatments were administered once as a spot-on at 0.12 mL per kg body weight to deliver the minimum label dosage (1.44 mg/kg esafoxolaner, 0.48 mg/kg eprinomectin, and 10.0 mg/kg praziquantel) to the NexGard® Combo-treated cats. To determine efficacy, geometric mean parasite counts seven to 12 days after treatment of placebo-treated (control) cats and NexGard® Combo-treated cats were compared. The efficacy of NexGard® Combo was 98.8% and 100% against adult T. cati in two studies; and 98.0%, 98.3% and 93.2% against D. caninum in three studies. No adverse events related to treatment were observed throughout the studies. These studies demonstrate high efficacy against these major feline endoparasites and excellent acceptability of the novel topical antiparasitic combination of esafoxolaner, eprinomectin and praziquantel.

TITLE: Efficacité d'une nouvelle association topique d'esafoxolaner, d'éprinomectine et de praziquantel chez le chat contre Toxocara cati et Dipylidium caninum. ABSTRACT: NexGard® Combo, un nouveau produit antiparasitaire topique pour chats combine l'insecticide/acaricide esafoxolaner avec le nématocide éprinomectine et le cestodicide praziquantel. L'efficacité de ce produit d'association a été évaluée contre deux endoparasites communs d'occurrence mondiale chez le chat, le nématode Toxocara cati et le cestode Dipylidium caninum, dans cinq études contrôlées utilisant des chats naturellement ou expérimentalement infectés par des parasites d'origine nord-américaine, sud-africaine ou européenne. Les chats évalués dans ces études présentaient une infection patente du parasite cible confirmée par un examen fécal avant le traitement. Dans chaque étude, les chats ont été répartis au hasard en deux groupes de taille égale (8 ou 10 chats par groupe et par étude), un groupe traité avec un placebo (huile minérale) et l'autre avec NexGard® Combo. Les deux traitements ont été administrés une fois par spot-on à 0,12 mL par kg de poids corporel pour délivrer la dose minimale indiquée sur l'étiquette (1,44 mg/kg d'esafoxolaner, 0,48 mg/kg d'éprinomectine et 10,0 mg/kg de praziquantel) pour les chats du groupe traité par NexGard® Combo. Pour déterminer l'efficacité, les nombres moyens géométriques de parasites sept à 12 jours après le traitement des chats traités par placebo (témoins) et des chats traités par NexGard® Combo ont été comparés. L'efficacité de NexGard® Combo était de 98,8 % et de 100 % contre T. cati adulte dans deux études, et de 98,0 %, 98,3 % et 93,2 % contre D. caninum dans trois études. Aucun événement indésirable lié au traitement n'a été observé tout au long des études. Ces études démontrent la grande efficacité contre ces principaux endoparasites félins et l'excellente acceptabilité de la nouvelle combinaison antiparasitaire topique d'esafoxolaner, d'éprinomectine et de praziquantel.

Efficacy of a novel topical combination of esafoxolaner, eprinomectin and praziquantel for the prevention of heartworm disease in cats.

NexGard® Combo is a novel topical endectoparasiticide formulation for cats combining the insecticide/acaricide esafoxolaner, the nematodicide eprinomectin and the cestodicide praziquantel. The efficacy of this novel formulation for the prevention of heartworm disease in cats was tested in two experimental studies using an induced infection model and a randomized, blinded, placebo-controlled study design, and two USA isolates of Dirofilaria immitis. In each study, 20 naïve cats were each inoculated sub-cutaneously with 100 third-stage larvae of D. immitis 30 days before treatment. Following randomization to two treatment groups of ten cats, each cat was treated topically once, either with the minimum recommended dose of the novel formulation, or with an identical volume of placebo. Five months after treatment (6 months after infections), the cats were humanely euthanized for parasite recovery and count. Efficacy was calculated by comparison of the numbers of adult D. immitis recovered in the control and in the novel formulation groups. In the control groups of each study, D. immitis were recovered in seven and nine cats (respective worm counts ranges 1-7 and 1-16, respective geometric means 1.6 and 5.1). In both studies, none of the treated cats harbored any D. immitis at necropsy and the calculated efficacy of the novel formulation was 100%. There were no adverse reactions related to treatment with the novel formulation. The results of these two studies demonstrate that a topical NexGard® Combo application at the minimum label dose is well-tolerated and efficacious in preventing heartworm disease in cats.

TITLE: Efficacité d'une nouvelle association topique d'esafoxolaner, d'éprinomectine et de praziquantel pour la prévention de la dirofilariose chez les chats. ABSTRACT: NexGard® Combo est une nouvelle formulation d'endectoparasiticide topique pour chats combinant l'insecticide/acaricide esafoxolaner, le nématodicide éprinomectine et le cestodicide praziquantel. L'efficacité de cette nouvelle formulation pour la prévention de la maladie du ver du cœur (dirofilariose) chez les chats a été testée dans deux études expérimentales utilisant un modèle d'infection induite et une conception d'étude randomisée, en aveugle et contrôlée par placebo, et deux isolats américains de Dirofilaria immitis. Dans chaque étude, vingt chats naïfs ont chacun été inoculés par voie sous-cutanée avec 100 larves de troisième stade de D. immitis 30 jours avant le traitement. Après randomisation dans deux groupes de traitement de dix chats, chaque chat a été traité par voie topique une fois, soit avec la dose minimale recommandée de la nouvelle formulation, soit avec un volume identique de placebo. Cinq mois après le traitement (6 mois après les infections), les chats ont été euthanasiés sans cruauté pour la récupération et le dénombrement des parasites. L'efficacité a été calculée en comparant les nombres de D. immitis adultes collectés dans le groupe contrôle et dans le groupe ayant reçu la nouvelle formulation. Dans les groupes témoins de chaque étude, D. immitis a été trouvé chez sept et neuf chats (les nombres de vers respectifs variaient de 1 à 7 et de 1 à 16, les moyennes géométriques respectives étaient 1,6 et 5,1). Dans les deux études, aucun des chats traités ne présentait de D. immitis lors de l'autopsie et l'efficacité calculée de la nouvelle formulation était de 100%. Il n'y a eu aucun effet indésirable lié au traitement avec la nouvelle formulation. Les résultats de ces deux études démontrent qu'une application topique de NexGard® Combo à la dose minimale indiquée sur l'étiquette est bien tolérée et efficace pour prévenir la dirofilariose chez les chats.

Loss of myoepithelial calponin-1 characterizes high-risk ductal carcinoma in situ cases, which are further stratified by T cell composition.

A hallmark of ductal carcinoma in situ (DCIS) progression is a loss of the surrounding ductal myoepithelium. However, whether compromise in myoepithelial differentiation, rather than overt cellular loss, can be used to predict the risk of DCIS progression is unknown. Here we address this question utilizing pure and mixed DCIS cases (N = 30) as surrogates for DCIS at low and high risk for progression, respectively. We used multiplex immunohistochemical staining to evaluate the relationship between myoepithelial cell differentiation and lymphoid immune cell types associated with poor prognostic DCIS. Our results show that myoepithelial calponin-1 discriminates between pure and mixed DCIS lesions better than histological subtype, presence of necrosis, or nuclear grade. Additionally, focal loss of myoepithelial cells associated with increased PD-1+CD8+ T cells, which suggests a link between the myoepithelium and immune surveillance. To identify associations between calponin-1 expression and immune response, we performed unsupervised hierarchical clustering of myoepithelial and immune cell biomarkers on 219 DCIS lesions from 30 cases. Notably, the majority of pure (low-risk) DCIS lesions clustered in a high calponin-1, T cell low group, whereas the majority of mixed (high-risk) DCIS lesions clustered in a low calponin-1, T cell high group, specifically with CD8+ and PD-1+CD8+ T cells. However, a subset of pure DCIS lesions had a similar calponin-1 and immune signature as the majority of mixed DCIS lesions, which have low calponin-1 and T cell enrichment-raising the possibility that these pure DCIS lesions might be at a high risk for progression.

High risk (B3) breast lesions: What is the incidence of malignancy for individual lesion subtypes? A systematic review and meta-analysis.

INTRODUCTION: Provide evidence to support evolving management strategies for high-risk (B3) breast lesions by assessing risk of carcinoma in subgroups of B3 lesions using systematic review and meta-analysis. METHODS: Databases identified observational studies between 1980 and 2015 that reported on underestimation of malignancy following B3 lesion diagnosis at core needle biopsy. Critical appraisal, quality assessment, data extraction and meta-analysis was undertaken to calculate rate of malignancy of the whole B3 group and individual lesions. Study heterogeneity and association between variables and underestimation rate was investigated using random effects logistic modelling. RESULTS: Meta-analysis, using data from 129 studies, assessed 11 423 lesions of which 2160 were upgraded to malignancy after surgical excision biopsy (17% malignancy rate, 95% CI 15-19%). Malignancy rates varied from 6% in radial scars with no atypia (95% CI 2-13%, I2 72.8%), to 32% in papillomas with atypia (95% CI 23-41%, I2 57.4%). Differences in upgrade rates between atypical and non-atypical lesions were statistically significant (p < 0.05). Study heterogeneity could not be explained by differences in core biopsy size or year of publication. CONCLUSIONS: This comprehensive, inclusive assessment of all published literature, provides an accurate estimate of malignancy risk in subgroups of B3 lesions, to guide tailored management strategies. Some lesions have a high risk of malignancy, while others have a much lower risk, and could be safely managed with surveillance strategies rather than surgery.

A METHOD FOR QUANTIFICATION OF CALPONIN EXPRESSION IN MYOEPITHELIAL CELLS IN IMMUNOHISTOCHEMICAL IMAGES OF DUCTAL CARCINOMA IN SITU.

Ductal carcinoma in situ (DCIS) is breast cancer confined within mammary ducts, surrounded by an intact myoepithelial cell layer that prevents local invasion. A DCIS diagnosis confers increased lifetime risk of developing invasive breast cancer (IBC) and results in surgical excision with radiation, and possibly endocrine- or chemo-therapy. DCIS is known to be over treated, with associated co-morbidities. Biomarkers are needed that delineate patients at low risk of DCIS progression from patients requiring more aggressive treatment. Investigating the role of myoepithelial cell differentiation in barrier function is anticipated to provide insight into DCIS progression and delineate between low and high risk lesions. Here, we develop a high throughput technique to assess loss of myoepithelial differentiation markers. This method facilitates automated analysis of a clinically relevant histopathologic feature, as demonstrated by a high correlation with pathologist annotation (r = 0.959), and further, contributes analytical foundations to a multiplexed immunohistochemistry (IHC) approach.

The future for diagnostic tests of acute kidney injury in critical care: evidence synthesis, care pathway analysis and research prioritisation.

BACKGROUND: Acute kidney injury (AKI) is highly prevalent in hospital inpatient populations, leading to significant mortality and morbidity, reduced quality of life and high short- and long-term health-care costs for the NHS. New diagnostic tests may offer an earlier diagnosis or improved care, but evidence of benefit to patients and of value to the NHS is required before national adoption. OBJECTIVES: To evaluate the potential for AKI in vitro diagnostic tests to enhance the NHS care of patients admitted to the intensive care unit (ICU) and identify an efficient supporting research strategy. DATA SOURCES: We searched ClinicalTrials.gov, The Cochrane Library databases, Embase, Health Management Information Consortium, International Clinical Trials Registry Platform, MEDLINE, metaRegister of Current Controlled Trials, PubMed and Web of Science databases from their inception dates until September 2014 (review 1), November 2015 (review 2) and July 2015 (economic model). Details of databases used for each review and coverage dates are listed in the main report. REVIEW METHODS: The AKI-Diagnostics project included horizon scanning, systematic reviewing, meta-analysis of sensitivity and specificity, appraisal of analytical validity, care pathway analysis, model-based lifetime economic evaluation from a UK NHS perspective and value of information (VOI) analysis. RESULTS: The horizon-scanning search identified 152 potential tests and biomarkers. Three tests, Nephrocheck® (Astute Medical, Inc., San Diego, CA, USA), NGAL and cystatin C, were subjected to detailed review. The meta-analysis was limited by variable reporting standards, study quality and heterogeneity, but sensitivity was between 0.54 and 0.92 and specificity was between 0.49 and 0.95 depending on the test. A bespoke critical appraisal framework demonstrated that analytical validity was also poorly reported in many instances. In the economic model the incremental cost-effectiveness ratios ranged from £11,476 to £19,324 per quality-adjusted life-year (QALY), with a probability of cost-effectiveness between 48% and 54% when tests were compared with current standard care. LIMITATIONS: The major limitation in the evidence on tests was the heterogeneity between studies in the definitions of AKI and the timing of testing. CONCLUSIONS: Diagnostic tests for AKI in the ICU offer the potential to improve patient care and add value to the NHS, but cost-effectiveness remains highly uncertain. Further research should focus on the mechanisms by which a new test might change current care processes in the ICU and the subsequent cost and QALY implications. The VOI analysis suggested that further observational research to better define the prevalence of AKI developing in the ICU would be worthwhile. A formal randomised controlled trial of biomarker use linked to a standardised AKI care pathway is necessary to provide definitive evidence on whether or not adoption of tests by the NHS would be of value. STUDY REGISTRATION: The systematic review within this study is registered as PROSPERO CRD42014013919. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Mammary Gland Involution Provides a Unique Model to Study the TGF-ß Cancer Paradox.

Transforming Growth Factor-ß (TGF-ß) signaling in cancer has been termed the "TGF-ß paradox", acting as both a tumor suppresser and promoter. The complexity of TGF-ß signaling within the tumor is context dependent, and greatly impacted by cellular crosstalk between TGF-ß responsive cells in the microenvironment including adjacent epithelial, endothelial, mesenchymal, and hematopoietic cells. Here we utilize normal, weaning-induced mammary gland involution as a tissue microenvironment model to study the complexity of TGF-ß function. This article reviews facets of mammary gland involution that are TGF-ß regulated, namely mammary epithelial cell death, immune activation, and extracellular matrix remodeling. We outline how distinct cellular responses and crosstalk between cell types during physiologically normal mammary gland involution contribute to simultaneous tumor suppressive and promotional microenvironments. We also highlight alternatives to direct TGF-ß blocking anti-cancer therapies with an emphasis on eliciting concerted microenvironmental-mediated tumor suppression.

ECMO: Incidence and Outcomes of Patients Undergoing the Hybrid Procedure.

OBJECTIVE: To document the extracorporeal membrane oxygenation (ECMO) incidence and outcome in patients undergoing the hybrid procedure at an institution that routinely performs this procedure. DESIGN: A retrospective chart review on all patients with single ventricle physiology that underwent the hybrid procedure between 7/2002 and 12/2014. Patients were excluded if they underwent the hybrid procedure after 60 days of birth or subsequently underwent a biventricular repair. SETTING: A single center, tertiary pediatric hospital. PATIENTS: One hundred eighty-one patients with single ventricle physiology that underwent the hybrid procedure between 7/2002 and 12/2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We studied a total of 181 patients (105 males: 76 females). Gestational age was 37.8 ± 2.0 weeks and birth weight was 3.0 ± 0.7 kg. Underlying diagnosis was hypoplastic left heart syndrome in 149 patients and other in 32 patients. Age at surgery was 7.8 ± 6.8 days and weight at surgery was 3.1 ± 0.6 kg. Two patients underwent ECMO support after the hybrid procedure. One patient had aortic atresia/mitral atresia and weighed 2.3 kg and the other patient had aortic atresia/mitral stenosis and weighed 2.1 kg at time of surgery. Both patients died. Incidence of ECMO support after hybrid procedure was 1.3% (2/149) for the hypoplastic left heart syndrome patients and 1.1% (2/181) for the entire cohort. CONCLUSION: Mortality in patients who underwent ECMO after the hybrid procedure was higher than reported for the Norwood procedure, however, the incidence of ECMO after hybrid procedure was also significantly lower than reported for the Norwood procedure. Future studies are needed to determine how to improve outcomes in this complex patient population.

Aortic root thrombosis with coronary embolization following neo-aortic reconstruction in a child with hypoplastic left heart syndrome.

In the recent era, the diagnosis, treatment options, postoperative management and outcomes of infants born with hypoplastic left heart syndrome (HLHS) have undergone dramatic changes. As is the case with many other novel treatment modalities used for congenital heart diseases, data concerning the long-term outcomes and complications of the various strategies become gradually more available as the numbers of survivors grow. In general, complications of the three-stage surgical palliation used for HLHS tend to occur most commonly following the first-stage surgery. Post-stage 2 complications are substantially less common, and centre on the procedure itself and the unique physiology of the cavopulmonary connection. In the following case report, we describe a relatively rare adverse outcome that occurred following a stage 2 surgery in the form of native aortic root thrombosis extending to the coronary arteries. The selected methods of treatment used in the catheterization laboratory and later in the operating theatre, as well as its outcomes are described.

Risk factors for emergency presentation with lung and colorectal cancers: a systematic review.

OBJECTIVE: To identify patient and practitioner factors that influence cancer diagnosis via emergency presentation (EP). DESIGN: Systematic review. DATA SOURCES: MEDLINE, EMBASE, CINAHL, EBM Reviews, Science and Social Sciences Citation Indexes, Conference Proceedings Citation Index-Science and Conference Proceedings Citation Index-Social Science and Humanities. Searches were undertaken from 1996 to 2014. No language restrictions were applied. STUDY SELECTION: Studies of any design assessing factors associated with diagnosis of colorectal or lung cancer via EP, or describing an intervention to impact on EP, were included. Studies involving previously diagnosed cancer patients, assessing only referral pathway effectiveness, outcomes related to diagnosis or post-EP management were excluded. The population was individual or groups of adult patients or primary care practitioners. Two authors independently screened studies for inclusion. RESULTS: 22 studies with over 200,000 EPs were included, most providing strong evidence. Five were graded 'insufficient', primarily due to missing information rather than methodological weakness. Older patient age was associated with EP for lung and colorectal cancers (OR 1.11-11.03 and 1.19-5.85, respectively). Women were more at risk of EP for lung but not colorectal cancer. Higher deprivation increased the likelihood of lung cancer EP, but evidence for colorectal was less conclusive. Being unmarried (or divorced/widowed) increased the likelihood of EP for colorectal cancer, which was also associated with pain, obstruction and weight loss. Lack of a regular source of primary care, and lower primary care use were positively associated with EP. Only three studies considered practitioner factors, two involving diagnostic tests. No conclusive evidence was found. CONCLUSIONS: Patient-related factors, such as age, gender and deprivation, increase the likelihood of cancer being diagnosed as the result of an EP, while cancer symptoms and patterns of healthcare utilisation are also relevant. Further work is needed to understand the context in which risk factors for EP exist and influence help-seeking.

Wnt5a suppresses tumor formation and redirects tumor phenotype in MMTV-Wnt1 tumors.

Wnt5a is a non-canonical signaling Wnt that has been implicated in tumor suppression. We previously showed that loss of Wnt5a in MMTV-PyVmT tumors resulted in a switch in tumor phenotype resulting in tumors with increased basal phenotype and high Wnt/ß-catenin signaling. The object of this study was to test the hypothesis that Wnt5a can act to inhibit tumors formed by activation of Wnt/ß-catenin signaling. To this end, we characterized tumor and non-tumor mammary tissue from MMTV-Wnt1 and double transgenic MMTV-Wnt1;MMTV-Wnt5a mice. Wnt5a containing mice demonstrated fewer tumors with increased latency when compared to MMTV-Wnt1 controls. Expression of markers for basal-like tumors was down-regulated in the tumors that formed in the presence of Wnt5a indicating a phenotypic switch. Reduced canonical Wnt signaling was detected in double transgenic tumors as a decrease in active ß-catenin protein and a decrease in Axin2 mRNA transcript levels. In non-tumor tissues, over-expression of Wnt5a in MMTV-Wnt1 mammary glands resulted in attenuation of phenotypes normally observed in MMTV-Wnt1 glands including hyperbranching and increased progenitor and basal cell populations. Even though Wnt5a could antagonize Wnt/ß-catenin signaling in primary mammary epithelial cells in culture, reduced Wnt/ß-catenin signaling was not detected in non-tumor MMTV-Wnt1;Wnt5a tissue in vivo. The data demonstrate that Wnt5a suppresses tumor formation and promotes a phenotypic shift in MMTV-Wnt1 tumors.

The Cancer Genomics Hub (CGHub): overcoming cancer through the power of torrential data.

The Cancer Genomics Hub (CGHub) is the online repository of the sequencing programs of the National Cancer Institute (NCI), including The Cancer Genomics Atlas (TCGA), the Cancer Cell Line Encyclopedia (CCLE) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) projects, with data from 25 different types of cancer. The CGHub currently contains >1.4 PB of data, has grown at an average rate of 50 TB a month and serves >100 TB per week. The architecture of CGHub is designed to support bulk searching and downloading through a Web-accessible application programming interface, enforce patient genome confidentiality in data storage and transmission and optimize for efficiency in access and transfer. In this article, we describe the design of these three components, present performance results for our transfer protocol, GeneTorrent, and finally report on the growth of the system in terms of data stored and transferred, including estimated limits on the current architecture. Our experienced-based estimates suggest that centralizing storage and computational resources is more efficient than wide distribution across many satellite labs. Database URL: https://cghub.ucsc.edu.

Neutrophil/Lymphocyte ratio and association with arch intervention in patients with hypoplastic left heart syndrome undergoing hybrid procedure.

BACKGROUND: Hybrid procedure is an alternative initial palliation for patients with hypoplastic left heart syndrome (HLHS). One major complication with this procedure is stenosis in the aortic arch isthmus possibly due to inflammation from the patent ductus arteriosus (PDA) stent. In adult studies, neutrophil/lymphocyte (N/L) ratio has been used as a marker for increased inflammation and has been associated with increased risk for coronary artery stent stenosis. The goal of this study was to determine if there were differences in N/L ratio between patients with HLHS undergoing hybrid procedure that required an arch intervention (AI-Group) vs. those that did not require an intervention (NAI-Group). METHODS: Retrospective chart review was performed on patients with HLHS undergoing hybrid procedure between July 2002 and January 2013. Complete blood counts as well as differentials were recorded at four time periods: 1 day prehybrid palliation, one day posthybrid palliation, 1 week posthybrid palliation, and 3 weeks posthybrid palliation. RESULTS: One hundred six patients were evaluated (AI-Group = 38, NAI-Group = 68). AI-Group generally had a higher N/L ratio vs. NAI-group and this was significant immediately 1 day posthybrid palliation: AI-Group vs. NAI-Group, prehybrid (2.95 ± 2.62 vs. 2.44 ± 1.71), 1 day posthybrid (5.95 ± 4.16 vs. 4.34 ± 3.87, P < .05), 1 week posthybrid (2.72 ± 3.01 vs. 2.28 ± 2.12), and 3 weeks posthybrid (1.85 ± 1.24 vs. 1.45 ± 1.16), respectively. Lymphocyte percentage was significantly lower in the AI-Group vs. NAI-Group 3 weeks posthybrid palliation (33.00 + 11.30% vs. 40.65 + 16.82%). CONCLUSION: Patients that required an arch intervention after hybrid palliation had a higher N/L ratio immediately after the procedure. This may signify increased inflammatory reaction that places these patients at risk for stenosis. Future studies are needed to determine if N/L ratio is a robust marker to risk stratify patients undergoing the hybrid procedure for arch complications.

Normal mammary development and function in mice with Ift88 deleted in MMTV- and K14-Cre expressing cells.

BACKGROUND: Primary cilia (PC) are non-motile microtubule based organelles present on almost every cell type and are known to serve as critical organizing centers for several signaling pathways crucial to embryonic and postnatal development. Alterations in the Hh pathway, the most studied signaling pathway regulated by PC, affect mammary gland development as well as maintenance of the stem and progenitor cell populations. RESULTS: We developed mouse models with deletion of PC in mammary luminal epithelial, basal epithelial, and stromal cells for evaluation of the function of PC in mammary development via MMTV-Cre, K14-Cre, and Prx1-Cre mediated deletion, respectively. The activity of Cre was confirmed using ROSA26 reporters. Mammary stem and progenitor cells were enriched through growth as mammospheres. Adenovirus-Cre mediated deletion of Ift88 was used to determine a role for PC in this population of cells. Disruption of Ift88 and PC were confirmed in using PCR and immunofluorescent methods. Prx1-Cre; Ift88Del mice demonstrated defects in terminal end buds during puberty. However, these Ift88Del glands exhibited typical terminal end bud formation as well as normal ductal histology when transplanted into wild type hosts, indicating that the phenotype observed was not intrinsic to the mammary gland. Furthermore, no discernable alterations to mammary development were observed in MMTV-Cre- or K14-Cre; Ift88Del lines. These mice were able to feed and support several litters of pups even though wide spread depletion of PC was confirmed. Cells grown in mammosphere culture were enriched for PC containing cells suggesting PC are preferentially expressed on mammary stem and progenitor cells. Deletion of Ift88 in mammary epithelial cells resulted in a significant reduction in the number of primary mammospheres established; however, there was no effect on outgrowth of secondary mammospheres in PC-depleted cells. CONCLUSIONS: PC regulate systemic factors that can affect mammary development in early puberty. PC on MMTV- or K14-expressing epithelial cells are not required for normal mammary development or function. PC are expressed at high levels on cells in mammosphere cultures. PC may be required for cells to establish mammospheres in culture; however, PC are not required for renewal of the cultures.