tbuckley/cabot-search huggingface dataset:
Mesalazine Reduces Mutations in Transforming Growth Factor β Receptor II and Activin Type II Receptor by Improvement of Replication Fidelity in Mononucleotide Repeats
Authors: Christoph Campregher, Clemens Honeder, Heekyung Chung, John M. Carethers, Christoph Gasche
Journal: Clinical Cancer Research (2010)

Mesalazine (5-aminosalicylic acid, 5-ASA) has chemopreventive properties in colitis-associated cancer. In vitro, it improves replication fidelity at (CA)13 microsatellites independent of mismatch repair proficiency. Therefore, 5-ASA might be advantageous in patients with hereditary nonpolyposis colorectal cancer. At this point, however, it is uncertain whether this improvement of replication fidelity is specific for (CA)13 repetitive sequences. Here, we tested the effect of 5-ASA on replication fidelity in mononucleotide, dinucleotide, and tetranucleotide repeats.HCT116 and HCT116+chr3 cells were transfected with pIREShyg2-EGFP reporter plasmids harboring the following microsatellites: A10, G10, (CA)13, (CA)26, (AAAG)17, poly-A tracts, and their flanking sequences of transforming growth factor beta receptor II (TGFBR2; A10) and activin type II receptor (ACVR2; A8). Stably transfected single-cell clones were selected, characterized by Southern blotting, sorted into six-well plates, and cultured with or without 5-ASA. Frameshift mutations that shift the enhanced green fluorescence protein into its proper reading frame were quantified by flow cytometry.In HCT116, 5-ASA reduced the mutant fraction at (CA)13 by 48.3%, at A10 by 35.6-43.6%, at G10 by 74.9-83.6%, and at (AAAG)17 by 37.6-44.4%. Similar results were observed in hMLH1-proficient HCT116+chr3 cells. Moreover, the presence of 5-ASA significantly reduced mutations in TGFBR2 (A10) and ACVR2 (A8) by 39.9% and 46.2%, respectively.5-ASA increases replication fidelity in mononucleotide, dinucleotide, and tetranucleotide repeats and reduces mutations in tumor suppressor genes TGFBR2 and ACVR2, a finding that may provoke in vivo studies for the prevention of colorectal cancer in hereditary nonpolyposis colorectal cancer.
Measuring intraepithelial lymphocytes, surface area, and volume of lamina propria in the jejunal mucosa of coeliac patients.
Authors: M Guix, J M Skinner, R Whitehead
Journal: Gut (1979)

An accurate morphometric method is described for quantifying the intraepithelial lymphocytes (IEL), the area of the epithelium, and the volume of the lamina propria in jejunal mucosa of coeliac patients. All measurements are related to a unit-length of muscularis mucosa which is unaltered by the disease process. The results show a significant decrease in the epithelial surface area and an increase in the volume of the lamina propria in coeliac jejunal mucosa compared with normal levels, even after treatment. The number of IEL is the same as normal before or after treatment. Other workers have shown an apparent increase in IEL in untreated disease which returns to normal levels after therapy. This discordance is explained and the importance of accurate quantitative methodology is stressed.
Prelamin A and lamin A appear to be dispensable in the nuclear lamina
Authors: L. G. Fong
Journal: Journal of Clinical Investigation (2006)

Lamin A and lamin C, both products of Lmna, are key components of the nuclear lamina. In the mouse, a deficiency in both lamin A and lamin C leads to slow growth, muscle weakness, and death by 6 weeks of age. Fibroblasts deficient in lamins A and C contain misshapen and structurally weakened nuclei, and emerin is mislocalized away from the nuclear envelope. The physiologic rationale for the existence of the 2 different Lmna products lamin A and lamin C is unclear, although several reports have suggested that lamin A may have particularly important functions, for example in the targeting of emerin and lamin C to the nuclear envelope. Here we report the development of lamin C-only mice (Lmna(LCO/LCO)), which produce lamin C but no lamin A or prelamin A (the precursor to lamin A). Lmna(LCO/LCO) mice were entirely healthy, and Lmna(LCO/LCO) cells displayed normal emerin targeting and exhibited only very minimal alterations in nuclear shape and nuclear deformability. Thus, at least in the mouse, prelamin A and lamin A appear to be dispensable. Nevertheless, an accumulation of farnesyl-prelamin A (as occurs with a deficiency in the prelamin A processing enzyme Zmpste24) caused dramatically misshapen nuclei and progeria-like disease phenotypes. The apparent dispensability of prelamin A suggested that lamin A-related progeroid syndromes might be treated with impunity by reducing prelamin A synthesis. Remarkably, the presence of a single Lmna(LCO) allele eliminated the nuclear shape abnormalities and progeria-like disease phenotypes in Zmpste24-/- mice. Moreover, treating Zmpste24-/- cells with a prelamin A-specific antisense oligonucleotide reduced prelamin A levels and significantly reduced the frequency of misshapen nuclei. These studies suggest a new therapeutic strategy for treating progeria and other lamin A diseases.
Is behavioral genetics ‘too-big-to-know’ science?
Authors: Marco Battaglia
Journal: Behavioral and Brain Sciences (2012)

Abstract Several new molecular findings and concepts furnish evidence in support of gene–environment interdependence, challenging some of the current tenets and basic statistics of behavioral genetics. I, however, argue that (1) some of the expectations evoked by “neogenomics” are contradicted by findings; and (2) while epigenetic and gene expression effects are complex, they can to some extent be incorporated into “classical” behavioral genetics modeling.
Prostanoid secretion by rat hepatic sinusoidal endothelial cells and its regulation by exogenous adenosine triphosphate
Authors: Naoaki Hashimoto, Tsuyoshi Watanabe, Yasushi Shiratori, Yusei Ikeda, Hirokazu Kato, Katsuken Han, Haruki Yamada, Gotaro Toda, Kiyoshi Kurokawa
Journal: Hepatology (1995)

We investigated the secretory profiles of prostanoids in two types of nonparenchymal cell from the rat liver, sinusoidal endothelial cells and Kupffer cells, in primary culture both under basal conditions and after stimulation with adenine nucleotides. Prostaglandin (PG) E2 was the main prostanoid secreted by both types of hepatic nonparenchymal cell in the basal and adenosine triphosphate (ATP)-stimulated states. Time- and concentration-dependent effects of ATP-mediated PGE2 secretion were noted in sinusoidal endothelial cells, whereas the profile of the relative potencies of individual nucleotides was consistent with the presence of P2y and P1 purinergic receptors. In Kupffer cells, the regulation of prostanoid secretion by adenine nucleotides was essentially the same as that in sinusoidal endothelial cells except that adenosine did not stimulate prostanoid secretion and that prostanoid secretion differed somewhat; Kupffer cells secreted relatively more PGF2 alpha and less 6-keto-PGF1 alpha than sinusoidal endothelial cells in the presence of ATP, suggesting the presence of only P2y receptors. In summary, PGE2 is the main prostanoid secreted by hepatic nonparenchymal cells and its secretion may be stimulated by adenine nucleotides and adenosine.
Down-regulation of sphingosine 1-phosphate receptor-1 in intestinal tumorigenesis
Authors: Sabino Zani, Michiko Momoi, Ji-Hye Paik, Tim Hla, Wayne A. I. Frederick
Journal: Clinical Cancer Research (2006)

A17   Introduction: The bioactive sphingolipid, Sphingosine 1-Phosphate (S1P) is implicated in the regulation of cellular proliferation, migration, and survival via its G protein-coupled receptors S1P1-5. While animal models of intestinal neoplasia have demonstrated a beneficial effect of dietary sphingolipids in chemoprevention, the role of S1P in colon cancer is still unclear. The purpose of this study was to help define the role of the S1P receptor-ligand system in colon cancer.Methods: Small intestine specimens of bigenic S1P1+/-Apcmin and S1P1+/+Apcmin mice were compared to determine effect of S1P1 heterozygosity on polyp number. Growth inhibition of RIE-1 cells was assessed using enforced expression of S1P1 receptor by adenoviral vector followed by treatment with S1P. Matched human normal and cancer colon tissue were obtained from surgical specimens. Differential expression of S1P1 between the tissues was evaluated utilizing western blot analysis and immunohistochemistry.Results: Bigenic S1P1+/-Apcmin mice revealed a 27% increase in polyp number when compared to control mice. Induced expression of S1P1 in RIE-1 cells caused growth inhibition with treatment of S1P. Western blot analysis and immunohistochemistry revealed an increased expression of S1P1 in the human normal tissue as compared with tumor tissue.Conclusions: Our results suggest that S1P1 receptor functions in the intestinal epithelium to inhibit tumorigenesis. Down-regulation of S1P1 in colorectal cancer may have functional consequences in the proliferation and or metastatic spread of cancer. Further evaluation of Sphingosine 1-phosphate receptor-1 is necessary to determine its potential for therapeutic intervention in colon cancer.
p38 Mitogen-Activated Protein Kinase Activates eNOS in Endothelial Cells by an Estrogen Receptor α-Dependent Pathway in Response to Black Tea Polyphenols
Authors: Elad Anter, Kai Chen, Oz M. Shapira, Richard H. Karas, John F. Keaney
Journal: Circulation Research (2005)

Black tea has been shown to improve endothelial function in patients with coronary artery disease and recent data indicate the polyphenol fraction of black tea enhances endothelial nitric oxide synthase (eNOS) activity through p38 MAP kinase (p38 MAPK) activation. Because the mechanisms for this phenomenon are not yet clear, we sought to elucidate the signaling events in response to black tea polyphenols. Bovine aortic endothelial cells (BAECs) exposed to black tea polyphenols demonstrated eNOS activation that was inhibited by the estrogen receptor (ER) antagonist ICI 182,780, and siRNA-mediated silencing of ER expression. Consistent with this observation, black tea polyphenols induced time-dependent phosphorylation of ERalpha on Ser-118 that was inhibited by ICI 182,780. Phosphorylation of ERalpha on Ser-118 was due to p38 MAP kinase (p38 MAPK) as, it was inhibited by SB203580 and overexpression of dominant-negative p38alpha MAPK. Conversely, constitutively active MKK6 induced p38 MAPK activation that recapitulated the effects of polyphenols by inducing ERalpha phosphorylation and downstream activation of Akt, and eNOS. The key role of ERalpha Ser-118 phosphorylation was confirmed in eNOS-transfected COS-7 cells, as polyphenol-induced eNOS activation required cotransfection with ERalpha subject to phosphorylation at Ser-118. This residue appeared critical for functional association of ERalpha with p38 MAPK as ERalpha with Ser-118 mutated to alanine could not form a complex with p38 MAPK. These findings suggest p38 MAP kinase-mediated eNOS activation requires ERalpha and these data uncover a new mechanism of ERalpha activation that has broad implications for NO bioactivity and endothelial cell phenotype.
Guidance on reporting under age sex is confusing
Authors: Rebecca Coombes
Journal: BMJ (2005)

The BMA is reporting a surge in telephone calls from doctors who are confused about new guidance that compels health professionals to report evidence of under age sexual activity to social workers and the police. Doctors are concerned that new guidance, already in use in some areas, does away with a child's right to confidential sexual health advice and could lead to an increase in under age pregnancies and sexually transmitted infections.

A number of area child protection committees have issued protocols, including the London Child Protection Committee, which covers all London boroughs, and Sheffield City Council. In parallel, the government is examining proposals to change the current national child protection guidance, Working Together to Safeguard Children , and compel health professionals to report all sexual activity in under …
CCR6 is expressed on an IL-10–producing, autoreactive memory T cell population with context-dependent regulatory function
Authors: Laura Rivino, Paola Gruarin, Barbara Häringer, Svenja Steinfelder, Laura Lozza, Bodo Steckel, Anja Weick, Elisa Sugliano, David Jarrossay, Anja A. Kühl, Christoph Loddenkemper, Sergio Abrignani, Federica Sallusto, Antonio Lanzavecchia, Jens Geginat
Journal: The Journal of Experimental Medicine (2010)

Interleukin (IL)-10 produced by regulatory T cell subsets is important for the prevention of autoimmunity and immunopathology, but little is known about the phenotype and function of IL-10–producing memory T cells. Human CD4+CCR6+ memory T cells contained comparable numbers of IL-17– and IL-10–producing cells, and CCR6 was induced under both Th17-promoting conditions and upon tolerogenic T cell priming with transforming growth factor (TGF)–β. In normal human spleens, the majority of CCR6+ memory T cells were in the close vicinity of CCR6+ myeloid dendritic cells (mDCs), and strikingly, some of them were secreting IL-10 in situ. Furthermore, CCR6+ memory T cells produced suppressive IL-10 but not IL-2 upon stimulation with autologous immature mDCs ex vivo, and secreted IL-10 efficiently in response to suboptimal T cell receptor (TCR) stimulation with anti-CD3 antibodies. However, optimal TCR stimulation of CCR6+ T cells induced expression of IL-2, interferon-γ, CCL20, and CD40L, and autoreactive CCR6+ T cell lines responded to various recall antigens. Notably, we isolated autoreactive CCR6+ T cell clones with context-dependent behavior that produced IL-10 with autologous mDCs alone, but that secreted IL-2 and proliferated upon stimulation with tetanus toxoid. We propose the novel concept that a population of memory T cells, which is fully equipped to participate in secondary immune responses upon recognition of a relevant recall antigen, contributes to the maintenance of tolerance under steady-state conditions.
Balloon Angioplasty in Acute and Chronic Coronary Artery Disease
Authors: D R Holmes, R E Vlietstra
Journal: JAMA (1989)

Percutaneous transluminal coronary angioplasty has grown exponentially since its introduction. Currently, selection criteria include single-vessel and multivessel disease, stable and unstable angina, and acute infarction. The outcome depends on specific patient and angiographic characteristics. In ideal lesions, success rates should be greater than 90%, with low morbidity and mortality. With more severe and diffuse multivessel disease, success rates are lower and complication rates are higher. In these cases, percutaneous transluminal coronary angioplasty still offers a reasonable option, provided complete revascularization can be achieved or the angina-producing lesion dilated. Numerous issues remain unresolved, including (1) the role of percutaneous transluminal coronary angioplasty vs coronary surgery (currently being tested), (2) restenosis, which occurs in approximately 30% of treated lesions, and (3) organizational adjustments such as training and certification to maintain high standards of care. (<i>JAMA</i>. 1989;261:2109-2115)
How to read a forest plot in a meta-analysis:
Authors: Philip Sedgwick
Journal: BMJ (2015)

Researchers undertook a meta-analysis of the effect of treating Helicobacter pylori with eradication therapy on the subsequent occurrence of gastric cancer. Randomised controlled trials were included if the intervention consisted of seven days or more of eradication therapy, and if the control treatment was placebo or no treatment. Participants were adults who tested positive for H pylori . They were otherwise healthy and asymptomatic at baseline and were followed for two or more years. The primary outcome was the diagnosis of gastric cancer.1

Six randomised controlled trials were eligible for inclusion. The results of the meta-analysis comparing the intervention with control treatment in the occurrence of gastric cancer were presented in a forest plot (figure⇓). Fifty one (1.6%) gastric cancers occurred in 3294 participants who received eradication therapy compared with 76 (2.4%) in 3203 control subjects (relative risk 0.66, 95% confidence interval 0.46 to 0.95).



Forest plot of randomised controlled trials of Helicobacter pylori eradication therapy: effect on subsequent occurrence of gastric cancer



Which of the following statements, if any, are true?

Statements b and d are true, whereas a , c, and e are false.

The aim of the meta-analysis was to combine the results of trials that investigated the effectiveness …
Does a centralized radiotherapy system provide adequate access to care?
Authors: W J Mackillop, P A Groome, J Zhang-Solomons, Y Zhou, D Feldman-Stewart, L Paszat, P Dixon, E J Holowaty, B J Cummings
Journal: Journal of Clinical Oncology (1997)

PURPOSE In the Canadian province of Ontario, all radiotherapy is provided by a centrally managed provincial network of nine cancer centers. The primary goal of this study was to determine whether this highly centralized radiotherapy system provides adequate and equitable access to care for the province's dispersed population. METHODS The Ontario Cancer Registry (OCR) was used to identify 295,386 cases of invasive cancer, excluding nonmelanoma skin cancer, which were diagnosed in Ontario between 1984 and 1991. Electronic radiotherapy records from each of the province's radiotherapy centers were linked to the registry at the level of the individual case. RESULTS The proportion of incident cases treated with radiotherapy was 18.8% at 4 months after diagnosis, 23.7% at 1 year, 25.8% at 2 years, 28.2% at 5 years, and 29.1% at 8 years. These rates of radiotherapy use are much lower than the accepted national and international targets, and lower than rates reported from other jurisdictions. The rate of radiotherapy use at 1 year varied significantly from county to county across Ontario (range, 18.6% to 32.4%; P &lt; 10(-6)), and the highest rates were recorded in communities close to radiotherapy centers. There was a common geographic pattern of rate variations among several disease groups, including breast cancer, lung cancer, the genitourinary malignancies, and the gastrointestinal malignancies. CONCLUSION The low and uneven rates of radiotherapy use across the province indicate that Ontario's centralized radiotherapy system does not, at present, provide adequate or equitable access to care.
Type I interferons protect neonates from acute inflammation through interleukin 10–producing B cells
Authors: Xiaoming Zhang, Edith Deriaud, Xinan Jiao, Deborah Braun, Claude Leclerc, Richard Lo-Man
Journal: The Journal of Experimental Medicine (2007)

Newborns and infants are highly susceptible to viral and bacterial infections, but the underlying mechanism remains poorly understood. We show that neonatal B cells effectively control the production of proinflammatory cytokines by both neonatal plasmacytoid and conventional dendritic cells, in an interleukin (IL) 10–dependent manner, after Toll-like receptor (TLR) 9 triggering. This antiinflammatory property of neonatal B cells may extend to other TLR agonists (Pam3CSK4, lipopolysaccharide, and R848) and viruses. In the absence of B cells or of CD5+ B cell subsets, neonatal mice developed stronger inflammatory responses and became lethally susceptible to CpG challenge after galactosamine sensitization, whereas wild-type (WT) mice were resistant. Paradoxically, interferon (IFN)-α/β enhanced the inflammatory response to CpG challenge in adult mice, whereas they helped to control neonatal acute inflammation by stimulating the secretion of IL-10 by neonatal B cells. Finally, WT neonatal B cells rescued IL-10−/− neonates from a lethal CpG challenge, whereas IFN-α/β receptor–deficient B cells did not. Our results show that type I IFNs support a negative regulatory role of neonatal B cells on TLR-mediated inflammation, with important implications for neonatal inflammation and infection.
Gene Therapy of a Mouse Model of Protoporphyria with a Self-Inactivating Erythroid-Specific Lentiviral Vector without Preselection
Authors: Emmanuel Richard, Manuel Mendez, Fréderic Mazurier, Carine Morel, Pierre Costet, Ping Xia, Antonio Fontanellas, Fabien Geronimi, Muriel Cario-André, Laurence Taine, Cecile Ged, Punam Malik, Hubert de Verneuil, François Moreau-Gaudry
Journal: Molecular Therapy (2001)

Successful treatment of blood disorders by gene therapy has several complications, one of which is the frequent lack of selective advantage of genetically corrected cells. Erythropoietic protoporphyria (EPP), caused by a ferrochelatase deficiency, is a good model of hematological genetic disorders with a lack of spontaneous in vivo selection. This disease is characterized by accumulation of protoporphyrin in red blood cells, bone marrow, and other organs, resulting in severe skin photosensitivity. Here we develop a self-inactivating lentiviral vector containing human ferrochelatase cDNA driven by the human ankyrin-1/beta-globin HS-40 chimeric erythroid promoter/enhancer. We collected bone marrow cells from EPP male donor mice for lentiviral transduction and injected them into lethally irradiated female EPP recipient mice. We observed a high transduction efficiency of hematopoietic stem cells resulting in effective gene therapy of primary and secondary recipient EPP mice without any selectable system. Skin photosensitivity was corrected for all secondary engrafted mice and was associated with specific ferrochelatase expression in the erythroid lineage. An erythroid-specific expression was sufficient to reverse most of the clinical and biological manifestations of the disease. This improvement in the efficiency of gene transfer with lentiviruses may contribute to the development of successful clinical protocols for erythropoietic diseases.