The effect of versican G3 domain on local breast cancer invasiveness and bony metastasis

Abstract Introduction Increased versican expression has been associated with local breast cancer invasiveness and a more aggressive tumor phenotype. The cellular mechanisms are not fully understood and this study evaluated versican G3 domain with its EGF-like motifs in influencing tumor invasion and metastasis. Methods One recombinant construct was synthesized (a signal peptide for product secretion and the versican G3 domain). The construct was stably transfected into human breast carcinoma MT-1 cells. Cell viability in vitro was evaluated in low serum and serum starvation conditions. In vivo study of tumor growth was evaluated in a nude mouse model. G3 effects on rodent vascular endothelial cells were evaluated in vitro on cell survival, apoptosis, migration, and vascular formation. The effects of VEGF, fibronectin, and G3 on vascular formation were examined. An intracardiac injection model of metastatic human breast carcinoma tested the effect of G3 on distant bony and soft tissue metastasis. Analysis of metastatic burden included histology, radiographs, and micro-CT quantification of osteolysis. Results A greater viability of cancer cells was observed in low serum and serum-free conditions in the presence of versican G3. Larger subcutaneous tumors were obtained in the G3 group following tumor cell injection into CD1 mice. G3 induced a greater degree of rodent vascular endothelial cell proliferation and migration in vitro. Simultaneous presence of fibronectin, VEGF, and G3 promoted endothelial cell migration in wound-healing assays as compared to the treatments containing none, one or two of these molecules. Systemic tumor burden to distant bony and soft tissue metastatic sites was greater in the G3 group using the intracardiac injection metastatic model Conclusion Versican G3 domain appears to be important in local and systemic tumor invasiveness of human breast cancer. Effects include enhancing cell viability, proliferation, migration and enhancing local tumor growth. Potential effects on angiogenesis include enhancing vascular endothelial proliferation, migration, and vessel formation. The interactions between tumor cells, surrounding stromal components and neo-vascularization in breast cancer may include interactions with VEGF and fibronectin. The propensity of versican G3 to influence tumor invasion to bone and the mechanisms of G3 mediated osteolysis warrants ongoing studies

Which game narratives do adolescents of different gameplay and sociodemographic backgrounds prefer? a mixed-methods analysis

OBJECTIVE: The aim of this study was to investigate which narrative elements of digital game narratives are preferred by the general adolescent population, and to examine associations with gender, socioeconomic status (SES), and gameplay frequency. Further, the study aims to discuss how results can be translated to serious digital games. MATERIALS AND METHODS: Adolescents were recruited through school to complete a survey on narrative preferences in digital games. The survey included questions on sociodemographic information, frequency of gameplay, and an open-ended question on what could be an appealing narrative for them. Data were analyzed in a mixed-methods approach, using thematic analysis and chi-square analyses to determine narrative preferences and the associations between game narrative elements and player characteristics (gender, SES, and frequency of gameplay). RESULTS: The sample consisted of 446 adolescents (12-15 years old) who described 30 narrative subthemes. Preferences included human characters as protagonists; nonhuman characters only as antagonists; realistic settings, such as public places or cities; and a strong conflict surrounding crime, catastrophe, or war. Girls more often than boys defined characters by their age, included avatars, located the narrative in private places, developed profession-related skills, and included a positive atmosphere. Adolescents of nonacademic education more often than adolescents of academic education defined characters by criminal actions. Infrequent players more often included human characters defined by their age than frequent players. After performing a Bonferroni correction, narrative preferences for several gender differences remained. CONCLUSION: Different narrative elements related to subgroups of adolescents by gender, SES, and frequency of gameplay. Customization of narratives in serious digital health games should be warranted for boys and girls; yet, further research is needed to specify how to address girls in particular

Comparing patient and healthcare worker experiences during a dengue outbreak in Singapore: understanding the patient journey and the introduction of a point-of-care test (POCT) toward better care delivery.

BACKGROUND: In the aftermath of an upsurge in the number of dengue cases in 2013 and 2014, the SD BIOLINE Dengue Duo rapid diagnostic Point-of-Care Test (POCT) kit was introduced in Tan Tock Seng Hospital, Singapore in June 2013. It is known that the success of POCT usage is contingent on its implementation within the health system. We evaluated health services delivery and the Dengue Duo rapid diagnostic test kit application in Singapore from healthcare workers' perspectives and patient experiences of dengue at surge times. METHODS: Focus group discussions were conducted with dengue patients, from before and after the POCT implementation period. In-depth interviews with semi-structured components with healthcare workers were carried out. A patient centred process mapping technique was used for evaluation, which mapped the patient's journey and was mirrored from the healthcare worker's perspective. RESULTS: Patients and healthcare workers confirmed a wide range of symptoms in adults, making it challenging to determine diagnosis. There were multiple routes to help seeking, and no 'typical patient journey', with patients either presenting directly to the hospital emergency department, or being referred there by a primary care provider. Patients groups diagnosed before and after POCT implementation expressed some differences between speed of diagnoses and attitudes of doctors, yet shared negative feelings about waiting times and a lack of communication and poor information delivery. However, the POCT did not in its current implementation do much to help waiting times. Healthcare workers expressed that public perceptions of dengue in recent years was a major factor in changing patient management, and that the POCT kit was helpful in improving the speed and accuracy of diagnoses. CONCLUSIONS: Health service delivery for dengue patients in Singapore was overall perceived to be of an acceptable clinical standard, which was enhanced by the introduction of the POCT. However, improvements can be focused on Adapting to outbreaks by reducing and rendering Waiting experiences more comfortable; Advancing education about symptom recognition, while also Recognising better communication strategies; and Expanding follow-up care options. This is presented as the Dengue AWARE model of care delivery

The influence of liver dysfunction on cyclosporine pharmacokinetics -A comparison between 70 per cent hepatectomy and complete bile duct ligation in dogs-

The influence of experimentally induced hepatic dysfunction on the pharmacokinetics of Cyclosporine A (CsA) was determined in dogs. The pharmacokinetics of oral (PO) and intravenous (IV) CsA were studied before and after 70 per cent hepatectomy or complete bile duct ligation (CBDL). Changes in liver function were monitored by serial measurements of serum bilirubin, and by the maximum removal rate (Rmax) and plasma disappearance rate (ICG-K) of indocyanine green (ICG). Concentrations of CsA in whole blood were measured by HPLC. Seventy per cent hepatectomy caused significant liver dysfunction: the ICG-Rmax decreased by 47.7±7.1 per cent (mean±SD) and the ICG-K decreased by 61.3±9.7 per cent during the first week after hepatectomy. At the same time, the systemic clearance (CLs) of IV-CsA decreased by 43.9±8.2 per cent, the area under the concentration curve (AUC) of IV-CsA increased by 35.4±20.8 per cent and the bioavailability of CsA decreased by 26.4±14.8 per cent. CBDL also induced significant liver dysfunction: the ICG-Rmax decreased by 39.1±12.8 per cent and the ICG-K decreased by 65.6±3.6 per cent in the second week after the operation. During the same period, the AUC of PO-CsA decreased by 69.9±10.7 per cent and the bioavailability of CsA also decreased markedly by 73.9±15.6 per cent. These data indicate that hepatic impairment significantly influences the pharmacokinetics of CsA, not only by the changes in intestinal absorption, but also by those in hepatic, metabolism. Dose adjustment is therefore necessary in the presence of hepatic dysfunction in order to maintain an adequate blood concentration of CsA without causing side effects. © 1989 The Japan Surgical Society

Electrified plasma in AdS/CFT correspondence

We construct new gravity backgrounds holographic dual to neutral plasma with U(1) global symmetry in the presence of constant electric field, considering its full back-reactions to the metric. As the electric field and the induced current cause a net energy in-flow to the system, the plasma is continually heated up and the corresponding gravity solution has an expanding horizon. After proposing a consistent late-time expansion scheme, we present analytic solutions in the scheme up to next-leading order, and our solutions are new time-dependent solutions of 5D asymptotic AdS Einstein-Maxwell(-Chern-Simons) theory. To extract dual CFT stress tensor and U(1) current from the solutions, we perform a rigorous holographic renormalization of Einstein-Maxwell-Chern-Simons theory including full back-reactions, which can in itself be an interesting addition to literatures. As by-products, we obtain interesting modifications of energy-momentum/current Ward identities due to the U(1) symmetry and its triangle anomaly.Comment: 27 pages, no figure, v3, minor typos fixed, matches with published versio

Physical activity and fitness in women with metastatic breast cancer.

PURPOSE: This study aimed to explore differences in physical activity and fitness between women with metastatic breast cancer compared to healthy controls and factors associated with their physical activity levels. METHODS: Seventy-one women with metastatic breast cancer, aged (mean (SD)) 57.7 (9.5) and 2.9 (3.1) years after the onset of metastatic disease, and 71 healthy controls aged 55.0 (9.4) years participated. Of those with metastatic disease, 27% had bone-only metastases, 35% visceral-only metastases and 38% bone and visceral metastases. Patient-reported outcomes and physical measures of muscle strength and aerobic fitness assessments were obtained. Participants wore a SenseWear® physical activity monitor over 7 days, and the average steps/day and the time spent in moderate-to-vigorous intensity physical activity were determined. RESULTS: Women with metastases were significantly (i) less aerobically fit than the control group (25.3 (5.4) vs. 31.9 (6.1) mL • kg(-1) • min(-1); P < 0.001); (ii) weaker (e.g. lower limb strength for the metastatic and control groups was 53.5 (23.7) vs. 76.0 (27.4) kg, respectively; P < 0.001); (iii) less active, with the metastatic group attaining only 56% of the mean daily step counts of the healthy women; and (iv) more symptomatic, reporting higher levels of fatigue and dyspnoea (P < 0.001). CONCLUSION: Women living in the community with metastatic breast cancer possessed lower aerobic fitness, reduced muscular strength and less daily physical activity compared to healthy counterparts. They also experienced poorer functioning and higher symptom burden. IMPLICATIONS FOR CANCER SURVIVORS: Women living with metastatic breast cancer may benefit from a physical activity programme to address their physical impairments

DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis.

Breast cancer genomes have revealed a novel form of mutation showers (kataegis) in which multiple same-strand substitutions at C:G pairs spaced one to several hundred nucleotides apart are clustered over kilobase-sized regions, often associated with sites of DNA rearrangement. We show kataegis can result from AID/APOBEC-catalysed cytidine deamination in the vicinity of DNA breaks, likely through action on single-stranded DNA exposed during resection. Cancer-like kataegis can be recapitulated by expression of AID/APOBEC family deaminases in yeast where it largely depends on uracil excision, which generates an abasic site for strand breakage. Localized kataegis can also be nucleated by an I-SceI-induced break. Genome-wide patterns of APOBEC3-catalyzed deamination in yeast reveal APOBEC3B and 3A as the deaminases whose mutational signatures are most similar to those of breast cancer kataegic mutations. Together with expression and functional assays, the results implicate APOBEC3B/A in breast cancer hypermutation and give insight into the mechanism of kataegis. DOI:http://dx.doi.org/10.7554/eLife.00534.001

Finding and Resolving Security Misusability with Misusability Cases

Although widely used for both security and usability concerns, scenarios used in security design may not necessarily inform the design of usability, and vice- versa. One way of using scenarios to bridge security and usability involves explicitly describing how design deci- sions can lead to users inadvertently exploiting vulnera- bilities to carry out their production tasks. This paper describes how misusability cases, scenarios that describe how design decisions may lead to usability problems sub- sequently leading to system misuse, address this problem. We describe the related work upon which misusability cases are based before presenting the approach, and illus- trating its application using a case study example. Finally, we describe some findings from this approach that further inform the design of usable and secure systems

The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells

Background/Aim: Tumors exhibiting constitutively activated PI(3) K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3) K/Akt/mTOR signaling. Methods: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. Results: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. Conclusion: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients. Copyright (c) 2007 S. Karger AG, Basel

Holographic Roberge-Weiss Transitions

We investigate N=4 SYM coupled to fundamental flavours at nonzero imaginary quark chemical potential in the strong coupling and large N limit, using gauge/gravity duality applied to the D3-D7 system, treating flavours in the probe approximation. The interplay between Z(N) symmetry and the imaginary chemical potential yields a series of first-order Roberge-Weiss transitions. An additional thermal transition separates phases where quarks are bound/unbound into mesons. This results in a set of Roberge-Weiss endpoints: we establish that these are triple points, determine the Roberge-Weiss temperature, give the curvature of the phase boundaries and confirm that the theory is analytic in mu^2 when mu^2~0.Comment: 37 pages, 13 figures; minor comments added, to appear in JHE