tbuckley/cabot-search huggingface dataset:
Long-Term Exposure to Tamoxifen Induces Hypersensitivity to Estradiol
Authors: Lev M. Berstein, Ji-Ping Wang, Hong Zheng, Wei Yue, Mark Conaway, Richard J. Santen
Journal: Clinical Cancer Research (2004)

Abstract In women with hormone-dependent breast cancer, tamoxifen (TAM) frequently induces tumor regression, but regrowth occurs with continuation of antiestrogen therapy. Studies of breast xenografts in nude mice suggest that this secondary resistance to TAM may reflect the development of enhanced sensitivity to the estrogenic properties of TAM. In the current study, we examined the hypothesis that TAM could also induce a state of hypersensitivity to estradiol (E2) itself. Oophorectomized nude mice with MCF-7 cell xenografts received 25-mg implants of TAM [long-term TAM treated (LTTT) mice] or cholesterol (C-MCF-7) over a 5-month period (phase 1). The LTTT group regressed to a lesser extent than did C-MCF-7 tumors. After 4 months of TAM exposure, the LTTT tumors begin to regrow, as did the C-MCF-7, as assessed by slope analysis. At 5 months, TAM or vehicle implants were removed, and the LTTT and C-MCF-7 subgroups were given vehicle or two doses of E2 to test estrogen sensitivity (phase 2). We used our “E2 clamp” technique to maintain levels of plasma E2 at either 1.25 or 20 pg/ml. Neither group responded to the very low concentrations of E2 (1.25 pg/ml) or vehicle. The LTTT tumors but not C-MCF-7 tumors exhibited a growth response on exposure to 20 pg/ml E2 during 7 weeks, as demonstrated with mixed models analysis. These studies provide evidence that long-term TAM exposure enhances sensitivity to the estrogenic effects of TAM and also to E2 itself.
Plasma Renin Activity in Patients with Coarctation of the Aorta
Authors: CLAUS WERNING, MANFRED SCHÖNBECK, PETER WEIDMANN, KLAUS BAUMANN, ETZEL GYSLING, PIERRE WIRZ, WALTER SIEGENTHALER
Journal: Circulation (1969)

In 10 patients with coarctation of the aorta, plasma renin activity was measured after recumbency and orthostatism in peripheral venous blood and, in some cases, in renal venous blood also. In nine of these patients, basic plasma renin values and those obtained under stimulatory conditions lay within normal range, and only in one patient were the values elevated. However, since this patient displayed the lowest gradient of mean arterial blood pressure proximal and distal to the stenosis, it can be regarded as improbable that the elevation in plasma renin activity was caused by the coarctation. Plasma renin activity in the renal venous blood of both kidneys, which was measured in three patients, showed no elevation. On the basis of observations of other authors and of our own studies it can be concluded that the kidneys can contribute to the development of prestenotic hypertension in acute constriction of the aorta in experiments with animals, but in chronic coarctation in animals or in man the humoral or renal theory has no importance to the pathogenesis of hypertension.
Pancreatitis--a retrospective study.
Authors: G Read, J M Braganza, H T Howat
Journal: Gut (1976)

A retrospective study has been made of all adult patients admitted to Manchester Royal Infirmary with exocrine pancreatic disease between 1968 and 1974, in order to define the factors which influence the variable mortality and morbidity rates in published accounts of patients with acute pancreatitis. The most plausible explanation is that some series with low mortality rates include a variable number of patients with relapsing acute pancreatitis and acute exacerbations of chronic pancreatitis. Both these pathological entities have a negligible mortality and morbidity rate compared with single attacks of acute pancreatitis. The difficulties encountered by the clinician in determining the prognosis of acute pancreatitis at the time of admission to hospital are discussed. Attention is drawn to the differing role of alcohol as an aetiological factor in relapsing chronic pancreatitis and acute pancreatitis.
Well-differentiated neurocytoma: What is the best available treatment?
Authors: Dirk Rades, Fabian Fehlauer, Katrin Lamszus, Steven E. Schild, Christian Hagel, Manfred Westphal, Winfried Alberti
Journal: Neuro-Oncology (2005)

Most neurocytomas are well differentiated, being associated with better long-term survival than the more aggressive atypical lesions. Atypical neurocytomas are characterized by an MIB-1 labeling index >3% or atyp-ical histologic features. This analysis focuses on well-differentiated neurocytomas in order to define the optimal treatment. A case with a follow-up of 132 months is presented. The patient developed two recurrences two and four years after first surgery, each showing an increasing proliferation activity. Furthermore, all published well-differentiated neurocytoma cases were reviewed for surgery, radiotherapy, and prognosis. Additional rel-evant data were obtained from the authors. Complete resection (CTR), complete resection plus radiotherapy (CTR + RT), incomplete resection (ITR), and incomplete resection plus radiotherapy (ITR + RT) were compared for outcome by using the Kaplan-Meier method and the log-rank test. Data were complete in 301 patients (CTR, 108; CTR + RT, 27; ITR, 81; ITR + RT, 85). Local control and survival were better after CTR than after ITR (P < 0.0001 and P = 0.0085, respectively). Radiotherapy improved local control after ITR (P < 0.0001) and after CTR (P = 0.0474), but not survival (P = 0.17 and P = 1.0, respectively). In the ITR + RT group, doses ≤54 Gy (n = 33) and >54 Gy (n = 32) were not significantly different for local control (P = 0.88) and survival (P = 0.95). The data demonstrated CTR to be superior to ITR for local control and survival. After CTR and ITR, radiotherapy improved local control, but not survival. A radiation dose of 54 Gy appeared sufficient. Application of postoperative radiotherapy should be decided individually, taking into account the risk of local failure, the need for another craniotomy, and potential radiation toxicity.
Decreased susceptibility to salt-induced hypertension in subtotally nephrectomized mice lacking the vasopressin V1a receptor
Authors: R. Oikawa, C. Hosoda, Y. Nasa, T. Daicho, A. Tanoue, G. Tsujimoto, N. Takagi, K. Tanonaka, S. Takeo
Journal: Cardiovascular Research (2010)

By examining vasopressin V1a receptor (V1aR) knockout (KO) mice, we previously found that the V1aR is critically involved in the regulation of normal blood pressure. The present study was undertaken to elucidate the role of the V1aR in salt-induced hypertension. We compared haemodynamic responses induced by subtotal nephrectomy + salt loading in V1aR KO mice with those of wild-type (WT) controls. The time course of changes in the systolic blood pressure and heart rate during the salt loading was attenuated in the KO mice compared with that for the WT mice. The elevation of the plasma norepinephrine level caused by the subtotal nephrectomy + salt loading was also reduced in the V1aR KO mice. A V1aR antagonist markedly lowered the arterial blood pressure in the salt-loaded WT mice but not in the normotensive WT mice or in the salt-loaded or normotensive V1aR KO mice. Whereas arginine vasopressin (AVP) administered to the lateral ventricle of the brain induced pressor and tachycardiac responses accompanied by sympathetic activation in the WT mice, these events were completely abolished in the V1aR KO mice. Also, pressor and tachycardiac responses induced by intraventricularly administered hypertonic saline in the WT mice were diminished in the V1aR KO mice. Moreover, the pressor response induced by intraventricularly administered AVP was reduced in α1d adrenoceptor KO mice, whereas the tachycardiac response did not differ from that of the WT mice. These results suggest that the V1aR is involved in the elevation of arterial blood pressure caused by dietary salt and that a V1aR antagonist, in particular regarding its effect in the brain, could have significant therapeutic potential in the treatment of hypertension.
<i>BRAF-V600E</i> expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups
Authors: Marie-Luise Berres, Karen Phaik Har Lim, Tricia Peters, Jeremy Price, Hitoshi Takizawa, Hélène Salmon, Juliana Idoyaga, Albert Ruzo, Philip J. Lupo, M. John Hicks, Albert Shih, Stephen J. Simko, Harshal Abhyankar, Rikhia Chakraborty, Marylene Leboeuf, Monique Beltrão, Sérgio A. Lira, Kenneth M. Heym, Björn E. Clausen, Venetia Bigley, Matthew Collin, Markus G. Manz, Kenneth McClain, Miriam Merad, Carl E. Allen
Journal: The Journal of Experimental Medicine (2014)

Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
Genome Scans of DNA Variability in Humans Reveal Evidence for Selective Sweeps Outside of Africa
Authors: J. F. Storz
Journal: Molecular Biology and Evolution (2004)

The last 50,000–150,000 years of human history have been characterized by rapid demographic expansions and the colonization of novel environments outside of sub-Saharan Africa. Mass migrations outside the ancestral species range likely entailed many new selection pressures, suggesting that genetic adaptation to local environmental conditions may have been more prevalent in colonizing populations outside of sub-Saharan Africa. Here we report a test of this hypothesis using genome-wide patterns of DNA polymorphism. We conducted a multilocus scan of microsatellite variability to identify regions of the human genome that may have been subject to continent-specific hitchhiking events. Using published polymorphism data for a total of 624 autosomal loci in multiple populations of humans, we used coalescent simulations to identify candidate loci for geographically restricted selective sweeps. We identified a total of 13 loci that appeared as outliers in replicated population comparisons involving different reference samples for Africa. A disproportionate number of these loci exhibited reduced levels of relative variability in non-African populations alone, suggesting that recent episodes of positive selection have been more prevalent outside of sub-Saharan Africa.
Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells
Authors: Marion Gabillot-Carré, Yves Lepelletier, Martine Humbert, Paulo de Sepuvelda, Nadine Ben Hamouda, Jean Pierre Zappulla, Roland Liblau, Antoine Ribadeau-Dumas, François Machavoine, Sébastien Letard, Cédric Baude, Aurélie Hermant, Ying Yang, Jacques Vargaftig, Christine Bodemer, Emmanuel Morelon, Olivier Lortholary, Christian Recher, Guy Laurent, Michel Dy, Michel Arock, Patrice Dubreuil, Olivier Hermine
Journal: Blood (2006)
Circulating B-Cell Chronic Lymphocytic Leukemia Cells Display Impaired Migration to Lymph Nodes and Bone Marrow
Authors: Tanja Nicole Hartmann, Valentin Grabovsky, Wei Wang, Petra Desch, Gabriele Rubenzer, Stefan Wollner, Inbal Binsky, Alexandra Vallon-Eberhard, Anita Sapoznikov, Meike Burger, Idit Shachar, Michal Haran, Marek Honczarenko, Richard Greil, Ronen Alon
Journal: Cancer Research (2009)

Homing to secondary lymphoid organs and bone marrow (BM) is a central aspect of leukemic pathophysiology. We investigated the roles of the two major lymphocyte integrins LFA-1 and VLA-4 on B-cell chronic lymphocytic leukemia (CLL) cells in these processes. We found that the majority of CLL cells expressed significantly reduced LFA-1 due to low beta2 integrin transcripts. VLA-4 expression was heterogeneous but underwent rapid activation by the BM chemokine CXCL12. CLL cells failed to transmigrate across VCAM-1-expressing, ICAM-1-expressing, and CXCL12-expressing endothelium, whereas when LFA-1 expression was regained in subsets of CLL cells, these lymphocytes rapidly transmigrated the endothelium. Furthermore, when injected into tail veins of immunodeficient mice, normal B cells rapidly homed to lymph nodes (LN) in a LFA-1-dependent manner, whereas CLL cells did not. Nevertheless, only residual CLL subsets could reenter BM, whereas both normal and CLL cells homed to the mice spleen in an LFA-1-independent and VLA-4-independent manner. Our results suggest that CLL cells have a reduced capacity to adhere and transmigrate through multiple vascular endothelial beds and poorly home to lymphoid organs other than spleen. Integrin blocking could thus be an efficient strategy to prevent circulating CLL cells from reaching prosurvival niches in LNs and BM but not in spleen.
Androgen Deprivation Therapy for Prostate Cancer
Authors: Nima Sharifi
Journal: JAMA (2005)

Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in US men. Androgen deprivation therapy (ADT), specifically surgical or medical castration, is the first line of treatment against advanced prostate cancer and is also used as an adjuvant to local treatment of high-risk disease.To review systematically the evidence on the risks and benefits of ADT for prostate cancer as well as clinical management of its adverse effects.We performed MEDLINE searches of English-language literature (1966 to March 2005) using the terms androgen deprivation therapy, hormone treatment, and prostate cancer. We reviewed bibliographies of literature to extract other relevant articles. Studies were selected based on clinical pertinence, with an emphasis on controlled study design.Androgen deprivation therapy is effective for palliation in many patients with advanced prostate cancer and improves outcomes for high-risk patients treated with radiation therapy for localized disease. Although patients with increasing prostate-specific antigen levels after local treatment without metastatic disease frequently undergo ADT, the benefits of this strategy are not clear. Adverse effects of ADT include decreased libido, impotence, hot flashes, osteopenia with increased fracture risk, metabolic alterations, and changes in cognition and mood.Androgen deprivation therapy has clear roles in the management of advanced prostate cancer and high-risk localized disease. The benefits of ADT in other settings need to be weighed carefully against substantial risks and adverse effects on quality of life.
Erythropoietin Is a Novel Vascular Protectant Through Activation of Akt1 and Mitochondrial Modulation of Cysteine Proteases
Authors: Zhao Zhong Chong, Jing-Qiong Kang, Kenneth Maiese
Journal: Circulation (2002)

Erythropoietin (EPO) is a critical regulator for the proliferation of immature erythroid precursors, but its role as a potential cytoprotectant in the cerebrovasculature system has not been defined.We examined the ability of EPO to regulate a cascade of apoptotic death-related cellular pathways during anoxia-induced vascular injury in endothelial cells (ECs). EC injury was evaluated by trypan blue, DNA fragmentation, membrane phosphatidylserine (PS) exposure, protein kinase B activity, mitochondrial membrane potential, and cysteine protease induction. Exposure to anoxia alone rapidly increased genomic DNA fragmentation from 2+/-1% to 40+/-5% and membrane PS exposure from 3+/-2% to 56+/-5% over 24 hours. Administration of a cytoprotective concentration of EPO (10 ng/mL) prevented DNA destruction and PS exposure. Cytoprotection by EPO was completely abolished by cotreatment with anti-EPO neutralizing antibody, which suggests that EPO was necessary and sufficient for the prevention of apoptosis. Protection by EPO was intimately dependent on the activation of protein kinase B (Akt1) and the maintenance of mitochondrial membrane potential. Subsequently, EPO inhibited caspase 8-, caspase 1-, and caspase 3-like activities that were linked to mitochondrial cytochrome c release.The present work serves to illustrate that EPO can offer novel cytoprotection during ischemic vascular injury through direct modulation of Akt1 phosphorylation, mitochondrial membrane potential, and cysteine protease activity.
The Na+/K+-ATPase α2-isoform regulates cardiac contractility in rat cardiomyocytes
Authors: F SWIFT, N TOVSRUD, U ENGER, I SJAASTAD, O SEJERSTED
Journal: Cardiovascular Research (2007)

The presence of both alpha1- and alpha2-isoforms of the Na+/K+-ATPase (NKA) in cardiomyocytes indicates different functions. We hypothesized that preferential localization of the alpha2-isoform to the t-tubules, locally controlling the Na+/Ca2+-exchanger (NCX), underlies a specific role in Ca2+ handling.We studied NKA isoform distribution in isolated cardiomyocytes from Wistar rats using immunocytochemistry. NKA pump and NCX currents (I(pump) and I(NCX)) were measured in control and detubulated cardiomyocytes. Intracellular Na+ concentration [Na+]i was assessed with the fluorescent dye SBFI.The alpha2-isoform abundance was higher in the t-tubules than in the surface sarcolemma. We established that 0.3 microM ouabain specifically blocked the alpha2-isoform in isolated rat cardiomyocytes. This low concentration blocked 10.7+/-0.6% of I(pump) in control, but only 6.0+/-0.5% in detubulated cardiomyocytes. Moreover, measured and calculated alpha1-specific and alpha2-specific I(pump) in control (547+/-29 pA and 66 pA, respectively) and in detubulated cells (495+/-30 pA and 31 pA, respectively) showed that 53% of the alpha2-isoform, but only 9.5% of the alpha1-isoform, were localized to the t-tubules. Despite the small abundance of the alpha2-isoform (approximately 11% of total NKA), selective inhibition of this isoform induced a 40% increase in contractility in field stimulated cardiomyocytes, but no increase in global [Na+]i. However, inhibition of the alpha2-isoform increased I(NCX) indicating local subsarcolemmal accumulation of Na+ near NCX.The alpha2-isoform of the NKA is functionally coupled to the NCX and can regulate Ca2+ handling without changing global [Na+]i.
Cl <sup>−</sup> -HCO <sub>3</sub> <sup>−</sup> Exchange in Developing Neonatal Rat Cardiac Cells
Authors: Irina Korichneva, Michel Pucéat, Robert Cassoly, Guy Vassort
Journal: Circulation Research (1995)

Abstract The Cl − -HCO 3 − exchanger is the main anionic exchanger (AE) that alleviates alkaline loads in cardiac cells. We recently identified in adult ventricular cells two membrane proteins (80 and 120 kD) immunologically related to the erythroid band 3 and likely to mediate the anion exchange. In the present study, we further investigated the Cl − -HCO 3 − exchanger activity concomitantly with the expression and intracellular localization of the band 3–like proteins during the development of neonatal rat cardiac cells maintained in culture for 17 days. Microspectrofluorometric measurements of pH i in single cells show that neonatal rat cardiomyocytes display a fully functional DIDS-sensitive Cl − -HCO 3 − exchanger at early stages of development. Neither basal pH i nor the anion exchange activity changes with different stages of the culture. In Western blotting with an anti–whole erythroid band 3 antibody, we found both the 80- and the 120-kD band 3–like proteins in whole heart and cultured neonatal cardiac cells. The 80-kD protein was also recognized by an anti-AE1 antiserum, whereas the 120-kD protein was specifically detected by an anti–cardiac AE3 antibody. Thus, we propose that the proteins are encoded by two different genes, AE1 and AE3, respectively. Subcellular fractionation of isolated and cultured cardiomyocytes revealed the presence of both proteins in the membrane, nuclear, and myofibril fractions. The results obtained in biochemical experiments corroborate the confocal images of immunostained neonatal cells, which demonstrate perinuclear location of band 3–like proteins at an early stage of development and their appearance within myofilaments after cell maturation. Colocalization of band 3–like proteins with specific markers of the Golgi apparatus, wheat germ agglutinin and CTR433 antibody, suggests the presence of these proteins in the Golgi area. The later decoration of repetitive striations between each sarcomere indicates that the band 3–like proteins are assigned in development within a compartment similar to costameres, areas of attachment of myofibrils to sarcolemma. These areas are likely to play a major role in signal transduction of neurohormonal stimuli.
The Zinc Finger Gene <i>ZIC2</i> Has Features of an Oncogene and Its Overexpression Correlates Strongly with the Clinical Course of Epithelial Ovarian Cancer
Authors: Sergio Marchini, Elizabeth Poynor, Richard R. Barakat, Luca Clivio, Michela Cinquini, Robert Fruscio, Luca Porcu, Cecilia Bussani, Maurizio D’Incalci, Eugenio Erba, Michela Romano, Giorgio Cattoretti, Dionyssios Katsaros, Andrew Koff, Lucio Luzzatto
Journal: Clinical Cancer Research (2012)

Epithelial ovarian tumors (EOT) are among the most lethal of malignancies in women. We have previously identified ZIC2 as expressed at a higher level in samples of a malignant form (MAL) of EOT than in samples of a form with low malignant potential (LMP). We have now investigated the role of ZIC2 in driving tumor growth and its association with clinical outcomes.ZIC2 expression levels were analyzed in two independent tumor tissue collections of LMP and MAL. In vitro experiments aimed to test the role of ZIC2 as a transforming gene. Cox models were used to correlate ZIC2 expression with clinical endpoints.ZIC2 expression was about 40-fold in terms of mRNA and about 17-fold in terms of protein in MAL (n = 193) versus LMP (n = 39) tumors. ZIC2 mRNA levels were high in MAL cell lines but undetectable in LMP cell lines. Overexpression of ZIC2 was localized to the nucleus. ZIC2 overexpression increases the growth rate and foci formation of NIH3T3 cells and stimulates anchorage-independent colony formation; downregulation of ZIC2 decreases the growth rate of MAL cell lines. Zinc finger domains 1 and 2 are required for transforming activity. In stage I MAL, ZIC2 expression was significantly associated with overall survival in both univariate (P = 0.046) and multivariate model (P = 0.049).ZIC2, a transcription factor related to the sonic hedgehog pathway, is a strong discriminant between MAL and LMP tumors: it may be a major determinant of outcome of EOTs.
Acrokeratosis paraneoplastica (Bazex syndrome) occurring with acquired ichthyosis in Hodgkin's disease
Authors: G.P.H. LUCKER, P.M. STEIJLEN
Journal: British Journal of Dermatology (1995)

We report a patient who exhibited two paraneoplastic skin disorders, acrokeratosis paraneoplastica and acquired ichthyosis, in association with Hodgkin disease. Treatment of the Hodgkin's disease resulted in rapid improvement of both skin disorders, confirming a causal relationship. The simultaneous presence of two paraneoplastic skin disorders suggests a common pathogenetic factor. Transforming growth factor a, produced by tumour cells, may play a part in the aetiopathogenesis of hyperproliferative paraneoplastic skin conditions.