Miracle-dz/UniFAR-FTUs huggingface dataset:
Chapter 2 The Metastatic Microenvironment

Metastasis is the major killer of cancer patients. Although increased understanding of the metastatic process was achieved in recent years, the mechanisms underlying the progression of cancer cells to form site-specific metastasis are still awaiting complete elucidation. The current consensus is that circulating tumor cells disseminate into future metastatic sites and that these disseminated tumor cells form micrometastasis in these sites. The micrometastases remain in a state of dormancy in these sites until ‘‘awakened’’ to progress towards overt metastases. Whereas the evidence implicating chemokine–chemokine receptor interactions as the mechanism responsible for the targeted migration of tumor cells to future metastatic sites is quite strong, the mechanisms that maintain dormancy of disseminated tumor cells and the mechanisms that awaken these dormant micrometastases, driving their progression towards frank metastasis, are still obscure. It is clear, however, that the metastatic microenvironment plays a major role in these events. Three topics are discussed in this review: Mechanisms that are involved in the targeted migration of tumor cells to future metastatic sites; Specific molecular signatures expressed by metastases and micrometastases and interactions between metastatic and micrometastatic cells with the metastatic microenvironment. In reviewing these topics we focused on studies performed in our lab with neuroblatoma lung and melanoma brain metastasis. S. Maman I. P. Witz Department of Cell Research and Immunology George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel S. Maman I. P. Witz Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA I. P. Witz (&) Department of Cell Research and Immunology George S, Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel e-mail: isaacw@tauex.tau. ac.il M. R. Shurin et al. (eds.), The Tumor Immunoenvironment, DOI: 10.1007/978-94-007-6217-6_2, Springer Science+Business Media Dordrecht 2013 15
Modified Supercritical Carbon Dioxide Extraction of Biologically Active Compounds from Feijoa Sellowiana Leaves

Abstract For the first time, the modified supercritical carbon dioxide extraction (MSCE) of biologically active compounds from Feijoa sellowiana leaves was investigated. Total yield (TY) and bioactivity of biocompounds in terms of DPPH• (%DPPHsc) and HO• (%HOsc) radicals scavenging were maximized via multivariate optimization. The optimized conditions were the pressure of 272.34 bar, supercritical carbon dioxide flow rate of 1.58 mL min−1, temperature of 52.48 °C, and dynamic extraction time of 110.62 min. The predicted values of the TY, %DPPHsc, and %HOsc were 81.12 mg g−1, 85.16 %, and 75.66 %, respectively. The chromatographic analysis demonstrated gallic acid as the main biophenolic (136.20 ± 0.16 mg g−1). The scanning electron microscopy images showed dramatic disruption of cells treated with MSCE. A comprehensive comparison was made between current findings and other techniques (conventional and ultrasonic waves assisted extraction). More TY was achieved using conventional method but the bioactivity of MSCE products was considerably better.
Spread of Tst–Positive Staphylococcus aureus Strains Belonging to ST30 Clone among Patients and Healthcare Workers in Two Intensive Care Units

Staphylococcus aureus is a major cause of infections. Toxic shock syndrome toxin (TSST-1) and Panton–Valentine leukocidin (PVL) are associated with severe clinical syndromes. S. aureus colonizing isolates recovered from healthcare workers and patients in the intensive care unit (ICU) of a university hospital comprising Group A were compared with those from adult non-ICU carriers (Group B). mecA, lukS/lukF-PV (Panton–Valentine leukocidin, PVL), and tst (toxic shock syndrome toxin) gene carriage was detected by PCR. Clones were identified in all methicillin-resistant S. aureus (MRSA) and toxin-positive methicillin-susceptible strains (MSSA) by pulsed-field gel electrophoresis (PFGE), agr groups, and multi locus sequencing typing (MLST). Group A included 90 S. aureus isolates, whereas Group B 53. PVL was more frequently found among MRSA vs. MSSA (p < 0.001) and in strains of Group B as compared to Group A (p < 0.001), consistent with the spread of ST80-IV. Higher incidence of tst gene carriage was identified among MSSA vs. MRSA (P 0.005) belonging mainly to ST30, and Group A vs. Group B (P 0.002). The wide dissemination of ST80-IV mainly in the community is responsible for a high percentage of PVL-positive MRSA, while silent spread of tst-positive S. aureus clones among ICU patients and personnel poses a threat of hospital transmission and possible severe infections.
MULTIVARIATE STOCHASTIC IMMUNIZATION THEORY

In the current paper, a new theory of immunization is introduced in which the approach is multivariate, and the goal is stochastic in the sense of minimizing stochastic risk. The risk measure utilized is reminiscent of the Markowitz [4] approach of variance minimization but generalized to also reflect a measure of worst-case risk. The approach is multivariate in that full yield curve risk to nonparallel shifts is reflected, as in Reitano [6-13], by modeling the yield curve as a vector of yield curve drivers. Explicit solutions to the risk minimization problems are developed, subject to constraints on portfolio returns and/or various portfolio directional durations. In addition, explicit solutions are determined that can be achieved by trading any given collection of assets. Applications are developed in detail and are exemplified by an analysis of the example introduced in Reitano [11].
Homeologous gene expression in response to growing temperature in a recent Allopolyploid (Coffea arabica L.).

Allopolyploidy is considered as a major factor contributing to speciation, diversification, and plant ecological adaptation. In particular, the expression of duplicate genes (homeologs) can be altered leading to functional plasticity and to phenotypic novelty. This study investigated the influence of growing temperatures on homeologous gene expression in Coffea arabica L. , a recent allopolyploid involving 2 closely related diploid parental species. The relative expression of homeologs of 13 genes all located in the same genomic region was analyzed using an SNP ratio quantification method based on dideoxy-terminated sequences of cDNA amplicons. The relative expression of homeologous genes varied depending on the gene, the organ, and the growing condition. Nevertheless, expression of both homeologs was always detected (i.e., no silencing). Although the growing conditions were suitable for one or other of the parental species, neither subgenome appeared preferentially expressed. Furthermore, relative homeologous expression showed moderate variations across organs and conditions and appeared uncorrelated between adjacent genes. These results indicate the absence of signs of subfunctionalization suggesting C. arabica has not undergone noticeable diploidization. Furthermore, these results suggest that the expression of homeologous genes in C. arabica is regulated by a shared trans-regulation mechanism acting similarly on the 2 subgenomes and that the observed biases in the relative homeolog expression may result from cis fine-scale factors.
Outcomes of a health coaching intervention delivered by medical students for older adults with uncontrolled type 2 diabetes

ABSTRACT Effective strategies are needed to address the health behaviors of older patients with diabetes. One approach is health coaching, the practice of health education and health promotion through a structured partnership designed to enhance well-being and facilitate the achievement of individuals’ health-related goals. The aim of this study was to describe the development of a pilot health coaching curriculum, investigate its effects on geriatric patient outcomes, and examine qualitative feedback by older patients and medical students to the curriculum. This mixed-methods study involved 29 first-year medical students randomly paired with 29 older adults with uncontrolled Type 2 diabetes. Health-related quality of life (HRQoL), stage of change movement, diabetes knowledge, locus of control, Body Mass Index (BMI), and glycosylated hemoglobin (HbA1c) were assessed. Focus groups were used to evaluate patients’ and medical students’ experiences. Results showed significant increases in patients’ HRQoL and stage of change for exercise improved significantly over time. There were no significant changes in stage of change for healthy diet and medication, diabetes knowledge, BMI, and HbA1c from baseline to end of study. Focus group data indicated positive responses by older patients and the medical students. A health coaching curriculum may improve patient outcomes and can provide medical students the skills needed to provide compassionate care for geriatric patients.
Assessment of shelf life of fish patties during refrigerated storage.

Fish patties prepared with addition of 5% rice flour or 2.5% corn flour as extender were compared with control. Processed patties were stored at 4±1oC in HDPE pouches and evaluated for quality parameters such as physico-chemical, microbiological and the sensory attributes. The sensory scores for all sensory attributes though declined progressively with progress of storage, but the patties made with incorporation of 5% rice flour or 2.5% corn flour were acceptable up to 16th day of storage. During storage moisture, fat and protein content declined steadily while the pH, TBA and tyrosine value increased significantly. Similarly, the total plate count and yeast and mould count increased significantly throughout refrigerated storage but were within the permissible limit. The control patties developed slight off flavour on 16th day of storage but rice and corn flour extended fish patties were acceptable up to 16th day of refrigerated storage.
From tools to toolkits in policy design studies: The new design orientation towards policy formulation research

A roadmap for ‘new policy design’ studies now exists in the orientation which has emerged in recent years towards the formulation of complex policy mixes. The new design orientation focuses on bundles or portfolios of tools and the interactive effects which occur when multiple tools are used over time in policy packages designed to address multiple goals, and upon more complex multi-policy and multi-level design contexts. This review article examines the differences between the ‘old’ instrument orientation and the ‘new’ design one, setting out the current research agenda in this field and its rationale.
IL‐13 and TNF‐α  inhibit dual‐tropic HIV‐1 in primary macrophages by reduction of surface expression of CD4, chemokine receptors CCR5, CXCR4 and post‐entry viral gene expression

We show that IL‐13 in the presence of TNF‐α effected an equal or greater antiviral activity against a dual‐tropic HIV‐1 (R5X4) in macrophages. A temporary or continued exposure of macrophages to both cytokines significantly decreased the infection and replication of R5X4 HIV‐189.6 (median, 128‐fold, n = 9, p = 0.024) in macrophages as compared to untreated controls when analyzed over six decreasing multiplicities of infection. A quantitative flow cytometric assay revealed that IL‐13 induced a significant (∼ 50 %) reduction in the number of CD4 and CC chemokine receptor 5 (CCR5) antibody binding sites while completely abrogating surface expression of CXC chemokine receptor 4 (CXCR4). In the presence of IL‐13 and TNF‐α, expression of CCR5 was completely abrogated while the expression of CD4 and CXCR4 remained significantly reduced as compared to untreated controls. A reduction in CD4 and HIV‐1 coreceptors was associated with a decrease in reverse‐transcribed viral DNA at 24 h post‐infection. Quantification of viral gene expression using amphotropic MLV Env pseudotyped luciferase reporter viruses suggested that IL‐13 inhibited HIV‐1 gene expression within 24 h by up to 90 % in the presence or absence of TNF‐α. In conclusion, our data suggest that IL‐13 is a powerful counter‐regulatory agent against TNF‐α‐induced HIV‐1 expression while also acting with TNF‐α in inhibiting de novo infection of macrophages.
The impact of interest rates on foreign direct investment: a case study of the Zimbabwean economy (February 2009-June 2011)

Foreign direct investment (FDI) is very low in Zimbabwe and this is resulting in low levels of economic growth and standards of living and has hindered efforts to promote economic prosperity and sustainable development for the country. Hence this research seeks to find the relationship and impact of interest rates on FDI inflows. It also sought to find out other determinants that significantly affected FDI inflows in Zimbabwe in the period February 2009 to June 2011. The research tested the hypothesis that high interest rates have a positive impact on FDI inflows. Secondary data was collected from various institutions like Reserve Bank of Zimbabwe, International Monetary Fund reports, World Bank reports, Ministry of Finance, Failed Nations. Monthly data was used to make a total of 29 observations. Data was analysed using the classical linear regression model, ordinary least squares approach. The paper found that interest rates had no significant impact on FDI inflows and hence cannot be used for policy making purposes. The research discovered that risk factors are the major determinant of FDI in Zimbabwe. International Journal of Management Sciences and Business Research, 2012, Vol. 1, No. 5. (ISSN: 2226-8235) 2 Policies that reduce country risk levels and campaigns that promote peace, anti-corruption and transparency should be encouraged if the economy is to realize long term inflows of FDI.
Bacterial Biofilm and Antibiotic Resistance

Biofilm is a structural and functional unit of microbial consortia encased in self-produced polymeric substances including protein, polysaccharide and e-DNA. Biofilm formation by bacteria represents one of the group behaviors in bacterial world which help them to acquire emergent properties in order to survive under unfavorable conditions. Multidrug resistance in bacterial biofilm is thus an increasing threat to global health. For example, Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus are causal agents of biofilm borne infections. The mechanisms of antibiotic resistance are often conferred by horizontal gene transfer promoting evolution and genetic diversity. The inactivation of antibiotics is also advocated by extracellular polymers and modifying enzymes and survival of bacteria at high antibiotic pressure involves enzymes such as chromosomal beta-lactamase, up-regulated efflux pumps and mutation in antibiotic target molecules. Ironically, detailed studies on effect of antibiotics on bacterial biofilm architectures and unraveling the alterations in molecular networks involved in bacterial biofilm formation in presence of antibiotics would be an upcoming avenue for a deeper understanding of biofilm physiology to develop better therapeutic strategies against biofilm mediated bacterial infections.
Effect of A High Dosage Opioid Prior Authorization Policy on Prescription Opioid Use, Misuse, and Overdose Outcomes

Background High dosage opioid use is a risk factor for opioid-related overdose commonly cited in guidelines, recommendations, and policies. In 2012, the Oregon Medicaid program developed a prior authorization policy for opioid prescriptions above 120 mg per day morphine equivalent dose (MED). This study aimed to evaluate the effects of that policy on utilization, prescribing patterns, and health outcomes. Methods Using administrative claims data from Oregon and a control state (Colorado) between 2011 and 2013, we used difference-in-differences analyses to examine changes in utilization, measures of high risk opioid use, and overdose after introduction of the policy. We also evaluated opioid utilization in a cohort of individuals who were high dosage opioid users before the policy. Results Following implementation of Oregon's high dosage policy, the monthly probability of an opioid fill over 120 mg MED declined significantly by 1.7 percentage points (95% confidence interval [CI]; -2.0% to -1.4%), whereas it increased significantly by 1.0 percentage points (95% CI 0.4% to 1.7%) for opioid fills < 61 mg MED. Fills of medications used to treat neuropathic pain also increased by 1.2 percentage points (95% CI 0.7% to 1.8%). The monthly probability of multiple pharmacy use declined by 0.1 percentage points (-0.2% to -0.0) following the prior authorization, but there were no significant changes in ED encounters or hospitalizations for opioid overdose. Among individuals who were using a high dosage opioid before the policy, there was a 20.3 percentage point (95% CI -15.3% to -25.3%) decline in estimated probability of having a high dosage fill after the policy. Conclusions Oregon's prior authorization policy was effective at reducing high dosage opioid prescriptions. While multiple pharmacy use also declined, we found no impact on opioid overdose were observed.
Platelet-Rich Plasma Releasate Promotes Regeneration and Decreases Inflammation and Apoptosis of Injured Skeletal Muscle

Background: Platelet-rich plasma (PRP) contains various cytokines and growth factors that may be beneficial to the healing process of injured muscle. Based on the authors’ previous study, PRP releasate can promote proliferation and migration of skeletal muscle cells in vitro, so animal studies are performed to support the use of PRP to treat muscle injury in vivo. Purpose: To investigate the effect of PRP releasate on regeneration of injured muscle, as well as its effect on inflammatory reaction and cell apoptosis, in the early stages of the muscle-healing process. Study Design: Controlled laboratory study. Methods: The gastrocnemius muscles of Sprague-Dawley rats were injured by partial transverse incision and then treated with PRP releasate. Hematoxylin and eosin stain was used to evaluate the healing process of injured muscle at 2, 5, and 10 days after injury. TUNEL assay was used to evaluate the cell apoptosis of injured muscle after PRP releasate treatment. Immunohistochemistry was used to stain the CD68-positive cells during the healing process. Muscle contractile properties, including fast-twitch and tetanic strength, were evaluated by electric stimulation. Results: The results revealed that PRP releasate treatment could enhance the muscle-healing process and decrease CD68-positive cells and apoptotic cells. Furthermore, the tetanic strength was significantly higher in injured muscle treated with PRP releasate. Conclusion: In conclusion, PRP releasate could enhance the healing process of injured muscle and decrease inflammatory cell infiltration as well as cell apoptosis. Clinical Relevance: PRP promotes skeletal muscle healing in association with decreasing inflammation and apoptosis of injured skeletal muscle. These findings provide in vivo evidence to support the use of PRP to treat muscle injury.
A pilot study to evaluate learning style-tailored information prescriptions for hypertensive emergency department patients.

OBJECTIVE This pilot study explored whether learning style-tailored education materials, "information prescriptions," are effective in increasing hypertension knowledge in emergency room patients. METHODS In a randomized trial, hypertensive emergency medicine patients received either standard care discharge instructions or discharge instructions in combination with an information prescription individualized to each patient's learning-style preference. Two weeks post-visit, the study team assessed changes in hypertension knowledge via a survey. RESULTS No significant difference was observed for changes in quiz scores on the hypertension knowledge assessment, though patients receiving the tailored information prescriptions reported higher levels of satisfaction with intervention materials. CONCLUSION The study demonstrated the workflow feasibility of implementing a learning-style approach to patient education in the emergency department setting. Further research is needed to develop more robust measures of high blood pressure knowledge among the emergency department patient population. This work will contribute to establishing a framework for developing customized information prescriptions that can be broadly adapted for use in varied settings and with varied health care conditions.
Heat stress in pregnant sows: Thermal responses and subsequent performance of sows and their offspring

Seasonal infertility is a significant problem in the swine industry, and may be influenced by photoperiod and heat stress. Heat stress during gestation in particular affects pregnancy, resulting in long‐term developmental damage to the offspring. This review summarizes what is known about how heat stress on the pregnant sow affects lactation and her offspring. Sows responded to heat stress during gestation with increased rectal temperature, respiration rate, and skin temperature, and tended to reduce their activity—which may have changed their body composition, increasing the adipose‐to‐muscle ratio. Heat stress during gestation caused temporary insulin resistance during lactation, but this metabolic state did not seem to affect health, lactation, or rebreeding performance of the sow. Heat‐stressed sows also presented with a shorter gestation period and reduced litter birth weight, although weaning weights are not affected when these sows are moved to thermoneutral conditions for lactation. The offspring of gestational heat‐stressed sows, however, possessed unique phenotypes, including elevated body temperature, greater fat deposition, and impaired gonad development. Thus, gestational heat stress may significantly impact a herd through its effects on sows and their offspring. Further work is necessary to determine the magnitude of the effects across fa cilities and breeds.
Dopamine D4 receptor stimulation prevents nigrostriatal dopamine pathway activation by morphine: relevance for drug addiction

Morphine is one of the most effective drugs used for pain management, but it is also highly addictive. Morphine elicits acute and long‐term adaptive changes at cellular and molecular level in the brain, which play a critical role in the development of tolerance, dependence and addiction. Previous studies indicated that the dopamine D4 receptor (D4R) activation counteracts morphine‐induced adaptive changes of the μ opioid receptor (MOR) signaling in the striosomes of the caudate putamen (CPu), as well as the induction of several Fos family transcription factors. Thus, it has been suggested that D4R could play an important role avoiding some of the addictive effects of morphine. Here, using different drugs administration paradigms, it is determined that the D4R agonist PD168,077 prevents morphine‐induced activation of the nigrostriatal dopamine pathway and morphological changes of substantia nigra pars compacta (SNc) dopamine neurons, leading to a restoration of dopamine levels and metabolism in the CPu. Results from receptor autoradiography indicate that D4R activation modulates MOR function in the substantia nigra pars reticulata (SNr) and the striosomes of the CPu, suggesting that these regions are critically involved in the modulation of SNc dopamine neuronal function through a functional D4R/MOR interaction. In addition, D4R activation counteracts the rewarding effects of morphine, as well as the development of hyperlocomotion and physical dependence without any effect on its analgesic properties. These results provide a novel role of D4R agonist as a pharmacological strategy to prevent the adverse effects of morphine in the treatment of pain.