tbuckley/cabot-search huggingface dataset:
Rapid Divergence of Gene Duplicates on the Drosophila melanogaster X Chromosome
Authors: Kevin Thornton, Manyuan Long
Journal: Molecular Biology and Evolution (2002)

The recent sequencing of several eukaryotic genomes has generated considerable interest in the study of gene duplication events. The classical model of duplicate gene evolution is that recurrent mutation ultimately results in one copy becoming a pseudogene, and only rarely will a beneficial new function evolve. Here, we study divergence between coding sequence duplications in Drosophila melanogaster as a function of the linkage relationship between paralogs. The mean Ka/Ks between all duplicates in the D. melanogaster genome is 0.2803, indicating that purifying selection is maintaining the structure of duplicate coding sequences. However, the mean Ka/Ks between duplicates that are both on the X chromosome is 0.4701, significantly higher than the genome average. Further, the distribution of Ka/Ks for these X-linked duplicates is significantly shifted toward higher values when compared with the distributions for paralogs in other linkage relationships. Two models of molecular evolution provide qualitative explanations of these observations—relaxation of selective pressure on the duplicate copies and, more likely, positive selection on recessive adaptations. We also show that there is an excess of X-linked duplicates with low Ks, suggesting a larger proportion of relatively young duplicates on the D. melanogaster X chromosome relative to autosomes.
Light In and Sound Out: Emerging Translational Strategies for Photoacoustic Imaging
Authors: S. Zackrisson, S.M.W.Y. van de Ven, S.S. Gambhir
Journal: Cancer Research (2014)

Abstract Photoacoustic imaging (PAI) has the potential for real-time molecular imaging at high resolution and deep inside the tissue, using nonionizing radiation and not necessarily depending on exogenous imaging agents, making this technique very promising for a range of clinical applications. The fact that PAI systems can be made portable and compatible with existing imaging technologies favors clinical translation even more. The breadth of clinical applications in which photoacoustics could play a valuable role include: noninvasive imaging of the breast, sentinel lymph nodes, skin, thyroid, eye, prostate (transrectal), and ovaries (transvaginal); minimally invasive endoscopic imaging of gastrointestinal tract, bladder, and circulating tumor cells (in vivo flow cytometry); and intraoperative imaging for assessment of tumor margins and (lymph node) metastases. In this review, we describe the basics of PAI and its recent advances in biomedical research, followed by a discussion of strategies for clinical translation of the technique. Cancer Res; 74(4); 979–1004. ©2014 AACR.
Intrapulmonary IFN-β Gene Therapy Using an Adenoviral Vector Is Highly Effective in a Murine Orthotopic Model of Bronchogenic Adenocarcinoma of the Lung
Authors: Michael J. Wilderman, Jing Sun, Arminder S. Jassar, Veena Kapoor, Mohamed Khan, Anil Vachani, Eiji Suzuki, Paul A. Kinniry, Daniel H. Sterman, Larry R. Kaiser, Steven M. Albelda
Journal: Cancer Research (2005)

Abstract Given previous work showing that an adenoviral vector expressing IFN-β (Ad.IFNβ) was highly effective in eradicating i.p. mesothelioma tumors, the antitumor efficacy of this agent was evaluated in an orthotopic model of bronchogenic adenocarcinoma of the lung. These transgenic mice have a conditionally expressed, oncogenic K-rasG12D allele that can be activated by intratracheal administration of an adenovirus expressing Cre recombinase (Ad.Cre). K-rasG12D mutant mice were given Ad.Cre intranasally to activate the oncogene. Mice were then given 109 plaque-forming units of a control vector (Ad.LacZ) or Ad.IFNβ intranasally 3 and 4 weeks later, a time when lung tumors had been established. Cells derived from K-ras-mutated lung tumors were also grown in the flanks of mice to study mechanisms of therapeutic responses. In two separate experiments, untreated tumor-bearing mice all died by day 57 (median survival, 49 days). Ad.LacZ-treated mice all died by day 71 (median survival, 65 days). In contrast, 90% to 100% of mice treated with Ad.IFNβ were long-term survivors (&amp;gt;120 days; P &amp;lt; 0.001). In addition, immunity to re-challenge with tumor cells was induced. In vitro and flank tumor studies showed that Ad.IFNβ induced direct tumor cell killing and that depleting natural killer or CD8+ T cells, but not CD4+ T cells, with antibodies attenuated the effect of Ad.IFNβ. These studies, showing remarkable antitumor activity in this orthotopic lung cancer model, provide strong preclinical support for a trial of Ad.IFNβ to treat human non–small cell lung cancer.
E-Cadherin Regulates the Association between β-Catenin and Actinin-4
Authors: Yasuharu Hayashida, Kazufumi Honda, Masashi Idogawa, Yoshinori Ino, Masaya Ono, Akihiko Tsuchida, Tatsuya Aoki, Setsuo Hirohashi, Tesshi Yamada
Journal: Cancer Research (2005)

Abstract The E-cadherin/catenin system acts as an invasion suppressor of epithelial malignancies. This invasion suppressive activity seems be mediated not only by the cell adhesive activity of E-cadherin but by other undetermined signaling pathways elicited by β-catenin. In fact, cancer cells that have infiltrated the stroma reduce the expression of E-cadherin and accumulate β-catenin. We attempted to identify the alternative partner proteins that make complexes with β-catenin in the absence of E-cadherin. An ∼100-kDa protein was constantly coimmunoprecipitated with β-catenin from SW480 colorectal cancer cells, which lack the expression of E-cadherin, and was identified as actinin-4 by mass spectrometry. Transfection of E-cadherin cDNA suppressed the association between β-catenin and actinin-4. Inhibition of E-cadherin by RNA interference transferred the β-catenin and actinin-4 proteins into the membrane protrusions of DLD-1 cells. Immunofluorescence histochemistry of clinical colorectal cancer specimens showed that the β-catenin and actinin-4 proteins were colocalized in colorectal cancer cells infiltrating the stroma. We reported previously that overexpression of actinin-4 induces cell motility and specifically promotes lymph node metastasis by colorectal cancer. The association between β-catenin and actinin-4 and its regulation by E-cadherin may represent a novel molecular link connecting cell adhesion and motility. Shutting down the signals mediating this association may be worth considering as a therapeutic approach to cancer invasion and metastasis.
Is pancreaticodoudenectomy with vascular resection a safe procedure in developing country? Early outcomes and review of national literature
Authors: Faisal Saud Dar, Abu Bakar Hafeez Bhatti, Abdul Wahab Dogar, Haseeb Zia, Ihsan Ulhaq, Atif Rana, Nasir Ayub Khan, Amna Liaqat, Muhammad Salih, Najmul Hassan Shah
Journal: International Journal of Surgery (2015)
Treatment of malignant obstruction of the superior vena cava with the self-expanding Wallstent.
Authors: K W Stock, A L Jacob, M Proske, C T Bolliger, C Rochlitz, W Steinbrich
Journal: Thorax (1995)

Obstruction of the superior vena cava (SVC) in malignant disease can cause considerable distress to patients. Symptomatic relief can be achieved by the percutaneous implantation of a self-expanding stent (Wallstent) into the stenosis.Fourteen patients with obstruction of the SVC were treated with one to three Wallstent endoprostheses. They suffered from advanced bronchogenic carcinoma (n = 12), thyroid carcinoma (n = 1), and breast carcinoma (n = 1). The indication for stent placement was symptomatic obstruction of the SVC and incurable disease. Stenting was performed for symptom relief, and before, during, and after courses of radiotherapy or chemotherapy as needed.Twelve patients experienced complete symptomatic relief within two days of stent placement. Two patients did not benefit. Three patients not given anticoagulation developed stent thrombosis between one week and eight months after initial placement, and within one day of endobronchial stent implantation with bronchial laser therapy or balloon dilatation in all three. Patency of the SVC was achieved again by a repeat procedure.Stent placement for obstruction of the SVC gives rapid symptomatic relief. Subsequent endobronchial stent implantation with bronchial laser therapy or balloon dilatation could be a risk for caval stent occlusion. Stent thrombosis remains a problem in patients who are not anticoagulated.
EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer
Authors: Xiaofeng Lin, Shuangshuang Zhong, Xiaofeng Ye, Yueling Liao, Feng Yao, Xiaohua Yang, Beibei Sun, Jie Zhang, Qi Li, Yong Gao, Yifan Wang, Jingyi Liu, Baohui Han, Y Eugene Chin, Binhua P Zhou, Jiong Deng
Journal: Molecular Cancer (2014)

GPRC5A is a retinoic acid inducible gene that is preferentially expressed in lung tissue. Gprc5a- knockout mice develop spontaneous lung cancer, indicating Gprc5a is a lung tumor suppressor gene. GPRC5A expression is frequently suppressed in majority of non-small cell lung cancers (NSCLCs), however, elevated GPRC5A is still observed in a small portion of NSCLC cell lines and tumors, suggesting that the tumor suppressive function of GPRC5A is inhibited in these tumors by an unknown mechanism.In this study, we examined EGF receptor (EGFR)-mediated interaction and tyrosine phosphorylation of GPRC5A by immunoprecipitation (IP)-Westernblot. Tyrosine phosphorylation of GPRC5A by EGFR was systematically identified by site-directed mutagenesis. Cell proliferation, migration, and anchorage-independent growth of NSCLC cell lines stably transfected with wild-type GPRC5A and mutants defective in tyrosine phosphorylation were assayed. Immunohistochemical (IHC) staining analysis with specific antibodies was performed to measure the total and phosphorylated GPRC5A in both normal lung and lung tumor tissues.We found that EGFR interacted with GPRC5A and phosphorylated it in two conserved double-tyrosine motifs, Y317/Y320 and Y347/ Y350, at the C-terminal tail of GPRC5A. EGF induced phosphorylation of GPRC5A, which disrupted GPRC5A-mediated suppression on anchorage-independent growth of NSCLC cells. On contrary, GPRC5A-4 F, in which the four tyrosine residues have been replaced with phenylalanine, was resistant to EGF-induced phosphorylation and maintained tumor suppressive activities. Importantly, IHC analysis with anti-Y317/Y320-P sites showed that GPRC5A was non-phosphorylated in normal lung tissue whereas it was highly tyrosine-phosphorylated in NSCLC tissues.GPRC5A can be inactivated by receptor tyrosine kinase via tyrosine phosphorylation. Thus, targeting EGFR can restore the tumor suppressive functions of GPRC5A in lung cancer.
Interleukin 10 promoter region polymorphisms and susceptibility to advanced alcoholic liver disease
Authors: J Grove
Journal: Gut (2000)

<h3>BACKGROUND</h3> The factors determining why less than 10% of heavy drinkers develop advanced alcoholic liver disease (ALD) remain elusive, although genetic factors may be important. Interleukin 10 (IL-10) is an important cytokine with anti-inflammatory, anti-immune, and antifibrotic functions. Several polymorphisms have been identified in the IL-10 promoter and recent evidence suggests that some of these may have functional effects on IL-10 secretion. <h3>AIMS</h3> To test the hypothesis that IL-10 promoter region polymorphisms are associated with susceptibility to ALD. <h3>METHODS</h3> The allele frequencies for the two single base pair substitutions at positions −627 (C→A) and −1117 (A→G) in the IL-10 promoter were determined in 287 heavy drinkers with biopsy proved advanced ALD, 107 heavy drinkers with no evidence of liver disease or steatosis only on biopsy, and 227 local healthy volunteers. <h3>RESULTS</h3> At position −627, 50% of patients with advanced ALD had a least one A allele compared with 33% of controls (p&lt;0.0001) and 34% of drinkers with no or mild disease (p=0.017). At position −1117, the slight excess of the A allele in drinkers with advanced disease was because of linkage disequilibrium between the A alleles at the two sites. <h3>CONCLUSIONS</h3> Among heavy drinkers, possession of the A allele at position −627 in the IL-10 promoter is associated with an increased risk of advanced liver disease. This is consistent with recent functional data that the −627*A allele is associated with low IL-10 expression which will favour inflammatory, immune mediated, and profibrotic mechanisms of alcohol related liver injury.
Convergent Targeting of a Common Host Protein-Network by Pathogen Effectors from Three Kingdoms of Life
Authors: Ralf Weßling, Petra Epple, Stefan Altmann, Yijian He, Li Yang, Stefan R. Henz, Nathan McDonald, Kristin Wiley, Kai Christian Bader, Christine Gläßer, M. Shahid Mukhtar, Sabine Haigis, Lila Ghamsari, Amber E. Stephens, Joseph R. Ecker, Marc Vidal, Jonathan D.G. Jones, Klaus F.X. Mayer, Emiel Ver Loren van Themaat, Detlef Weigel, Paul Schulze-Lefert, Jeffery L. Dangl, Ralph Panstruga, Pascal Braun
Journal: Cell Host & Microbe (2014)
Intravital FLIM-FRET Imaging Reveals Dasatinib-Induced Spatial Control of Src in Pancreatic Cancer
Authors: Max Nobis, Ewan J. McGhee, Jennifer P. Morton, Juliane P. Schwarz, Saadia A. Karim, Jean Quinn, Mike Edward, Andrew D. Campbell, Lynn C. McGarry, T.R. Jeffry Evans, Valerie G. Brunton, Margaret C. Frame, Neil O. Carragher, Yingxiao Wang, Owen J. Sansom, Paul Timpson, Kurt I. Anderson
Journal: Cancer Research (2013)

Abstract Cancer invasion and metastasis occur in a complex three-dimensional (3D) environment, with reciprocal feedback from the surrounding host tissue and vasculature-governing behavior. In this study, we used a novel intravital method that revealed spatiotemporal regulation of Src activity in response to the anti-invasive Src inhibitor dasatinib. A fluorescence lifetime imaging microscopy–fluorescence resonance energy transfer (FLIM-FRET) Src biosensor was used to monitor drug-targeting efficacy in a transgenic p53-mutant mouse model of pancreatic cancer. In contrast to conventional techniques, FLIM-FRET analysis allowed for accurate, time-dependent, live monitoring of drug efficacy and clearance in live tumors. In 3D organotypic cultures, we showed that a spatially distinct gradient of Src activity exists within invading tumor cells, governed by the depth of penetration into complex matrices. In parallel, this gradient was also found to exist within live tumors, where Src activity is enhanced at the invasive border relative to the tumor cortex. Upon treatment with dasatinib, we observed a switch in activity at the invasive borders, correlating with impaired metastatic capacity in vivo. Src regulation was governed by the proximity of cells to the host vasculature, as cells distal to the vasculature were regulated differentially in response to drug treatment compared with cells proximal to the vasculature. Overall, our results in live tumors revealed that a threshold of drug penetrance exists in vivo and that this can be used to map areas of poor drug-targeting efficiency within specific tumor microenvironments. We propose that using FLIM-FRET in this capacity could provide a useful preclinical tool in animal models before clinical translation. Cancer Res; 73(15); 4674–86. ©2013 AACR.
Papaveretum in women of childbearing potential.
Authors: J R Sneyd
Journal: BMJ (1991)

infant mortality, the denominator is also increased.The effect of this is to again render even quite large percentage changes in mortality over time liable to chance variation.For example, there was an apparent decrease of 12 1% in deaths from coronary heart disease from 1981 to 1989 for men aged 35-64 in Hull.However, the 95% confidence intervals for this change in mortality are wide (-2 7x 10 4 to 12x 10 3) and allow the possibility either of no change or of an increase in the true mortality for men of this age.Indeed, the same uncertainty is true of the district mortality trends for all the conditions suggested in The Health of the Nation.We suggest, therefore, that changes in death rates are a statistically inappropriate method of measuring variations over time in the health of a district population.This is a further argument for the need to develop measures of health that are not based on mortality for use at district level.
Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily
Authors: Angelika Bierhaus, Karl-Matthias Haslbeck, Per M. Humpert, Birgit Liliensiek, Thomas Dehmer, Michael Morcos, Ahmed A.R. Sayed, Martin Andrassy, Stephan Schiekofer, Jochen G. Schneider, Jörg B. Schulz, Dieter Heuss, Bernhard Neundörfer, Stefan Dierl, Jochen Huber, Hans Tritschler, Ann-Marie Schmidt, Markus Schwaninger, Hans-Ulrich Haering, Erwin Schleicher, Michael Kasper, David M. Stern, Bernd Arnold, Peter P. Nawroth
Journal: Journal of Clinical Investigation (2004)

Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-kappaB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-kappaBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-kappaB and NF-kappaB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-kappaB activation was blunted in RAGE-null (RAGE(-/-)) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE(-/-) mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-kappaB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches.
IgG antibodies and early intradermal reactions to hydrocortisone in patients with cutaneous delayed-type hypersensitivity to hydrocortisone
Authors: S.M. WILKINSON, D.L. MATTEY, M.H. BECK
Journal: British Journal of Dermatology (2006)

Seven of 25 patients with cutaneous delayed‐type hypersensitivity to hydrocortisone had an immediate reaction following the intradermal injection of hydrocortisone sodium succinate. Using an ELISA method, we found that these patients had significantly increased levels of IgG antibodies to hydrocortisone when compared with normal blood donors (P<0.005) and nickel‐allergic patients (P<0.05). We suggest that these patients are at risk of developing type III and possibly type I reactions following the systemic administration of hydrocortisone and that, if needed, an alternative systemic corticosteroid should be used, for example betamethasone or dexamethasone.
MOUSE THYMUS-INDEPENDENT AND THYMUS-DERIVED LYMPHOID CELLS
Authors: J.-P. Lamelin, B. Lisowska-Bernstein, A. Matter, J. E. Ryser, P. Vassalli
Journal: The Journal of Experimental Medicine (1972)

The simultaneous use on mouse lymphoid suspensions of heterologous antisera directed against thymus-derived (T) cell mouse-specific lymphocyte antigen and brain-associated theta antigen (MSLA and BAtheta) or thymus-independent (B) cell mouse-specific bone marrow-derived lymphocyte antigen (MBLA) surface antigens allowed direct proof of the different specificity of these antisera by double immunofluorescence (IF) staining with selective visualization of fluorochromes. These antisera and antisera against mouse Ig and its different types of chains were then used with technique of either double IF staining or IF combined with radioautography, allowing the following conclusions: (a) Surface Ig (sIg) was found exclusively on B cells and never on T cells, but not all B cells had sIg. Cells containing detectable amounts of Ig were MBLA+, but had less sIg than other B cells or none at all. There was evidence for the existence of a significant number of MBLA+ lymphocytes, neither bearing nor containing detectable Ig. (b) micro-Chains were the most frequent but not the only heavy chains found on spleen cells; however, it could not be decided with the technique used, if a single cell can bear more than one type of heavy chain. No cell containing gamma-chains was found to bear surface micro-chains, although a very few cells containing both micro- and gamma-chains were observed. (c) The antigen-binding cells detected after immunization with bacteriophage T4, bovine serum albumin, Maia squinado hemocyanin, and sheep erythrocytes were analyzed for MSLA, MBLA or sIg using double IF, a combination of IF and radioautography, or inhibition of "rosette" formation. Practically all the antigen-binding cells detected were MSLA-, MBLA+, sIg+. (d) More B cells than T cells were found among short-lived lymphoid cells labeled by repeated in vivo injections of tritiated thymidine, but the results did not support a simplified concept equating T cells to long-lived and B cells to short-lived lymphocytes. (e) Cells dividing rapidly in the lymph nodes draining the sites of immunization with various antigens were predominantly T cells 2 days after immunization and in majority B cells a few days later. (f) Incubation of lymphoid cells at 37 degrees C with rabbit anti-mouse Ig or anti-kappa chains led to complete disappearance of sIg and to decrease of MBLA ("antigenic modulation"). In the same conditions, anti-MBLA gave partial modulation of MBLA and of sIg; MBLA, however, reappeared much faster than sIg. No modulation of T cell surface antigens by the appropriate antisera was observed. Cell treatment with Pronase could remove MBLA, sIg, MSLA, and BAtheta, which reappeared within a few hours. Neuraminidase treatment was without detectable effect on these antigens.
Deregulation of E-cadherin by human papillomavirus is not confined to high-risk, cancer-causing types
Authors: C.-M. Leong, J. Doorbar, I. Nindl, H.-S. Yoon, M.H. Hibma
Journal: British Journal of Dermatology (2010)

E-cadherin is a tumour suppressor protein, which is normally expressed on keratinocytes and antigen-presenting Langerhans cells (LCs) in the epidermis. We have previously shown that E-cadherin is lost from tissues infected with the high-risk cancer-causing human papillomavirus (HPV) type 16.To test if E-cadherin dysregulation is associated with the cancer risk of the infecting HPV and to establish if it is conserved among HPVs in the α, β, γ and μ genera.Forty-seven lesions infected with low- or high-risk HPV types spanning four HPV genera were stained for E-cadherin, P-cadherin and CD1a to detect LCs.Surface E-cadherin was reduced in tissues infected with members of the α4, α7 and α9 species and the γ and μ genera but was equivalent to normal epidermis in the β only-infected lesions tested and patchy in α10-infected tissues. There was a direct relationship between atypical E-cadherin expression and a significant reduction in LCs. Expression of P-cadherin, a protein that is increased in the E-cadherin constitutive knockout mouse, was increased in lesions with reduced E-cadherin.These data show that E-cadherin dysregulation by HPV is widely conserved across the majority of HPV genera. E-cadherin expression was reduced or lost in epidermis irrespective of the cancer risk of the infecting HPV type or the ability of the virus to degrade retinoblastoma protein or p53. A correlation between dysregulated E-cadherin and reduced numbers of LCs supports viral regulation of surface E-cadherin contributing to viral evasion of the host immune system.