The oxytocinase subfamily of M1 aminopeptidases.

Abstract: The placental leucine aminopeptidase (P-LAP), adipocyte-derived leucine aminopeptidase (A-LAP) and leukocyte-derived aminopeptidase (L-RAP) belong to one distinct group of the M1 family of amimopeptidases, which we term the "Oxytocinase subfamily".

Abstract: They share HEXXH(X)18E Zn-binding and GAMEN motifs essential for the enzymatic activities.

Abstract: Intracellular localization is the characteristic feature of the subfamily members.

Abstract: While P-LAP is translocated from intracellular vesicles to plasma membrane in a stimulus-dependent manner, both A-LAP and L-RAP are retained in the endoplasmic reticulum.

Abstract: They contain sequences necessary for the specific localization in the cell.

Abstract: It is getting evident that the subfamily members play important roles in the maintenance of homeostasis including maintenance of normal pregnancy, memory retention, blood pressure regulation and antigen presentation.

Abstract: In this review, current situation of this newly identified subfamily is summarized.


Myc represses primitive endoderm differentiation in pluripotent stem cells.

Abstract: The generation of induced pluripotent stem cells (iPSCs) provides a novel method to facilitate investigations into the mechanisms that control stem cell pluripotency and self-renewal.

Abstract: Myc has previously been shown to be critical for murine embryonic stem cell (mESC) maintenance, while also enhancing directed reprogramming of fibroblasts by effecting widespread changes in gene expression.

Abstract: Despite several studies identifying in vivo target genes, the precise mechanism by which Myc regulates pluripotency remains unknown.

Abstract: Here we report that codeletion of c- and N-MYC in iPSCs and ESCs results in their spontaneous differentiation to primitive endoderm.

Abstract: We show that Myc sustains pluripotency through repression of the primitive endoderm master regulator GATA6, while also contributing to cell cycle control by regulation of the mir-17-92 miRNA cluster.

Abstract: Our findings demonstrate the indispensable requirement for c- or N-myc in pluripotency beyond proliferative and metabolic control.


[Vitamin D and latitude as environmental factors in multiple sclerosis].

Abstract: Multiple sclerosis (MS) shows a multifold increase in prevalence with an increase in latitudes, both north and south of the equator.

Abstract: One of the potential factors related to the difference of the prevalence is vitamin D, because the strength of ambient ultraviolet light, which is essential for vitamin D production, decreases with increasing latitude.

Abstract: It is known that vitamin D has immunomodulatory functions and suppresses an animal model of MS.

Abstract: It is also considered that vitamin D-related genes are critical susceptible genes for MS.

Abstract: An approach from environmental and genetic aspects is needed to investigate the association between vitamin D and MS.


Type 2 cytokines: mechanisms and therapeutic strategies

Abstract: Type 2 immune responses are defined by the cytokines interleukin-4 (IL-4), IL-5, IL-9 and IL-13, which can either be host protective or have pathogenic activity.

Abstract: Type 2 immunity promotes antihelminth immunity, suppresses type 1-driven autoimmune disease, neutralizes toxins, maintains metabolic homeostasis, and regulates wound repair and tissue regeneration pathways following infection or injury.

Abstract: Nevertheless, when type 2 responses are dysregulated, they can become important drivers of disease.

Abstract: Type 2 immunity induces a complex inflammatory response characterized by eosinophils, mast cells, basophils, type 2 innate lymphoid cells, IL-4-and/or IL-13-conditioned macrophages and T helper 2 (TH2) cells, which are crucial to the pathogenesis of many allergic and fibrotic disorders.

Abstract: As chronic type 2 immune responses promote disease, the mechanisms that regulate their maintenance are thought to function as crucial disease modifiers.

Abstract: This Review discusses the many endogenous negative regulatory mechanisms that antagonize type 2 immunity and highlights how therapies that target some of these pathways are being developed to treat type 2-mediated disease.


Implanted microvessels progress through distinct neovascularization phenotypes.

Abstract: We have previously demonstrated that implanted microvessels form a new microcirculation with minimal host-derived vessel investment.

Abstract: Our objective was to define the vascular phenotypes present during neovascularization in these implants and identify post-angiogenesis events.

Abstract: Morphological, functional and transcriptional assessments identified three distinct vascular phenotypes in the implants: sprouting angiogenesis, neovascular remodeling, and network maturation.

Abstract: A sprouting angiogenic phenotype appeared first, characterized by high proliferation and low mural cell coverage.

Abstract: This was followed by a neovascular remodeling phenotype characterized by a perfused, poorly organized neovascular network, reduced proliferation, and re-associated mural cells.

Abstract: The last phenotype included a vascular network organized into a stereotypical tree structure containing vessels with normal perivascular cell associations.

Abstract: In addition, proliferation was low and was restricted to the walls of larger microvessels.

Abstract: The transition from angiogenesis to neovascular remodeling coincided with the appearance of blood flow in the implant neovasculature.

Abstract: Analysis of vascular-specific and global gene expression indicates that the intermediate, neovascular remodeling phenotype is transcriptionally distinct from the other two phenotypes.

Abstract: Therefore, this vascular phenotype likely is not simply a transitional phenotype but a distinct vascular phenotype involving unique cellular and vascular processes.

Abstract: Furthermore, this neovascular remodeling phase may be a normal aspect of the general neovascularization process.

Abstract: Given that this phenotype is arguably dysfunctional, many of the microvasculatures present within compromised or diseased tissues may not represent a failure to progress appropriately through a normally occurring neovascularization phenotype.


Characterization of a highly variable eutherian microRNA gene.

Abstract: Mouse microRNAs (miRNAs) miR-290-miR295 are encoded by a cluster of partially homologous pre-miRNA hairpins and are likely to be functionally important in embryonic stem (ES) cells and preimplantation embryos.

Abstract: We present evidence that a spliced, capped, and polyadenylated primary transcript spans this entire Early Embryonic microRNA Cluster (EEmiRC).

Abstract: Partial Drosha processing yields additional large nuclear RNA intermediates.

Abstract: A conserved promoter element containing a TATA-box directs EEmiRC transcription.

Abstract: Sequence analysis shows that the EEmiRC transcription unit is remarkably variable and can only be identified bioinformatically in placental (eutherian) mammals.

Abstract: Consistent with eutherian-specific function, EEmiRC is expressed in trophoblastic stem (TS) cells.

Abstract: When analyzing evolutionary and functional relationships, the organization of the entire miRNA loci should be considered in addition to the mature miRNA sequences.

Abstract: Application of this concept suggests that EEmiRC is a recently acquired rapidly evolving gene important for eutherian development.


The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding

Abstract: How follicular helper T cells (TFH cells) differentiate to regulate B cell immunity is critical for effective protein vaccination.

Abstract: Here we define three transcription factor T-bet–expressing antigen-specific effector helper T cell subsets with distinguishable function, migratory properties and developmental programming in vivo.

Abstract: Expression of the transcriptional repressor Blimp-1 distinguished T zone 'lymphoid' effector helper T cells (CD62LhiCCR7hi) from CXCR5lo 'emigrant' effector helper T cells and CXCR5hi 'resident' TFH cells expressing the transcriptional repressor Bcl-6 (CD62LloCCR7lo).

Abstract: We then show by adoptive transfer and intact polyclonal responses that helper T cells with the highest specific binding of peptide–major histocompatibility complex class II and the most restricted T cell antigen receptor junctional diversity 'preferentially' developed into the antigen-specific effector TFH compartment.

Abstract: Our studies demonstrate a central function for differences in the binding strength of the T cell antigen receptor in the antigen-specific mechanisms that 'program' specialized effector TFH function in vivo.


Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice.

Abstract: Inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) have been implicated in atherogenesis.

Abstract: However, the precise role of TNF-alpha in atherogenesis is still unclear.

Abstract: To examine the effect of TNF-alpha on atherogenesis, we generated compound-deficient mice in apolipoprotein E (apoE) and TNF-alpha (apoE-/-/TNF-alpha-/-) and compared them with apoE-/- mice.

Abstract: Although serum total cholesterol levels were markedly elevated in both apoE-/-/TNF-alpha-/- and apoE-/- mice compared to wild-type mice, no differences were observed between apoE-/-/TNF-alpha-/- and apoE-/- mice.

Abstract: The atherosclerotic plaque area in the aortic luminal surface of apoE-/-/TNF-alpha-/- mice (n=8, 3.1+/-0.4%) was significantly smaller than that of apoE-/- mice (n=7, 4.7+/-0.4%, p<0.001) despite the lack of difference in serum cholesterol levels.

Abstract: The atherosclerotic lesion size in the aortic sinus of apoE-/-/TNF-alpha-/- mice (n=10, 5.1+/-0.3 x 10(5)microm(2)) was also significantly smaller than that of apoE-/- mice (n=11, 7.0+/-0.3 x 10(5)microm(2), p<0.0001).

Abstract: RT-PCR analysis indicated that the expression levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) were significantly higher in apoE-/- than apoE-/-/TNF-alpha-/- mice.

Abstract: Macrophages from apoE(-/-) mice showed higher uptake level of oxidized LDL and increased expression level of scavenger receptor class A (SRA) compared to those from apoE-/-/TNF-alpha-/- mice.

Abstract: These results indicate that TNF-alpha plays an atherogenic role by upregulating the expressions of ICAM-1, VCAM-1 and MCP-1 in the vascular wall, and by inducing SRA expression and oxidized LDL uptake in macrophages.


Differential expression of bcl-2 and susceptibility to anti-Fas-mediated cell death in peripheral blood lymphocytes, monocytes, and neutrophils.

Abstract: The recently identified Fas antigen (Ag) is a cell surface molecule that can mediate apoptosis.

Abstract: The cytoplasmic product of proto-oncogene bcl-2 has been shown to prolong the cellular survival by inhibiting apoptosis.

Abstract: To elucidate the physiologic significance of expression of both molecules, we examined the expression of Fas Ag and bcl-2 on blood leukocyte populations and evaluated their sensitivity to the cytolytic action of anti-Fas antibody.

Abstract: Although Fas Ag was expressed on a fraction of lymphocytes, both neutrophils and monocytes expressed Fas Ag constitutively.

Abstract: In contrast, there was marked difference among these leukocytes regarding bcl-2 expression.

Abstract: Lymphocytes expressed bcl-2 intensely, but monocytes showed weaker bcl-2 expression, and neutrophils were essentially absent for bcl-2 expression.

Abstract: Seemingly reflecting this lack of bcl-2-expression, neutrophils more easily underwent apoptotic cell death in vitro as compared with monocytes and lymphocytes.

Abstract: We showed that anti-Fas antibody affectively accelerated apoptotic cell death in neutrophils.

Abstract: However, the apoptosis-inducing effect of anti-Fas antibody was minimal on monocytes, and lymphocytes were resistant to this antibody.

Abstract: These results suggest that anti-Fas-mediated cell death may, in part, be determined by bcl-2 expression status in Fas+ lymphoid and hematopoietic cells.


Foxp2 and Foxp1 cooperatively regulate lung and esophagus development.

Abstract: The airways of the lung develop through a reiterative process of branching morphogenesis that gives rise to the intricate and extensive surface area required for postnatal respiration.

Abstract: The forkhead transcription factors Foxp2 and Foxp1 are expressed in multiple foregut-derived tissues including the lung and intestine.

Abstract: In this report, we show that loss of Foxp2 in mouse leads to defective postnatal lung alveolarization, contributing to postnatal lethality.

Abstract: Using in vitro and in vivo assays, we show that T1alpha, a lung alveolar epithelial type 1 cell-restricted gene crucial for lung development and function, is a direct target of Foxp2 and Foxp1.

Abstract: Remarkably, loss of a single Foxp1 allele in addition to complete loss of Foxp2 results in increased severity of morphological defects in mutant lungs and leads to perinatal loss of all Foxp2(-/-);Foxp1(+/-) mice.

Abstract: Expression of N-myc and Hop, crucial regulators of lung development, is compromised in Foxp2(-/-);Foxp1(+/-) mutants.

Abstract: In addition to the defects in lung development, esophageal muscle development is disrupted in Foxp2(-/-);Foxp1(+/-) embryos, a tissue where Foxp2 and Foxp1 are co-expressed.

Abstract: These data identify Foxp2 and Foxp1 as crucial regulators of lung and esophageal development, underscoring the necessity of these transcription factors in the development of anterior foregut-derived tissues and demonstrating functional cooperativity between members of the Foxp1/2/4 family in tissues where they are co-expressed.


Crystal structure of the eukaryotic 60S ribosomal subunit in complex with initiation factor 6.

Abstract: Protein synthesis in all organisms is catalyzed by ribosomes.

Abstract: In comparison to their prokaryotic counterparts, eukaryotic ribosomes are considerably larger and are subject to more complex regulation.

Abstract: The large ribosomal subunit (60S) catalyzes peptide bond formation and contains the nascent polypeptide exit tunnel.

Abstract: We present the structure of the 60S ribosomal subunit from Tetrahymena thermophila in complex with eukaryotic initiation factor 6 (eIF6), cocrystallized with the antibiotic cycloheximide (a eukaryotic-specific inhibitor of protein synthesis), at a resolution of 3.5 angstroms.

Abstract: The structure illustrates the complex functional architecture of the eukaryotic 60S subunit, which comprises an intricate network of interactions between eukaryotic-specific ribosomal protein features and RNA expansion segments.

Abstract: It reveals the roles of eukaryotic ribosomal protein elements in the stabilization of the active site and the extent of eukaryotic-specific differences in other functional regions of the subunit.

Abstract: Furthermore, it elucidates the molecular basis of the interaction with eIF6 and provides a structural framework for further studies of ribosome-associated diseases and the role of the 60S subunit in the initiation of protein synthesis.


Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas.

Abstract: The identification of brain tumor stem-like cells (BTSCs) has implicated a role of biological self-renewal mechanisms in clinical brain tumor initiation and propagation.

Abstract: The molecular mechanisms underlying the tumor-forming capacity of BTSCs, however, remain unknown.

Abstract: Here, we have generated molecular signatures of glioblastoma multiforme (GBM) using gene expression profiles of BTSCs and have identified both Sonic Hedgehog (SHH) signaling-dependent and -independent BTSCs and their respective glioblastoma surgical specimens.

Abstract: BTSC proliferation could be abrogated in a pathway-dependent fashion in vitro and in an intracranial tumor model in athymic mice.

Abstract: Both SHH-dependent and -independent brain tumor growth required phosphoinositide 3-kinase-mammalian target of rapamycin signaling.

Abstract: In human GBMs, the levels of SHH and PTCH1 expression were significantly higher in PTEN-expressing tumors than in PTEN-deficient tumors.

Abstract: In addition, we show that hyperactive SHH-GLI signaling in PTEN-coexpressing human GBM is associated with reduced survival time.

Abstract: Thus, distinct proliferation signaling dependence may underpin glioblastoma propagation by BTSCs.

Abstract: Modeling these BTSC proliferation mechanisms may provide a rationale for individualized glioblastoma treatment.


Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms.

Abstract: Nonreplicating and metabolically quiescent bacteria are implicated in latent tuberculosis infections and relapses following "sterilizing" chemotherapy.

Abstract: However, evidence linking bacterial dormancy and persistence in vivo is largely inconclusive.

Abstract: Here we measure the single-cell dynamics of Mycobacterium tuberculosis replication and ribosomal activity using quantitative time-lapse microscopy and a reporter of ribosomal RNA gene expression.

Abstract: Single-cell dynamics exhibit heterogeneity under standard growth conditions, which is amplified by stressful conditions such as nutrient limitation, stationary phase, intracellular replication, and growth in mouse lungs.

Abstract: Additionally, the lungs of chronically infected mice harbor a subpopulation of nongrowing but metabolically active bacteria, which are absent in mice lacking interferon-γ, a cytokine essential for antituberculosis immunity.

Abstract: These cryptic bacterial forms are prominent in mice treated with the antituberculosis drug isoniazid, suggesting a role in postchemotherapeutic relapses.

Abstract: Thus, amplification of bacterial phenotypic heterogeneity in response to host immunity and drug pressure may contribute to tuberculosis persistence.


Proteomic analysis reveals Warburg effect and anomalous metabolism of glutamine in pancreatic cancer cells.

Abstract: In this present work, we characterized the proteomes of pancreatic ductal adenocarcinoma (PDAC) cell line PANC-1 and normal pancreatic duct cells by mass spectrometry using LTQ-Orbitrap and identified more than 1700 proteins from each sample.

Abstract: On the basis of the spectra count label-free quantification approach, we identified a large number of differentially expressed metabolic enzymes and proteins involved in cytoskeleton, cell adhesion, transport, transcription, translation, and cell proliferation as well.

Abstract: The data demonstrated that metabolic pathways were altered in PANC-1, consistent with the Warburg effect.

Abstract: In addition, the comparative MS analysis unveiled anomalous metabolism of glutamine, suggesting that glutamine was largely consumed as a nitrogen donor in nucleotide and amino acid biosynthesis in PANC-1.

Abstract: Our analysis provides a potentially comprehensive picture of metabolism in PANC-1, which may serve as the basis of new diagnostics and treatment of PDAC.


Prevalence of attempting weight loss and strategies for controlling weight.

Abstract: CONTEXT Overweight and obesity are increasing in the United States.

Abstract: Changes in diet and physical activity are important for weight control.

Abstract: OBJECTIVES To examine the prevalence of attempting to lose or to maintain weight and to describe weight control strategies among US adults.

Abstract: DESIGN

Abstract: The Behavioral Risk Factor Surveillance System, a random-digit telephone survey conducted in 1996 by state health departments.

Abstract: Setting The 49 states (and the District of Columbia) that participated in the survey.

Abstract: PARTICIPANTS Adults aged 18 years and older (N = 107 804).

Abstract: MAIN OUTCOME MEASURES Reported current weights and goal weights, prevalence of weight loss or maintenance attempts, and strategies used to control weight (eating fewer calories, eating less fat, or using physical activity) by population subgroup.

Abstract: RESULTS The prevalence of attempting to lose and maintain weight was 28.8% and 35.1 % among men and 43.6% and 34.4% among women, respectively.

Abstract: Among those attempting to lose weight, a common strategy was to consume less fat but not fewer calories (34.9% of men and 40.0% of women); only 21.5% of men and 19.4% of women reported using the recommended combination of eating fewer calories and engaging in at least 150 minutes of leisure-time physical activity per week.

Abstract: Among men trying to lose weight, the median weight was 90.4 kg with a goal weight of 81.4 kg.

Abstract: Among women, the median weight was 70.3 kg with a goal weight of 59.0 kg.

Abstract: CONCLUSIONS Weight loss and weight maintenance are common concerns for US men and women.

Abstract: Most persons trying to lose weight are not using the recommended combination of reducing calorie intake and engaging in leisure-time physical activity 150 minutes or more per week.


Antibodies specific for Epstein-Barr virus nuclear antigen-1 cross-react with human heterogeneous nuclear ribonucleoprotein L.

Abstract: Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS), and antibodies to the EBV nuclear antigen-1 (EBNA-1) are consistently increased in MS patients.

Abstract: The hypothesis of this study is that anti-EBNA-1 antibodies cross-react with a self antigen in MS patients.

Abstract: We affinity purified anti-EBNA-1 antibodies from human plasma, used the anti-EBNA-1 to immunoprecipitate antigens from human brain, and identified bound antigens with mass spectrometry.

Abstract: Anti-EBNA-1 consistently bound heterogeneous nuclear ribonucleoprotein L (HNRNPL).

Abstract: We expressed both the long and short isoforms of this protein, and verified with Western blots and ELISA that the long isoform cross-reacts with EBNA-1.

Abstract: Immunohistochemistry demonstrated that anti-EBNA-1 bound to an antigen in the nucleus of cultured rat central nervous system cells.

Abstract: ELISA demonstrated the presence of antibodies to HNRNPL in the plasma of both healthy controls and MS patients, but anti-HNRNPL was not increased in MS patients.

Abstract: We conclude that HNRNPL is an autoantigen which cross-reacts with EBNA-1.

Abstract: The relevance of this autoantigen to MS and other autoimmune diseases remains to be investigated.


Roles of chromatin remodellers in DNA double strand break repair.

Abstract: Now that we have a good understanding of the DNA double strand break (DSB) repair mechanisms and DSB-induced damage signalling, attention is focusing on the changes to the chromatin environment needed for efficient DSB repair.

Abstract: Mutations in chromatin remodelling complexes have been identified in cancers, making it important to evaluate how they impact upon genomic stability.

Abstract: Our current understanding of the DSB repair pathways suggests that each one has distinct requirements for chromatin remodelling.

Abstract: Moreover, restricting the extent of chromatin modifications could be a significant factor regulating the decision of pathway usage.

Abstract: In this review, we evaluate the distinct DSB repair pathways for their potential need for chromatin remodelling and review the roles of ATP-driven chromatin remodellers in the pathways.


Epstein-Barr virus and virus human protein interaction maps.

Abstract: A comprehensive mapping of interactions among Epstein-Barr virus (EBV) proteins and interactions of EBV proteins with human proteins should provide specific hypotheses and a broad perspective on EBV strategies for replication and persistence.

Abstract: Interactions of EBV proteins with each other and with human proteins were assessed by using a stringent high-throughput yeast two-hybrid system.

Abstract: Overall, 43 interactions between EBV proteins and 173 interactions between EBV and human proteins were identified.

Abstract: EBV-EBV and EBV-human protein interaction, or "interactome" maps provided a framework for hypotheses of protein function.

Abstract: For example, LF2, an EBV protein of unknown function interacted with the EBV immediate early R transactivator (Rta) and was found to inhibit Rta transactivation.

Abstract: From a broader perspective, EBV genes can be divided into two evolutionary classes, "core" genes, which are conserved across all herpesviruses and subfamily specific, or "noncore" genes.

Abstract: Our EBV-EBV interactome map is enriched for interactions among proteins in the same evolutionary class.

Abstract: Furthermore, human proteins targeted by EBV proteins were enriched for highly connected or "hub" proteins and for proteins with relatively short paths to all other proteins in the human interactome network.

Abstract: Targeting of hubs might be an efficient mechanism for EBV reorganization of cellular processes.


Relation between Medicare screening reimbursement and stage at diagnosis for older patients with colon cancer.

Abstract: CONTEXT Medicare's reimbursement policy was changed in 1998 to provide coverage for screening colonoscopies for patients with increased colon cancer risk, and expanded further in 2001 to cover screening colonoscopies for all individuals.

Abstract: OBJECTIVE To determine whether the Medicare reimbursement policy changes were associated with an increase in either colonoscopy use or early stage colon cancer diagnosis.

Abstract: DESIGN, SETTING, AND PARTICIPANTS Patients in the Surveillance, Epidemiology, and End Results Medicare linked database who were 67 years of age and older and had a primary diagnosis of colon cancer during 1992-2002, as well as a group of Medicare beneficiaries who resided in Surveillance, Epidemiology, and End Results areas but who were not diagnosed with cancer.

Abstract: MAIN OUTCOME MEASURES Trends in colonoscopy and sigmoidoscopy use among Medicare beneficiaries without cancer were assessed using multivariate Poisson regression.

Abstract: Among the patients with cancer, stage was classified as early (stage I) vs all other (stages II-IV).

Abstract: Time was categorized as period 1 (no screening coverage, 1992-1997), period 2 (limited coverage, January 1998-June 2001), and period 3 (universal coverage, July 2001-December 2002).

Abstract: A multivariate logistic regression (outcome = early stage) was used to assess temporal trends in stage at diagnosis; an interaction term between tumor site and time was included.

Abstract: RESULTS Colonoscopy use increased from an average rate of 285/100,000 per quarter in period 1 to 889 and 1919/100,000 per quarter in periods 2 (P<.001) and 3 (P vs 2<.001), respectively.

Abstract: During the study period, 44,924 eligible patients were diagnosed with colorectal cancer.

Abstract: The proportion of patients diagnosed at an early stage increased from 22.5% in period 1 to 25.5% in period 2 and 26.3% in period 3 (P<.001 for each pairwise comparison).

Abstract: The changes in Medicare coverage were strongly associated with early stage at diagnosis for patients with proximal colon lesions (adjusted relative risk period 2 vs 1, 1.19; 95% confidence interval, 1.13-1.26; adjusted relative risk period 3 vs 2, 1.10; 95% confidence interval, 1.02-1.17) but weakly associated, if at all, for patients with distal colon lesions (adjusted relative risk period 2 vs 1, 1.07; 95% confidence interval, 1.01-1.13; adjusted relative risk period 3 vs 2, 0.97; 95% confidence interval, 0.90-1.05).

Abstract: CONCLUSIONS Expansion of Medicare reimbursement to cover colon cancer screening was associated with an increased use of colonoscopy for Medicare beneficiaries, and for those who were diagnosed with colon cancer, an increased probability of being diagnosed at an early stage.

Abstract: The selective effect of the coverage change on proximal colon lesions suggests that increased use of whole-colon screening modalities such as colonoscopy may have played a pivotal role.


Direct visualization of the endomitotic cell cycle in living megakaryocytes: differential patterns in low and high ploidy cells.

Abstract: Endomitosis in megakaryocytes (MKs) involves repeated DNA replication in the absence of cytokinesis and is a crucial part of MK development.

Abstract: However, chromosomal dynamics have never been observed in living MKs.

Abstract: We developed a new transgenic mouse model in which the expression of human histone H2B fused in-frame to green fluorescent protein is targeted to MKs.

Abstract: Ex vivo time-lapse microscopy analysis indicated that chromosomal condensation occurs at early mitosis in all MKs.

Abstract: In high ploidy MKs (>or=8N), late anaphase was marked by a ring-type alignment of chromosomes with multiple territories formed between them.

Abstract: By contrast, in low ploidy MKs mitotic chromosomes segregated to form two groups separated by a clear space before re-joining to one cluster.

Abstract: This is the first study to document chromosomal segregation patterns during endomitosis ex vivo and to indicate their potential differential regulation in low and high ploidy cells.


Aberrant expression and altered cellular localization of desmosomal and hemidesmosomal proteins are associated with aggressive clinicopathological features of oral squamous cell carcinoma

Abstract: Disruption of cell adhesion plays a central role in dedifferentiation, invasion, and metastasis of various cancers.

Abstract: The desmosome and hemidesmosome are anchoring junctions that control cell-cell and cell-matrix adhesion, respectively.

Abstract: To clarify their contributions in mediating the biological properties of oral cancer, we immunohistochemically examined the expression of desmoglein 1 (DSG1), DSG2, DSG3, desmocollin 2 (DSC2), integrin beta 4 (ITGB4), laminin gamma chain 2 (LAMC2), and collagen type 17 alpha 1 (COL17A1) in 51 cases of oral squamous cell carcinoma.

Abstract: On normal oral epithelial cells, DSG1, DSG3, DSC2, and COL17A1 were expressed on the plasma membrane, while ITGB4 and mature LAMC2 were present at the basement membrane.

Abstract: In cancer, the expression of DSG1, DSG3, DSC2, and COL17A1 decreased and internalized to the cytoplasm.

Abstract: Cytoplasmic expression of DSG2, ITGB4, and LAMC2 was induced in the cancer cells facing to the stroma.

Abstract: We scored immunohistochemical expression and correlated this to clinicopathological parameters including histologic differentiation, pattern of invasion, and presence of lymph node metastasis.

Abstract: Decrease of DSG3 and DSC2 expression correlated with a more aggressive cancer phenotype: less differentiated and more invasive histologic features and a higher incidence of nodal metastasis.

Abstract: Lower COL17A1 and higher LAMC2 expression were also associated with a more aggressive phenotype.

Abstract: The present study demonstrates that aberrant expression and altered cellular localization of desmosomal and hemidesmosomal proteins are associated with aggressive clinicopathological features of oral cancer.

Abstract: This reinforces the notion that disturbance of the keratin-associated anchoring junctions confers aggressive features to cancer cells.


Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs.

Abstract: Histone/protein deacetylases (HDACs) decrease histone and protein acetylation, typically leading to suppression of gene transcription and modulation of various protein functions.

Abstract: We found significant differences in expression of HDAC before and after stimulation of human T regulatory (Treg) and T effector cells, suggesting the potential for future selective targeting of Tregs with HDAC inhibitors (HDACi).

Abstract: Use of various HDACi small molecules enhanced, by up to 4.5-fold (average 2-fold), the suppressive functions of both freshly isolated and expanded human Tregs, consistent with our previous murine data.

Abstract: HDACi use increased Treg expression of CTLA-4, a key negative regulator of immune response, and we found a direct and significant correlation between CTLA-4 expression and Treg suppression.

Abstract: Hence, HDACi compounds are promising pharmacologic tools to increase Treg suppressive functions, and this action may potentially be of use in patients with autoimmunity or post-transplantation.


Enhanced pathological angiogenesis in mice lacking β3 integrin or β3 and β5 integrins

Abstract: Inhibition of αvβ3 or αvβ5 integrin function has been reported to suppress neovascularization and tumor growth, suggesting that these integrins are critical modulators of angiogenesis.

Abstract: Here we report that mice lacking β3 integrins or both β3 and β5 integrins not only support tumorigenesis, but have enhanced tumor growth as well.

Abstract: Moreover, the tumors in these integrin-deficient mice display enhanced angiogenesis, strongly suggesting that neither β3 nor β5 integrins are essential for neovascularization.

Abstract: We also observed that angiogenic responses to hypoxia and vascular endothelial growth factor (VEGF) are augmented significantly in the absence of β3 integrins.

Abstract: We found no evidence that the expression or functions of other integrins were altered as a consequence of the β3 deficiency, but we did observe elevated levels of VEGF receptor-2 (also called Flk-1) in β3-null endothelial cells.

Abstract: These data indicate that αvβ3 and αvβ5 integrins are not essential for vascular development or pathological angiogenesis and highlight the need for further evaluation of the mechanisms of action of αv-integrin antagonists in anti-angiogenic therapeutics.


A lineage of myeloid cells independent of Myb and hematopoietic stem cells.

Abstract: Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs).

Abstract: However, some macrophages develop in the embryo before the appearance of definitive HSCs.

Abstract: We thus reinvestigated macrophage development.

Abstract: We found that the transcription factor Myb was required for development of HSCs and all CD11b(high) monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80(bright) macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia--cell populations that all can persist in adult mice independently of HSCs.

Abstract: These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.


Heterogenic Loss of the Wild-Type BRCA Allele in Human Breast Tumorigenesis

Abstract: For individuals genetically predisposed to breast and ovarian cancer through inheritance of a mutant BRCA allele, somatic loss of heterozygosity affecting the wild-type allele is considered obligatory for cancer initiation and/or progression.

Abstract: However, several lines of evidence suggest that phenotypic effects may result from BRCA haploinsufficiency.

Abstract: Archival fixed and embedded tissue specimens from women with germ line deleterious mutations in BRCA1 or BRCA2 were identified.

Abstract: After pathologic review, focal areas of normal breast epithelium, atypical ductal hyperplasia, ductal carcinoma-in-situ, and invasive ductal carcinoma were identified from 14 BRCA1-linked and 9 BRCA2-linked breast cancers.

Abstract: Ten BRCA-linked prophylactic mastectomy specimens and 12 BRCA-linked invasive ovarian carcinomas were also studied.

Abstract: Laser catapult microdissection was used to isolate cells from the various pathologic lesions and corresponding normal tissues.

Abstract: After DNA isolation, real-time polymerase chain reaction assays were used to quantitate the proportion of wild-type to mutant BRCA alleles in each tissue sample.

Abstract: Quantitative allelotyping of microdissected cells revealed a high level of heterogeneity in loss of heterozygosity within and between preinvasive lesions and invasive cancers from BRCA1 and BRCA2 heterozygotes with breast cancer.

Abstract: In contrast, all BRCA-associated ovarian cancers displayed complete loss of the wild-type BRCA allele.

Abstract: These data suggest that loss of the wild-type BRCA allele is not required for BRCA-linked breast tumorigenesis, which would have important implications for the genetic mechanism of BRCA tumor suppression and for the clinical management of this patient population.


Targeted therapies in urothelial carcinoma.

Abstract: PURPOSE OF REVIEW Greater understanding of the biology and genetics of urothelial carcinoma is helping to identify and define the role of molecules and pathways appropriate for novel-targeted therapies.

Abstract: Here, we review the targeted therapies that have been reported or are in ongoing urothelial carcinoma clinical trials, and highlight molecular targets characterized in preclinical and clinical studies.

Abstract: RECENT FINDINGS Trials in nonmuscle-invasive bladder cancer are evaluating the role of immunotherapy and agents targeting vascular endothelial growth factor (VEGF) or fibroblast growth factor receptor-3.

Abstract: In muscle-invasive bladder cancer, neoadjuvant studies have focused on combining VEGF agents with chemotherapy; adjuvant studies are testing vaccines and agents targeting the human epidermal growth factor receptor 2, p53, and Hsp27.

Abstract: In the first-line treatment of metastatic urothelial carcinoma, tubulin, cytotoxic T-lymphocyte antigen 4, Hsp27, and p53 are novel targets in clinical trials.

Abstract: The majority of targeted agents studied in urothelial carcinoma are in the second-line setting; new targets include CD105, polo-like kinase-1, phosphatidylinositide 3-kinases (PI3K), transforming growth factor β receptor/activin receptor-like kinase β, estrogen receptor, and the hepatocyte growth factor receptor (HGFR or MET).

Abstract: SUMMARY Development of targeted therapies for urothelial carcinoma is still in early stages, consequently there have been no major therapeutic advances to date.

Abstract: However, greater understanding of urothelial carcinoma and solid tumor biology has resulted in a proliferation of clinical trials that could lead to significant advances in treatment strategies.


H2S and HS− donor NaHS releases nitric oxide from nitrosothiols, metal nitrosyl complex, brain homogenate and murine L1210 leukaemia cells

Abstract: Nitrosoglutathione [(GSNO), 500 nmol/l] relaxed the norepinephrine precontracted rat aortic rings.

Abstract: The relaxation effect was pronouncedly enhanced by H2S- and HS−-donor NaHS (30 μmol/l) at 7.5 pH but not at 6.3 pH. To study molecular mechanism of this effect, we investigated whether NaHS can release NO from NO donors.

Abstract: Using an electron paramagnetic resonance spectroscopy method of spin trap and by measuring the NO oxidation product, which is nitrite, by the Griess reaction, we report that NaHS released NO from nitrosothiols, namely from GSNO, S-nitroso-N-acetyl-dl-penicillamine (SNAP), from metal nitrosyl complex nitroprusside (SNP) and from rat brain homogenate and murine L1210 leukaemia cells.

Abstract: From the observation that the releasing effect was more pronounced at 8.0 pH than 6.0 pH, we suppose that HS−, rather than H2S, is responsible for the NO-releasing effect.

Abstract: Since in mammals, H2S and HS− are produced endogenously, we assume that their effect to release NO from nitrosothiols and from metal nitrosyl complexes are responsible for some of their biological activities and that this mechanism may be involved in S-nitrosothiol-signalling reactions.


Amitriptyline is effective in chronic but not in episodic tension-type headache: pathogenetic implications.

Abstract: The tricyclic antidepressant, amitriptyline, is an effective drug for the treatment of chronic tension-type headache and for other chronic pain syndromes, but it is also effective in the prophylaxis of an episodic type of headache such as migraine.

Abstract: However, its efficacy in episodic tension-type headache has not yet been clarified.

Abstract: We compared the efficacy of amitriptyline (25 mg/day) in 82 nondepressed patients with either chronic or episodic tension-type headache in an open-label study.

Abstract: Amitriptyline significantly reduced (P < 0.05) frequency and duration of headache as well as analgesic consumption in chronic, but not in episodic, tension-type headache.

Abstract: Further placebo-controlled trials, possibly with higher doses of amitriptyline, might confirm if the different pattern of response to amitriptyline can be explained in terms of different involvement of central nociception and of peripheral myofascial factors in the chronic and in the episodic forms of tension-type headache.


Kruppel-like factor 2 is required for trafficking but not quiescence in postactivated T cells.

Abstract: The transcription factor Kruppel-like factor 2 (KLF2) was proposed to regulate genes involved in cell cycle entry and T cell trafficking; however, the physiological role of its expression in postactivated T cells is not well defined.

Abstract: Previous studies suggested that the cytokines IL-2 and IL-15 differentially regulate KLF2 re-expression in postactivation T cells and that these cytokines also influence effector versus memory T cell differentiation.

Abstract: Using conditional and inducible KLF2-knockout model systems, we tested the specific role of KLF2 expression in activated CD8(+) T cells cultured with these cytokines.

Abstract: KLF2 was required for effective transcription of sphingosine-1-phosphate receptor-1 (S1P(1)) and CD62L in postactivation T cells.

Abstract: However, although different cytokines dramatically altered the expression of cell-cycle-related genes, endogenous KLF2 had a minimal impact.

Abstract: Correspondingly, KLF2-deficient T cells showed dysregulated trafficking but not altered proliferative characteristics following in vivo responses to Ag.

Abstract: Thus, our data help to define KLF2-dependent and -independent aspects of activated CD8(+) T cell differentiation and argue against a physiological role in cell cycle regulation.


Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials.

Abstract: OBJECTIVE To determine whether hypoalbuminemia is an independent risk factor for poor outcome in the acutely ill, and to assess the potential of exogenous albumin administration for improving outcomes in hypoalbuminemic patients.

Abstract: SUMMARY BACKGROUND DATA Hypoalbuminemia is associated with poor outcomes in acutely ill patients, but whether this association is causal has remained unclear.

Abstract: Trials investigating albumin therapy to correct hypoalbuminemia have proven inconclusive.

Abstract: METHODS A meta-analysis was conducted of 90 cohort studies with 291,433 total patients evaluating hypoalbuminemia as an outcome predictor by multivariate analysis and, separately, of nine prospective controlled trials with 535 total patients on correcting hypoalbuminemia.

Abstract: RESULTS Hypoalbuminemia was a potent, dose-dependent independent predictor of poor outcome.

Abstract: Each 10-g/L decline in serum albumin concentration significantly raised the odds of mortality by 137%, morbidity by 89%, prolonged intensive care unit and hospital stay respectively by 28% and 71%, and increased resource utilization by 66%.

Abstract: The association between hypoalbuminemia and poor outcome appeared to be independent of both nutritional status and inflammation.

Abstract: Analysis of dose-dependency in controlled trials of albumin therapy suggested that complication rates may be reduced when the serum albumin level attained during albumin administration exceeds 30 g/L.   CONCLUSIONS Hypoalbuminemia is strongly associated with poor clinical outcomes.

Abstract: Further well-designed trials are needed to characterize the effects of albumin therapy in hypoalbuminemic patients.

Abstract: In the interim, there is no compelling basis to withhold albumin therapy if it is judged clinically appropriate.


Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction.

Abstract: Reduced dietary methionine intake (0.17% methionine, MR) and calorie restriction (CR) prolong lifespan in male Fischer 344 rats.

Abstract: Although the mechanisms are unclear, both regimens feature lower body weight and reductions in adiposity.

Abstract: Reduced fat deposition in CR is linked to preservation of insulin responsiveness in older animals.

Abstract: These studies examine the relationship between insulin responsiveness and visceral fat in MR and test whether, despite lower food intake observed in MR animals, decreased visceral fat accretion and preservation of insulin sensitivity is not secondary to CR.

Abstract: Accordingly, rats pair fed (pf) control diet (0.86% methinone, CF) to match the food intake of MR for 80 weeks exhibit insulin, glucose, and leptin levels similar to control-fed animals and comparable amounts of visceral fat.

Abstract: Conversely, MR rats show significantly reduced visceral fat compared to CF and PF with concomitant decreases in basal insulin, glucose, and leptin, and increased adiponectin and triiodothyronine.

Abstract: Daily energy expenditure in MR animals significantly exceeds that of both PF and CF.

Abstract: In a separate cohort, insulin responses of older MR animals as measured by oral glucose challenge are similar to young animals.

Abstract: Longitudinal assessments of MR and CF through 112 weeks of age reveal that MR prevents age-associated increases in serum lipids.

Abstract: By 16 weeks, MR animals show a 40% reduction in insulin-like growth factor-1 (IGF-1) that is sustained throughout life; CF IGF-1 levels decline much later, beginning at 112 weeks.

Abstract: Collectively, the results indicate that MR reduces visceral fat and preserves insulin activity in aging rats independent of energy restriction.


Generation of T cell receptor–retrogenic mice: improved retroviral-mediated stem cell gene transfer

Abstract: The use of retrogenic mice offers a rapid and flexible approach to T cell receptor (TCR)-transgenic mice.

Abstract: By transducing bone marrow progenitor cells with a retrovirus that encodes a given TCR-α/β subunit, TCR-retrogenic mice can be generated in as few as 4–6 weeks, whereas conventional TCR transgenics can take 6 months or longer.

Abstract: In this updated protocol, we have increased the efficiency of the bone marrow transduction and bone marrow reconstitution compared with our previously published protocol.

Abstract: The main departure from the previous protocol is the implementation of spin transduction with the viral supernatant instead of coculture with the viral producer cell line.

Abstract: The changes in this protocol improve bone marrow viability, increase consistency of the bone marrow transduction and bone marrow engraftment, and they reduce the ratio of bone marrow donor mice to bone marrow recipients.


Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells.

Abstract: Telomere extension has been proposed as a means to improve cell culture and tissue engineering and to treat disease.

Abstract: However, telomere extension by nonviral, nonintegrating methods remains inefficient.

Abstract: Here we report that delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts increases telomerase activity transiently (24-48 h) and rapidly extends telomeres, after which telomeres resume shortening.

Abstract: Three successive transfections over a 4 d period extended telomeres up to 0.9 kb in a cell type-specific manner in fibroblasts and myoblasts and conferred an additional 28 ± 1.5 and 3.4 ± 0.4 population doublings (PDs), respectively.

Abstract: Proliferative capacity increased in a dose-dependent manner.

Abstract: The second and third transfections had less effect on proliferative capacity than the first, revealing a refractory period.

Abstract: However, the refractory period was transient as a later fourth transfection increased fibroblast proliferative capacity by an additional 15.2 ± 1.1 PDs, similar to the first transfection.

Abstract: Overall, these treatments led to an increase in absolute cell number of more than 10(12)-fold.

Abstract: Notably, unlike immortalized cells, all treated cell populations eventually stopped increasing in number and expressed senescence markers to the same extent as untreated cells.

Abstract: This rapid method of extending telomeres and increasing cell proliferative capacity without risk of insertional mutagenesis should have broad utility in disease modeling, drug screening, and regenerative medicine.


The death receptor CD95 activates adult neural stem cells for working memory formation and brain repair.

Abstract: Adult neurogenesis persists in the subventricular zone and the dentate gyrus and can be induced upon central nervous system injury.

Abstract: However, the final contribution of newborn neurons to neuronal networks is limited.

Abstract: Here we show that in neural stem cells, stimulation of the "death receptor" CD95 does not trigger apoptosis but unexpectedly leads to increased stem cell survival and neuronal specification.

Abstract: These effects are mediated via activation of the Src/PI3K/AKT/mTOR signaling pathway, ultimately leading to a global increase in protein translation.

Abstract: Induction of neurogenesis by CD95 was further confirmed in the ischemic CA1 region, in the naive dentate gyrus, and after forced expression of CD95L in the adult subventricular zone.

Abstract: Lack of hippocampal CD95 resulted in a reduction in neurogenesis and working memory deficits.

Abstract: Following global ischemia, CD95-mediated brain repair rescued behavioral impairment.

Abstract: Thus, we identify the CD95/CD95L system as an instructive signal for ongoing and injury-induced neurogenesis.


Umbilical Cord Blood Therapy Potentiated with Erythropoietin for Children with Cerebral Palsy: A Double-blind, Randomized, Placebo-Controlled Trial

Abstract: Allogeneic umbilical cord blood (UCB) has therapeutic potential for cerebral palsy (CP).

Abstract: Concomitant administration of recombinant human erythropoietin (rhEPO) may boost the efficacy of UCB, as it has neurotrophic effects.

Abstract: The objectives of this study were to assess the safety and efficacy of allogeneic UCB potentiated with rhEPO in children with CP.

Abstract: Children with CP were randomly assigned to one of three parallel groups: the pUCB group, which received allogeneic UCB potentiated with rhEPO; the EPO group, which received rhEPO and placebo UCB; and the Control group, which received placebo UCB and placebo rhEPO.

Abstract: All participants received rehabilitation therapy.

Abstract: The main outcomes were changes in scores on the following measures during the 6 months treatment period: the gross motor performance measure (GMPM), gross motor function measure, and Bayley scales of infant development-II (BSID-II) Mental and Motor scales (18).

Abstract: F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET/CT) and diffusion tensor images (DTI) were acquired at baseline and followed up to detect changes in the brain.

Abstract: In total, 96 subjects completed the study.

Abstract: Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at 6 months.

Abstract: DTI revealed significant correlations between the GMPM increment and changes in fractional anisotropy in the pUCB group.

Abstract: 18F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups.

Abstract: The incidence of serious adverse events did not differ between groups.

Abstract: In conclusion, UCB treatment ameliorated motor and cognitive dysfunction in children with CP undergoing active rehabilitation, accompanied by structural and metabolic changes in the brain.


Pituitary adenylate cyclase-activating polypeptide (PACAP(1-38)) enhances N-methyl-D-aspartate receptor function and brain-derived neurotrophic factor expression via RACK1.

Abstract: We recently identified a novel mechanism for modulation of the phosphorylation state and function of the N-methyl-d-aspartate (NMDA) receptor via the scaffolding protein RACK1.

Abstract: We found that RACK1 binds both the NR2B subunit of the NMDA receptor and the nonreceptor protein-tyrosine kinase, Fyn.

Abstract: RACK1 inhibits Fyn phosphorylation of NR2B and decreases NMDA receptor-mediated currents in CA1 hippocampal slices (Yaka, R., Thornton, C., Vagts, A. J., Phamluong, K., Bonci, A., and Ron, D. (2002) Proc.

Abstract: Natl.

Abstract: Acad.

Abstract: Sci.

Abstract: U. S. A. 99, 5710-5715).

Abstract: Here, we identified the signaling cascade by which RACK1 is released from the NMDA receptor complex and identified the consequences of the dissociation.

Abstract: We found that activation of the cAMP/protein kinase A pathway in hippocampal slices induced the release of RACK1 from NR2B and Fyn.

Abstract: This resulted in the induction of NR2B phosphorylation and the enhancement of NMDA receptor-mediated activity via Fyn.

Abstract: We identified the neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP(1-38)), as a ligand that induced phosphorylation of NR2B and enhanced NMDA receptor potentials.

Abstract: Finally, we found that activation of the cAMP/protein kinase A pathway induced the movement of RACK1 to the nuclear compartment in dissociated hippocampal neurons.

Abstract: Nuclear RACK1 in turn was found to regulate the expression of brain-derived neurotrophic factor induced by PACAP(1-38).

Abstract: Taken together our results suggest that activation of adenylate cyclase by PACAP(1-38) results in the release of RACK1 from the NMDA receptor and Fyn.

Abstract: This in turn leads to NMDA receptor phosphorylation, enhanced activity mediated by Fyn, and to the induction of brain-derived neurotrophic factor expression by RACK1.


MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signalling

Abstract: Nuclear factor-κB (NF-κB) is constitutively activated in diverse human malignancies by mechanisms that are not understood.

Abstract: The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and, similarly to NF-κB, blocks apoptosis and induces transformation.

Abstract: This study demonstrates that overexpression of MUC1 in human carcinoma cells is associated with constitutive activation of NF-κB p65.

Abstract: We show that MUC1 interacts with the high-molecular-weight IκB kinase (IKK) complex in vivo and that the MUC1 cytoplasmic domain binds directly to IKKβ and IKKγ.

Abstract: Interaction of MUC1 with both IKKβ and IKKγ is necessary for IKKβ activation, resulting in phosphorylation and degradation of IκBα.

Abstract: Studies in non-malignant epithelial cells show that MUC1 is recruited to the TNF-R1 complex and interacts with IKKβ–IKKγ in response to TNFα stimulation.

Abstract: TNFα-induced recruitment of MUC1 is dependent on TRADD and TRAF2, but not the death-domain kinase RIP1.

Abstract: In addition, MUC1-mediated activation of IKKβ is dependent on TAK1 and TAB2.

Abstract: These findings indicate that MUC1 is important for physiological activation of IKKβ and that overexpression of MUC1, as found in human cancers, confers sustained induction of the IKKβ–NF-κB p65 pathway.


Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes.

Abstract: Trihydroxytetraenes, a novel series of oxygenated derivatives formed from arachidonic acid in human leukocytes, were recently isolated [Serhan, C. N., Hamberg, M. & Samuelsson, B. (1984) Biochem.

Abstract: Biophys.

Abstract: Res.

Abstract: Commun.

Abstract: 118, 943-949].

Abstract: The structure of the major compound was established--i.e., 5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid.

Abstract: The present study reports the structure of a second member of the trihydroxytetraene series of compounds--i.e., 5D,14,15L-trihydroxy-6,8,10,12-icosatetraenoic acid.

Abstract: When added to human neutrophils, 5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid stimulated superoxide anion generation and degranulation at submicromolar concentrations without provoking a substantial aggregation response.

Abstract: With respect to superoxide anion generation, 5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid proved to be as potent as leukotriene B4.

Abstract: In contrast, the compound was approximately 2 orders of magnitude less potent than either leukotriene B4 or fMet-Leu-Phe at provoking degranulation.

Abstract: The results indicate that interaction(s) between the 5- and 15-lipoxygenase pathways of human leukocytes leads to formation of a new series of oxygenated derivatives of arachidonic acid that may be involved in regulating specific cellular responses.

Abstract: The trivial names lipoxin A (5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid) and lipoxin B (5D,14,15L-trihydroxy-6,8,10,12-icosatetraenoic acid) are proposed for the new compounds.


Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury.

Abstract: Besides synthesizing nitric oxide (NO), purified neuronal NO synthase (nNOS) can produce superoxide (.O2-) at lower L-Arg concentrations.

Abstract: By using electron paramagnetic resonance spin-trapping techniques, we monitored NO and .O2- formation in nNOS-transfected human kidney 293 cells.

Abstract: In control transfected cells, the Ca2+ ionophore A23187 triggered NO generation but no .O2- was seen.

Abstract: With cells in L-Arg-free medium, we observed .O2- formation that increased as the cytosolic L-Arg levels decreased, while NO generation declined.

Abstract: .O2- formation was virtually abolished by the specific NOS blocker, N-nitro-L-arginine methyl ester (L-NAME).

Abstract: Nitrotyrosine, a specific nitration product of peroxynitrite, accumulated in L-Arg-depleted cells but not in control cells.

Abstract: Activation by A23187 was cytotoxic to L-Arg-depleted, but not to control cells, with marked lactate dehydrogenase release.

Abstract: The cytotoxicity was largely prevented by either superoxide dismutase or L-NAME.

Abstract: Thus, with reduced L-Arg availability NOS elicits cytotoxicity by generating .O2- and NO that interact to form the potent oxidant peroxynitrite.

Abstract: Regulating arginine levels may provide a therapeutic approach to disorders involving .O2-/NO-mediated cellular injury.


Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach.

Abstract: The definition of sudden infant death syndrome (SIDS) originally appeared in 1969 and was modified 2 decades later.

Abstract: During the following 15 years, an enormous amount of additional information has emerged, justifying additional refinement of the definition of SIDS to incorporate epidemiologic features, risk factors, pathologic features, and ancillary test findings.

Abstract: An expert panel of pediatric and forensic pathologists and pediatricians considered these issues and developed a new general definition of SIDS for administrative and vital statistics purposes.

Abstract: The new definition was then stratified to facilitate research into sudden infant death.

Abstract: Another category, defined as unclassified sudden infant deaths, was introduced for cases that do not meet the criteria for a diagnosis of SIDS and for which alternative diagnoses of natural or unnatural conditions were equivocal.

Abstract: It is anticipated that these new definitions will be modified in the future to accommodate new understanding of SIDS and sudden infant death.


Inter-viral conflicts that exploit host CRISPR immune systems of Sulfolobus.

Abstract: Infection of Sulfolobus islandicus REY15A with mixtures of different Sulfolobus viruses, including STSV2, did not induce spacer acquisition by the host CRISPR immune system.

Abstract: However, coinfection with the tailed fusiform viruses SMV1 and STSV2 generated hyperactive spacer acquisition in both CRISPR loci, exclusively from STSV2, with the resultant loss of STSV2 but not SMV1.

Abstract: SMV1 was shown to activate adaptation while itself being resistant to CRISPR-mediated adaptation and DNA interference.

Abstract: Exceptionally, a single clone S-1 isolated from an SMV1 + STSV2-infected culture, that carried STSV2-specific spacers and had lost STSV2 but not SMV1, acquired spacers from SMV1.

Abstract: This effect was also reproducible on reinfecting wild-type host cells with a variant SMV1 isolated from the S-1 culture.

Abstract: The SMV1 variant lacked a virion protein ORF114 that was shown to bind DNA.

Abstract: This study also provided evidence for: (i) limits on the maximum sizes of CRISPR loci; (ii) spacer uptake strongly retarding growth of infected cultures; (iii) protospacer selection being essentially random and non-directional, and (iv) the reversible uptake of spacers from STSV2 and SMV1.

Abstract: A hypothesis is presented to explain the interactive conflicts between SMV1 and the host CRISPR immune system.


Lung Carcinogenesis by Diesel Exhaust Particles and the Carcinogenic Mechanism Via Active Oxygens.

Abstract: In an experiment to clarify the involvement of oxygen radicals in lung carcinogenesis induced by diesel exhaust particles (DEP), we found that there is a strong relation between lung tumor response and formation of 8-hydroxydeoxyguanosine (8-OHdG) in lung DNA of mice administered DEP by repeated intratracheal instillation.

Abstract: Repeated intratracheal instillation of DEP also induced the activity of cytochrome P-450 reductase in the lungs as a representative enzyme of superoxide generation, and two types of nitric oxide (NO) synthase, cNOS and iNOS, in the lungs.

Abstract: On the other hand, activities of CuZn-superoxide dismutase (SOD) and Mn-SOD antioxidant enzymes were depressed by the instillation of DEP.

Abstract: These results suggest that generation of superoxide, hydroxyI radical, and nitric oxide are increased in epithelial cells in airways, and that the increased superoxide and nitric oxide react very easily to produce peroxynitrite (ONOO(-)).

Abstract: The peroxynitrite also produce hydroxyI radical.

Abstract: The hydroxyl radical may play an important role in carcinogenesis by DEP.


Prion-induced amyloid heart disease with high blood infectivity in transgenic mice.

Abstract: We investigated extraneural manifestations in scrapie-infected transgenic mice expressing prion protein lacking the glycophosphatydylinositol membrane anchor.

Abstract: In the brain, blood, and heart, both abnormal protease-resistant prion protein (PrPres) and prion infectivity were readily detected by immunoblot and by inoculation into nontransgenic recipients.

Abstract: The titer of infectious scrapie in blood plasma exceeded 10(7) 50% infectious doses per milliliter.

Abstract: The hearts of these transgenic mice contained PrPres-positive amyloid deposits that led to myocardial stiffness and cardiac disease.


Circulating plasma microRNAs as a screening method for detection of colorectal adenomas.

Abstract: BACKGROUND MicroRNAs (miRNAs) are small non-coding RNA molecules.

Abstract: Reduced or increased levels of specific miRNAs are observed in colon and other cancers, supporting their role in carcinogenesis.

Abstract: Detection of colorectal polyps is the cornerstone of the Bowel Cancer Screening Programme in the UK.

Abstract: However, uptake of screening nationally remains under 60%.

Abstract: We aimed to see whether circulating plasma miRNAs can be used to screen for patients with colorectal polyps, adenomas, or both.

Abstract: METHODS Blood samples were taken from patients from the Bowel Cancer Screening Programme (asymptomatic but faecal occult blood testing [FOBt] positive).

Abstract: Plasma RNA was extracted, target miRNAs (19a, 98, 146b, 186, 191, 222*, 331-5p, 452, 625, 664, 1247) were identified on pooled case miRNA assay cards, and miRNA fraction was quantified by quantitative RT-PCR assay.

Abstract: Results were compared with endoscopy reports and with histology of any polyps identified and removed.

Abstract: Analysis was done with Excel (2011) and SPSS (version 20) software.

Abstract: FINDINGS 210 patients were included (117 with polyps, 12 with cancer, 81 healthy controls [FOBt positive]).

Abstract: The miRNA panel showed significant differences in expression (on t testing) for patients compared with controls for those with polyps, cancer, or both (miR-19a, p=0·0184; miR-98, p=0·0206; miR-146b, p=0·0029; miR-186, p=0·0006; miR-62,5 p=0·0008), polyps (miR-19a, p=0·0233; miR-98, p=0·0224; miR-146b, p=0·003; miR-186, p=0·0004; miR-625, p=0·001), adenomas (miR-19a, p=0·0339; miR-98, p=0·0266; miR-146b, p=0·0045; miR-186, p=0·0008; miR-625, p=0·0049), multiple adenomas (both sides of colon; miR-146b, p=0·0194; miR-186, p=0·0226; miR-625, p=0·0013), and right-sided adenomas (miR-98, p=0·031; miR-146b, p=0·0076; miR-186, p=0·0041; miR-331-5p, p=0·0142; miR-625, p=0·0049).

Abstract: Receiver operating characteristic analysis showed sensitivity of 60% or more, and specificity of 86% or more for men with polyps, men with adenomas, all patients with haemorrhoids or diverticulosis and polyps, and all patients with haemorrhoids or diverticulosis and adenomas.

Abstract: INTERPRETATION The target miRNAs that we identified showed significant differences in expression levels for patients with polyps and patients with adenomas from controls.

Abstract: Use of this panel has potential as a screening test.

Abstract: FUNDING Bowel Disease Research Foundation.


Short term persistence of human papillomavirus and risk of cervical precancer and cancer: population based cohort study

Abstract: OBJECTIVE To evaluate the cumulative incidence of cervical intraepithelial neoplasia II or worse (grade II+) or cervical intraepithelial neoplasia grade III+ after short term persistence of prevalently detected carcinogenic human papillomavirus (HPV).

Abstract: DESIGN Population based cohort study.

Abstract: SETTING Guanacaste, Costa Rica.

Abstract: PARTICIPANTS 2282 sexually active women actively followed after enrolment.

Abstract: MAIN OUTCOME MEASURES Primary end points: three year and five year cumulative incidence of histologically confirmed cervical intraepithelial neoplasia grade II+ (n=70).

Abstract: Cervical specimens collected at each visit tested for more than 40 HPV genotypes.

Abstract: HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82 were considered the primary carcinogenic genotypes.

Abstract: RESULTS Women who tested positive for a carcinogenic HPV at enrolment and after about one year (9-21 months) (positive/positive) had a three year cumulative incidence of cervical intraepithelial neoplasia grade II+ of 17.0% (95% confidence interval 12.1% to 22.0%).

Abstract: Those who tested negative/positive (3.4%, 0.1% to 6.8%), positive/negative (1.2%, -0.2% to 2.5%), and negative/negative (0.5%, 0.1% to 0.9%) were at a significantly lower risk.

Abstract: There was little difference in the cumulative incidence of cervical intraepithelial neoplasia grade II+ between testing positive twice for any carcinogenic HPV genotype (same genotype or different genotypes) v testing positive twice for the same carcinogenic genotype (17.0% v 21.3%, respectively).

Abstract: Short term persistence of HPV 16 strongly predicted cervical intraepithelial neoplasia grade II+, with a three year cumulative incidence of 40.8% (26.4% to 55.1%).

Abstract: Similar patterns were observed for the five year cumulative incidence of grade II+ and for three year and five year cumulative incidence of grade III+.

Abstract: CONCLUSIONS Short term persistence of a prevalently detected carcinogenic HPV infection, especially HPV 16, strongly predicts a subsequent diagnosis of cervical intraepithelial neoplasia II+ over the next few years.


Nature and anisotropy of cortical forces orienting Drosophila tissue morphogenesis

Abstract: The morphogenesis of developing embryos and organs relies on the ability of cells to remodel their contacts with neighbouring cells.

Abstract: Using quantitative modelling and laser nano-dissection, we probed the mechanics of a morphogenetic process, the elongation of Drosophila melanogaster embryos, which results from polarized cell neighbour exchanges.

Abstract: We show that anisotropy of cortical tension at apical cell junctions is sufficient to drive tissue elongation.

Abstract: We estimated its value through comparisons between in silico and in vivo data using various tissue descriptors.

Abstract: Nano-dissection of the actomyosin network indicates that tension is anisotropically distributed and depends on myosin II accumulation.

Abstract: Junction relaxation after nano-dissection also suggests that cortical elastic forces are dominant in this process.

Abstract: Interestingly, fluctuations in vertex position (points where three or more cells meet) facilitate neighbour exchanges.

Abstract: We delineate the contribution of subcellular tensile activity polarizing junction remodelling, and the permissive role of vertex fluctuations during tissue elongation.


The influence of some metabolic inhibitors on phagocytic activity of mouse macrophages in vitro.

Abstract: The action of different metabolic inhibitors on phagocytosis by macrophages from mouse peritoneal exudate cultured in vitro was studied.

Abstract: The following metabolic inhibitors were tested: sodium iodoacetate, sodium fluoride, sodium fluoroacetate, sodium malonate, 2-4-dinitrophenol, sodium azide, ouabain and cycloheximide, all at the concentration of 10(-3) M. Iodoacetate caused a strong inhibitory effect on phagocytosis; this observation confirms that glycolysis is the main source of energy for the phagocytic process.

Abstract: On the contrary, fluoride, although it is an effective inhibitor of glycolysis, did not exert any effect.

Abstract: This difference may be explained by the fact that sodium fluoride blocks anaerobic glycolysis only in vitro at an unphysiological temperature (0 degrees C).

Abstract: Fluoroacetate and malonate, two compounds which interfere with the Krebs cycle, did not inhibit phagocytosis, but it is known that the Krebs cycle activity is poorly developed in the macrophagic cells.

Abstract: Sodium azide and 2-4-dinitrophenol, two inhibitors of oxidative phosphorylation, showed an effect on phagocytosis only after 3 h of contact with the cell cultures.

Abstract: Ouabain blocks Na+ and K+ transport across the plasma membrane and, probably, it inhibited phagocytosis by interfering with the movements of the cell membrane.

Abstract: Finally, the mode of action of cycloheximide on phagocytosis is uncertain.

Abstract: This compound inhibits the protein synthesis and, perhaps, it can act by preventing the renewal of the cell membrane.


Two-tiered coupling between flowing actin and immobilized N-cadherin/catenin complexes in neuronal growth cones.

Abstract: Neuronal growth cones move forward by dynamically connecting actin-based motility to substrate adhesion, but the mechanisms at the individual molecular level remain unclear.

Abstract: We cultured primary neurons on N-cadherin-coated micropatterned substrates, and imaged adhesion and cytoskeletal proteins at the ventral surface of growth cones using single particle tracking combined to photoactivated localization microscopy (sptPALM).

Abstract: We demonstrate transient interactions in the second time scale between flowing actin filaments and immobilized N-cadherin/catenin complexes, translating into a local reduction of the actin retrograde flow.

Abstract: Normal actin flow on micropatterns was rescued by expression of a dominant negative N-cadherin construct competing for the coupling between actin and endogenous N-cadherin.

Abstract: Fluorescence recovery after photobleaching (FRAP) experiments confirmed the differential kinetics of actin and N-cadherin, and further revealed a 20% actin population confined at N-cadherin micropatterns, contributing to local actin accumulation.

Abstract: Computer simulations with relevant kinetic parameters modeled N-cadherin and actin turnover well, validating this mechanism.

Abstract: Such a combination of short- and long-lived interactions between the motile actin network and spatially restricted adhesive complexes represents a two-tiered clutch mechanism likely to sustain dynamic environment sensing and provide the force necessary for growth cone migration.


Cloning of factors related to HIV-inducible LBP proteins that regulate steroidogenic factor-1-independent human placental transcription of the cholesterol side-chain cleavage enzyme, P450scc.

Abstract: The cholesterol side-chain cleavage enzyme, cytochrome P450scc, initiates the biosynthesis of all steroid hormones.

Abstract: Adrenal and gonadal strategies for P450scc gene transcription are essentially identical and depend on the orphan nuclear receptor steroidogenic factor-1, but the placental strategy for transcription of P450scc employs cis-acting elements different from those used in the adrenal strategy and is independent of steroidogenic factor-1.

Abstract: Because placental expression of P450scc is required for human pregnancy, we sought factors that bind to the -155/-131 region of the human P450scc promoter, which participates in its placental but not adrenal or gonadal transcription.

Abstract: A yeast one-hybrid screen of 2.4 x 10(6) cDNA clones from human placental JEG-3 cells yielded two unique clones; one is the previously described transcription factor LBP-1b, which is induced by HIV, type I infection of lymphocytes, and the other is a new factor, termed LBP-9, that shares 83% amino acid sequence identity with LBP-1b.

Abstract: When expressed in transfected yeast, both factors bound specifically to the -155/-131 DNA; antisera to LBP proteins supershifted the LBP-9.DNA complex and inhibited formation of the LBP-1b.

Abstract: DNA complex.

Abstract: Reverse transcriptase-polymerase chain reaction detected LBP-1b in human placental JEG-3, adrenal NCI-H295A, liver HepG2, cervical HeLa, and monkey kidney COS-1 cells, but LBP-9 was detected only in JEG-3 cells.

Abstract: When the -155/-131 fragment was linked to a minimal promoter, co-expression of LBP-1b increased transcription 21-fold in a dose-dependent fashion, but addition of LBP-9 suppressed the stimulatory effect of LBP-1b.

Abstract: The roles of LBP transcription factors in normal human physiology have been unclear.

Abstract: Their modulation of placental but not adrenal P450scc transcription underscores the distinctiveness of placental strategies for steroidogenic enzyme gene transcription.


Functional reprogramming of polyploidization in megakaryocytes.

Abstract: Polyploidization is a natural process that frequently accompanies differentiation; its deregulation is linked to genomic instability and cancer.

Abstract: Despite its relevance, why cells select different polyploidization mechanisms is unknown.

Abstract: Here we report a systematic genetic analysis of endomitosis, a process in which megakaryocytes become polyploid by entering mitosis but aborting anaphase.

Abstract: Whereas ablation of the APC/C cofactor Cdc20 results in mitotic arrest and severe thrombocytopenia, lack of the kinases Aurora-B, Cdk1, or Cdk2 does not affect megakaryocyte polyploidization or platelet levels.

Abstract: Ablation of Cdk1 forces a switch to endocycles without mitosis, whereas polyploidization in the absence of Cdk1 and Cdk2 occurs in the presence of aberrant re-replication events.

Abstract: Importantly, ablation of these kinases rescues the defects in Cdc20 null megakaryocytes.

Abstract: These findings suggest that endomitosis can be functionally replaced by alternative polyploidization mechanisms in vivo and provide the cellular basis for therapeutic approaches aimed to discriminate mitotic and polyploid cells.


Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein.

Abstract: Enhancer of Zeste [E(z)] is a Polycomb-group transcriptional repressor and one of the founding members of the family of SET domain-containing proteins.

Abstract: Several SET-domain proteins possess intrinsic histone methyltransferase (HMT) activity.

Abstract: However, recombinant E(z) protein was found to be inactive in a HMT assay.

Abstract: Here we report the isolation of a multiprotein E(z) complex that contains extra sex combs, suppressor of zeste-12 [Su(z)12], and the histone binding proteins RbAp46/RbAp48.

Abstract: This complex, which we termed Polycomb repressive complex (PRC) 2, possesses HMT activity with specificity for Lys 9 (K9) and Lys 27 (K27) of histone H3.

Abstract: The HMT activity of PRC2 is dependent on an intact SET domain in the E(z) protein.

Abstract: We hypothesize that transcriptional repression by the E(z) protein involves methylation-dependent recruitment of PRC1.

Abstract: The presence of Su(z)12, a strong suppressor of position effect variegation, in PRC2 suggests that PRC2 may play a widespread role in heterochromatin-mediated silencing.


Simvastatin reduces platelet-endocardium adhesion in atrial fibrillation.

Abstract: OBJECTIVES To evaluate the relationship between CD40/CD40L system and increased thrombogenesis in AF, and to test the effects of simvastatin treatment.

Abstract: METHODS In vitro study using human tissue, University Hospital (tertiary referral center).

Abstract: Experiments on right atrial segments obtained before the onset of cardiopulmonary bypass were done in either presence or absence of 5 microM simvastatin.

Abstract: Two groups of patients in either chronic atrial fibrillation or sinus rhythm at the time of cardiac surgery.

Abstract: The endocardial expression of CD40, the release of CD40L, and adhesion of platelets to endocardium.

Abstract: Additionally, the thickness of platelet aggregates and the platelet distribution on the endocardium were also evaluated.

Abstract: RESULTS Atrial fibrillation was associated with a significant increase of endocardial CD40 expression (293.1+/-55.1 pg/ml vs. 230.9+/-53.3 pg/ml, p<0.01), and platelet-endocardial adhesion compared with sinus rhythm atria (10.8+/-2.2 vs. 5.2+/-1.3 platelet CD41 AU p<0.01).

Abstract: At immunofluorescence about 62% of fibrillating endocardium was covered by platelets, compared with 12% of not sinus rhythm atria.

Abstract: Addition of simvastatin significantly reduced CD40 expression as well as platelet adhesion to fibrillating atria; its efficacy was not reversed by the addition of mevalonic acid.

Abstract: CONCLUSIONS Chronic atrial fibrillation acutely upregulates CD40 expression as well as platelet adhesion to the endocardium.

Abstract: Simvastatin is effective in modulating this expression, thus it may potentially contribute to reduce the risk of intra-atrial thrombus formation.


Transmission of sporadic Creutzfeldt-Jakob disease by blood transfusion: risk factor or possible biases.

Abstract: BACKGROUND The occurrence of transfusion transmissions of variant Creutzfeldt-Jakob disease (CJD) cases has reawakened attention to the possible similar risk posed by other forms of CJD.

Abstract: STUDY DESIGN AND METHODS CJD with a definite or probable diagnosis (sporadic CJD, n = 741; genetic CJD, n = 175) and no-CJD patients with definite alternative diagnosis (n = 482) with available blood transfusion history were included in the study.

Abstract: The risk of exposure to blood transfusion occurring more than 10 years before disease onset and for some possible confounding factors was evaluated by calculating crude odds ratios (ORs).

Abstract: Variables with significant ORs in univariate analyses were included in multivariate logistic regression analyses.

Abstract: RESULTS In the univariate model, blood transfusion occurring more than 10 years before clinical onset is 4.1-fold more frequent in sporadic CJD than in other neurologic disorders.

Abstract: This significance is lost when the 10-year lag time was not considered.

Abstract: Multivariate analyses show that the risk of developing sporadic CJD after transfusion increases (OR, 5.05) after adjusting for possible confounding factors.

Abstract: Analysis conducted on patients with genetic CJD did not reveal any significant risk factor associated with transfusion.

Abstract: CONCLUSION This is the first case-control study showing a significant risk of transfusion occurring more than 10 years before clinical onset in sporadic CJD patients.

Abstract: It remains questionable whether the significance of these data is biologically plausible or the consequence of biases in the design of the study, but they counterbalance previous epidemiologic negative reports that might have overestimated the assessment of blood safety in sporadic CJD.


Advantages and pitfalls of fructosamine and glycated albumin in the diagnosis and treatment of diabetes.

Abstract: The efficient diagnosis and accurate monitoring of diabetic patients are cornerstones for reducing the risk of diabetic complications.

Abstract: The current diagnostic and prognostic strategies in diabetes are mainly based on two tests, plasma (or capillary) glucose and glycated hemoglobin (HbA1c).

Abstract: Nevertheless, these measures are not foolproof, and their clinical usefulness is biased by a number of clinical and analytical factors.

Abstract: The introduction of other indices of glucose homeostasis in clinical practice such as fructosamine and glycated albumin (GA) may be regarded as an attractive alternative, especially in patients in whom the measurement of HbA1c may be biased or even unreliable.

Abstract: These include patients with rapid changes of glucose homeostasis and larger glycemic excursions, and patients with red blood cell disorders and renal disease.

Abstract: According to available evidence, the overall diagnostic efficiency of GA seems superior to that of fructosamine throughout a broad range of clinical settings.

Abstract: The current method for measuring GA is also better standardized and less vulnerable to preanalytical variables than those used for assessing fructosamine.

Abstract: Additional advantages of GA over HbA1c are represented by lower reagent cost and being able to automate the GA analysis on many conventional laboratory instruments.

Abstract: Although further studies are needed to definitely establish that GA can complement or even replace conventional measures of glycemic control such as HbA1c, GA may help the clinical management of patients with diabetes in whom HbA1c values might be unreliable.


Catalytic-Independent Functions of PARP-1 Determine Sox2 Pioneer Activity at Intractable Genomic Loci.

Abstract: Pioneer transcription factors (TFs) function as genomic first responders, binding to inaccessible regions of chromatin to promote enhancer formation.

Abstract: The mechanism by which pioneer TFs gain access to chromatin remains an important unanswered question.

Abstract: Here we show that PARP-1, a nucleosome-binding protein, cooperates with intrinsic properties of the pioneer TF Sox2 to facilitate its binding to intractable genomic loci in embryonic stem cells.

Abstract: These actions of PARP-1 occur independently of its poly(ADP-ribosyl) transferase activity.

Abstract: PARP-1-dependent Sox2-binding sites reside in euchromatic regions of the genome with relatively high nucleosome occupancy and low co-occupancy by other transcription factors.

Abstract: PARP-1 stabilizes Sox2 binding to nucleosomes at suboptimal sites through cooperative interactions on DNA.

Abstract: Our results define intrinsic and extrinsic features that determine Sox2 pioneer activity.

Abstract: The conditional pioneer activity observed with Sox2 at a subset of binding sites may be a key feature of other pioneer TFs operating at intractable genomic loci.


Steroid regulation of C. elegans diapause, developmental timing, and longevity.

Abstract: Hormones play a critical role in driving major stage transitions and developmental timing events in many species.

Abstract: In the nematode C. elegans the steroid hormone receptor, DAF-12, works at the confluence of pathways regulating developmental timing, stage specification, and longevity.

Abstract: DAF-12 couples environmental and physiologic signals to life history regulation, and it is embedded in a rich architecture governing diverse processes.

Abstract: Here, we highlight the molecular insights, extraordinary circuitry, and signaling pathways governing life stage transitions in the worm and how they have yielded fundamental insights into steroid regulation of biological time.


A core subunit of Polycomb repressive complex 1 is broadly conserved in function but not primary sequence.

Abstract: Polycomb Group (PcG) proteins mediate heritable gene silencing by modifying chromatin structure.

Abstract: An essential PcG complex, PRC1, compacts chromatin and inhibits chromatin remodeling.

Abstract: In Drosophila melanogaster, the intrinsically disordered C-terminal region of PSC (PSC-CTR) mediates these noncovalent effects on chromatin, and is essential for viability.

Abstract: Because the PSC-CTR sequence is poorly conserved, the significance of its effects on chromatin outside of Drosophila was unclear.

Abstract: The absence of folded domains also made it difficult to understand how the sequence of PSC-CTR encodes its function.

Abstract: To determine the mechanistic basis and extent of conservation of PSC-CTR activity, we identified 17 metazoan PSC-CTRs spanning chordates to arthropods, and examined their sequence features and biochemical properties.

Abstract: PSC-CTR sequences are poorly conserved, but are all highly charged and structurally disordered.

Abstract: We show that active PSC-CTRs--which bind DNA tightly and inhibit chromatin remodeling efficiently--are distinguished from less active ones by the absence of extended negatively charged stretches.

Abstract: PSC-CTR activity can be increased by dispersing its contiguous negative charge, confirming the importance of this property.

Abstract: Using the sequence properties defined as important for PSC-CTR activity, we predicted the presence of active PSC-CTRs in additional diverse genomes.

Abstract: Our analysis reveals broad conservation of PSC-CTR activity across metazoans.

Abstract: This conclusion could not have been determined from sequence alignments.

Abstract: We further find that plants that lack active PSC-CTRs instead possess a functionally analogous PcG protein, EMF1.

Abstract: Thus, our study suggests that a disordered domain with dispersed negative charges underlies PRC1 activity, and is conserved across metazoans and plants.


Dietary status of trained female cyclists.

Abstract: Dietary status was evaluated in eight highly trained female cyclists.

Abstract: Each cyclist kept a 3-day weighed food record.

Abstract: Diets were analyzed for nutrient content using a computerized software package.

Abstract: Blood was also obtained and evaluated for hemoglobin, hematocrit, and albumin.

Abstract: For an athletic group, the cyclists' diets were found to be low in energy (85% RDA) and carbohydrate (4.4 gm/kg body weight per day).

Abstract: Mean daily dietary intakes were well below the RDAs for folacin (76% RDA), magnesium (81%), iron (59%), and zinc (48%).

Abstract: In addition, more than one-third of the cyclists failed to consume 67% of the RDA for the following micronutrients: pyridoxine, folacin, cobalamin, vitamin E, magnesium, iron, and zinc.

Abstract: Hemoglobin (135 gm/L), hematocrit (0.39), and albumin (45 gm/L) values were all normal, although most hemoglobin values were in the lower 50% of normal range.

Abstract: Foods such as meats, poultry, fish, beans, peas, and nuts were low or absent from the diets of most athletes.

Abstract: Dietary quality in this group of female cyclists could have been greatly improved with the addition of more of those foods.

Abstract: These athletes could benefit from nutrition education and diet counseling.


Regulation of Pax-3 expression in the dermomyotome and its role in muscle development.

Abstract: The segmented mesoderm in vertebrates gives rise to a variety of cell types in the embryo including the axial skeleton and muscle.

Abstract: A number of transcription factors containing a paired domain (Pax proteins) are expressed in the segmented mesoderm during embryogenesis.

Abstract: These include Pax-3 and a closely related gene, Pax-7, both of which are expressed in the segmental plate and in the dermomyotome.

Abstract: In this paper, we show that signals from the notochord pattern the expression of Pax-3, Pax-7 and Pax-9 in somites and the subsequent differentiation of cell types that arise from the somitic mesoderm.

Abstract: We directly assess the role of the Pax-3 gene in the differentiation of cell types derived from the dermomyotome by analyzing the development of muscle in splotch mouse embryos which lack a functional Pax-3 gene.

Abstract: A population of Pax-3-expressing cells derived from the dermomyotome that normally migrate into the limb are absent in homozygous splotch embryos and, as a result, limb muscles are lost.

Abstract: No abnormalities were detected in the trunk musculature of splotch embryos indicating that Pax-3 is necessary for the development of the limb but not trunk muscle.


Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium.

Abstract: Angiopoietin 2 (Ang2) was originally shown to be a competitive antagonist for Ang1 of the receptor tyrosine kinase Tie2 in endothelial cells (ECs).

Abstract: Since then, reports have conflicted on whether Ang2 is an agonist or antagonist of Tie2.

Abstract: Here we show that Ang2 functions as an agonist when Ang1 is absent but as a dose-dependent antagonist when Ang1 is present.

Abstract: Exogenous Ang2 activates Tie2 and the promigratory, prosurvival PI3K/Akt pathway in ECs but with less potency and lower affinity than exogenous Ang1.

Abstract: ECs produce Ang2 but not Ang1.

Abstract: This endogenous Ang2 maintains Tie2, phosphatidylinositol 3-kinase, and Akt activities, and it promotes EC survival, migration, and tube formation.

Abstract: However, when ECs are stimulated with Ang1 and Ang2, Ang2 dose-dependently inhibits Ang1-induced Tie2 phosphorylation, Akt activation, and EC survival.

Abstract: We conclude that Ang2 is both an agonist and an antagonist of Tie2.

Abstract: Although Ang2 is a weaker agonist than Ang1, endogenous Ang2 maintains a level of Tie2 activation that is critical to a spectrum of EC functions.

Abstract: These findings may reconcile disparate reports of Ang2's effect on Tie2, impact our understanding of endogenous receptor tyrosine kinase signal transduction mechanisms, and affect how Ang2 and Tie2 are targeted under conditions such as sepsis and cancer.


Bacteremia caused by a strain of Desulfovibrio related to the provisionally named Desulfovibrio fairfieldensis.

Abstract: Eight isolates of Desulfovibrio spp. have been obtained over 5 years from abdominal or brain abscesses or blood.

Abstract: Seven isolates were part of a mixed flora [corrected].

Abstract: One strain was isolated in pure culture from the blood of a patient with peritonitis of appendicular origin.

Abstract: According to the 16S rRNA gene sequences, this strain was close to Desulfovibrio fairfieldensis.

Abstract: The present report describes the fourth isolate of this recently described species to be isolated in pure culture or as a predominant part of the flora and to be associated with infectious processes.

Abstract: Thus, D. fairfieldensis may possess a higher pathogenic potential than other Desulfovibrio species.


Vitamin D: The "sunshine" vitamin.

Abstract: Vitamin D insufficiency affects almost 50% of the population worldwide.

Abstract: An estimated 1 billion people worldwide, across all ethnicities and age groups, have a vitamin D deficiency (VDD).

Abstract: This pandemic of hypovitaminosis D can mainly be attributed to lifestyle (for example, reduced outdoor activities) and environmental (for example, air pollution) factors that reduce exposure to sunlight, which is required for ultraviolet-B (UVB)-induced vitamin D production in the skin.

Abstract: High prevalence of vitamin D insufficiency is a particularly important public health issue because hypovitaminosis D is an independent risk factor for total mortality in the general population.

Abstract: Current studies suggest that we may need more vitamin D than presently recommended to prevent chronic disease.

Abstract: As the number of people with VDD continues to increase, the importance of this hormone in overall health and the prevention of chronic diseases are at the forefront of research.

Abstract: VDD is very common in all age groups.

Abstract: As few foods contain vitamin D, guidelines recommended supplementation at suggested daily intake and tolerable upper limit levels.

Abstract: It is also suggested to measure the serum 25-hydroxyvitamin D level as the initial diagnostic test in patients at risk for deficiency.

Abstract: Treatment with either vitamin D2 or vitamin D3 is recommended for deficient patients.

Abstract: A meta-analysis published in 2007 showed that vitamin D supplementation was associated with significantly reduced mortality.

Abstract: In this review, we will summarize the mechanisms that are presumed to underlie the relationship between vitamin D and understand its biology and clinical implications.


Cyclin D1 activation in B-cell malignancy: association with changes in histone acetylation, DNA methylation, and RNA polymerase II binding to both promoter and distal sequences.

Abstract: Cyclin D1 expression is deregulated by chromosome translocation in mantle cell lymphoma and a subset of multiple myeloma.

Abstract: The molecular mechanisms involved in long-distance gene deregulation remain obscure, although changes in acetylated histones and methylated CpG dinucleotides may be important.

Abstract: The patterns of DNA methylation and histone acetylation were determined at the cyclin D1 locus on chromosome 11q13 in B-cell malignancies.

Abstract: The cyclin D1 promoter was hypomethylated and hyperacetylated in expressing cell lines and patient samples, and methylated and hypoacetylated in nonexpressing cell lines.

Abstract: Domains of hyperacetylated histones and hypomethylated DNA extended over 120 kb upstream of the cyclin D1 gene.

Abstract: Interestingly, hypomethylated DNA and hyperacetylated histones were also located at the cyclin D1 promoter but not the upstream major translocation cluster region in cyclin D1-nonexpressing, nontumorigenic B and T cells.

Abstract: RNA polymerase II binding was demonstrated both at the cyclin D1 promoter and 3' immunoglobulin heavy-chain regulatory regions only in malignant B-cell lines with deregulated cyclin D1 expression.

Abstract: Our results suggest a model where RNA polymerase II bound at IgH regulatory sequences can activate the cyclin D1 promoter by either long-range polymerase transfer or tracking.


The physiological regulation of toll-like receptor expression and function in humans.

Abstract: Eleven mammalian toll-like receptors (TLRs 1-11) have been identified to date and are known to play a crucial role in the regulation of immune responses; however, the factors that regulate TLR expression and function in vivo are poorly understood.

Abstract: Therefore, in the present study, we investigated the physiological regulation of TLR expression and function in humans.

Abstract: To examine the influence of diurnal rhythmicity on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers (n = 8) at time points coinciding with the peak and nadir in the endogenous circulating cortisol concentration.

Abstract: While no diurnal rhythmicity in the expression of TLRs 1, 2, 4 or 9 was observed, the upregulation of costimulatory (CD80 and CD86) and antigen-presenting (MHC class II) molecules on CD14(+) monocytes following activation with specific TLR ligands was greater (P < 0.05) in samples obtained in the evening compared with the morning.

Abstract: To examine the influence of physical stress on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers (n = 11) at rest and following 1.5 h of strenuous exercise in the heat (34 degrees C).

Abstract: Strenuous exercise resulted in a decrease (P < 0.005) in the expression of TLRs 1, 2 and 4 on CD14(+) monocytes.

Abstract: Furthermore, the upregulation of CD80, CD86, MHC class II and interleukin-6 by CD14(+) monocytes following activation with specific TLR ligands was decreased (P < 0.05) in samples obtained following exercise compared with at rest.

Abstract: These results demonstrate that TLR function is subject to modulation under physiological conditions in vivo and provide evidence for the role of immunomodulatory hormones in the regulation of TLR function.