tbuckley/cabot-search huggingface dataset:
Dietary haem stimulates epithelial cell turnover by downregulating feedback inhibitors of proliferation in murine colon
Authors: Noortje IJssennagger, Anneke Rijnierse, Nicole de Wit, Denise Jonker-Termont, Jan Dekker, Michael Müller, Roelof van der Meer
Journal: Gut (2011)

<h3>Objective</h3> Colon cancer is a leading cause of cancer deaths in Western countries and is associated with diets high in red meat. Haem, the iron-porphyrin pigment of red meat, induces cytotoxicity of gut contents and damages the colon surface epithelium. Compensatory hyperproliferation leads to epithelial hyperplasia which increases the risk of colon cancer. The aim of this study was to identify molecules signalling from the surface epithelium to the crypt to initiate hyperproliferation upon stress induced by haem. <h3>Methods</h3> C57Bl6/J mice (n=9/group) received a 'westernised' control diet (40 en% fat) with or without 0.5 μmol/g haem for 14 days. Colon mucosa was used to quantify cell proliferation and for microarray transcriptome analysis. Gene expression profiles of surface and crypt cells were compared using laser capture microdissection. Protein levels of potential signalling molecules were quantified. <h3>Results</h3> Haem-fed mice showed epithelial hyperproliferation and decreased apoptosis, resulting in hyperplasia. Microarray analysis of the colon mucosa showed 3710 differentially expressed genes (false discovery rate (q) &lt;0.01), with many involved in the cell cycle. Expression levels of haem- and stress-related genes showed that haem affected surface cells but did not directly affect crypt cells. Injured surface cells should therefore signal to crypt cells to induce compensatory hyperproliferation. Haem downregulated the inhibitors of proliferation, Wnt inhibitory factor 1, Indian Hedgehog and bone morphogenetic protein 2. Interleukin-15 was also downregulated. Haem upregulated amphiregulin, epiregulin and cyclo-oxygenase-2 mRNA in surface cells. Their protein/metabolite levels were, however, not increased as haem induced surface-specific inhibition of translation by increasing 4E-BP1. <h3>Conclusions</h3> Haem induces colonic hyperproliferation and hyperplasia by inhibiting the surface to crypt signalling of feedback inhibitors of proliferation.
Gastric cancer associated structure in mucus glycoproteins shown as a clinically useful marker.
Authors: I Hakkinen, T Nevalainen, R Paasivuo, P Partanen, K Seppala, P Sipponen
Journal: Gut (1991)

A new monoclonal antibody has been developed which is capable of detecting structures in gastric mucus glycoproteins expressed in the fetus and in adult gastric mucosa in conditions such as gastric carcinoma. Cancer associated monoclonal antibodies were selected by testing them against various mucous glycoprotein samples from the alimentary tract, including salivary glycoproteins from both secretory and non-secretory subjects, and cancerous and normal gastric juice glycoproteins. They were tested against 1000 samples of gastric juice from an unselected population. Immunochemical characterisation suggested that the glycoproteins picked up by P4 and i11 include one of the compounds reacting with rabbit anti-fetal sulphoglycoprotein antigen serum. On the basis of a clinical trial and immunohistological evaluation further evidence was obtained of P4 as the most promising antibody for further experimentation. A total of 302 gastric juice specimens from patients with various gastric symptoms were analysed using the enzyme linked immunosorbent assay technique and P4 antibody. Of 10 gastric cancers, nine had P4 in the gastric juice. A positive correlation was found between gastric ulcer and the appearance of P4. Duodenal ulcers were not correlated to P4. Atrophic gastritis and P4 coincided less frequently. Raised P4 values were found in between 3% and 9% of subjects, depending on the population. Cancer cases showed high P4 values, which allows adjustment of the lower limit of a positive result to high level whereby a considerable number of non-cancerous P4 positives are omitted.
Impact of Exploratory Biomarkers on the Treatment Effect of Bevacizumab in Metastatic Breast Cancer
Authors: Adrian M. Jubb, Kathy D. Miller, Hope S. Rugo, Adrian L. Harris, Dafeng Chen, James D. Reimann, Melody A. Cobleigh, Maike Schmidt, Virginia K. Langmuir, Kenneth J. Hillan, Daniel S. Chen, Hartmut Koeppen
Journal: Clinical Cancer Research (2011)

The addition of bevacizumab to cytotoxic chemotherapy has demonstrated a progression-free survival (PFS) benefit in the first-line and second-line treatment of advanced or metastatic breast cancer (MBC). However, the addition of bevacizumab to capecitabine in heavily pretreated MBC patients did not show a PFS benefit (AVF2119g phase III trial). The aim of this study was to evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in retrospective subset analyses of the AVF2119g trial.
Disease severity in RSV and non-RSV bronchiolitis: Usefulness in clinical decision-making
Authors: Fabiola Stollar, Gabriel Alcoba, Alain Gervaix, Constance Barazzone Argiroffo
Journal: European Respiratory Journal (2013)

Background:  Bronchiolitis morbidity remains a major health problem and identifying risk factors for disease progression can help in clinical decision-making   Aims:  To assess differences in disease severity between RSV (respiratory syncytial virus) and non-RSV bronchiolitis during two consecutive RSV seasons (2010-2012).   Methods:  Medical records of all patients    Results:  We analyzed 479 patients (317M:162F) and 582 episodes of bronchiolitis. In the two models the number of children who required supplemental oxygen, the LOS and length of oxygen therapy were significantly higher for the RSV episodes. In model1 the number of children who required ICU (odds ratio[OR]=6.9; 95% confidence interval[CI]:2.4-20.0), non invasive ventilation (OR=10.6; 95%CI: 3.0-38.5) and a NGT (OR=17.7; 95%CI: 10.0-31.3) was significantly higher in the RSV group. In model2 the length of NGT was longer for children in the RSV group (5.4±4.7 vs. 3.3±2.4; P=0.01). However, the need for intubation did not differ between groups in both models. No death was documented.   Conclusions:  RSV episodes were more severe compared to non-RSV. Our findings show that viral diagnosis is useful not only for cohorting babies but also to determine the prognosis and to assist in clinical decision-making.
The E3 ubiquitin ligase Mule acts through the ATM–p53 axis to maintain B lymphocyte homeostasis
Authors: Zhenyue Hao, Gordon S. Duncan, Yu-Wen Su, Wanda Y. Li, Jennifer Silvester, Claire Hong, Han You, Dirk Brenner, Chiara Gorrini, Jillian Haight, Andrew Wakeham, Annick You-Ten, Susan McCracken, Andrew Elia, Qinxi Li, Jacqui Detmar, Andrea Jurisicova, Elias Hobeika, Michael Reth, Yi Sheng, Philipp A. Lang, Pamela S. Ohashi, Qing Zhong, Xiaodong Wang, Tak W. Mak
Journal: The Journal of Experimental Medicine (2012)

Cellular homeostasis is controlled by pathways that balance cell death with survival. Mcl-1 ubiquitin ligase E3 (Mule) is an E3 ubiquitin ligase that targets the proapoptotic molecule p53 for polyubiquitination and degradation. To elucidate the role of Mule in B lymphocyte homeostasis, B cell–specific Mule knockout (BMKO) mice were generated using the Cre–LoxP recombination system. Analysis of BMKO mice showed that Mule was essential for B cell development, proliferation, homeostasis, and humoral immune responses. p53 transactivation was increased by two- to fourfold in Mule-deficient B cells at steady state. Genetic ablation of p53 in BMKO mice restored B cell development, proliferation, and homeostasis. p53 protein was increased in resting Mule-deficient mouse embryonic fibroblasts (MEFs) and embryonic stem (ES) cells. Loss of Mule in both MEFs and B cells at steady state resulted in increased levels of phospho–ataxia telangiectasia mutated (ATM) and the ATM substrate p53. Under genotoxic stress, BMKO B cells were resistant to apoptosis, and control MEFs exhibited evidence of a physical interaction between Mule and phospho-ATM. Phospho-ATM, phospho-p53, and Brca1 levels were reduced in Mule-deficient B cells and MEFs subjected to genotoxic stress. Thus, Mule regulates the ATM–p53 axis to maintain B cell homeostasis under both steady-state and stress conditions.
PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury
Authors: Tomohisa Nagoshi, Takashi Matsui, Takuma Aoyama, Annarosa Leri, Piero Anversa, Ling Li, Wataru Ogawa, Federica del Monte, Judith K. Gwathmey, Luanda Grazette, Brian Hemmings, David A. Kass, Hunter C. Champion, Anthony Rosenzweig
Journal: Journal of Clinical Investigation (2005)

Acute activation of the serine-threonine kinase Akt is cardioprotective and reduces both infarction and dysfunction after ischemia/reperfusion injury (IRI). However, less is known about the chronic effects of Akt activation in the heart, and, paradoxically, Akt is activated in samples from patients with chronic heart failure. We generated Tg mice with cardiac-specific expression of either activated (myristoylated [myr]) or dominant-negative (dn) Akt and assessed their response to IRI in an ex vivo model. While dn-Akt hearts demonstrated a moderate reduction in functional recovery after IRI, no function was restored in any of the myr-Akt-Tg hearts. Moreover, infarcts were dramatically larger in myr-Akt-Tg hearts. Biochemical analyses demonstrated that chronic Akt activation induces feedback inhibition of PI3K activity through both proteasome-dependent degradation of insulin receptor substrate-1 (IRS-1) and inhibition of transcription of IRS-1 as well as that of IRS-2. To test the functional significance of these signaling changes, we performed in vivo cardiac gene transfer with constitutively active PI3K in myr-Akt-Tg mice. Restoration of PI3K rescued function and reduced injury after IRI. These data demonstrate that PI3K-dependent but Akt-independent effectors are required for full cardioprotection and suggest a mechanism by which chronic Akt activation can become maladaptive.
Vascular Smooth Muscle Cells Express the α <sub>1A</sub> Subunit of a P-/Q-Type Voltage-Dependent Ca <sup>2+</sup> Channel, and It Is Functionally Important in Renal Afferent Arterioles
Authors: Pernille B. Hansen, Boye L. Jensen, Ditte Andreasen, Ulla G. Friis, Ole Skøtt
Journal: Circulation Research (2000)

In the present study, we tested whether the alpha(1A) subunit, which encodes a neuronal isoform of voltage-dependent Ca(2+) channels (VDCCs) (P-/Q-type), was present and functional in vascular smooth muscle and renal resistance vessels. By reverse transcription-polymerase chain reaction and Southern blotting analysis, mRNA encoding the alpha(1A) subunit was detected in microdissected rat preglomerular vessels and vasa recta, in cultures of rat preglomerular vascular smooth muscle cells (VSMCs), and in cultured rat mesangial cells. With immunoblots, alpha(1A) subunit protein was demonstrated in rat aorta, brain, aortic smooth muscle cells (A7r5), VSMCs, and mesangial cells. Immunolabeling with an anti-alpha(1A) antibody was positive in acid-macerated, microdissected preglomerular vessels and in A7r5 cells. Patch-clamp experiments on aortic A7r5 cells showed 22+/-4% (n=6) inhibition of inward Ca(2+) current by omega-Agatoxin IVA (10(-8) mol/L), which in this concentration is a specific inhibitor of P-type VDCCs. Measurements of intracellular Ca(2+) in afferent arterioles with fluorescence-imaging microscopy showed 32+/-9% (n=10) inhibition of the K(+)-induced rise in Ca(2+) in the presence of 10(-8) mol/L omega-Agatoxin IVA. In microperfused rabbit afferent arterioles, omega-Agatoxin IVA inhibited depolarization-mediated contraction with an EC(50) of 10(-17) mol/L and complete blockade at 10(-14) mol/L. We conclude that the alpha(1A) subunit is expressed in VSMCs from renal preglomerular resistance vessels and aorta, as well as mesangial cells, and that P-type VDCCs contribute to Ca(2+) influx in aortic and renal VSMCs and are involved in depolarization-mediated contraction in renal afferent arterioles.
Prognostic factors in invasive bladder carcinoma in a prospective trial of preoperative adjuvant chemotherapy and radiotherapy.
Authors: C Y Fung, W U Shipley, R H Young, P P Griffin, K M Convery, D S Kaufman, A F Althausen, N M Heney, G R Prout
Journal: Journal of Clinical Oncology (1991)

Clinical and pathologic factors were analyzed in 40 patients with localized muscle-invasive bladder carcinoma treated in a prospective bladder-preserving program consisting of transurethral tumor resection, neoadjuvant chemotherapy (methotrexate, cisplatin, and vinblastine [MCV]), and 4,000 cGy radiotherapy with concurrent cisplatin. Patients with biopsy-proven complete response after chemotherapy and 4,000 cGy radiation received full-dose radiotherapy (6,480 cGy) with cisplatin. Cystectomy was recommended to patients with residual disease. Distant metastasis rate was associated with tumor stage and size: 0% in T2 patients, 39% in T3-4 patients (P = .035), 6% for tumors less than 5 cm, and 59% for tumors greater than or equal to 5 cm (P = .002). Risk of bladder tumor recurrence was higher in patients with tumor-associated carcinoma in situ (CIS; 40%) than those without CIS (6%; P = .075). Papillary tumors and solid tumors both had similar treatment outcomes. By multivariate analysis, tumor stage T2 (P = .04) and absence of CIS (P = .03) were significant predictors of complete response; CIS was predictive of local bladder recurrence (P = .07); and tumor size (P = .03), response after chemoradiotherapy (P = .02), and vascular invasion (P = .08) were associated with distant metastasis. Six of eight local bladder tumor recurrences were superficial tumors. The low actuarial distant metastasis rate of T2 patients (0% at 3 years), the 3-year actuarial overall survival rates for T2 (89%) and T3-4 (50%) patients, and the similar treatment outcomes for papillary versus solid tumors are encouraging when compared with published historical controls. These results provide preliminary evidence (median follow-up, 30 months) that the current chemoradiotherapy regimen may have beneficial effects in the treatment of muscle-invasive bladder carcinoma. The true efficacy of neoadjuvant chemotherapy remains to be proven by ongoing randomized trials.
Nuclear α1-Adrenergic Receptors Signal Activated ERK Localization to Caveolae in Adult Cardiac Myocytes
Authors: Casey D. Wright, Quanhai Chen, Nichole L. Baye, Yuan Huang, Chastity L. Healy, Sivakanthan Kasinathan, Timothy D. O'Connell
Journal: Circulation Research (2008)

We previously identified an α1-AR-ERK (α1A-adrenergic receptor–extracellular signal-regulated kinase) survival signaling pathway in adult cardiac myocytes. Here, we investigated localization of α1-AR subtypes (α1A and α1B) and how their localization influences α1-AR signaling in cardiac myocytes. Using binding assays on myocyte subcellular fractions or a fluorescent α1-AR antagonist, we localized endogenous α1-ARs to the nucleus in wild-type adult cardiac myocytes. To clarify α1 subtype localization, we reconstituted α1 signaling in cultured α1A- and α1B-AR double knockout cardiac myocytes using α1-AR–green fluorescent protein (GFP) fusion proteins. Similar to endogenous α1-ARs and α1A- and α1B-GFP colocalized with LAP2 at the nuclear membrane. α1-AR nuclear localization was confirmed in vivo using α1-AR-GFP transgenic mice. The α1-signaling partners Gαq and phospholipase Cβ1 also colocalized with α1-ARs only at the nuclear membrane. Furthermore, we observed rapid catecholamine uptake mediated by norepinephrine-uptake-2 and found that α1-mediated activation of ERK was not inhibited by a membrane impermeant α1-blocker, suggesting α1 signaling is initiated at the nucleus. Contrary to prior studies, we did not observe α1-AR localization to caveolae, but we found that α1-AR signaling initiated at the nucleus led to activated ERK localized to caveolae. In summary, our results show that nuclear α1-ARs transduce signals to caveolae at the plasma membrane in cardiac myocytes.
Electronic cigarettes: pro
Authors: J. Britton
Journal: Thorax (2015)

Smoking destroys lives, and does so from the point of conception. In 2014 smoking is likely to have caused the death of over 5000 unborn or newly born babies, over 20 000 babies to be born prematurely or with low birth weight, 40 sudden infant deaths and over 165 000 new cases of childhood illness.1 Smoking in England alone will have killed around 80 000 adults,2 caused nearly 500 000 admissions to National Health Service (NHS) hospitals2 and consumed around £5 billion of the NHS budget.3 The total financial cost of smoking to wider society will have been nearly £14 billion,3 £4 billion more than the tax that tobacco generates3 and around 15% of the current UK national budget deficit.4 Adult smoking will also have exacerbated adult and child poverty, and contributed to initiating the next generation of children into smoking.5 These health and social effects identify smoking as by far the largest avoidable cause of death and disability in the UK. Preventing smoking should therefore be the first priority of health and social policy.

The UK leads Europe in implementing tobacco control policy,6 and has achieved a profound reduction in the prevalence of smoking among adults, which in 2013 fell below 20% for the first time in nearly a century.7 However this prevalence figure translates into around 10 million UK adults alive today who smoke, and of whom half will die from their smoking unless they can be persuaded and helped to quit.8 The headline success in reducing smoking prevalence is also not universal across society, since smoking remains twice as common among people in unskilled and manual occupations than in professional and managerial groups,2 and much higher still …
Twenty-nail dystrophy (trachyonychia) caused by lichen planus in a patient with gold allergy
Authors: H. Yokozeki, S. Niiyama, K. Nishioka
Journal: British Journal of Dermatology (2005)

Journal Article Twenty‐nail dystrophy (trachyonychia) caused by lichen planus in a patient with gold allergy Get access H. Yokozeki, H. Yokozeki Department of Dermatology, Graduate School, Tokyo Medical and Dental University, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo, Japan *Department of Dermatology, Kitasato University, Kanagawa, Japan E‐mail: 3064derm@tmd.ac.jp Search for other works by this author on: Oxford Academic Google Scholar S. Niiyama, S. Niiyama Department of Dermatology, Graduate School, Tokyo Medical and Dental University, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo, Japan *Department of Dermatology, Kitasato University, Kanagawa, Japan E‐mail: 3064derm@tmd.ac.jp Search for other works by this author on: Oxford Academic Google Scholar K. Nishioka K. Nishioka Department of Dermatology, Graduate School, Tokyo Medical and Dental University, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo, Japan *Department of Dermatology, Kitasato University, Kanagawa, Japan E‐mail: 3064derm@tmd.ac.jp Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 152, Issue 5, 1 May 2005, Pages 1087–1089, https://doi.org/10.1111/j.1365-2133.2005.06581.x Published: 01 May 2005
The Transcription Factor ZEB1 Is Aberrantly Expressed in Aggressive Uterine Cancers
Authors: Nicole S. Spoelstra, Nicole G. Manning, Yujiro Higashi, Douglas Darling, Meenakshi Singh, Kenneth R. Shroyer, Russell R. Broaddus, Kathryn B. Horwitz, Jennifer K. Richer
Journal: Cancer Research (2006)

Abstract The transcription factor ZEB1 (δEF1 in mice) has been implicated in cellular processes during development and tumor progression including epithelial to mesenchymal transition. δEF1 null mice die at birth, but heterozygotes expressing a LacZ reporter inserted into the δEF1 gene live and reproduce. Using these mice, we observed ZEB1 promoter activity in the virgin myometrium, and stroma and myometrium of the pregnant uterus. ZEB1 protein is up-regulated in the myometrium and endometrial stroma after progesterone or estrogen treatment of ovariectomized mice. In the normal human uterus, ZEB1 protein is increased in the myometrium and stroma during the secretory stage of the menstrual cycle. ZEB1 is not expressed in the normal endometrial epithelium. In malignancies of the uterus, we find that ZEB1 (a) is overexpressed in malignant tumors derived from the myometrium (leiomyosarcomas), (b) is overexpressed in tumor-associated stroma of low-grade endometrioid adenocarcinomas, and (c) is aberrantly expressed in the tumor epithelial cells of aggressive endometrial cancers. Specifically, in grade 3 endometrioid adenocarcinomas and uterine papillary serous carcinomas, ZEB1 could be expressed in the epithelial-derived carcinoma cells as well as in the stroma. In malignant mixed Müllerian tumors, the sarcomatous component always expresses ZEB1, and the carcinomatous component can also be positive. In summary, ZEB1 is normally regulated by both estrogen and progesterone receptors, but in uterine cancers, it is likely no longer under control of steroid hormone receptors and becomes aberrantly expressed in epithelial-derived tumor cells, supporting a role for ZEB1 in epithelial to mesenchymal transitions associated with aggressive tumors. (Cancer Res 2006; 66(7): 3893-902)
Impact of Therapy With Chlorambucil, Fludarabine, or Fludarabine Plus Chlorambucil on Infections in Patients With Chronic Lymphocytic Leukemia: Intergroup Study Cancer and Leukemia Group B 9011
Authors: Vicki A. Morrison, Kanti R. Rai, Bercedis L. Peterson, Jonathan E. Kolitz, Laurence Elias, Frederick R. Appelbaum, John D. Hines, Lois Shepherd, Robert E. Martell, Richard A. Larson, Charles A. Schiffer
Journal: Journal of Clinical Oncology (2001)

PURPOSE: We sought to determine whether therapy with single-agent fludarabine compared with chlorambucil alone or the combination of both agents had an impact on the incidence and spectrum of infections among a series of previously untreated patients with B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Five hundred fifty-four previously untreated CLL patients with intermediate/high-risk Rai-stage disease were enrolled onto an intergroup protocol. Patients were randomized to therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Data pertaining to infection were available on 518 patients. Differences in infections among treatment arms were tested with the Kruskal-Wallis, Wilcoxon, and χ 2 tests. RESULTS: A total of 1,107 infections (241 major infections) occurred in 518 patients over the infection follow-up period (interval from study entry until either reinstitution of initial therapy, therapy with a second agent, or death). Patients treated with fludarabine plus chlorambucil had more infections than those receiving either single agent (P &lt; .0001). Comparing the two single-agent arms, there were more infections on the fludarabine arm (P = .055) per month of follow-up. Fludarabine therapy was associated with more major infections and more herpesvirus infections compared with chlorambucil (P = .008 and P = .004, respectively). Rai stage and best response to therapy were not associated with infection. A low serum immunoglobulin G was associated with number of infections (P = .02). Age was associated with incidence of major infection in the combination arm (P = .004). CONCLUSION: Combination therapy with fludarabine plus chlorambucil resulted in significantly more infections than treatment with either single agent. Patients receiving single-agent fludarabine had more major infections and herpesvirus infections compared with chlorambucil-treated patients.