tbuckley/cabot-search huggingface dataset:
Linoleic acid stimulates cell proliferation and alters gene expression in the breast cancer cell line T47D.
Authors: Niradiz Reyes, Ismael Reyes, Raj K. Tiwari, Jan Geliebter
Journal: Cancer Research (2004)

2500  Breast cancer remains the second leading cause of cancer-related deaths in American women, and to date, no effective treatment for metastatic disease exists. Clinical and pre-clinical studies have linked n-6 polyunsaturated fatty acids with mammary carcinogenesis. We investigated the cellular and molecular effects of linoleic acid on the human breast cancer cell line T47D. The XTT cell viability assay indicated that linoleic acid induced a significant and dose dependent (0-10,000 ng/ml) response in cell viability compared to controls. Maximal cell viability (56% over control values) was observed at 100 ng/ml. A 96 hour cell proliferation assay with 100 ng/ml of linoleic acid resulted in an approximately 35% increase in T47D cell number, compared to controls. Flow cytometric analysis indicated that the increase in cell number was accompanied by an approximately 50% increase in the number of cells in the S phase of the cell cycle (from 17.1% to 28.5% at 12 hours and from 14.1% to 21.0% at 24 hours). Affymetrix Human Genome U95Av2 Array GeneChips microarray analyses indicated that of the 12,558 genes on the microarray, approximately 5,795 genes were expressed in treated and untreated T47D cells, with 35 genes up-regulated and 9 genes down-regulated in linoleic acid treated cells. MAPPFinder analysis indicated that the highest Z scores for GO terms were associated with the biological “process” of transcription regulation, the nuclear component, and the DNA binding, protein serine/threonine kinase, and transcription factor molecular functions. MAPPs for biologically functional groups and pathways indicated that linoleic acid affected changes in transcriptional regulation, cell cycle, G protein signaling and the MAP kinase signal transduction cascade. Real-time RT-PCR was used to confirm microarray data in a select set of genes within these pathways.Supported by NCI grant 1R21CA88982-0-1 and AICR grant #97A072. Niradiz Reyes is the recipient of a Fulbright/Laspau/Colciencias scholarship.
Molecular Subgroups from the Agitg Max Trial; Right or Left Primary Site of Colorectal Cancer and Outcomes for Metastatic Colorectal Cancer (Mcrc)
Authors: T.J. Price, L. Buizen, J. Hardingham, C.K. Lee, A. Townsend, M. Bruhn, R.J. Simes, K. Wilson, V. Gebski, N.C. Tebbutt
Journal: Annals of Oncology (2014)
Colonic Myoelectrical Activity in Irritable-Bowel Syndrome
Authors: Mark A. Sullivan, Sidney Cohen, William J. Snape
Journal: New England Journal of Medicine (1978)

To determine the effect of a standard meal on colonic myoelectrical and motor activity in the irritable-bowel syndrome and to determine the effect of a single dose of an oral anticholinergic drug (clidinium bromide) on this response, we studied 10 patients. These patients showed a prolonged increase in both colonic spike (P less than 0.05) and motor activity (P less than 0.05) after eating as compared to normal subjects. Clidinium did not affect the frequency of colonic slow waves or the basal colonic spike and motor activity. However, the anticholinergic reduced the prolonged postprandial colonic spike and motor response in the patients and also reduced the postprandial increase in colonic contractions at 3 cycles per minute (P less than 0.05). These studies indicate that patients with the irritable-bowel syndrome show an abnormally prolonged post-prandial increase in colonic spike and motor activity. An anticholinergic drug reduces the duration and the magnitude of this abnormal colonic response.
Serum Alpha Interferon in Children with Right Iliac Fossa Pain
Authors: Y W Chia, R Carachi, A A Armstrong, G W McGarry, D Carrington
Journal: Journal of the Royal Society of Medicine (1993)

Serum α-interferon levels were analysed in 50 consecutive children admitted with right iliac fossa pain. Serum α-interferon levels were significantly raised in 33% of children without acute appendicitis when compared to 5.7% of children with histologically proven acute appendicitis and 9% of normal controls. This interesting phenomenon needs further investigation. A larger series may show it to be of clinical use in non-specific abdominal pain in childhood.
Abstract 4386: Docetaxel-trastuzumab stealth immunoliposome: design and non-clinical study in HER2+ and HER2- breast cancer models
Authors: Raphaelle R. Fanciullino, Jean-Michel Brunel, Florian Correard, Sarah Giacometti, Joseph Ciccolini
Journal: Cancer Research (2015)

Abstract Targeted liposomal drug delivery is expected to enhance the therapeutic effects of anti-cancer agents through both active and passive targeting of tumor cells. We have developed a stealth liposomal formulation of docetaxel anchored with trastuzumab (HER2-ANC) to target HER2+ breast cancers. Pegylated SUV liposomes with 95% docetaxel encapsulation yield were obtained using the thin-film method. Homogenous distribution in liposome size of 100-150 nm diameter was achieved by extrusion, prior to anchoring trastuzumab through maleimide coupling. Anchoring was evidenced by electronic microscopy with anti-mouse gold antibody. HER2-ANC antiproliferative activity was assessed on a representative panel of human breast cancer cells expressing (SKBR3, MDA-MB451) or not expressing HER2 (MDA-MB231). Free docetaxel and trastuzumab combination was used as control. Cytotoxicity was evaluated in vitro on 2D culture cells by MMT assay, and in 3D spheroids co-cultured with HMEC endothelial cells. HER2-ANC proved to have a similar efficacy than the free combination, including in triple negative MDA-MB231 cells in 2D models. In 3D models, the immunoliposome displayed higher efficacy as compared with the free combination, possibly because of a better and deeper diffusion of the antibody inside the spheroids. Surprisingly, and although less marked, this difference in favor of HER2-ANC was observed as well with the triple negative MDA-MB231 cells, thus suggesting that a better delivery of docetaxel was achieved with the liposomal form. Fluorescence imaging showed that HER2-ANC was internalized inside tumor cells. Measurement of HER2 expression and immunofluorescence staining of alpha-microtubulline supported this increase in efficacy observed in vitro. After tagging HER2-ANC with DIR fluorescent probe, in vivo preliminary distribution studies in nude mice bearing both the HER2+ SKBR3 and HER2- MDA-MB231 tumors showed that a more specific tumor uptake is achieved in HER2+ tumors, thus suggesting that higher antiproliferative effect and lower toxicities can be expected in further efficacy studies. Overall, this proof of concept study strongly suggest that redesigning existing combinations of biologics and cytotoxics as immunoliposomes could help to optimize the efficacy/toxicity balance of anticancer treatments. Citation Format: Raphaelle R. Fanciullino, Jean-Michel Brunel, Florian Correard, Sarah Giacometti, Joseph Ciccolini. Docetaxel-trastuzumab stealth immunoliposome: design and non-clinical study in HER2+ and HER2- breast cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4386. doi:10.1158/1538-7445.AM2015-4386
Relation of Serum Vitamins a and E and Carotenoids to the Risk of Cancer
Authors: Walter C. Willett, B. Frank Polk, Barbara A. Underwood, Meir J. Stampfer, Sara Pressel, Bernard Rosner, James O. Taylor, Kenneth Schneider, Curtis G. Hames
Journal: New England Journal of Medicine (1984)

Epidemiologic studies suggest that low carotene intake and low levels of serum retinol may be associated with an increased risk of cancer. Likewise, in some animal studies vitamin E has been associated with a reduced rate of induced cancers. Therefore, we measured retinol, retinol-binding protein, vitamin E (alpha-tocopherol), and total carotenoids in serum collected in 1973 from 111 participants in the Hypertension Detection and Follow-up Program who were free of cancer at the time but were diagnosed as having cancer during the subsequent five years. These measurements were compared with those in 210 controls who were matched for age, sex, race, and time of blood collection, and who remained free of cancer. Mean values for retinol were similar for cases and controls (67.3 and 68.7 micrograms per deciliter, respectively [95 per cent confidence limits for case-control difference, -6.7 to 3.5]). Values were also similar for retinol-binding protein (6.01 and 5.94 mg per deciliter [-0.42 to 0.56]), and carotenoids (114.5 and 111.6 micrograms per deciliter [-9.1 to 15.9]). The mean base-line retinol level in the 18 subjects with subsequent lung cancer was higher than that in their matched controls (79.0 vs. 71.4 micrograms per deciliter, -4.9 to 19.7). Serum vitamin E levels were somewhat lower in subjects who later had cancer than in controls (1.16 and 1.26 mg per deciliter, -0.22 to 0.02), in part because of the confounding effect of serum cholesterol levels (when adjusted for lipid levels, the case-control difference was -0.05 mg per deciliter; -0.17 to 0.07). These data do not support hypotheses relating intake or serum levels of antioxidant vitamins to a reduced cancer risk.
Abstract 1325: Evaluation of immuno-oncology related treatment in syngenic and human reconstituted immune systems
Authors: Marc Hillairet de Boisferon, Francis Bichat, Caroline Mignard, Xavier Tizon, Damien France, Jean-François Mirjolet
Journal: Cancer Research (2015)

Abstract Immunotherapy based on monoclonal antibodies targeting cancer cells is now developed as a valid approach to treat cancer. Modulation of novel immune checkpoints and other targets are highly promising approaches against cancer and many other diseases. They have the potential to activate the immune system and to establish an active defense against pathological conditions. In addition, antibodies, antibody fragments, and other biologics can also have a strong impact on the immune system which needs to be evaluated early on. In order to develop and accurately evaluate these immunology linked approaches, appropriate preclinical models with relevant immunological readouts are needed at different stages of therapy development. Ideally, methods should be available that allow predictive readouts in vivo and ex vivo. A comprehensive panel of tools was constructed and validated aiming at evaluating the modulation of the immune system by new therapies. In immunocompetent mice, immune cells were studied for the detection of their cell surface markers, induction of proliferative phenotype, antigen-specific T lymphocyte detection, secretion of soluble mediators using FACS phenotyping, cytometric bead assay (CBA) or Luminex multiplex technologies and ELISPOT. We report on a panel of syngenic tumor models (4T1, B16-F10, CT26, EMT6, AY27, LLC1, MBT-2 and Renca) our capacity to correlate subpopulation of immune infiltrating cells (as T cells, macrophages, NK cells, granulocytic and monocytic cells) and the therapeutic effects of critical antibodies directed against Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death 1 membrane protein (PD-1). In immunodeficient mice, the reconstitution of the mature human immune system with PBMC or naïve human immune system using hematopoietic stem cells was used to evaluate the modulation of those immune cells by therapies through human cytokine release and onset of graft versus host disease. All of these tools were used in the context either of rodent syngenic models or humanized mouse models. In addition to their use in immune system modulating anti-cancer therapies, these humanized or syngenic models also have a potential application in many other therapeutic areas such as autoimmune diseases, inflammation, anti-infectives. Citation Format: Marc Hillairet de Boisferon, Francis Bichat, Caroline Mignard, Xavier Tizon, Damien France, Jean-François Mirjolet. Evaluation of immuno-oncology related treatment in syngenic and human reconstituted immune systems. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1325. doi:10.1158/1538-7445.AM2015-1325
P119 Characterising non-eosinophilic COPD
Authors: K Hambleton, REK Russell, CE Brightling, M Bafadhel
Journal: Thorax (2015)

<h3>Background</h3> Phenotypes of COPD are increasingly recognised, with classification centred on inflammation and in particular microbes and inflammatory markers within the airways and peripheral blood. Studies focusing on eosinophilic inflammation in COPD have shown the validity of airway and peripheral eosinophilia as a marker to direct treatment with corticosteroids. However, the majority of COPD patients have low sputum and peripheral eosinophils, with a large proportion showing raised sputum neutrophils at exacerbation and stable state. The characteristics of this ‘Non-eosinophilic’ group are less well defined, making the identification of biomarkers and target pathways for drug development more challenging. <h3>Methods</h3> Baseline data from patients with COPD, previously recruited to a study identifying biomarkers was analysed using SPSS (SPSS version 22, IBM Corp, released 2013, Armonk, NY). A cut off of 3% sputum eosinophils was used to distinguish ‘Eosinophilic’ and ‘Non-eosinophilic’ groups. Parametric and non-parametric analyses were performed where appropriate. <h3>Results</h3> Of 149 patients, 96 had &lt;3% sputum eosinophils, with a median age of 69.5 years (47–88 range). There were no differences in gender and proportion of smokers between the two groups. There was an increase in percentage sputum neutrophils in the non-eosinophilic group (mean difference 15%, 95% confidence interval 9–17%, p = 0.01). The non-eosinophilic patients had more exacerbations/person/year compared to the eosinophilic group (3.52 vs. 3.11); this was independent of inhaled corticosteroid use. There were more significant co-morbidities in the non-eosinophilic group compared to the non-eosinophilic group (78% vs. 61%, p &lt; 0.01). Co-morbidity was defined as the presence of cardiovascular disease, endocrine disorders, depression, or musculoskeletal disease. There were more positive sputum cultures in the non-eosinophilic group compared to the eosinophilic group (33% vs. 11%, p = 0.16). There was also an increase in colony forming units in the non-eosinophilic group compared to the eosinophilic group (mean fold difference 0.4, 95% CI 0–0.8, p = 0.05). <h3>Conclusions</h3> Non-eosinophilic COPD subjects have more exacerbations, with more co-morbidities and bacterial burden (see Figure 1). Further work is required to understand the pathogenesis of this phenotype.
Multipolar Electrocoagulation in the Treatment of Active Upper Gastrointestinal Tract Hemorrhage
Authors: Loren Laine
Journal: New England Journal of Medicine (1987)

The benefit of nonsurgical therapy in the treatment of active nonvariceal upper gastrointestinal tract hemorrhage is uncertain. I performed a prospective controlled trial of endoscopic multipolar electrocoagulation for active upper gastrointestinal hemorrhage. Patients were considered for entry if they had a bloody nasogastric aspirate, melena, or hematochezia, and any of the following: unstable vital signs, a requirement of ≥2 units of blood per 12 hours, or a drop in hematocrit of ≥6 percent in 12 hours. Forty-four patients were randomly assigned to receive multipolar electrocoagulation or sham multipolar electrocoagulation if endoscopy revealed active bleeding from an ulcer (24 patients), a Mallory–Weiss tear (17), or a vascular malformation (3). The group receiving multipolar electrocoagulation did significantly better in terms of hemostasis (90 percent vs. 13 percent, P<0.0001), mean (±SE) transfusion requirements (2.4±0.9 vs. 5.4±0.9 U, P = 0.002), mean number of hospital days (4.4±0.8 vs. 7.2±1.1, P = 0.02), and percentage needing emergency surgery or another intervention (14 vs. 57 percent, P = 0.01). Although mortality was lower in the group receiving multipolar electrocoagulation (0 vs. 13 percent), this difference was not statistically significant. The mean cost of hospitalization for treated patients was less than half that for the controls ($3,420±750 vs. $7,550±1,480, P = 0.001). I conclude that multipolar electrocoagulation markedly improves the hospital course in patients with major, nonvariceal upper gastrointestinal hemorrhage. (N Engl J Med 1987;316:1613–7.)
Four-Agent Induction and Intensive Asparaginase Therapy for Treatment of Childhood Acute Lymphoblastic Leukemia
Authors: Luis A. Clavell, Richard D. Gelber, Harvey J. Cohen, Suzanne Hitchcock-Bryan, J. Robert Cassady, Nancy J. Tarbell, Stephen R. Blattner, Ramana Tantravahi, Pearl Leavitt, Stephen E. Sallan
Journal: New England Journal of Medicine (1986)

We prospectively assigned 289 consecutive children with acute lymphoblastic leukemia to receive one of two treatment programs on the basis of the presence or absence of certain risk factors at the time of diagnosis. Patients at high risk (62 percent of the total) had one or more of the following risk factors: age below two or above nine years, a white-cell count of 20,000 per cubic millimeter or more, the presence of T-cell immunologic markers, radiologic evidence of a mediastinal mass, and involvement of the central nervous system. Patients in both the standard-risk and high-risk groups were treated for two years, receiving intensive remission-induction therapy, central nervous system prophylaxis, weekly administration of high-dose asparaginase, and multiple-drug continuation therapy (which in the high-risk group included doxorubicin and a larger dose of prednisone). At a median follow-up of 35 months, the mean (+/- SE) event-free survival rates at four years among the patients in the standard-risk and high-risk groups were 86 +/- 4 percent and 71 +/- 4 percent, respectively (P = 0.003), for a total event-free survival of 77 +/- 3 percent. Within the high-risk group, the white-cell count at diagnosis and the sex of the patient were not significant prognostic indicators, but age below 12 months at diagnosis was associated with a very poor outcome. As compared with previous methods, this treatment program using four-drug induction and intensive asparaginase therapy has resulted in improved event-free survival in children with acute lymphoblastic leukemia.
Case 8-1993
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, James H. Maguire, Maureen R. Tierney
Journal: New England Journal of Medicine (1993)

Presentation of CaseA 62-year-old woman was seen in the neuro-oncology clinic because of a question of a suprasellar tumor.There was a 15-to-20-year history of “migraine headaches,” with nausea and vomiting. The patient was well otherwise until six months earlier, when she experienced the first of several episodes of visual blurring and horizontal diplopia for a few minutes, associated with headache. A cranial computed tomographic (CT) scan at another hospital showed “a tumor near the pituitary gland.” A magnetic resonance imaging (MRI) scan of the cranium verified the finding. Midline frontal headaches continued and occurred weekly; they persisted for . . .
A case of acquired hemophilia A and B as paraneoplastic syndromes of breast cancer
Authors: Natsuko Tsushita, Toshiyuki Arai, Yoshihide Kakimoto, Kanae Imai, Toshiyasu Sakai, Yuichiro Inagaki, Tomonori Kato, Keiko Niimi, Masashi Sawa
Journal: Annals of Oncology (2015)
Abstract 22: Calpain-Dependent Induction of Endoplasmic Reticulum Stress in Cardiomyocyte Apoptosis and Post--Myocardial Infarction Remodeling
Authors: Dong Zheng, Jian Ma, Meng Wei, Huaxi Xu, Tianqing Peng
Journal: Circulation Research (2012)

Background: Calpain is up-regulated and implicated in cardiomyocyte apoptosis and myocardial remodelling post myocardial infarction. Endoplasmic reticulum (ER) stress is induced and contributes to myocardial injury in a variety of cardiac diseases. This study was to investigate whether calpain plays a role in ER stress, thereby mediating apoptosis in cardiomyocytes and myocardial remodelling after infarction. Methods and Results: In rat cardiomyoblasts H9C2 cells, over-expression of calpain-1 increased the protein levels of Bip and CHOP, indicative of ER stress, and induced apoptosis determined by a decrease in Bcl-2 and increases in caspase-3 activation and DNA fragmentation. Inhibition of calpain activity or ER stress prevented apoptosis induced by calpain-1 over-expression. In contrast, over-expression of calpain-2 failed to induce apoptosis. The induction of ER stress by calpain-1 might be mediated through SERCA2a/Calcium signaling as up-regulation of calpain-1 reduced SERCA2a protein and elevated intracellular free Calcium in H9C2 cells. In a mouse model of myocardial infarction induced by coronary artery ligation, calpain activity was increased and ER stress was induced in the infracted heart. Up-regulation of calpastatin, the endogenous calpain inhibitor, inhibited calpain activation, prevented ER stress and apoptosis, reduced myocardial remodelling and improved myocardial function after infarction in calpastatin transgenic mice compared with their wild-type littermates. Conclusion: Calpain-1 induces ER stress through the proteolysis of SERCA2a, thereby mediating apoptosis in cardiomyocytes. Inhibition of calpain prevents ER stress and apoptosis, reduces myocardial remodelling and dysfunction after infarction. Thus, ER stress may represent a novel mechanism by which calpain mediates myocardial injury in the infracted heart.
CBIO-42DOWN REGULATION OF PYRUVATE DEHYDROGENASE ACTIVITY IS ESSENTIAL FOR CELL PROLIFERATION IN IDH1 MUTANT GLIOMA CELLS
Authors: Pavithra Viswanath, Jose L. Izquierdo-Garcia, Pia Eriksson, Larry Cai, Marina Radoul, Myriam M. Chaumeil, Michael Blough, H. Artee Luchmann, Samuel Weiss, J. Gregory Cairncross, Joanna J. Phillips, Russell O. Pieper, Sabrina M. Ronen
Journal: Neuro-Oncology (2015)

Somatic mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in 70-90% of low-grade gliomas. The mutation leads to the production of 2-hydroxyglutarate (2-HG), a novel “oncometabolite” that alters the epigenetic profile of DNA and inhibits cellular differentiation. Recent studies indicate that metabolic changes in IDH1 mutant cells extend beyond 2-HG production. We recently demonstrated that steady state levels of glutamate, lactate and phosphocholine were reduced in IDH1 mutant cells using two genetically engineered models, a U87 glioblastoma-based model and a normal human astrocyte (NHA) model. In this study, we explored the mechanism behind the reduction in glutamate levels in IDH1 mutant cells. We discovered that pyruvate dehydrogenase (PDH) activity was significantly reduced in U87 and NHA IDH1 mutant cells compared to wild-type cells. Reduced PDH activity was associated with increased inhibitory phosphorylation of PDH in both models. Examination of mRNA and protein levels for the pyruvate dehydrogenase kinases (PDKs) revealed that PDK3 expression was up-regulated in IDH1 mutant cells in both models. Levels of hypoxia inducible factor-1α (HIF-1α), an established regulator of PDK3 expression in cancer cells, was also higher in IDH1 mutant cells. Importantly, treatment of U87 and NHA IDH1 wild-type cells with 2-HG recapitulated the effects of the IDH1 mutation, with higher levels of HIF-1α and PDK3, and reduced PDH activity, in 2-HG treated cells. Importantly, pharmacological activation of PDH activity by treatment with dichloroacetate, a PDK inhibitor, completely abrogated the increase in clonogenicity conferred by the IDH1 mutation. Treatment of patient-derived mutant IDH1 neurosphere models (BT142 and BT54 cell lines) with dichloroacetate further confirmed that PDH activity is essential for cell proliferation. Thus, our results indicate that reversing the down regulation of PDH activity in IDH1 mutant glioma cells adversely affects their proliferation, a finding with therapeutic implications.