Anticancer Gene Transfer for Cancer Gene Therapy

Gene therapy vectors are among the treatments currently used to treat malignant tumors. Gene therapy vectors use a specific therapeutic transgene that causes death in cancer cells. In early attempts at gene therapy, therapeutic transgenes were driven by non-specific vectors which induced toxicity to normal cells in addition to the cancer cells. Recently, novel cancer specific viral vectors have been developed that target cancer cells leaving normal cells unharmed. Here we review such cancer specific gene therapy systems currently used in the treatment of cancer and discuss the major challenges and future directions in this field

Direct Type I IFN but Not MDA5/TLR3 Activation of Dendritic Cells Is Required for Maturation and Metabolic Shift to Glycolysis after Poly IC Stimulation

We thank the Rockefeller University Center for Clinical and Translational Science (UL1 TR000043 NCATS, NIH) for technical support

Cellular metabolism constrains innate immune responses in early human ontogeny

Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny

Epidemiology and interactions of Human Immunodeficiency Virus - 1 and Schistosoma mansoni in sub-Saharan Africa.

Human Immunodeficiency Virus-1/AIDS and Schistosoma mansoni are widespread in sub-Saharan Africa and co-infection occurs commonly. Since the early 1990s, it has been suggested that the two infections may interact and potentiate the effects of each other within co-infected human hosts. Indeed, S. mansoni infection has been suggested to be a risk factor for HIV transmission and progression in Africa. If so, it would follow that mass deworming could have beneficial effects on HIV-1 transmission dynamics. The epidemiology of HIV in African countries is changing, shifting from urban to rural areas where the prevalence of Schistosoma mansoni is high and public health services are deficient. On the other side, the consequent pathogenesis of HIV-1/S. mansoni co-infection remains unknown. Here we give an account of the epidemiology of HIV-1 and S. mansoni, discuss co-infection and possible biological causal relationships between the two infections, and the potential impact of praziquantel treatment on HIV-1 viral loads, CD4+ counts and CD4+/CD8+ ratio. Our review of the available literature indicates that there is evidence to support the hypothesis that S. mansoni infections can influence the replication of the HIV-1, cell-to-cell transmission, as well as increase HIV progression as measured by reduced CD4+ T lymphocytes counts. If so, then deworming of HIV positive individuals living in endemic areas may impact on HIV-1 viral loads and CD4+ T lymphocyte counts.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Neural Circuits Underlying Rodent Sociality: A Comparative Approach

All mammals begin life in social groups, but for some species, social relationships persist and develop throughout the course of an individual’s life. Research in multiple rodent species provides evidence of relatively conserved circuitry underlying social behaviors and processes such as social recognition and memory, social reward, and social approach/avoidance. Species exhibiting different complex social behaviors and social systems (such as social monogamy or familiarity preferences) can be characterized in part by when and how they display specific social behaviors. Prairie and meadow voles are closely related species that exhibit similarly selective peer preferences but different mating systems, aiding direct comparison of the mechanisms underlying affiliative behavior. This chapter draws on research in voles as well as other rodents to explore the mechanisms involved in individual social behavior processes, as well as specific complex social patterns. Contrasts between vole species exemplify how the laboratory study of diverse species improves our understanding of the mechanisms underlying social behavior. We identify several additional rodent species whose interesting social structures and available ecological and behavioral field data make them good candidates for study. New techniques and integration across laboratory and field settings will provide exciting opportunities for future mechanistic work in non-model species

Vitamin B-12 deficiency stimulates osteoclastogenesis via increased homocysteine and methylmalonic acid

The risk of nutrient deficiencies increases with age in our modern Western society, and vitamin B(12) deficiency is especially prevalent in the elderly and causes increased homocysteine (Hcy) and methylmalonic acid (MMA) levels. These three factors have been recognized as risk factors for reduced bone mineral density and increased fracture risk, though mechanistic evidence is still lacking. In the present study, we investigated the influence of B(12), Hcy, and MMA on differentiation and activity of bone cells. B(12) deficiency did not affect the onset of osteoblast differentiation, maturation, matrix mineralization, or adipocyte differentiation from human mesenchymal stem cells (hMSCs). B(12) deficiency caused an increase in the secretion of Hcy and MMA into the culture medium by osteoblasts, but Hcy and MMA appeared to have no effect on hMSC osteoblast differentiation. We further studied the effect of B(12), Hcy, and MMA on the formation of multinucleated tartrate-resistant acid phosphatase-positive osteoclasts from mouse bone marrow. We observed that B(12) did not show an effect on osteoclastogenesis. However, Hcy as well as MMA were found to induce osteoclastogenesis in a dose-dependent manner. On the basis of these results, we conclude that B(12) deficiency may lead to decreased bone mass by increased osteoclast formation due to increased MMA and Hcy levels

The ERK and JNK pathways in the regulation of metabolic reprogramming.

Most tumor cells reprogram their glucose metabolism as a result of mutations in oncogenes and tumor suppressors, leading to the constitutive activation of signaling pathways involved in cell growth. This metabolic reprogramming, known as aerobic glycolysis or the Warburg effect, allows tumor cells to sustain their fast proliferation and evade apoptosis. Interfering with oncogenic signaling pathways that regulate the Warburg effect in cancer cells has therefore become an attractive anticancer strategy. However, evidence for the occurrence of the Warburg effect in physiological processes has also been documented. As such, close consideration of which signaling pathways are beneficial targets and the effect of their inhibition on physiological processes are essential. The MAPK/ERK and MAPK/JNK pathways, crucial for normal cellular responses to extracellular stimuli, have recently emerged as key regulators of the Warburg effect during tumorigenesis and normal cellular functions. In this review, we summarize our current understanding of the roles of the ERK and JNK pathways in controlling the Warburg effect in cancer and discuss their implication in controlling this metabolic reprogramming in physiological processes and opportunities for targeting their downstream effectors for therapeutic purposes.Brunel Research Initiative & Enterprise Fund, Brunel University of London (to CB), Kay Kendall Leukemia Fund (KKL443) (to CB), 250 Great Minds Fellowship, University of Leeds (to SP), AMMF Cholangiocarcinoma Charity (to SP and PMC), and Bloodwise (17014) (to SP and CB)

Compositional variations in calciturbidites and calcidebrites in response to sea-level fluctuations (Exuma Sound, Bahamas)

compositional variation of Pleistocene carbonate gravity deposits from the Exuma Sound Basin, Bahamas, was determined. Two types of gravity deposit were present in the cores of ODP Leg 101, Site 632A, i.e., calciturbidites and calcidebrites. In analogy with earlier studies, the compositional variations in the calciturbidites could be linked to different sources on the carbonate margin, i.e., platform interior, platform edge, and platform slope. Calciturbidites deposited during interglacial, sea-level highstands show a dominance of non-skeletal grains, largely derived from the platform interior, while calciturbidites of glacial, sea-level lowstands, show a dominance of skeletal platform-edge to platform-slope-derived grains. Thus, the calciturbidite composition can be used to reconstruct the position of absolute sea level. In addition, the mud content of the calciturbidites increased after Marine Isotope Stage 11. In contrast, the composition of the calcidebrites remained unaltered through time and showed a clear dominance of platform-edge-derived sediments during varying sea-level positions. The Bahamian carbonate platform is located in a tectonically stable passive-margin setting and the gravity-flow deposits were laid down in an environment exclusively controlled by eustatic sea-level fluctuations. This study shows that all types of gravity-induced carbonate deposits, calciturbidites, and calcidebrites, were deposited in response to global eustatic sea-level variations. The sediment composition could be linked directly to sediment input from specific facies realms along the carbonate platform margin. Hence, sediment composition analysis is a strong tool that may be used to discriminate between gravity-induced deposition triggered by eustatic sea-level changes and that related to tectonic events, when analyzing resedimentation processes in sedimentary basins.Geoscience & EngineeringCivil Engineering and Geoscience

'It was not chest pain really, i can't explain it!' An exploratory study on the nature of symptoms experienced by women during their myocardial infarction

Aims and objectives. This study sought to explore the presenting nature of cardiac symptoms as experienced by women diagnosed with a myocardial infarction. The objectives were to use the participants' own words to gain a detailed understanding of how they perceived their evolving symptoms. Background. Women with coronary heart disease tend to delay seeking help despite experiencing symptoms. The classic hallmarks used to diagnose a myocardial infarction have been based on research primarily involving white middle-aged men with a focus on specific descriptions of chest pain. Whether these hallmarks apply to women in the same way as they apply to men is an area of increasing contention. Design. Using a purposive sample, a qualitative design was used to investigate the nature of cardiac symptoms experienced by women prior to and at the time of their myocardial infarction. Method. Twelve women participated in semi-structured in-depth tape-recorded interviews conducted while they were in hospital. Results. Three interlinking themes emerged, which reflect a changing dynamic status in health, mediated by the perceived threat of individual symptoms. These included gradual awareness, not having pain in the chest and reactions to symptoms. Conclusions. It would appear that symptom presentation and distribution amongst women may not follow the pattern traditionally associated with current understanding of a 'typical' myocardial infarction. These differences together with perceptions about their cardiac symptoms may influence their health-seeking behaviours. Relevance to clinical practice. Women with a myocardial infarction may present with non-specific chest symptoms, which are difficult to interpret or recognize by patients and health professionals alike. Skill in recording history and in performing a comprehensive assessment of initial and current symptoms will enable nurses to identify women with a differential diagnosis of chest pain readily. Additionally, to increase awareness of coronary heart disease, nurses must use any opportunity to educate women of all age groups. © 2007 Blackwell Publishing Ltd