Oncostatin M and leukemia inhibitory factor do not use the same functional receptor in mice.

Abstract: Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are members of the interleukin-6 (IL-6) subfamily of cytokines that use a common signal transducer gp130.

Abstract: Human OSM (hOSM) and LIF share a functional high-affinity receptor that is composed of gp130 and LIF receptor beta subunit (LIFRbeta).

Abstract: A second high-affinity receptor for hOSM was recently found to be formed by gp130 and the hOSM receptor beta subunit.

Abstract: However, the nature of murine OSM (mOSM) and its receptors has remained unknown.

Abstract: Using the recently cloned mOSM cDNA, we produced recombinant mOSM and studied its biological activity and receptor structure.

Abstract: Murine hematopoietic cell lines M1 and DA1.a, an embryonic stem cell line CCE, and Ba/F3 transfectants expressing gp130 and LIFRbeta responded to murine LIF (mLIF) and hOSM equally well, while these cells responded to mOSM only at a 30-fold to 100-fold higher concentration than those of mLIF and hOSM.

Abstract: In contrast, NIH3T3 cells responded to mOSM, but not to mLIF and hOSM.

Abstract: Scatchard plot analyses showed that mOSM bound to gp130 with low-affinity (kd = 2.8 to 4.2 nmol/L) and that the binding affinity did not increase in the presence of LIFRbeta.

Abstract: However, mOSM bound to NIH3T3 cells with high-affinity (kd = 660 pmol/L), whereas mLIF did not bind to NIH3T3 cells at all.

Abstract: These results indicate that unlike hOSM, mOSM and mLIF do not share the same functional receptor, and mOSM delivers signals only through its specific receptor complex.

Abstract: Further studies in mice will define the physiological roles of OSM.


Multifunctional in vivo vascular imaging using near-infrared II fluorescence

Abstract: In vivo real-time epifluorescence imaging of mouse hind limb vasculatures in the second near-infrared region (NIR-II) is performed using single-walled carbon nanotubes as fluorophores.

Abstract: Both high spatial (∼30 μm) and temporal (<200 ms per frame) resolution for small-vessel imaging are achieved at 1–3 mm deep in the hind limb owing to the beneficial NIR-II optical window that affords deep anatomical penetration and low scattering.

Abstract: This spatial resolution is unattainable by traditional NIR imaging (NIR-I) or microscopic computed tomography, and the temporal resolution far exceeds scanning microscopic imaging techniques.

Abstract: Arterial and venous vessels are unambiguously differentiated using a dynamic contrast-enhanced NIR-II imaging technique on the basis of their distinct hemodynamics.

Abstract: Further, the deep tissue penetration and high spatial and temporal resolution of NIR-II imaging allow for precise quantifications of blood velocity in both normal and ischemic femoral arteries, which are beyond the capabilities of ultrasonography at lower blood velocities.


Colorectal cancer survival in socioeconomic groups in England: variation is mainly in the short term after diagnosis.

Abstract: UNLABELLED The objective of this study was to examine differences in cancer survival between socioeconomic groups in England, with particular attention to survival in the short term of follow-up.

Abstract: PATIENTS AND METHODS Individuals diagnosed with colorectal cancer between 1996 and 2004 in England were identified from cancer registry records.

Abstract: Five-year cumulative relative survival and excess death rates were computed.

Abstract: RESULTS For colon cancer there was a very high excess death rate in the first month of follow-up, and the excess death rate was highest in the socioeconomically deprived groups.

Abstract: In subsequent periods, excess mortality rates were much lower and there was less socioeconomic variation.

Abstract: The pattern of variation in excess death rates was generally similar in rectal cancer but the socioeconomic difference in death rates persisted several years longer.

Abstract: If the excess death rates in the entire colorectal cancer patient population were the same as those observed in the most affluent socioeconomic quintile, the annual reduction would be 360 deaths in colon cancer and 336 deaths in rectal cancer patients.

Abstract: These deaths occurred almost entirely in the first month and the first year after diagnosis.

Abstract: CONCLUSION Recent developments in the national cancer control agenda have included an increasing emphasis on outcome measures, with short-term cancer survival an operational measure of variation and progress in cancer control.

Abstract: In providing clues to the nature of the survival differences between socioeconomic groups, the results presented here give strong support for this strategy.


Cardiac myocyte remodeling mediated by N-cadherin-dependent mechanosensing.

Abstract: Cell-to-cell adhesions are crucial in maintaining the structural and functional integrity of cardiac cells.

Abstract: Little is known about the mechanosensitivity and mechanotransduction of cell-to-cell interactions.

Abstract: Most studies of cardiac mechanotransduction and myofibrillogenesis have focused on cell-extracellular matrix (ECM)-specific interactions.

Abstract: This study assesses the direct role of intercellular adhesion, specifically that of N-cadherin-mediated mechanotransduction, on the morphology and internal organization of neonatal ventricular cardiac myocytes.

Abstract: The results show that cadherin-mediated cell attachments are capable of eliciting a cytoskeletal network response similar to that of integrin-mediated force response and transmission, affecting myofibrillar organization, myocyte shape, and cortical stiffness.

Abstract: Traction forces mediated by N-cadherin were shown to be comparable to those sustained by ECM.

Abstract: The directional changes in predicted traction forces as a function of imposed loads (gel stiffness) provide the added evidence that N-cadherin is a mechanoresponsive adhesion receptor.

Abstract: Strikingly, the mechanical sensitivity response (gain) in terms of the measured cell-spread area as a function of imposed load (adhesive substrate rigidity) was consistently higher for N-cadherin-coated surfaces compared with ECM protein-coated surfaces.

Abstract: In addition, the cytoskeletal architecture of myocytes on an N-cadherin adhesive microenvironment was characteristically different from that on an ECM environment, suggesting that the two mechanotransductive cell adhesion systems may play both independent and complementary roles in myocyte cytoskeletal spatial organization.

Abstract: These results indicate that cell-to-cell-mediated force perception and transmission are involved in the organization and development of cardiac structure and function.


NEAT1: A novel cancer‐related long non‐coding RNA

Abstract: Aberrant overexpression of the long non-coding RNA NEAT1 (nuclear paraspeckle assembly transcript 1) has been documented in different types of solid tumours, such as lung cancer, oesophageal cancer, colorectal cancer and hepatocellular carcinoma, in which its high levels are associated with poor prognosis.

Abstract: In contrast, NEAT1 is downregulated in acute promyelocytic leukaemia where it promotes leucocyte differentiation.

Abstract: In this review, we provide an overview of current evidence concerning the oncogenic role and potential clinical utilities of NEAT1.

Abstract: Further investigations are warranted to elucidate the upstream and downstream mechanisms of NEAT1 overexpression.


The Function and Therapeutic Potential of Long Non-coding RNAs in Cardiovascular Development and Disease

Abstract: The popularization of genome-wide analyses and RNA sequencing led to the discovery that a large part of the human genome, while effectively transcribed, does not encode proteins.

Abstract: Long non-coding RNAs have emerged as critical regulators of gene expression in both normal and disease states.

Abstract: Studies of long non-coding RNAs expressed in the heart, in combination with gene association studies, revealed that these molecules are regulated during cardiovascular development and disease.

Abstract: Some long non-coding RNAs have been functionally implicated in cardiac pathophysiology and constitute potential therapeutic targets.

Abstract: Here, we review the current knowledge of the function of long non-coding RNAs in the cardiovascular system, with an emphasis on cardiovascular development and biology, focusing on hypertension, coronary artery disease, myocardial infarction, ischemia, and heart failure.

Abstract: We discuss potential therapeutic implications and the challenges of long non-coding RNA research, with directions for future research and translational focus.


Oct4 links multiple epigenetic pathways to the pluripotency network

Abstract: Oct4 is a well-known transcription factor that plays fundamental roles in stem cell self-renewal, pluripotency, and somatic cell reprogramming.

Abstract: However, limited information is available on Oct4-associated protein complexes and their intrinsic protein-protein interactions that dictate Oct4's critical regulatory activities.

Abstract: Here we employed an improved affinity purification approach combined with mass spectrometry to purify Oct4 protein complexes in mouse embryonic stem cells (mESCs), and discovered many novel Oct4 partners important for self-renewal and pluripotency of mESCs.

Abstract: Notably, we found that Oct4 is associated with multiple chromatin-modifying complexes with documented as well as newly proved functional significance in stem cell maintenance and somatic cell reprogramming.

Abstract: Our study establishes a solid biochemical basis for genetic and epigenetic regulation of stem cell pluripotency and provides a framework for exploring alternative factor-based reprogramming strategies.


Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development.

Abstract: The Tet family of enzymes (Tet1/2/3) converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC).

Abstract: Mouse embryonic stem cells (mESCs) highly express Tet1 and have an elevated level of 5hmC. Tet1 has been implicated in ESC maintenance and lineage specification in vitro but its precise function in development is not well defined.

Abstract: To establish the role of Tet1 in pluripotency and development, we have generated Tet1 mutant mESCs and mice.

Abstract: Tet1(-/-) ESCs have reduced levels of 5hmC and subtle changes in global gene expression, and are pluripotent and support development of live-born mice in tetraploid complementation assay, but display skewed differentiation toward trophectoderm in vitro.

Abstract: Tet1 mutant mice are viable, fertile, and grossly normal, though some mutant mice have a slightly smaller body size at birth.

Abstract: Our data suggest that Tet1 loss leading to a partial reduction in 5hmC levels does not affect pluripotency in ESCs and is compatible with embryonic and postnatal development.


LDL-cholesterol concentrations: a genome-wide association study

Abstract: BACKGROUND LDL cholesterol has a causal role in the development of cardiovascular disease.

Abstract: Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets.

Abstract: We therefore did a genome-wide association study of LDL-cholesterol concentrations.

Abstract: METHODS We used genome-wide association data from up to 11,685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria.

Abstract: We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290,140 SNPs.

Abstract: We did replication studies in two independent populations consisting of up to 4979 participants.

Abstract: Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations.

Abstract: FINDINGS In our initial scan, we found two SNPs (rs599839 [p=1.7x10(-15)] and rs4970834 [p=3.0x10(-11)]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3.

Abstract: The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4.3x10(-9)]).

Abstract: Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1.2x10(-33)) and rs646776 (p=4.8x10(-20)) with LDL-cholesterol concentrations.

Abstract: SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L.   INTERPRETATION We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3.

Abstract: These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.


Population Density, Water Supply, and the Risk of Dengue Fever in Vietnam: Cohort Study and Spatial Analysis

Abstract: BACKGROUND Aedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas.

Abstract: We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk.

Abstract: METHODS AND FINDINGS We conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013).

Abstract: We applied space-time scan statistics and mathematical models to confirm the findings.

Abstract: We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km² prone to dengue outbreaks.

Abstract: In the study area, this population density was typical of villages and some peri-urban areas.

Abstract: Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks.

Abstract: The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range.

Abstract: Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks.

Abstract: CONCLUSIONS Rural areas may contribute at least as much to the dissemination of dengue fever as cities.

Abstract: Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts.

Abstract: Please see later in the article for the Editors' Summary.


Helicobacter pylori induces AGS cell motility and elongation via independent signaling pathways.

Abstract: Helicobacter pylori induces motogenic and cytoskeletal responses in gastric epithelial cells.

Abstract: We demonstrate that these responses can be induced via independent signaling pathways that often occur in parallel.

Abstract: The cag pathogenicity island appears to be nonessential for induction of motility, whereas the elongation phenotype depends on translocation and phosphorylation of CagA.


The Sequence Alignment/Map format and SAMtools

Abstract: SUMMARY The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms.

Abstract: It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released.

Abstract: SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments.

Abstract: AVAILABILITY http://samtools.sourceforge.net.


Characterization of two classes of small molecule inhibitors of Arp2/3 complex

Abstract: Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movements.

Abstract: However, questions remain regarding the relative contributions of Arp2/3 complex versus other mechanisms of actin filament nucleation to processes such as path finding by neuronal growth cones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells.

Abstract: Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments.

Abstract: CK-0944636 binds between Arp2 and Arp3, where it appears to block movement of Arp2 and Arp3 into their active conformation.

Abstract: CK-0993548 inserts into the hydrophobic core of Arp3 and alters its conformation.

Abstract: Both classes of compounds inhibit formation of actin filament comet tails by Listeria and podosomes by monocytes.

Abstract: Two inhibitors with different mechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.


Stresses at the cell-to-substrate interface during locomotion of fibroblasts

Abstract: Recent technological improvements in the elastic substrate method make it possible to produce spatially resolved measurements of the tractions exerted by single motile cells.

Abstract: In this study we have applied these developments to produce maps of the tractions exerted by 3T3 fibroblasts during steady locomotion.

Abstract: The resulting images have a spatial resolution of approximately 5 micrometers and a maximum intensity of approximately 10(2) kdyn/cm2 (10(4) pN/micrometers2).

Abstract: We find that the propulsive thrust for fibroblast locomotion, approximately 0.2 dyn, is imparted to the substratum within 15 micrometers of the leading edge.

Abstract: These observations demonstrate that the lamellipodium of the fibroblast is able to generate intense traction stress.

Abstract: The cell body and posterior seem to be mechanically passive structures pulled forward entirely by this action.


Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion.

Abstract: Early local tumor invasion in breast cancer results in a likely encounter between cancer cells and mature adipocytes, but the role of these fat cells in tumor progression remains unclear.

Abstract: We show that murine and human tumor cells cocultivated with mature adipocytes exhibit increased invasive capacities in vitro and in vivo, using an original two-dimensional coculture system.

Abstract: Likewise, adipocytes cultivated with cancer cells also exhibit an altered phenotype in terms of delipidation and decreased adipocyte markers associated with the occurrence of an activated state characterized by overexpression of proteases, including matrix metalloproteinase-11, and proinflammatory cytokines [interleukin (IL)-6, IL-1β].

Abstract: In the case of IL-6, we show that it plays a key role in the acquired proinvasive effect by tumor cells.

Abstract: Equally important, we confirm the presence of these modified adipocytes in human breast tumors by immunohistochemistry and quantitative PCR.

Abstract: Interestingly, the tumors of larger size and/or with lymph nodes involvement exhibit the higher levels of IL-6 in tumor surrounding adipocytes.

Abstract: Collectively, all our data provide in vitro and in vivo evidence that (i) invasive cancer cells dramatically impact surrounding adipocytes; (ii) peritumoral adipocytes exhibit a modified phenotype and specific biological features sufficient to be named cancer-associated adipocytes (CAA); and (iii) CAAs modify the cancer cell characteristics/phenotype leading to a more aggressive behavior.

Abstract: Our results strongly support the innovative concept that adipocytes participate in a highly complex vicious cycle orchestrated by cancer cells to promote tumor progression that might be amplified in obese patients.


Prevalence of cardiovascular disease risk factor in the Chinese population: the 2007-2008 China National Diabetes and Metabolic Disorders Study.

Abstract: AIMS Cardiovascular disease (CVD) is now the most prevalent and debilitating disease affecting the Chinese population.

Abstract: The goal of the present manuscript was to analyse cardiovascular risk factors and the prevalence of non-fatal CVDs from data gathered from the 2007-2008 China National Diabetes and Metabolic Disorders Study.

Abstract: METHODS AND RESULTS A nationally representative sample of 46 239 adults, 20 years of age or older, was randomly recruited using a multistage stratified design method.

Abstract: Lifestyle factors, diagnosis of CVD, stroke, diabetes, and family history of each subject were collected, and an oral glucose tolerance test or a standard meal test was performed.

Abstract: Various non-fatal CVDs were reported by the subjects.

Abstract: SUDAAN software was used to perform all weighted statistical analyses, with P < 0.05 considered statistically significant.

Abstract: The prevalence of coronary heart disease, stroke, and CVDs was 0.74, 1.07, and 1.78% in males; and 0.51, 0.60, and 1.10% in females, respectively.

Abstract: The presence of CVDs increased with age in both males and females.

Abstract: The prevalence of being overweight or obese, hypertension, dyslipidaemia, or hyperglycaemia was 36.67, 30.09, 67.43, and 26.69% in males; and 29.77, 24.79, 63.98, and 23.62% in females, respectively.

Abstract: In the total sample of 46 239 patients, the prevalence of one subject having 1, 2, 3, or ≥4 of the 5 defined risk factors (i.e. smoking, overweight or obese, hypertension, dyslipidaemia, or hyperglycaemia) was 31.17, 27.38, 17.76, and 10.19%, respectively.

Abstract: Following adjustment for gender and age, the odds ratio of CVDs for those who had 1, 2, 3, or ≥4 risk factors was 2.36, 4.24, 4.88, and 7.22, respectively, when compared with patients with no risk factors.

Abstract: CONCLUSION Morbidity attributed to the five defined cardiovascular risk factors was high in the Chinese population, with multiple risk factors present in the same individual.

Abstract: Therefore, reasonable prevention strategies should be designed to attenuate the rapid rise in cardiovascular morbidity.


Microvascular and Macrovascular Complications of Diabetes

Abstract: Diabetes is a group of chronic diseases characterized by hyperglycemia.

Abstract: Modern medical care uses a vast array of lifestyle and pharmaceutical interventions aimed at preventing and controlling hyperglycemia.

Abstract: In addition to ensuring the adequate delivery of glucose to the tissues of the body, treatment of diabetes attempts to decrease the likelihood that the tissues of the body are harmed by hyperglycemia.

Abstract: The importance of protecting the body from hyperglycemia cannot be overstated; the direct and indirect effects on the human vascular tree are the major source of morbidity and mortality in both type 1 and type 2 diabetes.

Abstract: Generally, the injurious effects of hyperglycemia are separated into macrovascular complications (coronary artery disease, peripheral arterial disease, and stroke) and microvascular complications (diabetic nephropathy, neuropathy, and retinopathy).

Abstract: It is important for physicians to understand the relationship between diabetes and vascular disease because the prevalence of diabetes continues to increase in the United States, and the clinical armamentarium for primary and secondary prevention of these complications is also expanding.

Abstract: ### Diabetic retinopathy  Diabetic retinopathy may be the most common microvascular complication of diabetes.

Abstract: It is responsible for ∼ 10,000 new cases of blindness every year in the United States alone.1 The risk of developing diabetic retinopathy or other microvascular complications of diabetes depends on both the duration and the severity of hyperglycemia.

Abstract: Development of diabetic retinopathy in patients with type 2 diabetes was found to be related to both severity of hyperglycemia and presence of hypertension in the U.K. Prospective Diabetes Study (UKPDS), and most patients with type 1 diabetes develop evidence of retinopathy within 20 years of diagnosis.2,3 Retinopathy may begin to develop as early as 7 years before the diagnosis of diabetes in patients with type 2 diabetes.1 There are several proposed pathological mechanisms by which diabetes may lead …


Involvement of S-nitrosylation of actin in inhibition of neurotransmitter release by nitric oxide

Abstract: BACKGROUND The role of the diffusible messenger nitric oxide (NO) in the regulation of pain transmission is still a debate of matter, pro-nociceptive and/or anti-nociceptive.

Abstract: S-Nitrosylation, the reversible post-translational modification of selective cysteine residues in proteins, has emerged as an important mechanism by which NO acts as a signaling molecule.

Abstract: The occurrence of S-nitrosylation in the spinal cord and its targets that may modulate pain transmission remain unclarified.

Abstract: The "biotin-switch" method and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry were employed for identifying S-nitrosylated proteins.

Abstract: RESULTS Here we show that actin was a major protein S-nitrosylated in the spinal cord by the NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP).

Abstract: Interestingly, actin was S-nitrosylated, more in the S2 fraction than in the P2 fraction of the spinal homogenate.

Abstract: Treatment of PC12 cells with SNAP caused rapid S-nitrosylation of actin and inhibited dopamine release from the cells.

Abstract: Just like cytochalasin B, which depolymerizes actin, SNAP decreased the amount of filamentous actin cytoskeleton just beneath the membrane.

Abstract: The inhibition of dopamine release was not attenuated by inhibitors of soluble guanylyl cyclase and cGMP-dependent protein kinase.

Abstract: CONCLUSION The present study demonstrates that actin is a major S-nitrosylated protein in the spinal cord and suggests that NO directly regulates neurotransmitter release by S-nitrosylation in addition to the well-known phosphorylation by cGMP-dependent protein kinase.


Independent Association of Lobular Involution and Mammographic Breast Density With Breast Cancer Risk

Abstract: BACKGROUND Lobular involution, or age-related atrophy of breast lobules, is inversely associated with breast cancer risk, and mammographic breast density (MBD) is positively associated with breast cancer risk.

Abstract: METHODS To evaluate whether lobular involution and MBD are independently associated with breast cancer risk in women with benign breast disease, we performed a nested cohort study among women (n = 2666) with benign breast disease diagnosed at Mayo Clinic between January 1, 1985, and December 31, 1991 and a mammogram available within 6 months of the diagnosis.

Abstract: Women were followed up for an average of 13.3 years to document any breast cancer incidence.

Abstract: Lobular involution was categorized as none, partial, or complete; parenchymal pattern was classified using the Wolfe classification as N1 (nondense), P1, P2 (ductal prominence occupying <25%, or >25% of the breast, respectively), or DY (extremely dense).

Abstract: Hazard ratios (HRs) and 95% confidence intervals (CIs) to assess associations of lobular involution and MBD with breast cancer risk were estimated using adjusted Cox proportional hazards model.

Abstract: All tests of statistical significance were two-sided.

Abstract: RESULTS After adjustment for MBD, having no or partial lobular involution was associated with a higher risk of breast cancer than having complete involution (none: HR of breast cancer incidence = 2.62, 95% CI = 1.39 to 4.94; partial: HR of breast cancer incidence = 1.61, 95% CI = 1.03 to 2.53; P(trend) = .002).

Abstract: Similarly, after adjustment for involution, having dense breasts was associated with higher risk of breast cancer than having nondense breasts (for DY: HR of breast cancer incidence = 1.67, 95% CI = 1.03 to 2.73; for P2: HR of breast cancer incidence = 1.96, 95% CI = 1.20 to 3.21; for P1: HR of breast cancer incidence = 1.23, 95% CI = 0.67 to 2.26; P(trend) = .02).

Abstract: Having a combination of no involution and dense breasts was associated with higher risk of breast cancer than having complete involution and nondense breasts (HR of breast cancer incidence = 4.08, 95% CI = 1.72 to 9.68; P = .006).

Abstract: CONCLUSION Lobular involution and MBD are independently associated with breast cancer incidence; combined, they are associated with an even greater risk for breast cancer.


Pleiotropy as a mechanism to stabilize cooperation

Abstract: Most genes affect many traits.

Abstract: This phenomenon, known as pleiotropy, is a major constraint on evolution because adaptive change in one trait may be prevented because it would compromise other traits affected by the same genes.

Abstract: Here we show that pleiotropy can have an unexpected effect and benefit one of the most enigmatic of adaptations—cooperation.

Abstract: A spectacular act of cooperation occurs in the social amoeba Dictyostelium discoideum, in which some cells die to form a stalk that holds the other cells aloft as reproductive spores.

Abstract: We have identified a gene, dimA, in D. discoideum that has two contrasting effects.

Abstract: It is required to receive the signalling molecule DIF-1 that causes differentiation into prestalk cells.

Abstract: Ignoring DIF-1 and not becoming prestalk should allow cells to cheat by avoiding the stalk.

Abstract: However, we find that in aggregations containing the wild-type cells, lack of the dimA gene results in exclusion from spores.

Abstract: This pleiotropic linkage of stalk and spore formation limits the potential for cheating in D. discoideum because defecting on prestalk cell production results in an even greater reduction in spores.

Abstract: We propose that the evolution of pleiotropic links between cheating and personal costs can stabilize cooperative adaptations.


The homeobox gene goosecoid controls cell migration in Xenopus embryos.

Abstract: Goosecoid (gsc), a homeobox gene expressed specifically in the dorsal blastopore lip of the Xenopus gastrula, is considered to play an important role in Spemann's organizer phenomenon.

Abstract: Lineage tracing and time-lapse microscopy were used to follow the fate of embryonic cells microinjected with gsc mRNA.

Abstract: Microinjected gsc has non-cell autonomous effects, recruiting neighboring uninjected cells into a twinned dorsal axis.

Abstract: Ectopic expression of gsc mRNA in ventral blastomeres as well as overexpression of gsc in dorsal blastomeres leads to cell movement toward the anterior of the embryo.

Abstract: The results suggest a function for gsc in the control of gastrulation movements in groups of cells, but not in dissociated cells, and demonstrate that a vertebrate homeobox gene can regulate region-specific cell migration.


Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers.

Abstract: Transcription factors (TFs) bind specifically to discrete regions of mammalian genomes called cis-regulatory elements.

Abstract: Among those are enhancers, which play key roles in regulation of gene expression during development and differentiation.

Abstract: Despite the recognized central regulatory role exerted by chromatin in control of TF functions, much remains to be learned regarding the chromatin structure of enhancers and how it is established.

Abstract: Here, we have analyzed on a genomic-scale enhancers that recruit FOXA1, a pioneer transcription factor that triggers transcriptional competency of these cis-regulatory sites.

Abstract: Importantly, we found that FOXA1 binds to genomic regions showing local DNA hypomethylation and that its cell-type-specific recruitment to chromatin is linked to differential DNA methylation levels of its binding sites.

Abstract: Using neural differentiation as a model, we showed that induction of FOXA1 expression and its subsequent recruitment to enhancers is associated with DNA demethylation.

Abstract: Concomitantly, histone H3 lysine 4 methylation is induced at these enhancers.

Abstract: These epigenetic changes may both stabilize FOXA1 binding and allow for subsequent recruitment of transcriptional regulatory effectors.

Abstract: Interestingly, when cloned into reporter constructs, FOXA1-dependent enhancers were able to recapitulate their cell type specificity.

Abstract: However, their activities were inhibited by DNA methylation.

Abstract: Hence, these enhancers are intrinsic cell-type-specific regulatory regions of which activities have to be potentiated by FOXA1 through induction of an epigenetic switch that includes notably DNA demethylation.


Leptin treatment ameliorates anxiety in ob/ob obese mice.

Abstract: We investigated whether or not administered leptin influences anxiety-like behavior in ob/ob mice.

Abstract: Repeated intraperitoneal administrations of leptin were continued for 5 days.

Abstract: Anxiety was assessed in the standard elevated plus maze.

Abstract: Body weight was measured daily.

Abstract: Repeated administrations of leptin significantly increased the percentage of the total number of entries in the open arms and the number of total entries.

Abstract: The body weight was significantly reduced by 13.2% after treatment.

Abstract: Leptin treatment ameliorated not only obesity but also anxiety in ob/ob mice.

Abstract: Our results indicate that the treatment of obesity may lead to the solution of psychological problems.


Predicting new molecular targets for known drugs

Abstract: Although drugs are intended to be selective, at least some bind to several physiological targets, explaining side effects and efficacy.

Abstract: Because many drug-target combinations exist, it would be useful to explore possible interactions computationally.

Abstract: Here we compared 3,665 US Food and Drug Administration (FDA)-approved and investigational drugs against hundreds of targets, defining each target by its ligands.

Abstract: Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations.

Abstract: Thirty were tested experimentally, including the antagonism of the beta(1) receptor by the transporter inhibitor Prozac, the inhibition of the 5-hydroxytryptamine (5-HT) transporter by the ion channel drug Vadilex, and antagonism of the histamine H(4) receptor by the enzyme inhibitor Rescriptor.

Abstract: Overall, 23 new drug-target associations were confirmed, five of which were potent (<100 nM).

Abstract: The physiological relevance of one, the drug N,N-dimethyltryptamine (DMT) on serotonergic receptors, was confirmed in a knockout mouse.

Abstract: The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs.


Bone loss and vascular calcification: A bi-directional interplay?

Abstract: Vascular calcification (VC) represents a recognized adverse predictor for cardiovascular morbidity and mortality.

Abstract: Previously considered passive and degenerative, VC is now recognized as an active process that resembles bone formation, and shares a number of histopathological features, mineral composition, and initiation mechanisms with bone development and metabolism.

Abstract: Oxidative stress and inflammation are key factors in both VC and osteoporosis (OP).

Abstract: Biochemical factors known to be primarily involved in the healthy bone metabolism also regulate VC.

Abstract: These biomarkers include vitamin D, osteoprotegerin, osteopontin, matrix Gla protein, cathepsin K, fibroblast growth factor-23, and fetuin-A. A better understanding of this highly controlled regulatory network, with multiple, nested feedback loops and cross talk between organs, may help to decrease the growing prevalence of calcific vasculopathy as well as OP in the aging population, and to advance in common preventive and therapeutic interventions targeted at both conditions.


Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns of dendritic cells.

Abstract: Chemokines orchestrate immune cell trafficking by eliciting either directed or random migration and by activating integrins in order to induce cell adhesion.

Abstract: Analyzing dendritic cell (DC) migration, we showed that these distinct cellular responses depended on the mode of chemokine presentation within tissues.

Abstract: The surface-immobilized form of the chemokine CCL21, the heparan sulfate-anchoring ligand of the CC-chemokine receptor 7 (CCR7), caused random movement of DCs that was confined to the chemokine-presenting surface because it triggered integrin-mediated adhesion.

Abstract: Upon direct contact with CCL21, DCs truncated the anchoring residues of CCL21, thereby releasing it from the solid phase.

Abstract: Soluble CCL21 functionally resembles the second CCR7 ligand, CCL19, which lacks anchoring residues and forms soluble gradients.

Abstract: Both soluble CCR7 ligands triggered chemotactic movement, but not surface adhesion.

Abstract: Adhesive random migration and directional steering cooperate to produce dynamic but spatially restricted locomotion patterns closely resembling the cellular dynamics observed in secondary lymphoid organs.


Local proliferation dominates lesional macrophage accumulation in atherosclerosis

Abstract: During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall.

Abstract: The observation that circulating monocytes give rise to lesional macrophages has reinforced the concept that monocyte infiltration dictates macrophage buildup.

Abstract: Recent work has indicated, however, that macrophage accumulation does not depend on monocyte recruitment in some inflammatory contexts.

Abstract: We therefore revisited the mechanism underlying macrophage accumulation in atherosclerosis.

Abstract: In murine atherosclerotic lesions, we found that macrophages turn over rapidly, after 4 weeks.

Abstract: Replenishment of macrophages in these experimental atheromata depends predominantly on local macrophage proliferation rather than monocyte influx.

Abstract: The microenvironment orchestrates macrophage proliferation through the involvement of scavenger receptor A (SR-A).

Abstract: Our study reveals macrophage proliferation as a key event in atherosclerosis and identifies macrophage self-renewal as a therapeutic target for cardiovascular disease.


Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain.

Abstract: The formation of beta-amyloid in the brains of individuals with Alzheimer disease requires the proteolytic cleavage of a membrane-associated precursor protein.

Abstract: The proteases that may be involved in this process have not yet been identified.

Abstract: Cathepsins are normally intracellular proteolytic enzymes associated with lysosomes; however, when sections from Alzheimer brains were stained by antisera to cathepsin D and cathepsin B, high levels of immunoreactivity were also detected in senile plaques.

Abstract: Extracellular sites of cathepsin immunoreactivity were not seen in control brains from age-matched individuals without neurologic disease or from patients with Huntington disease or Parkinson disease.

Abstract: In situ enzyme histochemistry of cathepsin D and cathepsin B on sections of neocortex using synthetic peptides and protein substrates showed that senile plaques contained the highest levels of enzymatically active cathepsin.

Abstract: At the ultrastructural level, cathepsin immunoreactivity in senile plaques was localized principally to lysosomal dense bodies and lipofuscin granules, which were extracellular.

Abstract: Similar structures were abundant in degenerating neurons of Alzheimer neocortex, and cathepsin-laden neuronal perikarya in various stages of disintegration could be seen within some senile plaques.

Abstract: The high levels of enzymatically competent lysosomal proteases abnormally localized in senile plaques represent evidence for candidate enzymes that may mediate the proteolytic formation of amyloid.

Abstract: We propose that amyloid precursor protein within senile plaques is processed by lysosomal proteases principally derived from degenerating neurons.

Abstract: Escape of cathepsins from the stringently regulated intracellular milieu provides a basis for an abnormal sequence of proteolytic cleavages of accumulating amyloid precursor protein.


Gastric juice miR-129 as a potential biomarker for screening gastric cancer

Abstract: MicroRNAs (miRNAs) play crucial roles during the occurrence and development of gastric cancer.

Abstract: Conventional serological tests for screening gastric cancer have limits on sensitivity and specificity.

Abstract: Several miRNAs in peripheral blood have been used as biomarkers of gastric cancer.

Abstract: However, most of these miRNAs are shared by several types of cancer.

Abstract: Thanks to the tissue specificity of gastric juice, here we examined the feasibility of using gastric juice miR-129-1/2, which are aberrantly expressed in gastric cancer, to screen gastric cancer.

Abstract: Total of 141 gastric juices samples from gastric cancer, gastric ulcer, atrophic gastritis, and minimal gastritis patients or subjects with normal mucosa were collected by gastroscopy.

Abstract: The gastric juice miR-129-1/2 levels were detected by quantitative reverse transcription-polymerase chain reaction.

Abstract: A receiver operating characteristic (ROC) curve was constructed for differentiating patients with gastric cancer from patients with benign gastric diseases.

Abstract: We showed that, compared with patients with benign gastric diseases, patients with gastric cancer had significantly lower levels of gastric juice miR-129-1-3p and miR-129-2-3p.

Abstract: The areas under ROC curve (AUC) were 0.639 and 0.651 for miR-129-1-3p and miR-129-2-3p, respectively.

Abstract: Using the parallel combination test, the AUC was up to 0.656.

Abstract: In summary, our results suggest that gastric juice miR-129-1-3p and miR-129-2-3p are potential biomarkers for the screening gastric cancer, and the detection of gastric juice miRNAs is a convenient non-invasion method for the diagnosis of gastric cancer.


Epidemiological expansion, structural studies, and clinical challenges of new β-lactamases from gram-negative bacteria.

Abstract: β-Lactamase evolution presents to the infectious disease community a major challenge in the treatment of infections caused by multidrug-resistant gram-negative bacteria.

Abstract: Because over 1,000 of these naturally occurring β-lactamases exist, attempts to correlate structure and function have become daunting.

Abstract: Although new enzymes in the extended-spectrum β-lactamase (ESBL) families are frequently identified, the older CTX-M-14 and CTX-M-15 enzymes have become the most prevalent ESBLs in global surveillance.

Abstract: Carbapenemases with either serine-based or zinc-facilitated hydrolysis mechanisms are posing some of the most critical problems.

Abstract: Most geographical regions now report KPC serine carbapenemases and the metallo-β-lactamases VIM, IMP, and NDM-1, even though NDM-1 was only recently identified.

Abstract: The rapid emergence of these newer enzymes, with multiple β-lactamases appearing in a single organism, makes the design of new β-lactamase inactivators or β-lactamase-stable β-lactams all the more difficult.

Abstract: Combination therapy will likely be required to counteract the continuing evolution of these insidious enzymes in multidrug-resistant pathogens.


Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells

Abstract: Circadian cycles and cell cycles are two fundamental periodic processes with a period in the range of 1 day.

Abstract: Consequently, coupling between such cycles can lead to synchronization.

Abstract: Here, we estimated the mutual interactions between the two oscillators by time-lapse imaging of single mammalian NIH3T3 fibroblasts during several days.

Abstract: The analysis of thousands of circadian cycles in dividing cells clearly indicated that both oscillators tick in a 1:1 mode-locked state, with cell divisions occurring tightly 5 h before the peak in circadian Rev-Erbα-YFP reporter expression.

Abstract: In principle, such synchrony may be caused by either unidirectional or bidirectional coupling.

Abstract: While gating of cell division by the circadian cycle has been most studied, our data combined with stochastic modeling unambiguously show that the reverse coupling is predominant in NIH3T3 cells.

Abstract: Moreover, temperature, genetic, and pharmacological perturbations showed that the two interacting cellular oscillators adopt a synchronized state that is highly robust over a wide range of parameters.

Abstract: These findings have implications for circadian function in proliferative tissues, including epidermis, immune cells, and cancer.


Identification of a Brainstem Circuit Controlling Feeding

Abstract: Hunger, driven by negative energy balance, elicits the search for and consumption of food.

Abstract: While this response is in part mediated by neurons in the hypothalamus, the role of specific cell types in other brain regions is less well defined.

Abstract: Here, we show that neurons in the dorsal raphe nucleus, expressing vesicular transporters for GABA or glutamate (hereafter, DRNVgat and DRNVGLUT3 neurons), are reciprocally activated by changes in energy balance and that modulating their activity has opposite effects on feeding-DRNVgat neurons increase, whereas DRNVGLUT3 neurons suppress, food intake.

Abstract: Furthermore, modulation of these neurons in obese (ob/ob) mice suppresses food intake and body weight and normalizes locomotor activity.

Abstract: Finally, using molecular profiling, we identify druggable targets in these neurons and show that local infusion of agonists for specific receptors on these neurons has potent effects on feeding.

Abstract: These data establish the DRN as an important node controlling energy balance.

Abstract: PAPERCLIP.


Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo

Abstract: Neutrophil extracellular traps (NETs) are released as neutrophils die in vitro in a process requiring hours, leaving a temporal gap that invasive microbes may exploit.

Abstract: Neutrophils capable of migration and phagocytosis while undergoing NETosis have not been documented.

Abstract: During Gram-positive skin infections, we directly visualized live polymorphonuclear cells (PMNs) in vivo rapidly releasing NETs, which prevented systemic bacterial dissemination.

Abstract: NETosis occurred during crawling, thereby casting large areas of NETs.

Abstract: NET-releasing PMNs developed diffuse decondensed nuclei, ultimately becoming devoid of DNA.

Abstract: Cells with abnormal nuclei showed unusual crawling behavior highlighted by erratic pseudopods and hyperpolarization consistent with the nucleus being a fulcrum for crawling.

Abstract: A requirement for both Toll-like receptor 2 and complement-mediated opsonization tightly regulated NET release.

Abstract: Additionally, live human PMNs injected into mouse skin developed decondensed nuclei and formed NETS in vivo, and intact anuclear neutrophils were abundant in Gram-positive human abscesses.

Abstract: Therefore early in infection NETosis involves neutrophils that do not undergo lysis and retain the ability to multitask.


Swim training suppresses tumor growth in mice.

Abstract: The present study was designed to determine the effects of physical training on the development of cancer induced by the injection of Ehrlich tumor cells in mice.

Abstract: Male Swiss mice were subjected to a swim training protocol (5 days/wk for 6 wk, 1 h at 50% of maximal capacity-trained groups) or remained sedentary in their cages (sedentary groups).

Abstract: The inoculation of Ehrlich tumor cells was performed at the end of the fourth week, and animals were killed after 6 wk of training.

Abstract: Heart and solid tumor weights were recorded, and tumor volumes were calculated.

Abstract: Portions of the tumors were used for the evaluation of macrophages and neutrophil accumulation or fixed in neutral 10% buffered formalin for histological analysis.

Abstract: The tumor volume and weight were, respectively, approximately 270% and 280% greater in sedentary mice than in trained mice.

Abstract: Macrophage infiltration in the tumor tissue was significantly lower in trained mice (0.65 +/- 0.16 vs. 1.78 +/-

Abstract: 0.43 macrophages x 10(3) in the sedentary group).

Abstract: Moreover, neutrophil accumulation in tumors was slightly reduced after exercise training, and the amount of tumor cells was reduced in trained mice.

Abstract: Exercise capacity was substantially increased in trained mice, as determined by a 440% increase in the exercise time at 50% of maximal capacity.

Abstract: In summary, swim training retarded the development of Ehrlich tumors in mice, accompanied by a reduction in macrophage infiltration and neutrophil accumulation.

Abstract: These findings provide conceptual support for clinical observations that controlled physical activities may be a therapeutically important approach to preventing cancer progression and may improve the outcome of cancer treatment.


Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4

Abstract: T cell trafficking into the lung is critical for lung immunity, but the mechanisms that mediate T cell lung homing are not well understood.

Abstract: Here, we show that lung dendritic cells (DCs) imprint T cell lung homing, as lung DC-activated T cells traffic more efficiently into the lung in response to inhaled antigen and at homeostasis compared with T cells activated by DCs from other tissues.

Abstract: Consequently, lung DC-imprinted T cells protect against influenza more effectively than do gut and skin DC-imprinted T cells.

Abstract: Lung DCs imprint the expression of CCR4 on T cells, and CCR4 contributes to T cell lung imprinting.

Abstract: Lung DC-activated, CCR4-deficient T cells fail to traffic into the lung as efficiently and to protect against influenza as effectively as lung DC-activated, CCR4-sufficient T cells.

Abstract: Thus, lung DCs imprint T cell lung homing and promote lung immunity in part through CCR4.


microRNAs: A Safeguard against Turmoil?

Abstract: Emerging data suggest that microRNAs (miRNAs) are instrumental in a variety of stress responses in addition to their more recognized role in development.

Abstract: Surprisingly, miRNAs, which normally suppress expression of target transcripts, may become activators of expression during stress.

Abstract: This might be partially explained by new interactions of miRNA/Argonaute complexes with RNA-binding proteins that relocate from different subcellular compartments during stress.


Vascular smooth muscle cell calcification is mediated by regulated exosome secretion.

Abstract: RATIONALE Matrix vesicles (MVs), secreted by vascular smooth muscle cells (VSMCs), form the first nidus for mineralization and fetuin-A, a potent circulating inhibitor of calcification, is specifically loaded into MVs.

Abstract: However, the processes of fetuin-A intracellular trafficking and MV biogenesis are poorly understood.

Abstract: OBJECTIVE The objective of this study is to investigate the regulation, and role, of MV biogenesis in VSMC calcification.

Abstract: METHODS AND RESULTS Alexa488-labeled fetuin-A was internalized by human VSMCs, trafficked via the endosomal system, and exocytosed from multivesicular bodies via exosome release.

Abstract: VSMC-derived exosomes were enriched with the tetraspanins CD9, CD63, and CD81, and their release was regulated by sphingomyelin phosphodiesterase 3.

Abstract: Comparative proteomics showed that VSMC-derived exosomes were compositionally similar to exosomes from other cell sources but also shared components with osteoblast-derived MVs including calcium-binding and extracellular matrix proteins.

Abstract: Elevated extracellular calcium was found to induce sphingomyelin phosphodiesterase 3 expression and the secretion of calcifying exosomes from VSMCs in vitro, and chemical inhibition of sphingomyelin phosphodiesterase 3 prevented VSMC calcification.

Abstract: In vivo, multivesicular bodies containing exosomes were observed in vessels from chronic kidney disease patients on dialysis, and CD63 was found to colocalize with calcification.

Abstract: Importantly, factors such as tumor necrosis factor-α and platelet derived growth factor-BB were also found to increase exosome production, leading to increased calcification of VSMCs in response to calcifying conditions.

Abstract: CONCLUSIONS This study identifies MVs as exosomes and shows that factors that can increase exosome release can promote vascular calcification in response to environmental calcium stress.

Abstract: Modulation of the exosome release pathway may be as a novel therapeutic target for prevention.


Vaccines against malaria

Abstract: There is no licenced vaccine against any human parasitic disease and Plasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers.

Abstract: This has led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates.

Abstract: Malaria vaccine development has been at the forefront of assessing many new vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept of community vaccination to block malaria transmission.

Abstract: Most current vaccine candidates target a single stage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown most success.

Abstract: A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials.

Abstract: However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage.

Abstract: The most attractive near-term approach to develop such a product is to combine existing partially effective pre-erythrocytic vaccine candidates.


MicroRNA-21 is Induced by Rapamycin in a Model of Tuberous Sclerosis (TSC) and Lymphangioleiomyomatosis (LAM)

Abstract: Lymphangioleiomyomatosis (LAM), a multisystem disease of women, is manifest by the proliferation of smooth muscle-like cells in the lung resulting in cystic lung destruction.

Abstract: Women with LAM can also develop renal angiomyolipomas.

Abstract: LAM is caused by mutations in the tuberous sclerosis complex genes (TSC1 or TSC2), resulting in hyperactive mammalian Target of Rapamycin (mTOR) signaling.

Abstract: The mTOR inhibitor, Rapamycin, stabilizes lung function in LAM and decreases the volume of renal angiomyolipomas, but lung function declines and angiomyolipomas regrow when treatment is discontinued, suggesting that factors induced by mTORC1 inhibition may promote the survival of TSC2-deficient cells.

Abstract: Whether microRNA (miRNA, miR) signaling is involved in the response of LAM to mTORC1 inhibition is unknown.

Abstract: We identified Rapamycin-dependent miRNA in LAM patient angiomyolipoma-derived cells using two separate screens.

Abstract: First, we assayed 132 miRNA of known significance to tumor biology.

Abstract: Using a cut-off of >1.5-fold change, 48 microRNA were Rapamycin-induced, while 4 miRs were downregulated.

Abstract: In a second screen encompassing 946 miRNA, 18 miRs were upregulated by Rapamycin, while eight were downregulated.

Abstract: Dysregulation of miRs 29b, 21, 24, 221, 106a and 199a were common to both platforms and were classified as candidate "RapamiRs.

Abstract: " Validation by qRT-PCR confirmed that these microRNA were increased.

Abstract: miR-21, a pro-survival miR, was the most significantly increased by mTOR-inhibition (p<0.01).

Abstract: The regulation of miR-21 by Rapamycin is cell type independent.

Abstract: mTOR inhibition promotes the processing of the miR-21 transcript (pri-miR-21) to a premature form (pre-miR-21).

Abstract: In conclusion, our findings demonstrate that Rapamycin upregulates multiple miRs, including pro-survival miRs, in TSC2-deficient patient-derived cells.

Abstract: The induction of miRs may contribute to the response of LAM and TSC patients to Rapamycin therapy.


Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer.

Abstract: Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib.

Abstract: However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M.

Abstract: Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase-activating protein encoded by the NF1 gene.

Abstract: Erlotinib failed to fully inhibit RAS-ERK signaling when neurofibromin levels were reduced.

Abstract: Treatment of neurofibromin-deficient lung cancers with a MAP-ERK kinase (MEK) inhibitor restored sensitivity to erlotinib.

Abstract: Low levels of NF1 expression were associated with primary and acquired resistance of lung adenocarcinomas to EGFR TKIs in patients.

Abstract: These findings identify a subgroup of patients with EGFR-mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors.


Human IRGM induces autophagy to eliminate intracellular mycobacteria.

Abstract: Immunity-related p47 guanosine triphosphatases (IRG) play a role in defense against intracellular pathogens.

Abstract: We found that the murine Irgm1 (LRG-47) guanosine triphosphatase induced autophagy and generated large autolysosomal organelles as a mechanism for the elimination of intracellular Mycobacterium tuberculosis.

Abstract: We also identified a function for a human IRG protein in the control of intracellular pathogens and report that the human Irgm1 ortholog, IRGM, plays a role in autophagy and in the reduction of intracellular bacillary load.


Implementation of a Clinical Pharmacy Education Program in a Teaching Hospital: Resident Oriented Documentation and Intervention

Abstract: The aim of this study was to provide a clinical pharmacy education program at Masih Daneshvari hospital, a University affiliated hospital, located in Tehran, Iran.

Abstract: For this purpose, the most common pharmacist involved interventions and aspects of potential fields for pharmacy students and residents education was firstly identified.

Abstract: Clinical pharmacy interventions and drug information forms were filled during the study period, from January 2006 till January 2007.

Abstract: Based on the results of this study, a total number of 772 interventions were conducted during the study year.

Abstract: Drug information had the highest rate of 22.30% among all interventions, followed by dose adjustment, and therapeutic reduction or addition.

Abstract: The mean number of medications per patient was 8.62 ± 7.54.

Abstract: In conclusion, it could be said that although in our country the challenge for the pharmacy as a profession is in its initial stages compared to the developed countries, the result of this study revealed a high demand for this service among health care providers.


The surgical anatomy of the conduction tissues.

Abstract: On the basis of our collective experience we have reviewed the disposition of the cardiac conduction tissues as they might be observed by the surgeon in both normal and abnormal hearts.

Abstract: The sinus node lies subepicardially in the terminal sulcus; because of its variable blood supply the entire superior cavoatrial junction is a potential danger area.

Abstract: There are no morphologically discrete tracts extending through the atrial tissues between sinus and atrioventricular nodes.

Abstract: The atrioventricular node, the atrial extent of the atrioventricular conduction axis, is contained exclusively within the triangle of Koch.

Abstract: The axis penetrates through the central fibrous body and branches on the muscular ventricular septum immediately beneath the interventricular component of the membranous septum.

Abstract: The landmarks to these structures are described as they might be seen through the right atrium, left atrium, and aorta.

Abstract: Consideration is then given to the surgical anatomy of the abnormal muscular atrioventricular connections that underscore the ventricular pre-excitation syndromes.

Abstract: Finally, rules are developed whereby the disposition of the conduction tissues can be predicted with accuracy in congenitally malformed hearts, in the settings of both normal and abnormal chamber connections.

Abstract: The most important variables in this respect are alignment between the atrial and ventricular septal structures and the pattern of ventricular architecture present.


Agreement between an online dietary assessment tool (myfood24) and an interviewer-administered 24-h dietary recall in British adolescents aged 11-18 years.

Abstract: myfood24 Is an online 24-h dietary assessment tool developed for use among British adolescents and adults.

Abstract: Limited information is available regarding the validity of using new technology in assessing nutritional intake among adolescents.

Abstract: Thus, a relative validation of myfood24 against a face-to-face interviewer-administered 24-h multiple-pass recall (MPR) was conducted among seventy-five British adolescents aged 11-18 years.

Abstract: Participants were asked to complete myfood24 and an interviewer-administered MPR on the same day for 2 non-consecutive days at school.

Abstract: Total energy intake (EI) and nutrients recorded by the two methods were compared using intraclass correlation coefficients (ICC), Bland-Altman plots (using between and within-individual information) and weighted κ to assess the agreement.

Abstract: Energy, macronutrients and other reported nutrients from myfood24 demonstrated strong agreement with the interview MPR data, and ICC ranged from 0·46 for Na to 0·88 for EI.

Abstract: There was no significant bias between the two methods for EI, macronutrients and most reported nutrients.

Abstract: The mean difference between myfood24 and the interviewer-administered MPR for EI was -230 kJ (-55 kcal) (95 % CI -490, 30 kJ (-117, 7 kcal); P=0·4) with limits of agreement ranging between 39 % (3336 kJ (-797 kcal)) lower and 34 % (2874 kJ (687 kcal)) higher than the interviewer-administered MPR.

Abstract: There was good agreement in terms of classifying adolescents into tertiles of EI (κ w =0·64).

Abstract: The agreement between day 1 and day 2 was as good for myfood24 as for the interviewer-administered MPR, reflecting the reliability of myfood24.

Abstract: myfood24 Has the potential to collect dietary data of comparable quality with that of an interviewer-administered MPR.


Modulation of cancer chemotherapy by green tea.

Abstract: Biochemical modulation has played an important role in the development of cancer chemotherapy.

Abstract: We have directed our attention to the intake of common beverages and investigated the effects of green tea and tea components on the antitumor activity of doxorubicin.

Abstract: We carried out the combined treatment of toxorubicin and green tea on Ehrlich ascites carcinoma tumor-bearing mice.

Abstract: The oral administration of green tea enhanced 2.5-fold the inhibitory effects of doxorubicin on tumor growth.

Abstract: The Doxorubicin concentration in the tumor was increased by the combination of green tea with doxorubicin.

Abstract: In contrast, the increase in doxorubicin concentration was not observed in normal tissues after green tea combination.

Abstract: Furthermore, the enhancement of antitumor activity of doxorubicin induced by green tea was observed in M5076 ovarian sarcoma, which has low sensitivity to doxorubicin.

Abstract: These results suggest that drinking green tea can encourage cancer chemotherapy and may improve the quality of life of clinical patients.


Histone deacetylase 5 interacts with Krüppel-like factor 2 and inhibits its transcriptional activity in endothelium.

Abstract: AIMS Vascular endothelial dysfunction and inflammation are hallmarks of atherosclerosis.

Abstract: Krüppel-like factor 2 (KLF2) is a key mediator of anti-inflammatory and anti-atherosclerotic properties of the endothelium.

Abstract: However, little is known of the molecular mechanisms for regulating KLF2 transcriptional activation.

Abstract: METHODS AND RESULTS Here, we found that histone deacetylase 5 (HDAC5) associates with KLF2 and represses KLF2 transcriptional activation.

Abstract: HDAC5 resided with KLF2 in the nuclei of human umbilical cord vein endothelial cells (HUVECs).

Abstract: Steady laminar flow attenuated the association of HDAC5 with KLF2 via stimulating HDAC5 phosphorylation-dependent nuclear export in HUVEC.

Abstract: We also mapped the KLF2-HDAC5-interacting domains and found that the N-terminal region of HDAC5 interacts with the C-terminal domain of KLF2.

Abstract: Chromatin immunoprecipitation and luciferase reporter assays showed that HDAC5 through a direct association with KLF2 suppressed KLF2 transcriptional activation.

Abstract: HDAC5 overexpression inhibited KLF2-dependent endothelial nitric oxide synthesis (eNOS) promoter activity in COS7 cell and gene expression in both HUVECs and bovine aortic endothelial cells (BAECs).

Abstract: Conversely, HDAC5 silencing enhanced KLF2 transcription and hence eNOS expression in HUVEC.

Abstract: Moreover, we observed that the level of eNOS protein in the thoracic aorta isolated from HDAC5 knockout mice was higher, whereas expression of pro-inflammatory vascular cell adhesion molecule 1 was lower, compared with those of HDAC5 wild-type mice.

Abstract: CONCLUSIONS We reveal a novel role of HDAC5 in modulating the KLF2 transcriptional activation and eNOS expression.

Abstract: These findings suggest that HDAC5, a binding partner and modulator of KLF2, could be a new therapeutic target to prevent vascular endothelial dysfunction associated with cardiovascular diseases.


N348I in HIV-1 reverse transcriptase can counteract the nevirapine-mediated bias toward RNase H cleavage during plus-strand initiation.

Abstract: Drug resistance-associated mutations in HIV-1 reverse transcriptase (RT) can affect the balance between polymerase and ribonuclease H (RNase H) activities of the enzyme.

Abstract: We have recently demonstrated that the N348I mutation in the connection domain causes selective dissociation from RNase H-competent complexes, whereas the functional integrity of the polymerase-competent complex remains largely unaffected.

Abstract: N348I has been associated with resistance to the non-nucleoside RT inhibitor (NNRTI), nevirapine; however, a possible mechanism that links changes in RNase H activity to changes in NNRTI susceptibility remains to be established.

Abstract: To address this problem, we consider recent findings suggesting that NNRTIs may affect the orientation of RT on its nucleic acid substrate and increase RNase H activity.

Abstract: Here we demonstrate that RNase H-mediated primer removal is indeed more efficient in the presence of NNRTIs; however, the N348I mutant enzyme is able to counteract this effect.

Abstract: Efavirenz, a tight binding inhibitor, restricts the influence of the mutation.

Abstract: These findings provide strong evidence to suggest that N348I can thwart the inhibitory effects of nevirapine during initiation of (+)-strand DNA synthesis, which provides a novel mechanism for resistance.

Abstract: The data are in agreement with clinical data, which demonstrate a stronger effect of N348I on susceptibility to nevirapine as compared with efavirenz.


Cancer survivorship research: the challenge of recruiting adult long term cancer survivors from a cooperative clinical trials group

Abstract: INTRODUCTION With the growing number of adult cancer survivors, there is increasing need for information that links potential late and long term effects with specific treatment regimens.

Abstract: Few adult cancer patients are treated on clinical trials; however, patients previously enrolled in these trials are an important source of information about treatment-related late effects.

Abstract: METHODS Focusing on colorectal cancer survivors, we used the database from five phase III randomized clinical trials from the National Surgical Adjuvant Breast & Bowel Project (NSABP) to recruit and enroll long term survivors in a study of late health outcomes and quality of life.

Abstract: We describe the challenges to recruitment of patients more than 5 -20 years after treatment.

Abstract: RESULTS Sixty-five NSABP treatment sites were invited to enroll patients in the study.

Abstract: Sixty participated with the potential to recruit 2,408 patients.

Abstract: We received registration forms on only 976 patients (41%) of whom 744 (76%) expressed interest in participating and 708 completed interviews (95% of those expressing interest; 29% of total potential sample).

Abstract: There were multiple barriers to recruitment (difficulty locating patients, lack of institutional commitment, lack of patient interest).

Abstract: CONCLUSIONS Patients treated on clinical trials are an important potential source for examining the late effects of cancer treatments.

Abstract: Retrospective recruitment has substantial limitations.

Abstract: In the future, mechanisms should be established for prospective long-term follow-up to identify and understand the frequency and type of late effects associated with cancer treatments.

Abstract: IMPLICATIONS FOR CANCER SURVIVORS As cancer patients are living longer, it will be important to learn from participants in clinical trials whether or not specific treatment regimens are associated with any serious late effects.


Arylsulfatase B Improves Locomotor Function after Mouse Spinal Cord Injury

Abstract: Bacterial chondroitinase ABC (ChaseABC) has been used to remove the inhibitory chondroitin sulfate chains from chondroitin sulfate proteoglycans to improve regeneration after rodent spinal cord injury.

Abstract: We hypothesized that the mammalian enzyme arylsulfatase B (ARSB) would also enhance recovery after mouse spinal cord injury.

Abstract: Application of the mammalian enzyme would be an attractive alternative to ChaseABC because of its more robust chemical stability and reduced immunogenicity.

Abstract: A one-time injection of human ARSB into injured mouse spinal cord eliminated immunoreactivity for chondroitin sulfates within five days, and up to 9 weeks after injury.

Abstract: After a moderate spinal cord injury, we observed improvements of locomotor recovery assessed by the Basso Mouse Scale (BMS) in ARSB treated mice, compared to the buffer-treated control group, at 6 weeks after injection.

Abstract: After a severe spinal cord injury, mice injected with equivalent units of ARSB or ChaseABC improved similarly and both groups achieved significantly more locomotor recovery than the buffer-treated control mice.

Abstract: Serotonin and tyrosine hydroxylase immunoreactive axons were more extensively present in mouse spinal cords treated with ARSB and ChaseABC, and the immunoreactive axons penetrated further beyond the injury site in ARSB or ChaseABC treated mice than in control mice.

Abstract: These results indicate that mammalian ARSB improves functional recovery after CNS injury.

Abstract: The structural/molecular mechanisms underlying the observed functional improvement remain to be elucidated.


The World Health Organization Adult ADHD Self-Report Scale (ASRS): a short screening scale for use in the general population.

Abstract: BACKGROUND A self-report screening scale of adult attention-deficit/hyperactivity disorder (ADHD), the World Health Organization (WHO) Adult ADHD Self-Report Scale (ASRS) was developed in conjunction with revision of the WHO Composite International Diagnostic Interview (CIDI).

Abstract: The current report presents data on concordance of the ASRS and of a short-form ASRS screener with blind clinical diagnoses in a community sample.

Abstract: METHOD The ASRS includes 18 questions about frequency of recent DSM-IV Criterion A symptoms of adult ADHD.

Abstract: The ASRS screener consists of six out of these 18 questions that were selected based on stepwise logistic regression to optimize concordance with the clinical classification.

Abstract: ASRS responses were compared to blind clinical ratings of DSM-IV adult ADHD in a sample of 154 respondents who previously participated in the US National Comorbidity Survey Replication (NCS-R), oversampling those who reported childhood ADHD and adult persistence.

Abstract: RESULTS Each ASRS symptom measure was significantly related to the comparable clinical symptom rating, but varied substantially in concordance (Cohen's kappa in the range 0.16-0.81).

Abstract: Optimal scoring to predict clinical syndrome classifications was to sum unweighted dichotomous responses across all 18 ASRS questions.

Abstract: However, because of the wide variation in symptom-level concordance, the unweighted six-question ASRS screener outperformed the unweighted 18-question ASRS in sensitivity (68.7% v. 56.3%), specificity (99.5% v. 98.3%), total classification accuracy (97.9% v. 96.2%), and kappa (0.76 v. 0.58).

Abstract: CONCLUSIONS Clinical calibration in larger samples might show that a weighted version of the 18-question ASRS outperforms the six-question ASRS screener.

Abstract: Until that time, however, the unweighted screener should be preferred to the full ASRS, both in community surveys and in clinical outreach and case-finding initiatives.


Human milk proresolving mediators stimulate resolution of acute inflammation

Abstract: Human milk contains nutrients and bioactive products relevant to infant development and immunological protection.

Abstract: Here, we investigated the proresolving properties of milk using human milk lipid mediator isolates (HLMIs) and determined their impact on resolution programs in vivo and with human macrophages.

Abstract: HLMIs reduced the maximum neutrophil numbers (14.6±1.2 × 106–11.0±1.0 × 106 cells per exudate) and shortened the resolution interval (Ri; 50% neutrophil reduction) by 54% compared with peritonitis.

Abstract: Using rigorous liquid-chromatography tandem-mass spectrometry (LC-MS-MS)-based lipid mediator (LM) metabololipidomics, we demonstrated that human milk possesses a proresolving LM-specialized proresolving mediator (LM-SPM) signature profile, containing SPMs (e.g. resolvins (Rv), protectins (PDs), maresins (MaRs), and lipoxins (LXs)) at bioactive levels (pico-nanomolar concentrations) that enhanced human macrophage efferocytosis and bacterial containment.

Abstract: SPMs identified in human milk included D-series Rvs (e.g., RvD1, RvD2, RvD3, AT-RvD3, and RvD4), PD1, MaR1, E-series Rvs (e.g. RvE1, RvE2, and RvE3), and LXs (LXA4 and LXB4).

Abstract: Of the SPMs identified in human milk, RvD2 and MaR1 (50 ng per mouse) individually shortened Ri by ∼75%.

Abstract: Milk from mastitis gave higher leukotriene B4 and prostanoids and lower SPM levels.

Abstract: Taken together, these findings provide evidence that human milk has proresolving actions via comprehensive LM-SPM profiling, describing a potentially novel mechanism in maternal–infant biochemical imprinting.


Cerebral perfusion and stroke.

Abstract: Stroke is a heterogeneous syndrome caused by multiple disease mechanisms, but all result in a disruption of cerebral blood flow with subsequent tissue damage.

Abstract: This review covers the mechanisms responsible for regulation of the normal cerebral circulation, and how they are disrupted in disease states.

Abstract: A central concept in treating patients with acute ischaemic stroke is the existence of an ischaemic penumbra of potentially salvageable tissue, and the evidence for its existence in humans is reviewed.


Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation.

Abstract: Methyl-CpG binding protein 1 (MBD1) regulates gene expression via a DNA methylation-mediated epigenetic mechanism.

Abstract: We have previously demonstrated that MBD1 deficiency impairs adult neural stem/progenitor cell (aNSC) differentiation and neurogenesis, but the underlying mechanism was unclear.

Abstract: Here, we show that MBD1 regulates the expression of several microRNAs in aNSCs and, specifically, that miR-184 is directly repressed by MBD1.

Abstract: High levels of miR-184 promoted proliferation but inhibited differentiation of aNSCs, whereas inhibition of miR-184 rescued the phenotypes associated with MBD1 deficiency.

Abstract: We further found that miR-184 regulates the expression of Numblike (Numbl), a known regulator of brain development, by binding to the 3'-UTR of Numbl mRNA and affecting its translation.

Abstract: Expression of exogenous Numbl could rescue the aNSC defects that result from either miR-184 overexpression or MBD1 deficiency.

Abstract: Therefore, MBD1, miR-184, and Numbl form a regulatory network that helps control the balance between proliferation and differentiation of aNSCs.


Landscape of genetic lesions in 944 patients with myelodysplastic syndromes

Abstract: High-throughput DNA sequencing significantly contributed to diagnosis and prognostication in patients with myelodysplastic syndromes (MDS).

Abstract: We determined the biological and prognostic significance of genetic aberrations in MDS.

Abstract: In total, 944 patients with various MDS subtypes were screened for known/putative mutations/deletions in 104 genes using targeted deep sequencing and array-based genomic hybridization.

Abstract: In total, 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12).

Abstract: Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in >10% of cases.

Abstract: Many mutations were associated with higher risk groups and/or blast elevation.

Abstract: Survival was investigated in 875 patients.

Abstract: By univariate analysis, 25/48 genes (resulting from 47 genes tested significantly plus PRPF8) affected survival (P<0.05).

Abstract: The status of 14 genes combined with conventional factors revealed a novel prognostic model ('Model-1') separating patients into four risk groups ('low', 'intermediate', 'high', 'very high risk') with 3-year survival of 95.2, 69.3, 32.8, and 5.3% (P<0.001).

Abstract: Subsequently, a 'gene-only model' ('Model-2') was constructed based on 14 genes also yielding four significant risk groups (P<0.001).

Abstract: Both models were reproducible in the validation cohort (n=175 patients; P<0.001 each).

Abstract: Thus, large-scale genetic and molecular profiling of multiple target genes is invaluable for subclassification and prognostication in MDS patients.


Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease.

Abstract: PURPOSE To define copy number alterations and gene expression signatures underlying pediatric high-grade glioma (HGG).

Abstract: PATIENTS AND METHODS We conducted a high-resolution analysis of genomic imbalances in 78 de novo pediatric HGGs, including seven diffuse intrinsic pontine gliomas, and 10 HGGs arising in children who received cranial irradiation for a previous cancer using single nucleotide polymorphism microarray analysis.

Abstract: Gene expression was analyzed with gene expression microarrays for 53 tumors.

Abstract: Results were compared with publicly available data from adult tumors.

Abstract: RESULTS Significant differences in copy number alterations distinguish childhood and adult glioblastoma.

Abstract: PDGFRA was the predominant target of focal amplification in childhood HGG, including diffuse intrinsic pontine gliomas, and gene expression analyses supported an important role for deregulated PDGFRalpha signaling in pediatric HGG.

Abstract: No IDH1 hotspot mutations were found in pediatric tumors, highlighting molecular differences with adult secondary glioblastoma.

Abstract: Pediatric and adult glioblastomas were clearly distinguished by frequent gain of chromosome 1q (30% v 9%, respectively) and lower frequency of chromosome 7 gain (13% v 74%, respectively) and 10q loss (35% v 80%, respectively).

Abstract: PDGFRA amplification and 1q gain occurred at significantly higher frequency in irradiation-induced tumors, suggesting that these are initiating events in childhood gliomagenesis.

Abstract: A subset of pediatric HGGs showed minimal copy number changes.

Abstract: CONCLUSION Integrated molecular profiling showed substantial differences in the molecular features underlying pediatric and adult HGG, indicating that findings in adult tumors cannot be simply extrapolated to younger patients.

Abstract: PDGFRalpha may be a useful target for pediatric HGG, including diffuse pontine gliomas.


Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.

Abstract: Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge.

Abstract: Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data.

Abstract: The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation.

Abstract: We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer.

Abstract: Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common.

Abstract: The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.


The evolution of RNAs with multiple functions.

Abstract: Increasing numbers of transcripts have been reported to transmit both protein-coding and regulatory information.

Abstract: Apart from challenging our conception of the gene, this observation raises the question as to what extent this phenomenon occurs across the genome and how and why such dual encoding of function has evolved in the eukaryotic genome.

Abstract: To address this question, we consider the evolutionary path of genes in the earliest forms of life on Earth, where it is generally regarded that proteins evolved from a cellular machinery based entirely within RNA.

Abstract: This led to the domination of protein-coding genes in the genomes of microorganisms, although it is likely that RNA never lost its other capacities and functionalities, as evidenced by cis-acting riboswitches and UTRs.

Abstract: On the basis that the subsequent evolution of a more sophisticated regulatory architecture to provide higher levels of epigenetic control and accurate spatiotemporal expression in developmentally complex organisms is a complicated task, we hypothesize: (i) that mRNAs have been and remain subject to secondary selection to provide trans-acting regulatory capability in parallel with protein-coding functions; (ii) that some and perhaps many protein-coding loci, possibly as a consequence of gene duplication, have lost protein-coding functions en route to acquiring more sophisticated trans-regulatory functions; (iii) that many transcripts have become subject to secondary processing to release different products; and (iv) that novel proteins have emerged within loci that previously evolved functionality as regulatory RNAs.

Abstract: In support of the idea that there is a dynamic flux between different types of informational RNAs in both evolutionary and real time, we review recent observations that have arisen from transcriptomic surveys of complex eukaryotes and reconsider how these observations impact on the notion that apparently discrete loci may express transcripts with more than one function.

Abstract: In conclusion, we posit that many eukaryotic loci have evolved the capacity to transact a multitude of overlapping and potentially independent functions as both regulatory and protein-coding RNAs.


In Vitro–expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes

Abstract: The low number of CD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype, and diverse antigen specificity present major challenges to harnessing this potent tolerogenic population to treat autoimmunity and transplant rejection.

Abstract: In this study, we describe a robust method to expand antigen-specific Tregs from autoimmune-prone nonobese diabetic mice.

Abstract: Purified CD4+ CD25+ Tregs were expanded up to 200-fold in less than 2 wk in vitro using a combination of anti-CD3, anti-CD28, and interleukin 2.

Abstract: The expanded Tregs express a classical cell surface phenotype and function both in vitro and in vivo to suppress effector T cell functions.

Abstract: Most significantly, small numbers of antigen-specific Tregs can reverse diabetes after disease onset, suggesting a novel approach to cellular immunotherapy for autoimmunity.


Stathmin overexpression identifies high-risk patients and lymph node metastasis in endometrial cancer.

Abstract: PURPOSE Overexpression of the oncogen Stathmin has been linked to aggressive endometrial carcinoma and a potential for PI3Kinase inhibitors in this disease.

Abstract: We wanted to validate the prognostic value of Stathmin expression in a large prospective multicenter setting.

Abstract: As lymph node sampling is part of current surgical staging, we also aimed to test if Stathmin expression in endometrial curettage specimens could predict lymph node metastasis.

Abstract: EXPERIMENTAL DESIGN A total of 1,076 endometrial cancer patients have been recruited from 10 centers to investigate the biological tumor marker Stathmin in relation to clinicopathologic variables, including lymph node status and survival.

Abstract: Stathmin immunohistochemical staining was carried out in 477 hysterectomy and 818 curettage specimens.

Abstract: RESULTS Seventy-one percent of the patients (n = 763) were subjected to lymph node sampling, of which 12% had metastatic nodes (n = 94).

Abstract: Overexpression of Stathmin was detected in 37% (302 of 818) of the curettage and in 18% (84 of 477) of the hysterectomy specimens investigated.

Abstract: Stathmin overexpression in curettage and hysterectomy specimens were highly correlated and significantly associated with nonendometrioid histology, high grade, and aneuploidy.

Abstract: Stathmin analysis in preoperative curettage samples significantly correlated with, and was an independent predictor of, lymph node metastases.

Abstract: High Stathmin expression was associated with poor disease-specific survival (P ≤ 0.002) both in curettage and hysterectomy specimens.

Abstract: CONCLUSIONS Stathmin immunohistochemical staining identifies endometrial carcinomas with lymph node metastases and poor survival.

Abstract: The value, as a predictive marker for response to PI3Kinase inhibition and as a tool to stratify patients for lymph node sampling in endometrial carcinomas, remains to be determined.


Statin prophylaxis and inflammatory mediators following cardiopulmonary bypass: a systematic review

Abstract: INTRODUCTION Induction of an inflammatory response is thought to have a significant role in the complications that follow cardiopulmonary bypass (CPB).

Abstract: The statin drugs are increasingly being recognized as having potent anti-inflammatory effects and hence have potential to influence an important mechanism of injury in CPB, although there is no current confirmation that this is indeed the case.

Abstract: Our objective was to systematically review if pre-operative prophylactic statin therapy, compared with placebo or standard of care, can decrease the inflammatory response in people undergoing heart surgery with CPB.

Abstract: METHODS We performed a systematic and comprehensive literature search for all randomized controlled trials (RCTs) of open heart surgery with CPB in adults or children who received prophylactic statin treatment prior to CPB, with reported outcomes which included markers of inflammation.

Abstract: Two authors independently identified eligible studies, extracted data, and assessed study quality using standardized instruments.

Abstract: Weighted mean difference (WMD) was the primary summary statistic with data pooled using a random effects model.

Abstract: Descriptive analysis was used when data could not be pooled.

Abstract: RESULTS Eight RCTs were included in the review, with the number of trials for each inflammatory outcome being even more limited.

Abstract: Pooled data demonstrated benefit with the use of statin to attenuate the post-CPB increase in interleukins 6 and 8 (IL-6, IL-8), peak high sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-alpha (TNF-alpha) post-CPB (WMD [95% confidence interval (CI)] -23.5 pg/ml [-36.6 to -10.5]; -23.4 pg/ml [-35.8 to -11.0]; -15.3 mg/L [CI -26.9 to -3.7]; -2.10 pg/ml [-3.83 to -0.37] respectively).

Abstract: Very limited RCT evidence suggests that prophylactic statin therapy may also decrease adhesion molecules following CPB including neutrophil CD11b and soluble P (sP)-selectin.

Abstract: CONCLUSIONS Although the RCT evidence may suggest a reduction in post-CPB inflammation by statin therapy, the evidence is not definitive due to significant limitations.

Abstract: Several of the trials were not methodologically rigorous and statin intervention was highly variable in this small number of studies.

Abstract: This systematic review demonstrates that there is a significant gap that exists in the current literature in regards to the potential anti-inflammatory effect of statin therapy prior to CPB.


Array-based Comparative Genomic Hybridization for Genome-Wide Screening of DNA Copy Number in Bladder Tumors

Abstract: Genome-wide copy number profiles were characterized in 41 primary bladder tumors using array-based comparative genomic hybridization (array CGH).

Abstract: In addition to previously identified alterations in large chromosomal regions, alterations were identified in many small genomic regions, some with high-level amplifications or homozygous deletions.

Abstract: High-level amplifications were detected for 192 genomic clones, most frequently at 6p22.3 (E2F3), 8p12 (FGFR1), 8q22.2 (CMYC), 11q13 (CCND1, EMS1, INT2), and 19q13.1 (CCNE).

Abstract: Homozygous deletions were detected in 51 genomic clones, with four showing deletions in more than one case: two clones mapping to 9p21.3 (CDKN2A/p16, in nine cases), one at 8p23.1 (three cases), and one at 11p13 (two cases).

Abstract: Significant correlations were observed between copy number gain of clones containing CCNE1 and gain of ERBB2, and between gain of CCND1 and deletion of TP53.

Abstract: In addition, there was a significant complementary association between gain of CCND1 and gain of E2F3.

Abstract: Although there was no significant relationship between copy number changes and tumor stage or grade, the linked behavior among genomic loci suggests that array CGH will be increasingly important in understanding pathways critical to bladder tumor biology.


Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6

Abstract: Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status.

Abstract: Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered.

Abstract: However, the regulation of immunity and inflammation by Tet proteins independent of their role in modulating DNA methylation remains largely unknown.

Abstract: Here we show that Tet2 selectively mediates active repression of interleukin-6 (IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages.

Abstract: Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6, at late phase during the response to lipopolysaccharide challenge.

Abstract: Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL-6 production compared to wild-type mice.

Abstract: IκBζ, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of IκBζ at initial and resolution phases of inflammation.

Abstract: For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 and repressed transcription of Il6 via histone deacetylation.

Abstract: We provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.


Control of immunity by the TNFR-related molecule OX40 (CD134).

Abstract: TNFR/TNF superfamily members can control diverse aspects of immune function.

Abstract: Research over the past 10 years has shown that one of the most important and prominent interactions in this family is that between OX40 (CD134) and its partner OX40L (CD252).

Abstract: These molecules strongly regulate conventional CD4 and CD8 T cells, and more recent data are highlighting their ability to modulate NKT cell and NK cell function as well as to mediate cross-talk with professional antigen-presenting cells and diverse cell types such as mast cells, smooth muscle cells, and endothelial cells.

Abstract: Additionally, OX40-OX40L interactions alter the differentiation and activity of regulatory T cells.

Abstract: Blocking OX40L has produced strong therapeutic effects in multiple animal models of autoimmune and inflammatory disease, and, in line with a prospective clinical future, reagents that stimulate OX40 signaling are showing promise as adjuvants for vaccination as well as for treatment of cancer.


The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis.

Abstract: Cholesterol homeostasis is required to maintain normal cellular function and avoid the deleterious effects of hypercholesterolemia.

Abstract: Here we show that the Drosophila DHR96 nuclear receptor binds cholesterol and is required for the coordinate transcriptional response of genes that are regulated by cholesterol and involved in cholesterol uptake, trafficking, and storage.

Abstract: DHR96 mutants die when grown on low levels of cholesterol and accumulate excess cholesterol when maintained on a high-cholesterol diet.

Abstract: The cholesterol accumulation phenotype can be attributed to misregulation of npc1b, an ortholog of the mammalian Niemann-Pick C1-like 1 gene NPC1L1, which is essential for dietary cholesterol uptake.

Abstract: These studies define DHR96 as a central regulator of cholesterol homeostasis.


A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children.

Abstract: Because children are becoming overweight, unhealthy, and unfit, understanding the neurocognitive benefits of an active lifestyle in childhood has important public health and educational implications.

Abstract: Animal research has indicated that aerobic exercise is related to increased cell proliferation and survival in the hippocampus as well as enhanced hippocampal-dependent learning and memory.

Abstract: Recent evidence extends this relationship to elderly humans by suggesting that high aerobic fitness levels in older adults are associated with increased hippocampal volume and superior memory performance.

Abstract: The present study aimed to further extend the link between fitness, hippocampal volume, and memory to a sample of preadolescent children.

Abstract: To this end, magnetic resonance imaging was employed to investigate whether higher- and lower-fit 9- and 10-year-old children showed differences in hippocampal volume and if the differences were related to performance on an item and relational memory task.

Abstract: Relational but not item memory is primarily supported by the hippocampus.

Abstract: Consistent with predictions, higher-fit children showed greater bilateral hippocampal volumes and superior relational memory task performance compared to lower-fit children.

Abstract: Hippocampal volume was also positively associated with performance on the relational but not the item memory task.

Abstract: Furthermore, bilateral hippocampal volume was found to mediate the relationship between fitness level (VO(2) max) and relational memory.

Abstract: No relationship between aerobic fitness, nucleus accumbens volume, and memory was reported, which strengthens the hypothesized specific effect of fitness on the hippocampus.

Abstract: The findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain.