Search

The article focuses on the study of D.G. DeNardo and colleagues regarding the effect of immune cells in promoting malignant breast tumour progression. It states that DeNardo and colleagues show that breast tumours with low cytitixic T cells numbers and high numbers of tumour-associated macrophages (TAMs) poorly response to chemotheraphy before surgery. It also mentions that TAMs ability to limit tumour's response to chemotheraphy is due to antitumour function suppression of cytotoxic T cells.

The pace of locomotor development is a critical component of lifetime evolutionary fitness. Developmental researchers often divide species into two broad categories based on functional competence at birth: precocial infants who can independently stand and locomote soon after birth versus altricial infants who are either incapable of independent movement or can only do so in a rudimentary manner. However, investigating the lower level neuromotor and biomechanical traits that account for perinatal variation in motor development is complicated by the lack of experimental control inherent to all comparative analyses. Precocial and altricial animals often differ along a host of dimensions that can obfuscate the specific factors controlling motor development per se. Here, we propose an alternative approach of examining locomotor development in a nominally precocial species—the domestic pig (Sus scrofa)—in which gestation length has been experimentally manipulated, thereby creating "functionally altricial" cohorts for comparison. We have used standard biomechanical testing to evaluate balance and locomotor performance in preterm pigs born at 94% full-term gestation (N  = 29 individuals) and compared these data to a similar dataset on age-matched full-term piglets (N  = 15 individuals). Static balance tests showed that preterm pigs were characterized by increased postural sway, particularly in the fore-aft (anteroposterior) direction. Locomotor analyses showed that preterm piglets tended to take shorter, more frequent strides, use higher duty factors, and preferentially choose gait patterns that ensured they were supported by at least three limbs during most of the stride cycle, though differences between preterm and full-term animals were often modulated by variation in locomotor speed. Morphometric analysis showed no differences in relative extensor muscle mass between preterm and full-term animals, suggesting that neurological immaturity might be more determinant of preterm piglet motor dysfunctions than musculoskeletal immaturity per se (though much work remains to be done to fully document the neuromotor phenotype of the preterm infant pig model). In many ways, the postural and locomotor deficits shown by the preterm piglets paralleled the locomotor phenotype of altricial mammals. Overall, our study demonstrates the utility of a "within-species" design for studying the biomechanical correlates and neuromotor basis of evolutionary variation in motor skill at birth. [ABSTRACT FROM AUTHOR]

Studies cell populations derived from primary breast carcinoma. Cytokine release assay; Secretion of epidermal growth factor (EGF) by cells with characteristic morphological and immunophenotypic profile of activated macrophages.

Oncolytic viruses (OV) promote anti-tumour responses through the initiation of immunogenic cancer cell death which activates the host's systemic anti-tumour immunity. We have previously shown that intravenously administered HSV1716 is an effective treatment for mammary cancer. However, intravenous administration of a virus has the potential to result in neutralization and sequestration of the virus which may reduce efficacy. Here, we show that the oncolytic virus HSV1716 can be administered within a cellular carrier (macrophages). PyMT and 4T1 murine mammary cancer cell lines were implanted into immuno-competent murine models (orthotopic primary, early metastatic and brain metastasis models). HSV1716 or macrophages armed with HSV1716 (M-HSV1716) were administered intravenously, and tumour size was quantified using caliper measurement or bioluminescence imaging. Administration of M-HSV1716 led to tumour shrinkage and increased the survival of animals. Furthermore, these results were achieved with a 100-fold lower viral load, which has the potential for decreased toxicity. Our results demonstrate that M-HSV1716 is associated with activity against murine mammary cancers and provides an alternative platform for the systemic delivery of OV. [ABSTRACT FROM AUTHOR]

Abstract: Tumor-associated macrophages (TAMs) are a prominent inflammatory cell population in many tumor types residing in both perivascular and avascular, hypoxic regions of these tissues. Analysis of TAMs in human tumor biopsies has shown that they express a variety of tumor-promoting factors and evidence from transgenic murine tumor models has provided unequivocal evidence for the importance of these cells in driving angiogenesis, lymphangiogenesis, immunosuppression, and metastasis. This review will summarize the mechanisms by which monocytes are recruited into tumors, their myriad, tumor-promoting functions within tumors, and the influence of the tumor microenvironment in driving these activities. We also discuss recent attempts to both target/destroy TAMs and exploit them as delivery vehicles for anti-cancer gene therapy. [Copyright &y& Elsevier]

Abstract: The presence of multiple areas of hypoxia (low oxygen tension) is a hallmark feature of human and experimental tumours. Monocytes are continually recruited into tumours where they differentiate into tumour-associated macrophages (TAM) and often accumulate in hypoxic and/or necrotic areas. A number of recent studies have shown that macrophages respond to hypoxia by up-regulating transcription factors such as HIF-1α and HIF-2α, which in turn up-regulate the expression of a broad array of mitogenic, pro-invasive, pro-angiogenic and pro-metastatic genes. Here we show that primary human macrophages but not monocytes rapidly up-regulate HIF-1α and HIF-2α proteins upon exposure to hypoxia, and that these proteins then translocate to the nucleus. We also demonstrate differences in the temporal expression and responses to re-oxygenation for HIF-1α and HIF-2α in macrophages. Here we found that, compared to HIF-1α, HIF-2α expression was prolonged and persisted with re-oxygenation. ATF-4 and Egr-1 were also found to be hypoxia-responsive transcription factors in macrophages but not monocytes, but only early after exposure to hypoxia. Taken together, these findings indicate that a number of transcription factors work together in a tightly regulated fashion to control macrophage activities in ischaemic areas of diseased tissues. [Copyright &y& Elsevier]

The article focuses on the development of cancer gene therapy protocol that use bacteria. Researchers revealed that non-pathogenic obligate anaerobic and facultative anaerobic bacteria could infiltrate and selectivity replicate within solid tumors. The author of this article evaluates the efficacy of these cancer therapies.

In this paper we present a new model framework for studying vascular tumour growth, in which the blood vessel density is explicitly considered. Our continuum model comprises conservation of mass and momentum equations for the volume fractions of tumour cells, extracellular material and blood vessels. We include the physical mechanisms that we believe to be dominant, namely birth and death of tumour cells, supply and removal of extracellular fluid via the blood and lymph drainage vessels, angiogenesis and blood vessel occlusion. We suppose that the tumour cells move in order to relieve the increase in mechanical stress caused by their proliferation. We show how to reduce the model to a system of coupled partial differential equations for the volume fraction of tumour cells and blood vessels and the phase averaged velocity of the mixture. We consider possible parameter regimes of the resulting model. We solve the equations numerically in these cases, and discuss the resulting behaviour. The model is able to reproduce tumour structure that is found in vivo in certain cases. Our framework can be easily modified to incorporate the effect of other phases, or to include the effect of drugs. [Copyright &y& Elsevier]

Background: The concept of evidence-based practice is globally relevant in current healthcare climates. However, students and teachers struggle with integrating evidence based practice effectively into a curriculum. This has implications for nurse education and in particular the way in which research is presented and delivered to students. A new undergraduate Evidence Based Practice module (Evidence Based Nursing 1) was developed in a large University within the United Kingdom. It commenced in October 2014 running in year one of a 3 year undergraduate nursing programme. This study sought to formally evaluate attitudes and beliefs, knowledge level and utilization of evidence based practice though using two validated questionnaires: Evidence Based Practice Beliefs Scale© and Evidence Based Practice Implementation Scale©. Method: This was a pilot study using quantitative pre and post-test design. Anonymised data was collected from Year 1 undergraduate student nurses in the September 2014 intake (n = 311) at two time points. Time 1: pre-module in September 2014; and Time 2: post -module in August 2015. All data was collected via Survey Monkey. Results: Results demonstrate that the educational initiative positively impacted on both the beliefs and implementation of evidence based practice. Analysis highlighted statistically significant changes (p < 0.05) in both the Evidence Based Practice Beliefs Scale (7/16 categories) and the Evidence Based Practice Implementation Scale (13/18 categories). Conclusions: The significance of integrating evidence based practice into undergraduate nurse education curriculum cannot be underestimated if evidence based practice and its positive impact of patient care are to be appreciated in healthcare settings internationally. [ABSTRACT FROM AUTHOR]

Tumor relapse after chemotherapy-induced regression is a major clinical problem, because it often involves inoperable metastatic disease. Tumor-associated macrophages (TAM) are known to limit the cytotoxic effects of chemotherapy in preclinical models of cancer. Here, we report that an alternatively activated (M2) subpopulation of TAMs (MRC1+TIE2HiCXCR4Hi) accumulate around blood vessels in tumors after chemotherapy, where they promote tumor revascularization and relapse, in part, via VEGF-A release. A similar perivascular, M2-related TAM subset was present in human breast carcinomas and bone metastases after chemotherapy. Although a small proportion of M2 TAMs were also present in hypoxic tumor areas, when we genetically ablated their ability to respond to hypoxia via hypoxia-inducible factors 1 and 2, tumor relapse was unaffected. TAMs were the predominant cells expressing immunoreactive CXCR4 in chemotherapy-treated mouse tumors, with the highest levels expressed by MRC1+ TAMs clustering around the tumor vasculature. Furthermore, the primary CXCR4 ligand, CXCL12, was upregulated in these perivascular sites after chemotherapy, where it was selectively chemotactic for MRC1+ TAMs. Interestingly, HMOX-1, a marker of oxidative stress, was also upregulated in perivascular areas after chemotherapy. This enzyme generates carbon monoxide from the breakdown of heme, a gas known to upregulate CXCL12. Finally, pharmacologic blockade of CXCR4 selectively reduced M2-related TAMs after chemotherapy, especially those in direct contact with blood vessels, thereby reducing tumor revascularization and regrowth. Our studies rationalize a strategy to leverage chemotherapeutic efficacy by selectively targeting this perivascular, relapse-promoting M2-related TAM cell population. [ABSTRACT FROM AUTHOR]

The objectives are to report the estimated prevalence of pregnancy complications and adverse pregnancy outcomes in a defined population of Alaska Native women and also examine factors contributing to an intensive and successful collaboration between a tribal health center and the Centers for Disease Control and Prevention. Investigators abstracted medical record data from a random sample of singleton deliveries to residents of the study region occurring between 1997 and 2005. We used descriptive statistics to estimate the prevalence and 95 % confidence intervals of selected pregnancy complications and adverse pregnancy outcomes. Records were examined for 505 pregnancies ending in a singleton delivery to 469 women. Pregnancy complication rates were 5.9 % (95 % CI 4.0, 8.4) for gestational diabetes mellitus, 6.1 % (95 % CI 4.2, 8.6 %) for maternal chronic hypertension and 11.5 % (95 % CI 8.8, 14.6) for pregnancy associated hypertension, and 22.9 % (95 % CI 19.2-26.5 %) for anemia. The cesarean section rate was 5.5 % (95 % CI 3.5, 7.5) and 3.8 % (95 % CI 2.3, 5.8) of newborns weighed >4,500 g. Few previous studies reported pregnancy outcomes among Alaska Native women in a specific geographic region of Alaska and regarding the health needs in this population. We highlight components of our collaboration that contributed to the success of the study. Studies focusing on special populations such as Alaska Native women are feasible and can provide important information on health indicators at the local level. [ABSTRACT FROM AUTHOR]

Objective To examine the potential effects of prenatal smokeless tobacco use on selected birth outcomes. Design A population-based, case-control study using a retrospective medical record review. Population Singleton deliveries 1997-2005 to Alaska Native women residing in western Alaska. Methods Hospital discharge codes were used to identify potential case deliveries and a random control sample. Data on tobacco use and confirmation of pregnancy outcomes were abstracted from medical records for 1123 deliveries. Logistic regression was used to examine associations between tobacco use and pregnancy outcomes. Adjusted odds ratios ( OR), 95% confidence intervals (95% CI), and p-values were calculated. Main outcomes measures Preterm delivery, pregnancy-associated hypertension, and placental abruption. Results In unadjusted analysis, smokeless tobacco use was not significantly associated with preterm delivery ( OR 1.44, 95% CI 0.97-2.15). After adjustment for parity, pre-pregnancy body mass index, and maternal age, the point estimate was attenuated and remained non-significant. No significant associations were observed between smokeless tobacco use and pregnancy-associated hypertension (adjusted OR 0.92, 95% CI 0.56-1.51) or placental abruption (adjusted OR 1.11, 95% CI 0.53-2.33). Conclusions Prenatal smokeless tobacco use does not appear to reduce risk of pregnancy-associated hypertension or to substantially increase risk of abruption. An association between smokeless tobacco and preterm delivery could not be ruled out. Components in tobacco other than nicotine likely play a major role in decreased pre-eclampsia risk in smokers. Nicotine adversely affects fetal neurodevelopment and our results should not be construed to mean that smokeless tobacco use is safe during pregnancy. [ABSTRACT FROM AUTHOR]

Objective. To examine the effects of maternal prenatal smokeless tobacco use on infant birth size. Design. A retrospective medical record review of 502 randomly selected deliveries. Population and Setting. Singleton deliveries to Alaska Native women residing in a defined geographical region in western Alaska, 1997-2005. Methods. A regional medical center's electronic records were used to identify singleton deliveries. Data on maternal tobacco exposure and pregnancy outcomes were abstracted from medical records. Logistic models were used to estimate adjusted mean birthweight, length and head circumference for deliveries to women who used no tobacco ( n=121), used smokeless tobacco ( n=237) or smoked cigarettes ( n=59). Differences in mean birthweight, length and head circumference, 95% confidence intervals and p-values were calculated using non-users as the reference group. Main Outcome Measures. Infant birthweight, crown-heel length and head circumference. Results. After adjustment for gestational age and other potential confounders, the mean birthweight of infants of smokeless tobacco users was reduced by 78g compared with that of infants of non-users ( p=0.18) and by 331g in infants of smokers ( p<0.01). No association was found between maternal smokeless tobacco use and infant length or infant head circumference. Conclusions. We found a modest but non-significant reduction in the birthweight of infants of smokeless tobacco users compared with infants of tobacco non-users. Because smokeless tobacco contains many toxic compounds that could affect other pregnancy outcomes, results of this study should not be construed to mean that smokeless tobacco use is safe during pregnancy. [ABSTRACT FROM AUTHOR]

Vascular-disrupting agents (VDAs) such as combretastatin A4 phosphate (CA4P) selectively disrupt blood vessels in tumors and induce tumor necrosis. However, tumors rapidly repopulate after treatment with such compounds. Here, we show that CA4P-induced vessel narrowing, hypoxia, and hemorrhagic necrosis in murine mammary tumors were accompanied by elevated tumor levels of the chemokine CXCL12 and infiltration by proangiogenic TIE2-expressing macrophages (TEMs). Inhibiting TEM recruitment to CA4P-treated tumors either by interfering pharmacologically with the CXCL12/CXCR4 axis or by genetically depleting TEMs in tumor-bearing mice markedly increased the efficacy of CA4P treatment. These data suggest that TEMs limit VDA-induced tumor injury and represent a potential target for improving the clinical efficacy of VDA-based therapies. [ABSTRACT FROM AUTHOR]

Angiopoietin 2 (ANGPT2) is a proangiogenic cytokine whose expression is often upregulated by endothelial cells in tumors. Expression of its receptor, TIE2, defines a highly proangiogenic subpopulation of myeloid cells in circulation and tumors called TIE2-expressing monocytes/macrophages (TEMs). Genetic depletion of TEMs markedly reduces tumor angiogenesis in various tumor models, emphasizing their essential role in driving tumor progression. Previously, we demonstrated that ANGPT2 augments the expression of various proangiogenic genes, the potent immunosuppressive cytokine, IL-10, and a chemokine for regulatory T cells (Tregs), CCL17 by TEMs in vitro. We now show that TEMs also express higher levels of IL-10 than TIE2- macrophages in tumors and that ANGPT2-stimulated release of IL-10 by TEMs suppresses T cell proliferation, increases the ratio of CD4+ T cells to CD8+ T cells, and promotes the expansion of CD4+CD25highFOXP3+ Tregs. Furthermore, syngeneic murine tumors expressing high levels of ANGPT2 contained not only high numbers of TEMs but also increased numbers of Tregs, whereas genetic depletion of tumor TEMs resulted in a marked reduction in the frequency of Tregs in tumors. Taken together, our data suggest that ANGPT2-stimulated TEMs represent a novel, potent immunosuppressive force in tumors. [ABSTRACT FROM AUTHOR]

Abstract: The cytokine MIF is over-expressed in tumors and is associated with tumor proliferation, angiogenesis and metastasis. Hypoxia, a hallmark feature of tumors, increases MIF expression from tumor cells. We examined the role of hypoxia-inducible transcription factors on MIF secretion from MCF-7 breast carcinoma cells. Secretion of MIF was induced by hypoxia after 24h but up-regulation of MIF mRNA was minimal. Inhibition of HIF-1α, HIF-2α, NF-κB and C/EBPβ using siRNA had no effect on hypoxia-induced MIF secretion. However, inhibition of transcription and translation significantly decreased MIF production, suggesting that hypoxia-induced secretion of MIF in MCF-7 cells is via an alternative pathway. [Copyright &y& Elsevier]

Tumor-infiltrating myeloid cells are involved in crucial processes during tumor development. A subset of monocytes that express the angiopoietin receptor Tie2 play an important role in tumor angiogenesis. Selective depletion of these Tie2-expressing monocytes (TEMs) in tumor-bearing mice inhibits tumor angiogenesis and growth, suggesting that they might regulate angiogenic processes in tumors by providing paracrine support to nascent blood vessels. TEMs have also been identified in human blood and tumors. We discuss here the therapeutic opportunities emanating from the discovery of TEMs, which include the identification of new antitumor targets, monitoring TEMs as surrogate markers for clinical responses in cancer patients, and the possible use of TEMs as cellular vehicles for gene delivery to tumors. [Copyright &y& Elsevier]

Tumour hypoxia is associated with poor drug delivery and low rates of cell proliferation, factors that limit the efficacy of therapies that target proliferating cells. Since macrophages localise within hypoxic regions, a promising way to target hypoxic tumour cells involves engineering macrophages to express therapeutic genes under hypoxia. In this paper we develop mathematical models to compare the responses of avascular tumour spheroids to two modes of action: either the macrophages deliver an enzyme that activates an externally applied prodrug (bystander model), or they deliver cytotoxic factors directly (local model). The models we develop comprise partial differential equations for a multiphase mixture of tumour cells, macrophages and extracellular fluid, coupled to a moving boundary representing the spheroid surface. Chemical constituents, such as oxygen and drugs, diffuse within the multiphase mixture. Simulations of both models show the spheroid evolving to an equilibrium or to a travelling wave (multiple stable solutions are also possible). We uncover the parameter dependence of the wave speed and steady-state tumour size, and bifurcations between these solution forms. For some parameter sets, adding extra macrophages has a counterintuitive deleterious effect, triggering a bifurcation from bounded to unbounded tumour growth. While these features are common to the bystander and local models, the crucial difference is where cell death occurs. The bystander model is comparable to traditional chemotherapy, with poor targeting of hypoxic tumour cells; however, the local mode of action is more selective for hypoxic regions. We conclude that effective targeting of hypoxic tumour cells may require the use of drugs with limited mobility or whose action does not depend on cell proliferation. [ABSTRACT FROM AUTHOR]

The article presents a study about the role of sigma factors σE and σS in survival of Salmonella enterica serovar Typhimurium during refrigeration, and starvation. Here, the researchers examined the relative contribution of σE and σ5, the sigma factors regulating extracytoplasmic and general stress response functions.

The article examines the use of optimized Escherichia coli two-plasmid system to identify and locate Salmonella enterica serovar Typhimurium (S. Typhimurium) σE regulon. The deduced functions of the identified genes are described in relation to the virulence of S. Typhimurium. Several functions have emerged, including a role in DNA repair and recombination and outer-membrane protein assembly.

The maintenance of vascular integrity and control of blood loss are regulated by a sophisticated system of circulating and cell-associated hemostatic factors. These factors control local platelet aggregation, the conversion of soluble fibrinogen to an insoluble fibrin polymer, and the dissolution of fibrin. However, hemostatic factors are also involved in a number of physiologic processes, including development, tissue remodeling, wound repair, reproduction, inflammation, and angiogenesis. In this review, we outline ways in which angiogenesis is coordinated with and regulated by hemostasis. We focus on inhibitors of angiogenesis contained within platelets or harbored as cryptic fragments of hemostatic proteins and assess the experimental and preclinical evidence for their ability to inhibit tumor angiogenesis and, thus, their potential to be anticancer agents. Finally, we review the results of recent clinical trials involving angiogenesis inhibitors and the evidence that antiangiogenic therapy may be associated with hemostatic complications. [ABSTRACT FROM AUTHOR]