tbuckley/cabot-search huggingface dataset:
Expression of defined genes identified by pretreatment tumor profiling: Association with clinical responses to the GSK MAGE- A3 immunotherapeutic in metastatic melanoma patients (EORTC 16032–18031)
Authors: J. Louahed, O. Gruselle, S. Gaulis, T. Coche, A. M. Eggermont, W. Kruit, B. Dreno, V. Chiarion Sileni, F. Lehmann, V. G. Brichard
Journal: Journal of Clinical Oncology (2008)

9045 Background: Gene expression profiling by microarrays was used to identify markers predictive of the clinical activity of the MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) recorded in a phase II study in metastatic melanoma. Methods: 75 patients with progressive, unresectable stage III or stage IV M1a MAGE-A3 (+) melanomas, were randomized as 1st-line therapy between immunization with MAGE-A3 protein combined with GSK proprietary Adjuvant Systems AS15 or AS02B. Gene expression profiling was performed on tumor biopsies taken prior to any immunization. Results: Initial analysis using supervised hierarchical clustering of 2 objective responders (OR) with 7 non-responders identified 2 gene clusters based on differential expression. The correlation of this gene expression signature (GS) and objective response was further confirmed on 22 patients. Interestingly, mixed response (MR) and stable disease > 6 months (SD) clustered with OR, suggesting a strong association between the identified signature and the MAGE-A3 induced clinical benefit. Independent validation on additional 30 patients confirmed the association of clinical benefit and the molecular signature. Most of the identified genes are immune-related, defining a particular biological context present in the tumor environment before immunization. The signature was randomly distributed in the 2 study arms and identified all patients with clinical benefit (OR, MR, SD). The AS15 arm has shown to induce a higher MAGE-A3 immune response and more frequent clinical activity. The predictive signature improves significantly the median time to treatment failure (2.3 months in the GS (-) and 10.3 months in the GS (+) population (HR = 0.31; 95% CI: 0.13–0.76). Conclusions: The gene expression in metastatic melanoma reported here is strongly correlated with a clinical response to the MAGE-A3 ASCI treatment. This signature reflects an immune microenvironment in the tumor present prior to any therapeutic intervention following MAGE-A3 ASCI administration. Such molecular signature could be used to select patients with a higher likelihood of clinical response the MAGE-A3 ASCI. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline Biologicals GlaxoSmithKline Biologicals
AB0665 Hypocholesterolemia at Diagnosis Can Predict the Relapse in Patients with Takayasu Arteritis
Authors: S. Fukui, K. Ichinose, S. Tsuji, M. Umeda, A. Nishino, Y. Nakashima, T. Suzuki, Y. Horai, T. Koga, S. Kawashiri, N. Iwamoto, Y. Hirai, M. Tamai, H. Nakamura, T. Origuchi, A. Kawakami
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Takayasu arteritis (TA) is a rare large vessel vasculitis which predominantly affects young women and often experiences the relapse even after the remission is once introduced. Predicting factors toward the relapse of TA are not well known, however, the co-exsistence of metabolic syndrome is reported to associate with the relapse in patients with ANCA associated vasculitis<sup>1</sup>. <h3>Objectives</h3> The aim of this study is to identify the variables at diagnosis to predict the relapse in patients with TA including inflammatory markers, HLA-B52 and metabolic indices. <h3>Methods</h3> We retrospectively analyzed 25 patients with TA in Nagasaki University Hospital from April in 2003 to March in 2014. They were all newly diagnosed patients with TA who could be followed up at least 6 months at our hospital. Patients gave their informed consent to be subjected to the protocol, which was approved by the Institutional Review Board of Nagasaki University. We have colletced the baseline variables including clinical symptoms and signs, laboratory data and HLA-B52 by medical records and tried to investigate the associations of these indices with the subsequent relapse. The relapse was judged by Japan College of Rhematology-certified rheumatologists by confirmation of the recurrence with active disease as previously described<sup>2</sup>. <h3>Results</h3> The patients were one male and 24 female (96%). The median age at onset was 37.1 years old and that of follow-up duration was 6.1 years. HLA-B52 was found in 11 patients (44%). The relapse was noted in 11 patients (44%). Several indices including fever (&gt;38°), general fatigue, high erythrocyte sedimentation rate (ESR) [median, 57.3 mm/hr (non-relaspe) vs. 89.7 mm/hr (relapse)] and low total cholesterol (Tcho) [median, 192mg/dL (non-relapse) vs. 142 mg/dL (relapse)] were preferentially distributed in the relapse group as compared with non-relapse group. Multivariate analysis in conjunction with the Kaplan-Meier method have found that hypocholesterolemia (&lt;150 mg/dL) at diagnosis is the only predictor toward the subsequent relapse (Odds ratio: 11.6, 95%CI: 1.03-131, non-relapse survival curve is shown in Fig. 1). <h3>Conclusions</h3> We have found for the first time that hypocholesterolemia at diagnosis is a predictor of the subsequent relapse in patients with TA. Our findings may also show the importance of lipid profiles in consideration of the outcome of vasculitis syndrome. <h3>References</h3> Petermann Smits DR, Wilde B, Kianersi Adegani M, et al. Metabolic syndrome in ANCA-associated vasculitis. Rheumatology (Oxford) 2013;52:197-203. Dagna L, Salvo F, Tiraboschi M, et al. Pentraxin-3 as a Marker of Disease Activity in Takayasu Arteritis. Ann Intern Med 2011;155:425-33. <h3>Disclosure of Interest</h3> None declared
Case 43-1963
Authors: Arthur S. Pier, Benjamin Castleman
Journal: New England Journal of Medicine (1963)

Presentation of CaseA forty-two-year-old woman was referred to the hospital for evaluation of a mediastinal mass.During the previous year the patient had noticed gradually increasing swelling of the upper portion of the left arm associated with discomfort in the arm and lower neck. Three months before entry dyspnea on exertion, tightness of the chest and a persistent cough developed after an upper respiratory infection characterized by a sore throat, a dry cough and a mild fever. At that time she became aware of increasing fullness at the base of the left side of the neck. The dyspnea progressed . . .
Abstract #2505: G-protein synergies promoting Her2/neu-induced mammary tumor growth
Authors: Walter Imagawa, Rajkumar Lakshmanaswamy, Rene Roberts
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Only about 30% of Her 2 expressing breast cancers respond to therapeutic antibodies and these cancers eventually become refractory to this therapy. These outcomes suggest that therapies targeting as yet unknown Her 2 related synergistic pathways remain to be elucidated and exploited for their therapeutic potential. These pathways may well involve local and systemic factors and pathways that affect Her2 oncogenesis. The model system used for these studies was primary mouse mammary tumor cells expressing MMTV-driven activated Her 2/neu cultured within collagen gels and in serum-free medium. A key factor enabling the proliferation of these cells in the absence of serum was lysophosphatidic acid (LPA). LPA's primary role was found to be that of a synergist allowing the growth-stimulatory potential of specific growth factors to be expressed. LPA had limited proliferative capacity alone but synergized with EGF, FGF-2 and FGF-7 to stimulate multifold (10-fold) proliferation in serum-free culture media. EGF alone could stimulate limited growth (2-fold) while FGFs-2, -7 alone were relatively less stimulatory to growth. Real time RTPCR shows that G protein-coupled LPA receptors (LPAR1, 2, 3) are expressed in the tumor cells. Furthermore, proliferative synergy between LPA and growth factors was inhibited by pertussis toxin, an inhibitor of Gαi signaling suggesting that this G-protein-coupled receptor pathway can have a critical impact upon Her 2/neu tumor cell proliferation. LPA receptors are also expressed in the stroma of mouse mammary glands raising the possibility that the growth and progression of Her 2/neu mammary tumors is potentially dependent upon synergistic interactions between bioactive lipids and growth factors, both of which can be synthesized locally as components of a stromal-epithelial regulatory network.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2505.
Determination of anti-angiogenic therapeutic targets by gene array analysis of differentially expressed angiogenic factors by malignant melanoma
Authors: Lucy Kwee, Cindy E. Vermeulen, Sjoerd Jb Holwerda, Alexander Mm Eggermont, Timo Lm Ten Hagen
Journal: Cancer Research (2006)

241   The population of patients with malignant melanoma is one of the most rapidly increasing cancer groups worldwide. Because current therapeutic methods for metastatic melanoma are poorly efficacious, enhanced understanding of melanoma development is required. Previous research has shown a possible correlation between the degree of vascularization of melanoma and their metastasizing capacity. Inhibition of angiogenesis, the development of new blood vessels out of pre-existing ones, could therefore be a potential therapy. Tumor cells initiate the onset of new blood vessel formation by releasing VEGF and numerous other angiogenic factors. In this study we focused on melanoma-mediated endothelial cell survival. Six human melanoma cell lines, which differ in degree of aggressiveness, were cultured under normoxic (20%O 2 ) and hypoxic (1%O 2 ) conditions, since hypoxia strongly induces angiogenic factor production. Melanoma-conditioned medium of all cell lines was capable of augmenting endothelial cell survival after hypoxia. The activity of VEGF and the determination of differentially expressed pro- and anti-angiogenic factors by the selected melanoma cells was determined by means of RT-PCR, ELISA and Affymetrix-based microarray analyses. Clearly, the melanoma-induced endothelial cell survival was not solely dependent on VEGF. Our observations suggest that, instead of focusing on a single factor, efficient anti-angiogenic treatment of melanoma may require identification and blocking of several factors.
Clinical recommendations for pain, sedation, withdrawal and delirium assessment in critically ill infants and children: an ESPNIC position statement for healthcare professionals
Authors: Julia Harris, Anne-Sylvie Ramelet, Monique van Dijk, Pavla Pokorna, Joke Wielenga, Lyvonne Tume, Dick Tibboel, Erwin Ista
Journal: Intensive Care Medicine (2016)

This position statement provides clinical recommendations for the assessment of pain, level of sedation, iatrogenic withdrawal syndrome and delirium in critically ill infants and children. Admission to a neonatal or paediatric intensive care unit (NICU, PICU) exposes a child to a series of painful and stressful events. Accurate assessment of the presence of pain and non-pain-related distress (adequacy of sedation, iatrogenic withdrawal syndrome and delirium) is essential to good clinical management and to monitoring the effectiveness of interventions to relieve or prevent pain and distress in the individual patient.A multidisciplinary group of experts was recruited from the members of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC). The group formulated clinical questions regarding assessment of pain and non-pain-related distress in critically ill and nonverbal children, and searched the PubMed/Medline, CINAHL and Embase databases for studies describing the psychometric properties of assessment instruments. Furthermore, level of evidence of selected studies was assigned and recommendations were formulated, and grade or recommendations were added on the basis of the level of evidence.An ESPNIC position statement was drafted which provides clinical recommendations on assessment of pain (n = 5), distress and/or level of sedation (n = 4), iatrogenic withdrawal syndrome (n = 3) and delirium (n = 3). These recommendations were based on the available evidence and consensus amongst the experts and other members of ESPNIC.This multidisciplinary ESPNIC position statement guides professionals in the assessment and reassessment of the effectiveness of treatment interventions for pain, distress, inadequate sedation, withdrawal syndrome and delirium.
A Randomized Double-Blind Study of Acetohydroxamic Acid in Struvite Nephrolithiasis
Authors: John J. Williams, John S. Rodman, Charles M. Peterson
Journal: New England Journal of Medicine (1984)

We studied the effects of the bacterial urease inhibitor acetohydroxamic acid on the growth of struvite stones in the urinary tract. Eighteen patients who received acetohydroxamic acid (15 mg per kilogram of body weight per day, in divided oral doses) for a mean of 15.8 months were compared in a randomized double-blind study with 19 patients who received placebo for a mean of 19.6 months. Seven patients given placebo reached a pre-determined end point: a 100 per cent increase in the two-dimensional surface area of their stones. No patient who received acetohydroxamic acid had a doubling of stone size (P less than 0.01). Nine patients receiving the drug and one patient receiving placebo required a decrease in dosage or cessation of treatment because of adverse effects (P less than 0.01). Episodes of tremulousness (n = 5, P less than 0.05), which reversed with a decrease in drug dose, and phlebothrombosis (n = 3, P not significant) were limited to the group given acetohydroxamic acid. We conclude that acetohydroxamic acid effectively inhibits the growth of struvite stones in the short term in patients infected with urea-splitting bacteria, but the prevalence of adverse reactions appears to be high and the toxicity and effectiveness of long-term therapy for struvite nephrolithiasis remain to be defined.
Human Parvovirus Infection in Pregnancy and Hydrops Fetalis
Authors: Aditi Anand, Elizabeth S. Gray, Thomas Brown, Jonathan P. Clewley, Bernard J. Cohen
Journal: New England Journal of Medicine (1987)

Human parvovirus is the causative agent of erythema infectiosum, a mild epidemic illness. In a recent outbreak in northeast Scotland, six women had serologic evidence of having contracted human parvovirus infection during pregnancy. Two of the women had midtrimester abortions, and both abortuses were grossly hydropic with anemia. They had similar microscopical histopathological features--a pronounced leukoerythroblastic reaction, hepatitis, excessive iron pigment in the liver, and eosinophilic changes in the hematopoietic cell nuclei. Dot hybridization with radiolabeled human parvovirus DNA probes revealed viral DNA in several tissues from both fetuses, indicating that they had been infected by the virus in utero. The remaining four women had uncomplicated pregnancies and delivered apparently healthy babies, none of whom had human parvovirus-specific IgM antibody at delivery. We conclude that this common virus may pose a serious risk to the fetus after maternal infection.
The treatment of pathological panic states with propranolol
Authors: J F Heiser, D Defrancisco
Journal: American Journal of Psychiatry (1976)

The authors report on the effects of propranolol, a beta-adrenergic blocking agent, on 10 patients with pathological panic states. Propranolol was effective in treating acute pathological panic, but modest doses of the drug administered for brief periods of time did not alleviate chronic panic attacks associated with agoraphobia. The drug suppressed panic associated with depressive syndromes but did not affect the depression and had no clear effect on anticipatory anxiety. The authors suggest that further study of these findings may clarify other clinical problems.
Evaluation of below-the-Knee Amputation in the Treatment of Diabetic Gangrene
Authors: Carl S. Hoar, José Torres
Journal: New England Journal of Medicine (1962)

FOR more than ten years there has been a tendency to use below-the-knee rather than supracondylar amputation at the New England Deaconess Hospital in the management of diabetic gangrene when more peripheral procedures are not feasible. At this institution a large number of diabetic patients with peripheral vascular problems are followed continuously. Among these patients the surgeon is confronted repeatedly with the problem of choosing between the two operations. It has seemed apparent that there was somewhat more risk involved in the lower procedure so far as nonhealing is concerned. Postoperative hospitalization and convalescence before the use of a prosthesis . . .
The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease
Authors: Christa L. Blenck, Pamela A. Harvey, Jane F. Reckelhoff, Leslie A. Leinwand
Journal: Circulation Research (2016)

Nearly one-third of deaths in the United States are caused by cardiovascular disease (CVD) each year. In the past, CVD was thought to mainly affect men, leading to the exclusion of women and female animals from clinical studies and preclinical research. In light of sexual dimorphisms in CVD, a need exists to examine baseline cardiac differences in humans and the animals used to model CVD. In humans, sex differences are apparent at every level of cardiovascular physiology from action potential duration and mitochondrial energetics to cardiac myocyte and whole-heart contractile function. Biological sex is an important modifier of the development of CVD with younger women generally being protected, but this cardioprotection is lost later in life, suggesting a role for estrogen. Although endogenous estrogen is most likely a mediator of the observed functional differences in both health and disease, the signaling mechanisms involved are complex and are not yet fully understood. To investigate how sex modulates CVD development, animal models are essential tools and should be useful in the development of therapeutics. This review will focus on describing the cardiovascular sexual dimorphisms that exist both physiologically and in common animal models of CVD.
Survival with adjuvant surgical oophorectomy and tamoxifen in premenopausal women with operable breast cancer
Authors: R. R. Love, N. V. Dinh, T. T. Quy, N. D. Linh, E. M. Hade, G. S. Young, D. Jarjoura
Journal: Journal of Clinical Oncology (2007)

552 Background: Reports of randomized trials evaluating adjuvant ovarian suppression or ablation with and without tamoxifen are limited in number, useful comparative data and long-term follow-up. Methods: From 1993–99 we recruited 709 Vietnamese and Chinese premenopausal women with clinical stage II-III operable breast cancer to a multi-site randomized prospective clinical trial of immediate pre-mastectomy adjuvant surgical oophorectomy followed by tamoxifen for 5 years (n=356) or mastectomy alone with the same combined hormonal therapy on recurrence of disease (n=353).The primary study endpoints were disease-free and overall survival.This report provides analyses for an extended follow-up period after 5 years. Results: With a median follow up of 7 years, disease-free and overall survival were significantly better with adjuvant therapy (log-rank p-values of 0.0003 and 0.0002). Ten year DFS probabilities of 62% and 51% (95%CI 4–22%), and OS probabilities of 70% and 52% (95% CI 6–34%) between adjuvant and observation groups were observed. In the estrogen receptor positive patient subset, 5 and 10 year DFS probabilities were 83% and 61%, and 66% and 47%; and 5 and 10 year OS probabilities were 88% and 74% and 82% and 74% in adjuvant and observation groups respectively. Conclusions: In women with estrogen receptor positive operable breast cancers, 5 and 10 year disease free and overall survival rates following adjuvant oophorectomy and tamoxifen compare favorably with those from other adjuvant regimens. In estrogen receptor positive patients, the hazard function with adjuvant therapy increases after year six. No significant financial relationships to disclose.
Abstract 19: Reversal of Adverse Remodeling in Chronic Rat Myocardial Infarction by Cardiospheres: Role of the Tgf-beta Pathway
Authors: ELENI TSELIOU, Geoffrey de Couto, John Terrovitis, Baiming Sun, Weixin Liu, Ryan Middleton, Linda Marbán, Eduardo Marbán
Journal: Circulation Research (2014)

Background: Self-assembling three-dimensional cardiospheres (CSps) are known to be effective in improving function and attenuating remodeling as adjunctive therapy in acute myocardial infarction (MI), and they exert functional benefits in large animals with convalescent MI. The effect of cardiospheres in chronically-remodeled myocardium post-MI, and the mechanisms of benefit are unknown. Methods: We performed permanent LAD ligation in Wistar Kyoto female rats. One month later the animals underwent repeat thoracotomy and were randomly assigned to one of two groups: vehicle-treated controls, or CSp-treated, where CSps (at a seeding dose of 2X10 6 cells) were injected in the peri-infarct area. Mechanisms were also probed in vitro . Results: CSps downregulated the canonical Tgfβ1-smad2/3 pathway in co-cultures with fibroblasts and reduced fibroblast proliferation in vitro . Soluble endoglin, abundantly expressed in CSps, was found to limit the Tgfβ1-induced fibrosis in a dose-dependent manner. In vivo , left ventricular function gradually increased one month post-CSp injection with further improvement after up to six months of follow up. Immunoblots verified Tgfβ1/smad cascade downregulation one month post-CSp injection and upregulation of soluble endoglin. In addition, scar mass was reduced one month post-CSp injection compared to controls. Collagen density was attenuated within the infarcted region of the treated group, while immunostaining showed enhanced vessel density in the same region. Six months post-transplantation, cardiomyocyte hypertrophy was reduced in the CSp-treated group compared to control. Conclusions: CSps injected into the peri-infarct zone enhance angiogenesis and reduce established fibrosis in chronically-infarcted myocardium, thereby reversing, at least partially, adverse remodeling of the heart. The underlying mechanism involves modification of Tgfβ1/smad signaling, a key pathway in the cardiac response to injury.