tbuckley/cabot-search huggingface dataset:
Altered ErbB Receptor Signaling and Gene Expression in Cisplatin-Resistant Ovarian Cancer
Authors: Kenneth Macleod, Peter Mullen, Jane Sewell, Genevieve Rabiasz, Sandra Lawrie, Eric Miller, John F. Smyth, Simon P. Langdon
Journal: Cancer Research (2005)

The majority of ovarian cancer patients are treated with platinum-based chemotherapy, but the emergence of resistance to such chemotherapy severely limits its overall effectiveness. We have shown that development of resistance to this treatment can modify cell signaling responses in a model system wherein cisplatin treatment has altered cell responsiveness to ligands of the erbB receptor family. A cisplatin-resistant ovarian carcinoma cell line PE01CDDP was derived from the parent PE01 line by exposure to increasing concentrations of cisplatin, eventually obtaining a 20-fold level of resistance. Whereas PE01 cells were growth stimulated by the erbB receptor-activating ligands, such as transforming growth factor-alpha (TGFalpha), NRG1alpha, and NRG1beta, the PE01CDDP line was growth inhibited by TGFalpha and NRG1beta but unaffected by NRG1alpha. TGFalpha increased apoptosis in PE01CDDP cells but decreased apoptosis in PE01 cells. Differences in extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling were also found, which may be implicated in the altered cell response to ligands. Microarray analysis revealed 51 genes whose mRNA increased by at least 2-fold in PE01CDDP cells relative to PE01 (including FRA1, ETV4, MCM2, AXL, MT3, TRAP1, and FANCG), whereas 36 genes (including IGFBP3, TRAM1, and KRT4 and KRT19) decreased by a similar amount. Differential display reverse transcriptase-PCR identified altered mRNA expression for TCP1, SLP1, proliferating cell nuclear antigen, and ZXDA. Small interfering RNA inhibition of FRA1, TCP1, and MCM2 expression was associated with reduced growth and FRA1 inhibition with enhanced cisplatin sensitivity. Altered expression of these genes by cytotoxic exposure may provide survival advantages to cells including deregulation of signaling pathways, which may be critical in the development of drug resistance.
Absence of Thrombospondin-2 Causes Age-Related Dilated Cardiomyopathy
Authors: Melissa Swinnen, Davy Vanhoutte, Geert C. Van Almen, Nazha Hamdani, Mark W.M. Schellings, Jan D'hooge, Jolanda Van der Velden, Matthew S. Weaver, E. Helene Sage, Paul Bornstein, Fons K. Verheyen, Thierry VandenDriessche, Marinee K. Chuah, Dirk Westermann, Walter J. Paulus, Frans Van de Werf, Blanche Schroen, Peter Carmeliet, Yigal M. Pinto, Stephane Heymans
Journal: Circulation (2009)

Background— The progressive shift from a young to an aged heart is characterized by alterations in the cardiac matrix. The present study investigated whether the matricellular protein thrombospondin-2 (TSP-2) may affect cardiac dimensions and function with physiological aging of the heart. Methods and Results— TSP-2 knockout (KO) and wild-type mice were followed up to an age of 60 weeks. Survival rate, cardiac function, and morphology did not differ at a young age in TSP-2 KO compared with wild-type mice. However, &gt;55% of the TSP-2 KO mice died between 24 and 60 weeks of age, whereas &lt;10% of the wild-type mice died. In the absence of TSP-2, older mice displayed a severe dilated cardiomyopathy with impaired systolic function, increased cardiac dilatation, and fibrosis. Ultrastructural analysis revealed progressive myocyte stress and death, accompanied by an inflammatory response and replacement fibrosis, in aging TSP-2 KO animals, whereas capillary or coronary morphology or density was not affected. Importantly, adeno-associated virus-9 gene–mediated transfer of TSP-2 in 7-week-old TSP-2 KO mice normalized their survival and prevented dilated cardiomyopathy. In TSP-2 KO animals, age-related cardiomyopathy was accompanied by increased matrix metalloproteinase-2 and decreased tissue transglutaminase-2 activity, together with impaired collagen cross-linking. At the cardiomyocyte level, TSP-2 deficiency in vivo and its knockdown in vitro decreased the activation of the Akt survival pathway in cardiomyocytes. Conclusion— TSP-2 expression in the heart protects against age-dependent dilated cardiomyopathy.
Inhibition of Notch1-Dependent Cardiomyogenesis Leads to a Dilated Myopathy in the Neonatal Heart
Authors: Konrad Urbanek, Mauricio Castro Cabral-da-Silva, Noriko Ide-Iwata, Silvia Maestroni, Francesca Delucchi, Hanqiao Zheng, João Ferreira-Martins, Barbara Ogórek, Domenico D'Amario, Michael Bauer, Gianpaolo Zerbini, Marcello Rota, Toru Hosoda, Ronglih Liao, Piero Anversa, Jan Kajstura, Annarosa Leri
Journal: Circulation Research (2010)

Rationale: Physiological hypertrophy in the developing heart has been considered the product of an increase in volume of preexisting fetal cardiomyocytes in the absence of myocyte formation. Objective: In this study, we tested whether the mouse heart at birth has a pool of cardiac stem cells (CSCs) that differentiate into myocytes contributing to the postnatal expansion of the parenchymal cell compartment. Methods and Results: We have found that the newborn heart contains a population of c-kit–positive CSCs that are lineage negative, self-renewing, and multipotent. CSCs express the Notch1 receptor and show the nuclear localization of its active fragment, N1ICD. In 60% of cases, N1ICD was coupled with the presence of Nkx2.5, indicating that the commitment of CSCs to the myocyte lineage is regulated by Notch1. Importantly, overexpression of N1ICD in neonatal CSCs significantly expanded the proportion of transit-amplifying myocytes. To establish whether these in vitro findings had a functional counterpart in vivo, the Notch pathway was blocked in newborn mice by administration of a γ-secretase inhibitor. This intervention resulted in the development of a dilated myopathy and high mortality rates. Ventricular decompensation was characterized by a 62% reduction in amplifying myocytes, which resulted in a 54% decrease in myocyte number. After cessation of Notch blockade and recovery of myocyte regeneration, cardiac anatomy and function were largely restored. Conclusions: Notch1 signaling is a critical determinant of CSC growth and differentiation; when this cascade of events is altered, cardiomyogenesis is impaired, physiological cardiac hypertrophy is prevented, and a life-threatening myopathy supervenes.
Role of the Sphingosine 1-Phosphate Receptor EDG-1 in Vascular Smooth Muscle Cell Proliferation and Migration
Authors: Michael J. Kluk, Timothy Hla
Journal: Circulation Research (2001)

Abstract— Sphingosine 1-phosphate (S1P), a platelet-derived ligand for the EDG-1 family of G protein–coupled receptors (GPCRs), has recently emerged as a regulator of vascular development. Although S1P has potent effects on endothelial cells and vascular smooth muscle cells (VSMCs), the functions of the specific S1P receptors in the latter cell type are not known. Here we show that pup-intimal VSMCs express higher levels of EDG-1 mRNA than adult-medial VSMCs. Stable transfection of EDG-1 into adult-medial VSMCs enhanced their proliferative response to S1P, concomitant with induction of p70 S6 kinase activity and expression of cyclin D1. Pertussis toxin treatment inhibited S1P-induced p70 S6 kinase activation, cyclin D1 expression and proliferation, suggesting that EDG-1–coupling to the G i pathway is critical. Furthermore, blocking p70 S6 kinase phosphorylation with rapamycin inhibited cyclin D1 expression and proliferation, suggesting that activation of p70 S6 kinase is critical in EDG-1/G i –mediated cell proliferation. EDG-1 expression also profoundly enhanced the migratory response of adult-medial VSMCs to S1P. S1P-induced migration of adult-medial VSMCs expressing exogenous EDG-1 required G i activation but not p70 S6 kinase. These results suggest that enhanced expression of EDG-1 in VSMCs dramatically stimulates both the proliferative and migratory responses to S1P. Since EDG-1 is expressed in the pup-intimal phenotype of VSMCs, S1P signaling via EDG-1 may play a role in vascular diseases in which the proliferation and migration of VSMCs are dysregulated.
Continuous Thrombus in the Right and Left Atria Penetrating the Patent Foramen Ovalis
Authors: Atsushi Fukumoto, Hitoshi Yaku, Kiyoshi Doi, Hirotoshi Ito, Satoshi Numata, Kyoko Hayashida, Tomoya Inoue, Satoshi Akabame, Youhei Oda, Hiroaki Matsubara, Tsunehiko Nishimura
Journal: Circulation (2005)
Bullous pemphigoid showing unusual ocular changes
Authors: None Kiyokawa, None Fujito, None Mori, None Mochizuki, None Hashimoto
Journal: British Journal of Dermatology (1998)

We describe a 68-year-old Japanese woman with erythematous and bullous skin lesions. Antibasement membrane zone antibodies of IgG class were detected in the serum, which reacted with the 230 kDa and 180 kDa bullous pemphigoid antigens on immunoblot analysis. The patient later developed corneal opacity in both eyes and a detachment of the epithelium in the centre of the cornea. However, no change was seen in the conjunctiva. These ocular lesions are different from those of cicatricial pemphigoid. The ocular lesions could be reproduced by injection of IgG from this patient into the stroma of the corneas of rabbits. Both the cutaneous and ocular lesions responded well to oral corticosteroid therapy. We diagnosed this patient as having bullous pemphigoid associated with a unique ocular lesion.
Longitudinal association between lung function and health-related quality of life in cystic fibrosis
Authors: Janice Abbott, Margaret A Hurley, Alison M Morton, Steven P Conway
Journal: Thorax (2012)

<h3>Background</h3> Lung function is an important indicator of cystic fibrosis disease status and those with better forced expiratory volume in 1 s (FEV<sub>1</sub>)% predicted have tended to report a better health-related quality of life (HRQoL) in cross-sectional studies. The relationship between lung function and HRQoL over time is unknown. This work assesses the natural progression of HRQoL reporting over many years and compares assessments across a whole decade and evaluates the relationship between lung function and HRQoL longitudinally. <h3>Methods</h3> Demographic (age, gender), clinical (FEV<sub>1</sub>% predicted, body mass index, diabetes, <i>Burkholderia cepacia</i> complex, intravenous access device and nutritional status) and HRQoL (Cystic Fibrosis Quality of Life Questionnaire) variables were obtained every 2 years over a 12-year period (seven time points from 1998 to 2010). <h3>Results</h3> HRQoL and lung function declined slowly over time and significant decade changes were observed for FEV<sub>1</sub>% predicted and the nine domains of the Cystic Fibrosis Quality of Life Questionnaire. The results of random coefficient modelling indicated that, at the population level, decreasing FEV<sub>1</sub>% predicted was associated with decreasing HRQoL after adjusting for confounding variables. However, the percentage of patients for whom a decrease in lung function was associated with a decrease in HRQoL differed according to the quality of life domain. <h3>Conclusions</h3> HRQoL and FEV<sub>1</sub>% predicted decline slowly; nevertheless, a decrease in lung function predicted a decrease in HRQoL over time.
Measurement of Tumor VEGF-A Levels with 89Zr-Bevacizumab PET as an Early Biomarker for the Antiangiogenic Effect of Everolimus Treatment in an Ovarian Cancer Xenograft Model
Authors: Arne R.M. van der Bilt, Anton G.T. Terwisscha van Scheltinga, Hetty Timmer-Bosscha, Carolien P. Schröder, Linda Pot, Jos G.W. Kosterink, Ate G.J. van der Zee, Marjolijn N. Lub-de Hooge, Steven de Jong, Elisabeth G.E. de Vries, Anna K.L. Reyners
Journal: Clinical Cancer Research (2012)

Abstract Purpose: The mTOR pathway is frequently activated in ovarian cancers. mTOR inhibitors, such as everolimus, can reduce VEGF-A production by cancer cells. We investigated whether early everolimus treatment effects could be monitored by positron emission tomography (PET) with 89Zr-bevacizumab. Experimental Design: The effect of everolimus on VEGF-A secretion was determined in a panel of human ovarian cancer cell lines and in A2780luc+ ovarian cancer cells xenografted subcutaneously in BALB/c mice. Mice received daily 10 mg/kg everolimus intraperitoneally (i.p.) for 14 days. PET scans with the tracer 89Zr-labeled bevacizumab were conducted before and after treatment. Ex vivo89Zr-bevacizumab biodistribution and correlative tissue analyses were conducted. Tumor VEGF-A levels were measured with ELISA and mean vascular density (MVD) was determined with immunohistochemistry. Results: Everolimus treatment reduced VEGF-A levels in the supernatant of all cell lines. Everolimus lowered 89Zr-bevacizumab tumor uptake by 21.7% ± 4.0% [mean standardized uptake value (SUVmean) 2.3 ± 0.2 vs. 2.9 ± 0.2, P &amp;lt; 0.01]. Ex vivo biodistribution also showed lower tracer uptake in the tumors of treated as compared with control animals (7.8 ± 0.8%ID/g vs. 14.0 ± 1.7%ID/g, P &amp;lt; 0.01), whereas no differences were observed for other tissues. This coincided with lower VEGF-A protein levels in tumor lysates in treated versus untreated tumors (P = 0.04) and reduced MVD (P &amp;lt; 0.01). Conclusion: Tumor VEGF-A levels are decreased by everolimus. 89Zr-bevacizumab PET could be used to monitor tumor VEGF-A levels as an early biomarker of the antiangiogenic effect of mTOR inhibitor therapy. Clin Cancer Res; 18(22); 6306–14. ©2012 AACR.
Frequency of Anxiety Disorders in Psychiatric Outpatients With Major Depressive Disorder
Authors: Mark Zimmerman, Wilson McDermut, Jill I. Mattia
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: The authors determined the frequency of anxiety disorders in a large group of depressed outpatients seeking treatment. METHOD: The Structured Clinical Interview for DSM-IV was administered to 373 depressed outpatients. RESULTS: More than one-half of the patients met the full criteria for a current anxiety disorder, and more than one-half of the patients with an anxiety disorder had more than one. When partial remissions and anxiety disorder diagnoses classified as “not otherwise specified” were included, two-thirds of the patients had a current anxiety disorder and three-quarters had a lifetime history of an anxiety disorder. CONCLUSIONS: The majority of patients with a principal diagnosis of unipolar major depressive disorder have a comorbid anxiety disorder. Because antidepressant medications have differential efficacies for anxiety disorders, knowledge of the presence of a comorbid anxiety disorder in a depressed patient may have treatment implications.
Leukocyte subpopulations elicited by a nontumorigenic variant of B16 melanoma: their role in direct rejection of the melanoma and in prevention of tumorigenesis in Winn assays.
Authors: T A Calvelli, V H Freedman, S C Silverstein, S Silagi
Journal: The Journal of Experimental Medicine (1982)

The mechanisms by which various leukocyte subpopulations elicited by an immunogenic, nontumorigenic subclone (C3471) of B16 melanoma caused rejection of the tumorigenic parental melanoma (B559), were investigated. Leukocytes from C3471-immune mice were co-injected with B559 tumor cells in Winn assays into normal syngeneic recipients. Tumor formation by B559 cells was prevented when C3471-immune (a) unfractionated peritoneal leukocytes, or (b) glass-adherent peritoneal cells (90% macrophages), or (c) nylon wool purified nonadherent cells (95% Thy-1.2+) were used in the Winn assays. If the C3471-immunized mice were treated with antithymocyte serum before harvest of their peritoneal cells, none of these leukocyte populations were effective in the Winn assay. However, macrophages from these immunologically compromised donors regained their tumoricidal activity after incubation in vitro with T lymphocytes from untreated C3471-immune donors; similarly, C3471-immune lymphocytes rendered normal resident peritoneal macrophages tumoricidal in Winn assays. When C3471-immunized mice were irradiated or treated with antithymocyte serum before direct challenge with B559 cells, melanomas developed, thus providing additional evidence for the need for intact T cell function to establish immunity against the melanoma. Furthermore, when Winn assay recipients were treated with antithymocyte serum, neither C3471-immune macrophages nor T cells were able to prevent tumor formation. These findings indicate that antithymocyte serum-sensitive (Thy-1.2+) lymphocytes are necessary both for the generation of tumoricidal leukocytes in C3471-immunized mice, and for the rejection of B559 melanoma by demonstrably tumoricidal macrophages in Winn assay recipients. In addition, long-lasting immunity developed in 50% of the normal mice that had received both C3471-immune peritoneal cells and B559 tumor cells, as manifested by their capacity to reject a second challenge with B559 cells 40-60 d later.
Long-Term Functional Evaluation of the Treated Kidney in a Prospective Series of Patients Who Underwent Laparoscopic Partial Nephrectomy for Small Renal Tumors
Authors: Francesco Porpiglia, Cristian Fiori, Riccardo Bertolo, Ivano Morra, Roberto Russo, Giorgina Piccoli, Tiziana Angusti, Valerio Podio
Journal: European Urology (2012)
P.M.-G.M. SUCCINYLCHOLINE-MODIFIED ELECTRO-SHOCKTHERAPY WITHOUT BARBITURATES
Authors: DAVID J. IMPASTATO, ANTHONY R. GABRIEL
Journal: American Journal of Psychiatry (1958)

PM-GM Succinylcholine-modified electroshocktherapy without barbiturates has the following advantages: 1. Only 10 mg. of succinylcholine are needed to produce sufficient relaxation to prevent fractures in practically 100% of all patients. 2. It dispenses entirely with the need of barbiturates. 3. It does not produce any more apnea than is produced following an unmodified alternating current treatment. In fact, due to the laryngeal relaxation produced by the SCC, patients breathe sooner and better with the PM-GM method than after unmodified alternating current treatment. 4. There is no need of oxygen following the convulsion. 5. The technic is very simple, and requires the least personnel for its administration. The psychiatrist can effectively give the treatment himself assisted only by one nurse. It can be given to a large number of patients within a short time. 6. Following the convulsion the patients are awake and clear within a relatively short time. This is advantageous in ambulatory patients. 7. Study of the problem of fear which occurs in a small number of patients with this method shows that the fear produced is not due to the method itself, but is inherent in the patient and sometimes is caused by imperfect treatment technic. Suggestions as to how to avoid fear are made. 8. We believe that the PM-GM technic is the safest electroshocktherapy technic so far developed and recommend its use.
Finding the most effective cerumenolytic
Authors: Clair Saxby, Richard Williams, Simon Hickey
Journal: International Journal of Surgery (2013)

Aim  To conduct an in-vitro study to determine the most effective topical cerumenolytic.  Method  Cerumen was collected from patients who attended the ENT out-patient clinic. The collected cerumen was formed into a homogeneous ball. Discs of wax were punched out and weighed to create samples of uniform shape and size. Each cerumen sample was placed in a tube which contained one of six test solutions. The tubes were observed at specific time points. Digital photographs were taken to record the degree of cerumen disintegration. The cerumen discs were then removed from the solutions, dried and re-weighed.  Results  Distilled water caused the greatest reduction in the mass of the cerumen disc. Cerumen placed in distilled water and in sodium bicarbonate solution showed substantial disintegration at 12 hours. Cerumen placed in solutions containing oil-based agents showed no visible sign of disintegration and no reduction in dried weight.  Conclusion  Distilled water resulted in the greatest degree of cerumenolysis. Oil-based cerumenolytics were ineffective.
Patterns of Diversifying Selection in the Phytotoxin-like scr74 Gene Family of Phytophthora infestans
Authors: Zhenyu Liu, Jorunn I. B. Bos, Miles Armstrong, Stephen C. Whisson, Luis da Cunha, Trudy Torto-Alalibo, Joe Win, Anna O. Avrova, Frank Wright, Paul R. J. Birch, Sophien Kamoun
Journal: Molecular Biology and Evolution (2004)

Phytophthora infestans, the organism responsible for the Irish famine, causes late blight, a re-emerging disease of potato and tomato. Little is known about the molecular evolution of P. infestans genes. To identify candidate effector genes (virulence or avirulence genes) that may have co-evolved with the host, we mined expressed sequence tag (EST) data from infection stages of P. infestans for secreted and potentially polymorphic genes. This led to the identification of scr74, a gene that encodes a predicted 74-amino acid secreted cysteine-rich protein with similarity to the Phytophthora cactorum phytotoxin PcF. The expression of scr74 was upregulated approximately 60-fold 2 to 4 days after inoculation of tomato and was also significantly induced during early stages of colonization of potato. The scr74 gene was found to belong to a highly polymorphic gene family within P. infestans with 21 different sequences identified. Using the approximate and maximum likelihood (ML) methods, we found that diversifying selection likely caused the extensive polymorphism observed within the scr74 gene family. Pairwise comparisons of 17 scr74 sequences revealed elevated ratios of nonsynonymous to synonymous nucleotide-substitution rates, particularly in the mature region of the proteins. Using ML, all 21 polymorphic amino acid sites were identified to be under diversifying selection. Of these 21 amino acids, 19 are located in the mature protein region, suggesting that selection may have acted on the functional portions of the proteins. Further investigation of gene copy number and organization revealed that the scr74 gene family comprises at least three copies located in a region of no more than 300 kb of the P. infestans genome. We found evidence that recombination contributed to sequence divergence within at least one gene locus. These results led us to propose an evolutionary model that involves gene duplication and recombination, followed by functional divergence of scr74 genes. This study provides support for using diversifying selection as a criterion for identifying candidate effector genes from sequence databases.