The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment.

Amplification and overexpression of erbB2/neu proto-oncogene is observed in 20-30% human breast cancer and is inversely correlated with the survival of the patient. Despite this, somatic activating mutations within erbB2 in human breast cancers are rare. However, we have previously reported that a splice isoform of erbB2, containing an in-frame deletion of exon 16 (herein referred to as ErbB2ΔEx16), results in oncogenic activation of erbB2 because of constitutive dimerization of the ErbB2 receptor. Here, we demonstrate that the ErbB2ΔEx16 is a major oncogenic driver in breast cancer that constitutively signals from the cell surface. We further show that inducible expression of the ErbB2ΔEx16 variant in mammary gland of transgenic mice results in the rapid development of metastatic multifocal mammary tumors. Genetic and biochemical characterization of the ErbB2ΔEx16-derived mammary tumors exhibit several unique features that distinguish this model from the conventional ErbB2 ones expressing the erbB2 proto-oncogene in mammary epithelium. Unlike the wild-type ErbB2-derived tumors that express luminal keratins, ErbB2ΔEx16-derived tumors exhibit high degree of intratumoral heterogeneity co-expressing both basal and luminal keratins. Consistent with these distinct pathological features, the ErbB2ΔEx16 tumors exhibit distinct signaling and gene expression profiles that correlate with activation of number of key transcription factors implicated in breast cancer metastasis and cancer stem cell renewal

Percepção de autoeficácia, assertividade sexual e uso do preservativo em jovens colombianos

El uso correcto y consistente del condón en las relaciones sexuales es un procedimiento altamente eficaz para la prevención del VIH/SIDA, así como para otras infecciones de transmisión sexual (ITS). Algunos estudios reportan que las habilidades psicosociales y de interrelación favorecen el desarrollo de prácticas sexuales protegidas, como con el uso de preservativos. El objetivo del presente estudio fue determinar en qué medida la percepción de autoeficacia y la asertividad sexual predicen el uso del condón en las relaciones sexuales en un grupo de jóvenes. Se realizó un estudio descriptivo correlacional y predictivo con una muestra de 631 jóvenes con edades entre 19 y 26 años que reportaron haber tenido relaciones o ser activos sexualmente. Los resultados muestran que la percepción de autoeficacia y la asertividad sexual fueron fuertes predictores del uso del condón en las relaciones sexuales de las mujeres, mientras que para el caso de los hombres, solo la asertividad sexual predijo su uso.O uso correto e consistente do preservativo nas relações sexuais é um procedimento altamente eficaz para a prevenção do HIV/ Aids, bem como para outras infecções de transmissão sexual (ITS). Alguns estudos mostram que as habilidades psicossociais e de inter-relação favorecem o desenvolvimento de práticas sexuais protegidas, como com o uso do preservativo. O objetivo do presente estudo foi determinar em que medida a percepção de autoeficácia e a assertividade sexual predizem o uso do preservativo nas relações sexuais em um grupo de jovens. Realizou-se um estudo descritivo correlacional e preditivo com uma amostra de 631 jovens com idades entre 19 e 26 anos que relataram ter tido relações ou ser ativos sexualmente. Os resultados mostram que a percepção de autoeficácia e a assertividade sexual foram fortes indicadores do uso do preservativo nas relações sexuais das mulheres, enquanto para o caso dos homens, só a assertividade sexual predisse seu uso.The correct and consistent use of condoms during sexual intercourse is a highly effective procedure for the prevention of HIV / AIDS as well as other sexually transmitted infections (STIs). Some studies report that psychosocial skills and interaction promote the development of safe sexual relations by using condoms. The objective of this study was to determine to what extent the perception of self-efficacy and sexual assertiveness predicts condom use in sexual activity in a group of young people. The study was descriptive correlational and predictive.The sample consisted of 645 young people aged between 19 and 26 years who reported having had sex or being sexually active. Results showed that, unlike men, the perception of selfefficacy coupled with sexual assertiveness are strong predictors of condom use in women's sexual relations, whereas for men only sexual assertiveness predicts condom use in sexual relations

Brucella bacteremia in patients with acute leukemia: a case series

<p>Abstract</p> <p>Background</p> <p>Brucellosis may cause serious infections in healthy individuals living in countries that are endemic for the infection. However, reports of brucella infections in immunocompromised hosts are relatively rare.</p> <p>Case Presentations</p> <p>Reported here are two patients with acute leukemia who developed <it>Brucella melitensis </it>bacteremia during their follow up at the Armed Forces Hospital in Riyadh. The first patient developed <it>B. melitensis </it>bacteremia during the transformation of his myelodysplasia into acute myeloid leukemia. The second patient developed <it>B. melitensis </it>bacteremia while his acute lymphoblastic leukemia was under control. Interestingly, he presented with acute cholecystitis during the brucella sepsis. Both brucella infections were associated with a marked reduction in the hematological parameters in addition to other complications. The bacteremic episodes were successfully treated with netilmicin, doxycycline and ciprofloxacin.</p> <p>Conclusion</p> <p>Brucellosis can cause systemic infections, complicated bacteremia and serious morbidity in patients with acute leukemia living in endemic areas. These infections may occur at the presentation of the leukemia or even when the leukemia is in remission. Nevertheless, the early diagnosis of brucellosis and the administration of appropriate antimicrobial therapy for sufficient duration usually improves the outcome in these immunocompromised patients.</p

Willingness to volunteer in a Phase I/II HIV vaccine trial: a study among police officers in Dar es Salaam, Tanzania

Background: As HIV infection continues to be a public health problem, development of an effective preventive HIV vaccine is a priority. For the ultimate development of an AIDS vaccine, clinical trials are being conducted throughout the world. However, the process of developing the vaccine does not only depend on identification of suitable trial candidates, but also requires knowledge of incentives to participate in the community where the trial is being conducted. Therefore, the studies presented in this thesis are components of a HIV/AIDS and HIV vaccine trial project in Dar es Salaam, Tanzania to address motivations and deterrents of participating in an HIV vaccine trial. Aim: To examine the motivations and deterrents for participating in preventive HIV vaccine trials. Methods: Data were collected from participants and volunteers who were considered for participation or participated in a phase I/II HIV vaccine trial. Four studies with different designs were conducted. In Study I, a semi-structured interview administered questionnaire was used to assess willingness to volunteer for a phase I/II HIV vaccine trial. A convenience sample of 329 individuals from the police force cohort was recruited for the study in 2005-2006. In Study II, focus group discussions were conducted to explore factors that would influence participation in an HIV vaccine trial among members of the police force in 2006-2007. In Study III, face-to-face interviews were used to identify reasons for declining to enrol in an HIV vaccine trial among those who agreed to enrol at the start and were randomized for the trial in 2007-2009. In Study IV, we used focus group discussions to evaluate the experiences of those who participated in the phase I/II trial in 2009. Results: Willingness to volunteer for an HIV vaccine trial was associated with intention to tell others, positive outcome of the trial, personal decision and expectation of obtaining protection against HIV infection. Participation in an HIV vaccine trial would be negatively influenced by sexual partners, friends, family members, relatives or parents (significant others) and fear of vaccine side-effects. Personal fears and negative influences from significant others were the main reasons for declining to enrol in an HIV vaccine trial. Despite the negative comments from significant others, volunteers in the HIV vaccine trial managed to stay on until the end of the trial as a result of personal decision and trial-related interventions. Conclusion: Personal decision is both a motivation to participate in an HIV vaccine trial and a reason to stay on until the end of trial. On the contrary, significant others are the deterrents to participation in the HIV vaccine trial and the reason for declining to enrol in the HIV vaccine trial. Awareness of these issues before trial implementation may help to maximize resource use and enhance retention of those who volunteer in the HIV vaccine trials

Only the best? Exploring cross-border investor preferences in US gateway cities

Despite heady growth in cross-border investment into commercial real estate over recent decades, there are few studies that examine differences in investment preferences between domestic and cross-border investors at a micro level. We address the gap by examining the characteristics of assets acquired by cross border investors in six major US metro areas, comparing them with the purchases made by US investors in those same areas. Our study uses data on more than 67 500 transactions recorded by Real Capital Analytics (RCA) over the period from Q1 2003 to Q3 2016. As well as examining cross-border investors in aggregate, we isolate and examine purchases by investors from each of the four principal source nations for cross-border real estate investment in these cities. This is important since treating cross-border investors as a single group may obscure important differences between them. We employ multilevel logit techniques and we find across a number of specifications that cross-border investors prefer larger assets, newer assets and CBD locations regardless of nationality. However, temporal and sectoral patterns of investment, as well as evidence for return chasing behavior, vary with the nationality of investor being studied

Rhythmic potassium transport regulates the circadian clock in human red blood cells.

Circadian rhythms organize many aspects of cell biology and physiology to a daily temporal program that depends on clock gene expression cycles in most mammalian cell types. However, circadian rhythms are also observed in isolated mammalian red blood cells (RBCs), which lack nuclei, suggesting the existence of post-translational cellular clock mechanisms in these cells. Here we show using electrophysiological and pharmacological approaches that human RBCs display circadian regulation of membrane conductance and cytoplasmic conductivity that depends on the cycling of cytoplasmic K+ levels. Using pharmacological intervention and ion replacement, we show that inhibition of K+ transport abolishes RBC electrophysiological rhythms. Our results suggest that in the absence of conventional transcription cycles, RBCs maintain a circadian rhythm in membrane electrophysiology through dynamic regulation of K+ transport

ActEarly: a City Collaboratory approach to early promotion of good health and wellbeing

Economic, physical, built, cultural, learning, social and service environments have a profound effect on lifelong health. However, policy thinking about health research is dominated by the ‘biomedical model’ which promotes medicalisation and an emphasis on diagnosis and treatment at the expense of prevention. Prevention research has tended to focus on ‘downstream’ interventions that rely on individual behaviour change, frequently increasing inequalities. Preventive strategies often focus on isolated leverage points and are scattered across different settings. This paper describes a major new prevention research programme that aims to create City Collaboratory testbeds to support the identification, implementation and evaluation of upstream interventions within a whole system city setting. Prevention of physical and mental ill-health will come from the cumulative effect of multiple system-wide interventions. Rather than scatter these interventions across many settings and evaluate single outcomes, we will test their collective impact across multiple outcomes with the goal of achieving a tipping point for better health. Our focus is on early life (ActEarly) in recognition of childhood and adolescence being such critical periods for influencing lifelong health and wellbeing

Respiratory-gated (4D) contrast-enhanced FDG PET-CT for radiotherapy planning of lower oesophageal carcinoma: Feasibility and impact on planning target volume

Background: To assess the feasibility and potential impact on target delineation of respiratory-gated (4D) contrast-enhanced 18 Fluorine fluorodeoxyglucose (FDG) positron emission tomography - computed tomography (PET-CT), in the treatment planning position, for a prospective cohort of patients with lower third oesophageal cancer. Methods: Fifteen patients were recruited into the study. Imaging included 4D PET-CT, 3D PET-CT, endoscopic ultrasound and planning 4D CT. Target volume delineation was performed on 4D CT, 4D CT with co-registered 3D PET and 4D PET-CT. Planning target volumes (PTV) generated with 4D CT (PTV 4DCT), 4D CT co-registered with 3D PET-CT (PTV 3DPET4DCT) and 4D PET-CT (PTV 4DPETCT ) were compared with multiple positional metrics. Results: Mean PTV 4DCT , PTV 3DPET4DCT and PTV 4DPETCT were 582.4 ± 275.1 cm 3 , 472.5 ± 193.1 cm 3 and 480.6 ± 236.9 cm 3 respectively (no significant difference). Median DICE similarity coefficients comparing PTV 4DCT with PTV 3DPET4DCT, PTV 4DCT with PTV 4DPETCT and PTV 3DPET4DCT with PTV 4DPETCT were 0.85 (range 0.65-0.9), 0.85 (range 0.69-0.9) and 0.88 (range 0.79-0.9) respectively. The median sensitivity index for overlap comparing PTV 4DCT with PTV 3DPET4DCT, PTV 4DCT with PTV 4DPETCT and PTV 3DPET4DCT with PTV 4DPETCT were 0.78 (range 0.65-0.9), 0.79 (range 0.65-0.9) and 0.89 (range 0.68-0.94) respectively. Conclusions: Planning 4D PET-CT is feasible with careful patient selection. PTV generated using 4D CT, 3D PET-CT and 4D PET-CT were of similar volume, however, overlap analysis demonstrated that approximately 20% of PTV 3DPETCT and PTV 4DPETCT are not included in PTV 4DCT , leading to under-coverage of target volume and a potential geometric miss. Additionally, differences between PTV 3DPET4DCT and PTV 4DPETCT suggest a potential benefit for 4D PET-CT. Trial registration: ClinicalTrials.gov Identifier - NCT02285660(Registered 21/10/2014)

West Antarctic ice loss influenced by internal climate variability and anthropogenic forcing

Recent ice loss from the West Antarctic Ice Sheet has been caused by ocean melting of ice shelves in the Amundsen Sea. Eastward wind anomalies at the shelf break enhance the import of warm Circumpolar Deep Water onto the Amundsen Sea continental shelf, which creates transient melting anomalies with an approximately decadal period. No anthropogenic influence on this process has been established. Here, we combine observations and climate model simulations to suggest that increased greenhouse gas forcing caused shelf-break winds to transition from mean easterlies in the 1920s to the near-zero mean zonal winds of the present day. Strong internal climate variability, primarily linked to the tropical Pacific, is superimposed on this forced trend. We infer that the Amundsen Sea experienced decadal ocean ariability throughout the twentieth century, with warm anomalies gradually becoming more prevalent, offering a credible explanation for the ongoing ice loss. Existing climate model projections show that strong future greenhouse gas forcing creates persistent mean westerly shelf-break winds by 2100, suggesting a further enhancement of warm ocean anomalies. These wind changes are weaker under a scenario in which greenhouse gas concentrations are stabilized

Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice.

Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting. HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix. Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels. Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate. In addition, cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans. Taken together our findings identify a new genetic cause of orofacial clefting in humans and mice, and define the first molecular cause of human cor triatriatum sinister, illustrating the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development