tbuckley/cabot-search huggingface dataset:
Nectin-2 is a potential target for antibody therapy of breast and ovarian cancers
Authors: Tsutomu Oshima, Shuji Sato, Junichi Kato, Yuki Ito, Takahiro Watanabe, Isamu Tsuji, Akira Hori, Tomofumi Kurokawa, Toshio Kokubo
Journal: Molecular Cancer (2013)

Nectin-2 is a Ca(2+)-independent cell-cell adhesion molecule that is one of the plasma membrane components of adherens junctions. However, little has been reported about the involvement of Nectin-2 in cancer.To determine the expression of Nectin-2 in cancer tissues and cancer cell lines, we performed gene expression profile analysis, immunohistochemistry studies, and flow cytometry analysis. We also investigated the potential of this molecule as a target for antibody therapeutics to treat cancers by generating and characterizing an anti-Nectin-2 rabbit polyclonal antibody (poAb) and 256 fully human anti-Nectin-2 monoclonal antibodies (mAbs). In addition, we tested anti-Nectin-2 mAbs in several in vivo tumor growth inhibition models to investigate the primary mechanisms of action of the mAbs.In the present study, we found that Nectin-2 was over-expressed in clinical breast and ovarian cancer tissues by using gene expression profile analysis and immunohistochemistry studies. Nectin-2 was over-expressed in various cancer cell lines as well. Furthermore, the polyclonal antibody specific to Nectin-2 suppressed the in vitro proliferation of OV-90 ovarian cancer cells, which express endogenous Nectin-2 on the cell surface. The anti-Nectin-2 mAbs we generated were classified into 7 epitope bins. The anti-Nectin-2 mAbs demonstrated antibody-dependent cellular cytotoxicity (ADCC) and epitope bin-dependent features such as the inhibition of Nectin-2-Nectin-2 interaction, Nectin-2-Nectin-3 interaction, and in vitro cancer cell proliferation. A representative anti-Nectin-2 mAb in epitope bin VII, Y-443, showed anti-tumor effects against OV-90 cells and MDA-MB-231 breast cancer cells in mouse therapeutic models, and its main mechanism of action appeared to be ADCC.We observed the over-expression of Nectin-2 in breast and ovarian cancers and anti-tumor activity of anti-Nectin-2 mAbs via strong ADCC. These findings suggest that Nectin-2 is a potential target for antibody therapy against breast and ovarian cancers.
The Syk Tyrosine Kinase Localizes to the Centrosomes and Negatively Affects Mitotic Progression
Authors: Déborah Zyss, Philippe Montcourrier, Benjamin Vidal, Christelle Anguille, Fabrice Mérezègue, Alain Sahuquet, Paul H. Mangeat, Peter J. Coopman
Journal: Cancer Research (2005)

Abstract We showed previously that the spleen tyrosine kinase Syk is expressed by mammary epithelial cells and that it suppresses malignant growth of breast cancer cells. The exact molecular mechanism of its tumor-suppressive activity remains, however, to be identified. Here, we show that Syk colocalizes and copurifies with the centrosomal component γ-tubulin and exhibits a catalytic activity within the centrosomes. Moreover, its centrosomal localization depends on its intact kinase activity. Centrosomal Syk expression is persistent in interphase but promptly drops during mitosis, obviously resulting from its ubiquitinylation and proteasomal degradation. Conversely, unrestrained exogenous expression of a fluorescently tagged Discosoma sp. red fluorescent protein (DsRed)-Syk chimera engenders abnormal cell division and cell death. Transient DsRed-Syk overexpression triggers an abrupt cell death lacking hallmarks of classic apoptosis but reminiscent of mitotic catastrophe. Surviving stable DsRed-Syk–transfected cells exhibit multipolar mitotic spindles and contain multiple abnormally sized nuclei and supernumerary centrosomes, revealing anomalous cell division. Taken together, these results show that Syk is a novel centrosomal kinase that negatively affects cell division. Its expression is strictly controlled in a spatiotemporal manner, and centrosomal Syk levels need to decline to allow customary progression of mitosis.
Metabolic Associations of Reduced Proliferation and Oxidative Stress in Advanced Breast Cancer
Authors: Livnat Jerby, Lior Wolf, Carsten Denkert, Gideon Y. Stein, Mika Hilvo, Matej Oresic, Tamar Geiger, Eytan Ruppin
Journal: Cancer Research (2012)

Abstract Aberrant metabolism is a hallmark of cancer, but whole metabolomic flux measurements remain scarce. To bridge this gap, we developed a novel metabolic phenotypic analysis (MPA) method that infers metabolic phenotypes based on the integration of transcriptomics or proteomics data within a human genome-scale metabolic model. MPA was applied to conduct the first genome-scale study of breast cancer metabolism based on the gene expression of a large cohort of clinical samples. The modeling correctly predicted cell lines' growth rates, tumor lipid levels, and amino acid biomarkers, outperforming extant metabolic modeling methods. Experimental validation was obtained in vitro. The analysis revealed a subtype-independent “go or grow” dichotomy in breast cancer, where proliferation rates decrease as tumors evolve metastatic capability. MPA also identified a stoichiometric tradeoff that links the observed reduction in proliferation rates to the growing need to detoxify reactive oxygen species. Finally, a fundamental stoichiometric tradeoff between serine and glutamine metabolism was found, presenting a novel hallmark of estrogen receptor (ER)+ versus ER− tumor metabolism. Together, our findings greatly extend insights into core metabolic aberrations and their impact in breast cancer. Cancer Res; 72(22); 5712–20. ©2012 AACR.
Retinol esterification by microsomes from the mucosa of human small intestine. Evidence for acyl-Coenzyme A retinol acyltransferase activity.
Authors: P Helgerud, L B Petersen, K R Norum
Journal: Journal of Clinical Investigation (1983)

The mechanism of the intestinal esterification of retinol has been obscure. Recently, an acyl-Coenzyme A (CoA):retinol acyltransferase (ARAT) was found in rat intestinal microsomes, and experiments were therefore conducted to determine whether a corresponding enzyme exists in human small intestine. When microsomes were incubated with [3H]retinol and palmitoyl-CoA, or retinol and [1-14C]palmitoyl-CoA, radioactive retinyl palmitate was formed as identified by alumina column chromatography and reverse-phase high-pressure liquid chromatography. Heating the microsomes for 30 min at 60 degrees C resulted in loss of activity. The esterification was negligible without exogenous acyl-CoA and markedly stimulated by palmitoyl-, oleoyl-, and stearoyl-CoA in concentrations up to 20 microM. The acyl-CoA was successfully replaced by an acyl-CoA generating system, but not by unactivated palmitate (2.5-200 microM). The assay was dependent on the presence of albumin with optimum activity at 2-10 mg/ml. The optimal retinol concentration was 20-30 microM and pH approximately 7.4. The esterifying activity was completely inhibited by 8 mM of taurocholate and to 90% by 1 mM of 5,5'-dithiobis(2-nitrobenzoic acid). Activity was found throughout the small intestine. In jejunum the rate of retinol esterification was: 3.44 +/- 2.24 nmol [3H]retinyl ester formed . mg microsomal protein-1 . min-1 (mean +/- SD, n = 12). The corresponding activity in whole homogenates of biopsies were 1.17 +/- 0.28 (n = 8). It is concluded that human small intestine contains a microsomal acyl-CoA:retinol acyltransferase. Due to its high activity in vitro this enzyme is likely to be responsible for the intestinal esterification of retinol.
Mechanisms of mouse spleen dendritic cell function in the generation of influenza-specific, cytolytic T lymphocytes.
Authors: R Nonacs, C Humborg, J P Tam, R M Steinman
Journal: The Journal of Experimental Medicine (1992)

We have evaluated the capacity of dendritic cells to function as antigen-presenting cells (APCs) for influenza and have examined their mechanism of action. Virus-pulsed dendritic cells were 100 times more efficient than bulk spleen cells in stimulating cytotoxic T lymphocyte (CTL) formation. The induction of CTLs required neither exogenous lymphokines nor APCs in the responding T cell population. Infectious virus entered dendritic cells through intracellular acidic vacuoles and directed the synthesis of several viral proteins. If ultraviolet (UV)-inactivated or bromelain-treated viruses were used, viral protein synthesis could not be detected, and there was poor induction of CTLs. This indicated that dendritic cells were not capable of processing noninfectious virus onto major histocompatibility complex (MHC) class I molecules. However, UV-inactivated and bromelain-treated viruses were presented efficiently to class II-restricted CD4+ T cells. The CD4+ T cells crossreacted with different strains of influenza and markedly amplified CTL formation. Cell lines that lacked MHC class II, and consequently the capacity to stimulate CD4+ T cells, failed to induce CTLs unless helper lymphokines were added. Similarly, dendritic cells pulsed with the MHC class I-restricted nucleoprotein 147-155 peptide were poor stimulators in the absence of exogenous helper factors. We conclude that the function of dendritic cells as APCs for the generation of virus-specific CTLs in vitro depends measurably upon: (a) charging class I molecules with peptides derived from endogenously synthesized viral antigens, and (b) stimulating a strong CD4+ helper T cell response.
Comparison of Human and Rat Uterine Leiomyomata: Identification of a Dysregulated Mammalian Target of Rapamycin Pathway
Authors: Judy S. Crabtree, Scott A. Jelinsky, Heather A. Harris, Sung E. Choe, Monette M. Cotreau, Michelle L. Kimberland, Ewa Wilson, Kathryn A. Saraf, Wei Liu, Adrienne S. McCampbell, Bhuvanesh Dave, Russell R. Broaddus, Eugene L. Brown, Wenling Kao, Jerauld S. Skotnicki, Magid Abou-Gharbia, Richard C. Winneker, Cheryl L. Walker
Journal: Cancer Research (2009)

Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyomata. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyomata. An unbiased pathway analysis using a method of gene-set enrichment based on the sigPathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly up-regulated pathways in both human and rat tumors. To validate this pathway as a therapeutic target for uterine leiomyomata, preclinical studies were conducted in Eker rats. These rats develop uterine leiomyomata as a consequence of loss of Tsc2 function and up-regulation of mTOR signaling. Inhibition of mTOR in female Eker rats with the rapamycin analogue WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity, and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly show the dependence of uterine leiomyomata with activated mTOR on this signaling pathway for growth.
Clinical Trial Participation and Time to Treatment Among Adolescents and Young Adults With Cancer: Does Age at Diagnosis or Insurance Make a Difference?
Authors: Helen M. Parsons, Linda C. Harlan, Nita L. Seibel, Jennifer L. Stevens, Theresa H.M. Keegan
Journal: Journal of Clinical Oncology (2011)

Because adolescent and young adult (AYA) patients with cancer have experienced variable improvement in survival over the past two decades, enhancing the quality and timeliness of cancer care in this population has emerged as a priority area. To identify current trends in AYA care, we examined patterns of clinical trial participation, time to treatment, and provider characteristics in a population-based sample of AYA patients with cancer.
Coronally advanced flap and combination therapy for root coverage. Clinical strategies based on scientific evidence and clinical experience
Authors: Pierpaolo Cortellini, Giovanpaolo Pini Prato
Journal: Periodontology 2000 (2012)

Abstract During the past three decades, several surgical techniques have been proposed to treat single and multiple gingival recessions. Evidence indicates that coronally advanced flap‐based approaches result in the best clinical results. Among all the different techniques, the use of a graft under a coronally advanced flap results in the best short‐ and long‐term outcomes in terms of root coverage and gain in keratinized tissue. The use of a coronally advanced flap + connective tissue graft would appear to be the best choice for root coverage. However, harvesting a graft from the palate adds morbidity, surgical chair‐time and requires increased surgical skills. A potential alternative could be the use of enamel matrix derivatives under a coronally advanced flap, and this achieves similar clinical outcomes and is less invasive, but adds economic costs to the treatment. Evidence shows that a coronally advanced flap alone in many instances results in complete root coverage and is stable over time. A coronally advanced flap is less invasive for the patient, requires less chair‐time and probably less surgical skill. It would therefore be desirable to use a coronally advanced flap approach when indicated. It has been hypothesized that a coronally advanced flap approach alone could be successfully applied when the residual gingiva is thick and wide, although existing evidence does not support this hypothesis in full. Accordingly, the adjunctive use of a graft or enamel matrix derivatives could be restricted to sites at which there is thin and narrow residual gingiva.
High-concentration (20 μg g<sup>−1</sup> ) tacalcitol ointment in the treatment of facial psoriasis: an 8-week open-label clinical trial
Authors: J.W. Choi, J-W. Choi, I-H. Kwon, J-I. Youn
Journal: British Journal of Dermatology (2010)

Journal Article High‐concentration (20 μg g−1) tacalcitol ointment in the treatment of facial psoriasis: an 8‐week open‐label clinical trial Get access J.W. Choi, J.W. Choi Department of Dermatology, Seoul National University College of Medicine, 28‐Yongon‐dong, Chongno‐gu, Seoul 110‐744, Korea Search for other works by this author on: Oxford Academic Google Scholar J‐W. Choi, J‐W. Choi Department of Dermatology, Seoul National University College of Medicine, 28‐Yongon‐dong, Chongno‐gu, Seoul 110‐744, Korea Search for other works by this author on: Oxford Academic Google Scholar I‐H. Kwon, I‐H. Kwon Department of Dermatology, Seoul National University College of Medicine, 28‐Yongon‐dong, Chongno‐gu, Seoul 110‐744, Korea Search for other works by this author on: Oxford Academic Google Scholar J‐I. Youn J‐I. Youn Department of Dermatology, Seoul National University College of Medicine, 28‐Yongon‐dong, Chongno‐gu, Seoul 110‐744, Korea Jai‐Il Youn. E‐mail: jaiil@snu.ac.kr Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 162, Issue 6, 1 June 2010, Pages 1359–1364, https://doi.org/10.1111/j.1365-2133.2010.09758.x Published: 01 June 2010
High-Risk Neuroblastoma Treated With Tandem Autologous Peripheral-Blood Stem Cell–Supported Transplantation: Long-Term Survival Update
Authors: Rani E. George, Shuli Li, Cheryl Medeiros-Nancarrow, Donna Neuberg, Karen Marcus, Robert C. Shamberger, Michael Pulsipher, Stephan A. Grupp, Lisa Diller
Journal: Journal of Clinical Oncology (2006)

To provide an update on long-term survival of patients with high-risk neuroblastoma treated with tandem cycles of myeloablative therapy and peripheral-blood stem-cell rescue (PBSCR).Ninety-seven patients with high-risk neuroblastoma were treated between 1994 and 2002. Patients underwent induction therapy with five cycles of standard agents, resection of the primary tumor and local radiation, and two consecutive courses of myeloablative therapy (including total-body irradiation) with PBSCR.Fifty-one patients have experienced relapse or died. Median follow-up time among the 46 patients who remain alive without progression is 5.6 years (range, 15.1 months to 9.9 years). Progression-free survival (PFS) rate at 5 years from diagnosis was 47% (95% CI, 36% to 56%), and PFS rate at 7 years was 45% (95% CI, 34% to 55%). Overall survival rate was 60% (95% CI, 48% to 69%) and 53% (95% CI, 40% to 64%) at 5 and 7 years, respectively. The 5- and 7- year PFS rates from time of first transplantation for 82 patients who completed both transplants were 54% (95% CI, 42% to 64%) and 52% (95% CI, 40% to 63%), respectively. Five patients died from treatment-related toxicity after tandem transplantation. Relapse occurred in 37 (42%) of 89 patients, mainly within 3 years of transplantation and primarily in diffuse osseous sites. No primary CNS relapse or secondary leukemia was seen. One patient developed synovial cell sarcoma 8 years after therapy.High-dose therapy with tandem autologous stem-cell rescue is effective for treating high-risk neuroblastoma, with encouraging long-term survival. CNS relapse and secondary malignancies are rare after this therapy.
Phase II Multicenter Study of Neoadjuvant Biochemotherapy for Patients With Stage III Malignant Melanoma
Authors: Karl D. Lewis, William A. Robinson, Martin McCarter, Nathan Pearlman, Steven J. O'Day, Clay Anderson, Thomas T. Amatruda, Anna Baron, Chan Zeng, Maude Becker, Susan Dollarhide, Karen Matijevich, Rene Gonzalez
Journal: Journal of Clinical Oncology (2006)

To determine the relapse-free survival, overall survival, and response rate of patients with stage III melanoma treated with neoadjuvant biochemotherapy in a multicenter setting.Patients with pathologically proven stage III melanoma, either via clinical detection or sentinel lymph node positivity, were eligible for enrollment. Patients received two cycles of preoperative biochemotherapy followed by complete regional lymphadenectomy and two postoperative courses of biochemotherapy. The biochemotherapy regimen consisted of the following: cisplatin 20 mg/m2 on days 1 to 4, dacarbazine 800 mg/m2 on day 1 only, vinblastine 1.6 mg/m2 on days 1 to 4, interleukin-2 total dose of 36 MU/m2 during 4 days, and interferon alfa 5 MU/m2 on days 1 to 5. Growth factor support was administered with each cycle.Ninety-two patients were eligible for the study. At a median follow-up of 40.4 months, relapse-free survival and overall survival are 64% and 78%, respectively. There was a lower relapse rate and improved survival for patients with a positive sentinel lymph node compared with patients with clinically detected lymph nodes, although this difference did not reach statistical significance. Of the 50 patients with measurable disease, the overall response rate was 26%. Toxicity of the biochemotherapy was high but generally manageable.The current study has expanded the preliminary evidence on neoadjuvant biochemotherapy for stage III melanoma.
Users of antiasthma drugs in Iceland: a drug utilization study
Authors: T Gislason, O Olafsson, A Sigvaldason
Journal: European Respiratory Journal (1997)

There has been an increasing consensus worldwide on how to treat asthma, and, simultaneously, an increase in the sales of antiasthma drugs. However, little is known about actual drug use, dosage, combinations of drugs, etc., or about the clinical characteristics of patients using these drugs. All individuals with prescriptions for antiasthma drugs, who came to Icelandic pharmacies during March 1994, were invited to participate. By means of questionnaires, the pharmacists recorded the age and gender of the patient, the specialty of the prescribing doctor, as well as the name of the drug, total amount prescribed, and dosage. The patients were asked to answer another questionnaire on their clinical diagnosis, usage of other antiasthma drugs, etc. The pharmacists registered 2,026 individuals, with 2,687 prescriptions: 1,574 for beta2-agonists, 838 for inhaled corticosteroids, 208 for theophylline, 48 for anticholinergic drugs, and 19 for cromoglycates. One thousand, three hundred and fifty one patients answered the questionnaires. The majority (67%) claimed to have asthma, 18% chronic bronchitis, 11% emphysema and 5% other diseases or symptoms. Among those aged > or = 16 yrs with asthma, 93% used beta2-agonists, 62% inhaled corticosteroids, 19% theophylline, and very few used other drugs. The most commonly used combination (57%) was beta2-agonists with inhaled corticosteroids. Thirty one per cent used beta2-agonists as monotherapy, and 5% used only inhaled corticosteroids. Theophylline was used mainly in combination with beta2-agonists and inhaled corticosteroids. In conclusion, our data suggest that two thirds of antiasthma drug users have asthma and that most are treated according to present guidelines. The use of inhaled corticosteroids, however, seems somewhat less than optimal.
IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin
Authors: Elizabeta Nemeth, Seth Rivera, Victoria Gabayan, Charlotte Keller, Sarah Taudorf, Bente K. Pedersen, Tomas Ganz
Journal: Journal of Clinical Investigation (2004)

Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.
Resistance versus endurance training in patients with COPD and peripheral muscle weakness
Authors: M.A. Spruit, R. Gosselink, T. Troosters, K. De Paepe, M. Decramer
Journal: European Respiratory Journal (2002)

The effects of endurance training on exercise capacity and health-related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD) patients have been studied thoroughly, while resistance training has been rarely evaluated. This study investigated the effects of resistance training in comparison with endurance training in patients with moderate to severe COPD and peripheral muscle weakness (isometric knee extension peak torque &lt;75% predicted). Forty-eight patients (age 64±8 yrs, forced expiratory volume in one second 38±17% pred) were randomly assigned to resistance training (RT, n=24) or endurance training (ET, n=24). The former consisted of dynamic strengthening exercises. The latter consisted of walking, cycling and arm cranking. Respiratory and peripheral muscle force, exercise capacity, and HRQL were re-evaluated in all patients who completed the 12-week rehabilitation (RT n=14, ET n=16). Statistically significant increases in knee extension peak torque (RT 20±21%, ET 42±21%), maximal knee flexion force (RT 31±39%, ET 28±37%), elbow flexion force (RT 24±19%, ET 33±25%), 6-min walking distance (6MWD) (RT 79±74 m, ET 95±57 m), maximum workload (RT 15±16 Watt, ET 14±13 Watt) and HRQL (RT 16±25 points, ET 16±15 points) were observed. No significant differences in changes in HRQL and 6MWD were seen between the two treatments. Resistance training and endurance training have similar effects on peripheral muscle force, exercise capacity and health-related quality of life in chronic obstructive pulmonary disease patients with peripheral muscle weakness.