tbuckley/cabot-search huggingface dataset:
Loss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell Growth
Authors: Tsutomu Ohta, Kumiko Iijima, Mamiko Miyamoto, Izumi Nakahara, Hiroshi Tanaka, Makiko Ohtsuji, Takafumi Suzuki, Akira Kobayashi, Jun Yokota, Tokuki Sakiyama, Tatsuhiro Shibata, Masayuki Yamamoto, Setsuo Hirohashi
Journal: Cancer Research (2008)

Abstract Oxidative and electrophilic stresses are sensed by Keap1, which activates Nrf2 to achieve cytoprotection by regulating the expression of drug-metabolizing and antioxidative stress enzymes/proteins. Because oxidative and electrophilic stresses cause many diseases, including cancer, we hypothesized that an abnormality in the Nrf2-Keap1 system may facilitate the growth of cancer cells. We sequenced the KEAP1 gene of 65 Japanese patients with lung cancer and identified five nonsynonymous somatic mutations at a frequency of 8%. We also identified two nonsynonymous somatic KEAP1 gene mutations and two lung cancer cell lines expressing KEAP1 at reduced levels. In lung cancer cells, low Keap1 activity (due to mutations or low-level expression) led to nuclear localization and constitutive activation of Nrf2. The latter resulted in constitutive expression of cytoprotective genes encoding multidrug resistance pumps, phase II detoxifying enzymes, and antioxidative stress enzymes/proteins. Up-regulation of these target genes in lung cancer cells led to cisplatin resistance. Nrf2 activation also stimulated growth of lung cancer–derived cell lines expressing KEAP1 at low levels and in mutant cell lines and in Keap1-null mouse embryonic fibroblasts under homeostatic conditions. Thus, inhibition of NRF2 may provide new therapeutic approaches in lung cancers with activation of Nrf2. [Cancer Res 2008;68(5):1303–9]
Strategies for Delaying or Treating<i>In vivo</i>Acquired Resistance to Trastuzumab in Human Breast Cancer Xenografts
Authors: Jeanne M. du Manoir, Giulio Francia, Shan Man, Miriam Mossoba, Jeffrey A. Medin, Alicia Viloria-Petit, Daniel J. Hicklin, Urban Emmenegger, Robert S. Kerbel
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Acquired resistance to trastuzumab (Herceptin) is common in patients whose breast cancers show an initial response to the drug. The basis of this acquired resistance is unknown, hampering strategies to delay or treat such acquired resistance, due in part to the relative lack of appropriate in vivo tumorigenic models. Experimental Design: We derived an erbB-2–positive variant called 231-H2N, obtained by gene transfection from the highly tumorigenic erbB-2/HER2–negative human breast cancer cell line, MDA-MB-231. Unlike MDA-MB-231, the 231-H2N variants was sensitive to trastuzumab both in vitro and especially in vivo, thus allowing selection of variant resistant to drug treatment in the latter situation after showing an initial response. Results: The growth of established orthotopic tumors in severe combined immunodeficient mice was blocked for 1 month by trastuzumab, after which rapid growth resumed. These relapsing tumors were found to maintain resistance to trastuzumab, both in vitro and in vivo. We evaluated various therapeutic strategies for two purposes: (a) to delay such tumor relapses or (b) to treat acquired trastuzumab resistance once it has occurred. With respect to the former, a daily oral low-dose metronomic cyclophosphamide regimen was found to be particularly effective. With respect to the latter, an anti–epidermal growth factor receptor antibody (cetuximab) was effective as was the anti–vascular endothelial growth factor (anti-VEGF) antibody bevacizumab, which was likely related to elevated levels of VEGF detected in trastuzumab-resistant tumors. Conclusions: Our results provide a possible additional rationale for combined biological therapy using drugs that target both erbB-2/HER2 and VEGF and also suggest the potential value of combining less toxic metronomic chemotherapy regimens not only with targeted antiangiogenic agents but also with other types of drug such as trastuzumab.
Intraepidermal bullous haemorrhage during anticoagulation with low-molecular-weight heparin: two cases
Authors: H. Beltraminelli, P. Itin, L. Cerroni
Journal: British Journal of Dermatology (2009)

Journal Article Intraepidermal bullous haemorrhage during anticoagulation with low‐molecular‐weight heparin: two cases Get access H. Beltraminelli, H. Beltraminelli Research Unit Dermatopathology, Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, A‐8036 Graz, AustriaDepartment of Dermatology, University Hospital of Basel, Basel, Switzerland Search for other works by this author on: Oxford Academic Google Scholar P. Itin, P. Itin Department of Dermatology, University Hospital of Basel, Basel, Switzerland Search for other works by this author on: Oxford Academic Google Scholar L. Cerroni L. Cerroni Research Unit Dermatopathology, Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, A‐8036 Graz, Austria Correspondence: Lorenzo Cerroni. E‐mail: lorenzo.cerroni@medunigraz.at Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 161, Issue 1, 1 July 2009, Pages 191–193, https://doi.org/10.1111/j.1365-2133.2009.09163.x Published: 01 July 2009
Reproductive effects in birds exposed to pesticides and industrial chemicals.
Authors: D M Fry
Journal: Environmental Health Perspectives (1995)

Environmental contamination by agricultural chemicals and industrial waste disposal results in adverse effects on reproduction of exposed birds. The diversity of pollutants results in physiological effects at several levels, including direct effects on breeding adults as well as developmental effects on embryos. The effects on embryos include mortality or reduced hatchability, failure of chicks to thrive (wasting syndrome), and teratological effects producing skeletal abnormalities and impaired differentiation of the reproductive and nervous systems through mechanisms of hormonal mimicking of estrogens. The range of chemical effects on adult birds covers acute mortality, sublethal stress, reduced fertility, suppression of egg formation, eggshell thinning, and impaired incubation and chick rearing behaviors. The types of pollutants shown to cause reproductive effects include organochlorine pesticides and industrial pollutants, organophosphate pesticides, petroleum hydrocarbons, heavy metals, and in a fewer number of reports, herbicides, and fungicides. o,p'-DDT, polychlorinated biphenyls (PCBs), and mixtures of organochlorines have been identified as environmental estrogens affecting populations of gulls breeding in polluted
HISTORY OF THE DEVELOPMENT OF NEUROPSYCHIATRY IN THE EUROPEAN THEATRE OF OPERATIONS
Authors: JESSE F. CASEY
Journal: American Journal of Psychiatry (1946)

During the year 1942 the NP. cases in the E. T. O. were cared for by the NP. sections of the station and general hospitals then functioning in the theatre. On August 12, 1942, Colonel Lloyd J. Thompson was appointed senior consultant in neuropsychiatry in the theatre. On January 23, 1943, the first specialized NP. hospital, the 36th Station Hospital, was established in Exeter, Devonshire, England. As the troop strength increased in the E. T. O. definite neuropsychiatric needs developed. These were found to be (1) facilities for the diagnosis and treatment of salvable NP. cases, (2) facilities for the neuropsychiatric screening of combat units (pre-invasion), (3) facilities for the immediate care, treatment and eventual disposition of non-salvable NP. cases. The specialized NP. hospital was found to have a definite value as it was able to (1) provide more definitive therapy than was practicable in an ordinary general hospital, (2) help standardize the management of all NP. cases in the theatre, (3) provide for the physical separation of psychotics and all other non-salvable NP. cases from the salvable ones, (4) provide adequate clinical material and a teaching staff for a school of neuropsychiatry in the E. T. O. In providing for the needs outlined above plans were made calling for 12,000 to 15,000 NP. beds to be set up in the NP. sections of approximately 150 general hospitals and by the establishment of three specialized NP. units. Of these, the 36th Station and the 96th General Hospitals functioned as diagnostic and therapeutic centers for the more serious psychiatric cases. The 312th Station Hospital was known as the "Neurosis Center" designed to provide definitive therapy for the less serious cases in order that they might remain in the theatre in some useful capacity. Simultaneously with the establishment of the specialized NP. units, a school of neuropsychiatry was set up. This was originally in the 36th Station Hospital, serving as a means for refresher courses for younger psychiatrists in the theatre as well as a training center for medical officers not previously trained in psychiatry. Later it was moved to the 312th Station Hospital where most emphasis was placed on training for the management of NP. cases in the field under combat conditions. After the invasion of the Continent of Europe, need for a specialized NP. unit soon developed there. The 130th General Hospital was reorganized for this purpose and was eventually established in Ciney, Belgium. Due to being close to the, front line, this unit was not able to function exclusively as a NP. hospital. It did so, however, after the Ardennes campaign, its primary mission being that of a neurosis center. Finally the management of NP. casualties in the field was discussed.
Effective ovarian cancer treatment is underused, US study finds
Authors: Michael McCarthy
Journal: BMJ (2015)

Six years after the US National Cancer Institute issued a special clinical announcement encouraging the use of intraperitoneal and intravenous chemotherapy for ovarian cancer, less than half of eligible women were being treated with it, a new study has found.1

The institute issued the recommendation in 2006 after a randomized trial by the Gynecologic Oncology Group, the GOG-172 trial, showed that, when compared with intravenous chemotherapy alone, intraperitoneal and intravenous chemotherapy was associated with an improvement of 16 months in median overall survival among women with optimally …
SCUBE1 — A new scoop in vascular biology?
Authors: S LINDEMANN, M GAWAZ
Journal: Cardiovascular Research (2006)

See article by Tu et al.  [6]  (pages 486–495) in this issue. 

Platelets represent an important link between inflammation, thrombosis, and vascular and tissue repair mechanisms. Once activated, platelets generate and release an arsenal of potent inflammatory, proliferative, and mitogenic substances into the local microenvironment of vascular lesions [1]. Thereby, platelets control and effect multiple mechanisms of cellular function involved in vascular and tissue repair.

The epidermal growth factor (EGF) superfamily is a group of growth factors, cytokine-like mediators, and extracellular matrix proteins. A new gene of an EGF-related protein was isolated 6 years ago in developing mice [2]. This new mammalian gene encodes a protein with a signal peptide at the amino-terminus followed by several EGF-like repeats and one CUB-domain at the carboxyl terminus. This gene family was termed SCUBE for s ignal-peptide- CUB - E GF-like domain-containing proteins. … 

* Corresponding authors. Tel.: +49 7071 29 83688; fax: +49 7071 29 5749. Email address: stephan.lindemann{at}med.uni-tuebingen.de meinrad.gawaz{at}med.uni-tuebingen.de
Long-Term Benefit of High-Dose Epirubicin in Adjuvant Chemotherapy for Node-Positive Breast Cancer: 15-Year Efficacy Results of the Belgian Multicentre Study
Authors: Evandro de Azambuja, Marianne Paesmans, Marc Beauduin, Anita Vindevoghel, Nathalie Cornez, Claude Finet, Fernand Ries, Marie Thérèse Closon-Dejardin, Joseph Kerger, Philippe Gobert, Christian Focan, Alain Tagnon, Stella Dolci, Jean M. Nogaret, Angelo di Leo, Martine J. Piccart-Gebhart
Journal: Journal of Clinical Oncology (2008)

The 4-year results of this trial demonstrated that a higher dose of epirubicin with cyclophosphamide (HEC) is superior to a lower dose of epirubicin, 60 mg/m(2) (EC), for event-free survival (EFS; 27% reduction), but is not superior to classical oral cyclophosphamide, methotrexate, and fluorouracil (CMF) in the adjuvant treatment of node-positive breast cancer. Herein we report the 15-year data on efficacy and long-term toxicity of this three-arm Belgian multicenter trial.Between March 1988 and December 1996, 777 eligible patients were randomly assigned to six cycles of CMF, eight cycles of EC, or eight cycles HEC.The 15-year EFS was 45% for patients who received CMF, 39% for patients who received EC, and 50% for patients who received HEC. The hazard ratios (HR) were 0.77 for HEC versus EC (95% CI, 0.60 to 0.98; P = .03), 0.90 for HEC versus CMF (P = .39), and 0.86 for EC versus CMF (P = .21). No difference in overall survival (OS) was seen. Cardiac toxicity was more frequent with HEC than with CMF (11 patients v 1 patient; P = .006), but no more than with EC (P = .21).Treatment with HEC demonstrated superior EFS when compared with lower-dose epirubicin. However, we do not recommend the use of HEC regimen in daily clinical practice, mainly because of the higher risk of cardiotoxicity related to the cumulative doses of epirubicin and the lack of superiority of anthracyclines over CMF in our study.
Hepatic Conversion of Bilirubin Monoglucuronide to Diglucuronide in Uridine Diphosphate-Glucuronyl Transferase-Deficient Man and Rat by Bilirubin Glucuronoside Glucuronosyltransferase
Authors: J. Roy Chowdhury, P. L. M. Jansen, E. B. Fischberg, A. Daniller, I. M. Arias
Journal: Journal of Clinical Investigation (1978)

The microsomal enzyme uridine diphosphate (UDP) glucuronate glucuronyltransferase (E.C. 2.4.1.17) catalyzes formation of bilirubin mono-glucuronide from bilirubin and UDPglucuronic acid. Bilirubin glucuronoside glucuronosyltransferase (E.C. 2.4.1.95), an enzyme concentrated in plasma membrane-enriched fractions of rat liver, converts bilirubin monoglucuronide to bilirubin diglucuronide. Bilirubin glucuronoside glucuronosyltransferase activity was studied in homogenates of liver biopsy specimens obtained from patients with the Crigler-Najjar syndrome (Type I) and in subcellular liver fractions of rats homozygous for UDP glucuronate glucuronyltransferase deficiency (Gunn strain). In patients with the Crigler-Najjar syndrome (Type I) and in Gunn rats, hepatic UDPglucuronate glucuronyltransferase activity was not measurable; however, bilirubin glucuronoside glucuronosyltransferase activity was similar to that in normal controls. The subcellular distribution of bilirubin glucuronoside glucuronosyltransferase activity in Gunn rat liver was similar to the distribution observed in normal Wistar rat liver.
Axon Reflex Sweating in Rheumatoid Arthritis
Authors: J. L. Kalliomaki, H. A. Saarimaa, P. Toivanen
Journal: Annals of the Rheumatic Diseases (1963)

Inanaxonreflex, impulses areconveyed from thepoints ofstimulation centripetally through branches oframifying axonsandagaincentrifugally (without anyinterpolated cell inits path) to theeffector organs(Collins andWeiner, 1961). Thearteriolar flare produced byinjury orbythe action ofhistamine, thepilomotor reaction to faradic stimulation, andthesweating produced by faradic stimulation inthevicinity ofelectrodes are examples ofthis axonreflex mechanism. Thelocal sweating response produced byintradermal injection ofnicotine hasalsobeendemonstrated tobemediated through thelocal reflex arc (CoonandRothman,1941). The axonreflex function inrheumatoid arthritis hasnot,sofar asweknow,beenstudied earlier. However, many signs exist inrheumatoid arthritis (cold clammy  liver hands; darkdiscoloration ofdorsal skinoffinger joints; Raynaud's syndrome, etc.), thepathogenesis ofwhichisobscure. Thispaper reports ourobservations on axonreflex sweating produced bynicotine inrheumatoid arthritis, with special reference tothecorrelation between this nicotine sweatresponse andsomeoftheclinical signs ofrheumatoid arthritis.
Re-contacting participants for inclusion in the database of Genotypes and Phenotypes (dbGaP): Findings from three case-control studies of lung cancer
Authors: Michele L Cote, M Jay Harrison, Angela S Wenzlaff, Ann G Schwartz
Journal: Genome Medicine (2014)

Since January 2008, the National Institutes of Health (NIH) has required that all investigators who receive NIH support submit de-identified high-throughput genomic data to the database of Genotypes and Phenotypes (dbGaP). The purpose of this study was to explore the feasibility of re-consenting participants from three inactive studies, conducted from 2000 through 2009, to submit their data to dbGaP.Participants were those enrolled in one of three prior population-based case-control studies of lung cancer who had given a DNA sample. Consent to release de-identified data to dbGaP took place via mailed forms and follow-up phone calls. Chi-squared tests were used to examine differences in re-contact and consent proportions between groups.A total of 2,471 participants were initially eligible for re-contact. Six hundred and thirty-eight participants were found to be deceased (n = 627) or did not give permission to re-contact (n = 11). Of the 1,833 remaining participants, 42.3% provided written consent, 37.0% could not be located, 13.7% verbally agreed to have their data released but never returned written consent, 5.3% refused, and 1.6% were too ill at the time of contact. There were significant differences in ability to locate participants by age, race, gender, and case-control status; however, once located, there were no differences in re-consent rates.This study demonstrates that while most previous study participants agreed to release data, a small proportion are opposed to submitting their data to dbGaP. In addition, it demonstrates the difficulty studies based on existing samples may have in locating inactive participants for re-consent.
Comparative Pharmacokinetic Study of Continuous Venous Infusion Fluorouracil and Oral Fluorouracil With Eniluracil in Patients With Advanced Solid Tumors
Authors: Alex A. Adjei, Joel M. Reid, Robert B Diasio, Jeff A. Sloan, Deborah A. Smith, Joseph Rubin, Henry C. Pitot, Steven R. Alberts, Richard M. Goldberg, Lorelei J. Hanson, Pamela Atherton, Matthew M. Ames, Charles Erlichman
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m2 BID for 7 days) during the first study period, followed by 5-FU (300 mg/m2 CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary α–fluoro-β-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for ≥ 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean ± SD steady-state plasma concentration (CP) and area under the curve (AUC)144-168h for CVI 5-FU (104 ± 45 ng/mL and 2,350 ± 826 ng·h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 ± 7.7 ng/mL and 722 ± 182 ng·h/mL, respectively [P < .00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state CP and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.
Large Cleaved and Immunoblastic Lymphoma May Represent Two Distinct Clinicopathologic Entities Within the Group of Diffuse Large B-Cell Lymphomas
Authors: Pascale De Paepe, Ruth Achten, Gregor Verhoef, Iwona Wlodarska, Michel Stul, Vera Vanhentenrijk, Marleen Praet, Chris De Wolf-Peeters
Journal: Journal of Clinical Oncology (2005)

Purpose The reliability of immunohistochemistry for subdividing diffuse large B-cell lymphomas (DLBCL) into germinal center B-cell-like (GCB) and non-GCB prognostic subgroups is debated. In this study we evaluated the prognostic significance of such subgrouping on a series of 153 DLBCL patients. Furthermore, we investigated whether both subgroups could comprise clinicopathologic entities recognized by their morphology and characterized by a distinct phenotype, specific genetic abnormalities, and clinical characteristics. Patients and Methods All samples from patients were reviewed and morphologically subdivided into large cleaved, immunoblastic, and not otherwise specified DLBCL. GCB and non-GCB immunohistochemical profiles were established. The presence of chromosomal translocations involving BCL2, BCL6, and MYC and/or rearrangements of these genes was investigated. Results Subdividing DLBCL with either a GCB or non-GCB immunophenotypic profile was not of prognostic significance. Nevertheless, CD10 expression was a predictor of favorable outcome, whereas high bcl-2 expression and BCL6 rearrangement were adverse predictors of disease-free survival. Interestingly, large cleaved DLBCL was clearly associated with a GCB immunophenotypic profile, CD10 expression, BCL2 rearrangement, age younger than 60 years, and low to low/intermediate International Prognostic Index risk, but was not of prognostic significance. In contrast, immunoblastic morphology was associated with a non-GCB profile and was a significant predictor of unfavorable DFS. Conclusion Subdividing DLBCL into subgroups based on their immunohistochemical profile was not of prognostic significance. Nevertheless, it allowed the additional characterization of two lymphoma subgroups previously recognized in the Working Formulation. Both correspond to two distinct clinicopathologic entities within the DLBCL.
Emotional-cognitive integration, the self, and cortical midline structures
Authors: Georg Northoff
Journal: Behavioral and Brain Sciences (2005)

Lewis discusses the dynamic mechanisms of emotional-cognitive integration. I argue that he neglects the self and its neural correlate. The self can be characterized as an emotional-cognitive unity, which may be accounted for by the interplay between anterior and posterior medial cortical regions. I propose that these regions form an anatomical, physiological, and psychological unity, the cortical midline structures (CMSs).