tbuckley/cabot-search huggingface dataset:
Involvement of PI3K/Akt and Erk1/2 pathways on the regulation of estrogen and progesterone receptor expression in murine mammary tumors.
Authors: Victoria Arnoni, Cecilia Bottino, Stephen Hewitt, Alfredo Molinolo, Silvio Gutkind, Claudia Lanari, Virginia Novaro
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

1002 

The acquisition of hormone independence is a crucial event in breast cancer since it is involved in the progression into a hormone resistant and more aggressive phenotype. We have developed an experimental model in which the continuous administration of medroxyprogesterone acetate (MPA) induces mammary carcinomas in female BALB/c mice. As most breast cancers, these ductal mammary carcinomas express high levels of estrogen (ER) and progesterone receptors (PR) and transit through different stages of hormone dependence. Hormone dependent (HD) tumor variants need exogenous administration of progestin to grow while hormone-independent (HI) tumor variants grow without exogenous hormone supply, even though they maintain high levels of ER and PR. We have previously provided evidence that these receptors are still playing a pivotal role regulating HI growth. The aim of the current study was to investigate which transduction pathways were involved in the steroid receptor expression and activation that could be leading to hormone independence. Two different approaches were used: a) a tissue array involving five different HD tumors and several HI variants to evaluate key proteins from the Akt pathway, and b) in vitro studies in primary cultures derived from HI and HD tumors using specific inhibitors of PI3K/Akt (LY294002) and Erk1/2 (PD98059) to evaluate the role of these pathways on steroid receptor expression and cell proliferation. Analysis of the arrays showed high levels of phospho Akt (pAkt, Ser473 and Thr 308) in the nuclei of most HI and HD tumors and, in agreement, low levels of GSK3 α/β. The in vitro studies involving the inhibitors LY294002 and PD98059 indicated that both kinases are responsible for maintaining cell proliferation and high levels of ERα, PRA and PRB in primary cultures derived from HD and HI variants. No differences between the HD and the HI tumors were observed suggesting that in this tumor model the acquisition of constitutive activation of those pathways is not restricted to hormone-independent variants. Finally, we present evidence showing that inhibiting the PI3K/Akt pathway causes an up-regulation of Erk1/2 levels, indicating that they regulate each other and suggesting that the overall control of steroid receptor expression and function might depend on a delicate balance between the relative activity of these two kinase pathways. In summary, in this study we demonstrate that deregulated Akt and Erk1/2 pathways are involved in maintainace of high levels of ER and PR in MPA-induced tumors. Our results show the involvement of alternative pathways on the regulation of steroid receptor expression and could contribute to the understanding of the acquisition of different hormone responsiveness in breast cancer progression.
Label Free Quantitative Mass Spectrometry Identifies Processes Linked to Platelet Degranulation As Early Events during Platelet Storage
Authors: Maaike Rijkers, Floris P. van Alphen, Pieter F. van der Meer, Dirk de Korte, Frank W.G. Leebeek, Alexander B. Meijer, Jan Voorberg, Gerard AJG Jansen
Journal: Blood (2016)
P16.12 Malignant brain tumors mimicking hemerrhagic stroke: two cases report
Authors: C. Kim, J. Cheong
Journal: Neuro-Oncology (2017)

Introduction: Most brain tumors present with subtle neurological symptoms or signs. However, some intracranial tumors represent catastrophic manifestations by intratumoral hemorrhage. When it is presented with intracerebral hemorrhage (ICH) without previous clinical informations, it may be misdiagnosed as the stroke. We report two cases with brain tumor masquering as the hemorrhagic stroke. Materials and Methods: A 73-year-old woman presented with headache and dysarthria. Brain computed tomography (CT) scans revealed a large intracerebral hemorrhage in right temporoparietal lobe and subdural hemorrhage in right frontotemporoparietal convexity and subtentorium. There was not observed abnormal intracranial enhancement in the hematoma. On admission day, her mentality was altered to stupor and showed left sided motor weakness. The other case was a 69-year- old woman presented with headache and dizziness, and Brain CT scans showed ICH in the median cerebellar hemisphere and vermian area, accompanying hydrocephalus. Results: The first patient underwent decompressive craniectomy and removal of hematomas. Pathological examination of surgical specimen revealed the findings of anaplastic astrocytoma. The second case underwent external ventricular drainage, and she recovered from first attack and discharged. However she revisited by rebleeding two months later. We took brain magnetic resonance (MR) imaging and found a 6.4 x 4.2 x 5.2 cm sized well-enhancing mass in the hemorrhagic site. This tumor implicated high grade glial cell tumors We could not confirm her pathology because she self-discharged. Conclusions: When we encounter the catastrophic intracranial stroke without any underlying informations, it is important to take meticulous investigations including brain MR imaging and angiography.
ARB: Phase II window of opportunity study of short-term preoperative treatment with enzalutamide in ER-positive and triple-negative breast cancer.
Authors: Peter Schmid, Duncan A Wheatley, Alastair Mark Thompson, Pankaj Roy, Nigel J Bundred, Anand David Purushotham, Stuart McINTOSH, Sherko Kummel, Nadia Harbeck, Ulrike Nitz, David Barnes, Shah-Jalal Sarker, Kelly Mousa, Javier Cortes
Journal: Journal of Clinical Oncology (2016)

TPS619 Background: Theandrogen receptor (AR) is expressed in 60-80% of breast cancers (BC) across all molecular phenotypes, with a higher incidence in oestrogen receptor positive (ER+) BC compared to ER negative tumours. In ER+ disease, AR-expression has been linked to endocrine resistance which might be reversed with combined treatment targeting ER and AR. In triple negative BCs (TNBC), preclinical and clinical investigations have described a subset of patients that express the AR and are sensitive to androgen blockade, providing a novel therapeutic target. Enzalutamide, a potent 2ndgeneration anti-androgen, has demonstrated substantial preclinical and clinical anti-tumour activity in AR+ breast cancer. Short-term preoperative window of opportunity studies are a validated strategy for novel treatments to provide proof-of-concept and define the most appropriate patient population by directly assessing treatment effects in tumour tissue before and after treatment. The ARB study aims to assess the anti-tumour effects of enzalutamide in early ER+ breast cancer and TNBC, to identify the optimal target population for further studies and to directly explore the biologic effects of enzalutamide on BC and stromal cells. Methods: ARB is an international, investigator sponsored WOO phase II study in women with newly diagnosed primary ER+ BC or AR+ TNBC of ≥ 1cm. The study has two cohorts. In the ER+ cohort, postmenopausal patients will be randomised 2:1 to receive either enzalutamide (160mg OD) plus exemestane (50mg OD) or exemestane (25mg OD). In the TNBC cohort, AR+ will receive single agent treatment with enzalutamide (160mg OD). Study treatment is planned for 15–29 days, followed by surgery or neo-adjuvant therapy. Tissue and blood samples are collected before treatment and on the last day of study treatment. The primary endpoint is inhibition of tumour-cell proliferation, as measured by change in Ki67 expression, determined centrally by 2 investigators. Secondary endpoints include induction of apoptosis (Caspase3), circulating hormone levels and safety. ARB aims to recruit ≈235 patients from ≈40 sites in the UK, Germany, Spain and USA. The study is open to recruitment.
Self-Monitoring of Blood Glucose
Journal: Diabetes Care (1994)

elf-monitoring of blood glucose (SMBG) is an important component of the treatment plan of patients with diabetes mellitus.Its use was the subject of an American Diabetes Association Consensus Conference in 1986 that dealt with issues regarding the intended and actual use of SMBG, the design, accuracy, and reliability of SMBG devices, how well patients were instructed in SMBG, and how patients and health care providers used the information generated to influence metabolic control.Over the ensuing 7 years, these devices have improved in portability and ease of use.Diabetes educators are teaching an everincreasing number of people with diabetes to use SMBG.In addition, the recent publication of the results of the Diabetes Control and Complications Trial has given validity to the concept that better metabolic control can significantly reduce the onset and progression of the microvascular and neuropathic complications of insulin-dependent diabetes (IDDM).
A woman with intermittent heartburn
Authors: Hao Chen
Journal: BMJ (2017)

A 68-year-old woman presented to the hospital with intermittent retrosternal heartburn that had been ongoing for several years. Physical examination and electrocardiogram revealed no abnormalities. A plain chest radiograph was obtained (fig 1⇓). What does the radiograph show?



Fig 1  Chest radiograph



The chest radiograph shows retrocardiac opacity consistent with a diagnosis of hiatal hernia.

### Discussion

The differential diagnoses for a retrocardiac opacity include retromediastinal tumour, aortic aneurysm, and spinal abscess. The patient’s stable condition, mild symptoms, the presence on radiology of an air shadow (fig 2⇓, white arrow) inside the rounded opacity (fig 2⇓, black arrows), and absence of …
P04.18 Response assessment of bevacizumab for malignant glioma &lt;: &gt; comparison between PET and pathological studies
Authors: K. Miyake, D. Ogawa
Journal: Neuro-Oncology (2017)

Introduction: Diagnostic imaging such as magnetic resonance imaging (MRI) is the most commonly used morphological method for determination of size and location of brain tumors. However, it is difficult to evaluate the effect of bevacizumab for malignant gliomas by using only MRI. In contrast, positron emission tomography (PET) uses radiotracers to achieve metabolic and molecular imaging, and this approach can improve diagnoses. Notably, 11C-Methionine (MET) and 18F-Fluoromisonidazole (FMISO) are expected to lead ways for novel applications aimed at achieving efficient malignancy grading and treatment of gliomas. Because of difficulty evaluating the effect of bevacizumab, aim of this study was to assess MET and FMISO PET studies to evaluate pathological examinations induced by bevacizumab in malignant glioma patients. METHODS: Thirty-three patients with malignant gliomas were treated biweekly with bevacizumab at a dose of 10 mg/kg from July 2013 to July 2016. MRI, as well as MET and FMISO PET scans were obtained. Five glioblastoma patients out of thirty-three malignant glioma patients had been treated by resection after bevacizumab therapy. Based on MET and FMISO accumulation, intraoperative biopsies were selected by surgeon and investigated for histological characteristics, Ki-67 proliferative indices, and expression levels of VEGF and HIF-1 alpha. We determined that MET accumulation with a tumor to normal (T/N) ratio cutoff of > 3 and FMISO accumulation with a tumor to blood (T/B) ratio cutoff of > 1.6 were related to metabolically active tumor cells. Sensitivities, specificities, positive predictive values (PPVs) and negative predictive values (NPVs) for evaluation between presence of tumor and accumulation of PET radiotracers were calculated. Results: MET accumulation correlated with presence of tumor for sensitivity of 88.5%, specificity of 39.5%, PPV of 50% and NPV of 83.3% (p-value <: > 0.022). FMISO accumulation correlated with presence of tumor for sensitivity of 91.9%, specificity of 55.6%, PPV of 73.9% and NPV of 83.3% (p-value <: > <0.0001). Pathological studies could not detect increased microvasculature and expression levels of VEGF in the tumors with low accumulation levels of MET (T/N < 3) and FMISO (T/B < 1.6). Ki-67 labeling index was less than 1%. However, in the tumors with high accumulation levels of MET (T/N > 3) and FMISO (T/B > 1.6), we could detect high microvessel density and high expression levels of VEGF and HIF-1 alpha. Ki-67 labeling index was more than 50%. In the region with a little high MET T/N ratio and low FMISO T/B ratio, we detected the metabolically non-active tumor and necrosis areas. Conclusions: We suspect that high accumulation areas of MET and FMISO are related to the resistance of bevacizumab therapy, and MET and FMISO may be useful biomarkers for the evaluation of pathological examination of malignant gliomas during bevacizumab therapy.
Myc and Bcl2 Overexpression and Traslocation Assessed By Immunohystochemistry (IHC) and FISH: Retrospective Analysis in a Series of De Novo DLBCL Homogeneously Treated with Rituximab-CHOP
Authors: Chiara Ciochetto, Maria Stella Scalzo, Barbara Botto, Alessia Castellino, Annalisa Chiappella, Mattia Novo, Maura Nicolosi, Elisa Santambrogio, Federica Cavallo, Paola Ghione, Andrea Evangelista, Giovannino Ciccone, Roberto Chiarle, Domenico Novero, Umberto Vitolo
Journal: Blood (2016)
Feasibility trial for primary stroke prevention in children with sickle cell anemia in Nigeria (SPIN trial)
Authors: Najibah A. Galadanci, Shehu Umar Abdullahi, Leah D. Vance, Abdulkadir Musa Tabari, Shehi Ali, Raymond Belonwu, Auwal Salihu, Aisha Amal Galadanci, Binta Wudil Jibir, Halima Bello‐Manga, Kathleen Neville, Fenella J. Kirkham, Yu Shyr, Sharon Phillips, Brittany V. Covert, Adetola A. Kassim, Lori C. Jordan, Muktar H. Aliyu, Michael R. DeBaun
Journal: American Journal of Hematology (2017)

Abstract The vast majority of children with sickle cell anemia (SCA) live in Africa, where evidence‐based guidelines for primary stroke prevention are lacking. In Kano, Nigeria, we conducted a feasibility trial to determine the acceptability of hydroxyurea therapy for primary stroke prevention in children with abnormal transcranial Doppler (TCD) measurements. Children with SCA and abnormal non‐imaging TCD measurements (≥200 cm/s) received moderate fixed‐dose hydroxyurea therapy (∼20 mg/kg/day). A comparison group of children with TCD measurements &lt;200 cm/s was followed prospectively. Approximately 88% (330 of 375) of families agreed to be screened, while 87% (29 of 33) of those with abnormal TCD measurements, enrolled in the trial. No participant elected to withdraw from the trial. The average mean corpuscular volume increased from 85.7 fl at baseline to 95.5 fl at 24 months (not all of the children who crossed over had a 24 month visit), demonstrating adherence to hydroxyurea. The comparison group consisted of initially 210 children, of which four developed abnormal TCD measurements, and were started on hydroxyurea. None of the monthly research visits were missed ( n = total 603 visits). Two and 10 deaths occurred in the treatment and comparison groups, with mortality rates of 2.69 and 1.81 per 100 patient‐years, respectively ( P = .67). Our results provide strong evidence, for high family recruitment, retention, and adherence rates, to undertake the first randomized controlled trial with hydroxyurea therapy for primary stroke prevention in children with SCA living in Africa.
P06.08 BRAINTuNE: Brain Tumor Neoepitope Evaluation for personalized glioma immunotherapy
Authors: K. Sanghvi, E. Green, L. Bunse, G. P. Balasubramanian, A. Hertenstein, T. Bunse, D. Jones, F. Sahm, W. Wick, M. Platten
Journal: Neuro-Oncology (2017)

Background: Checkpoint inhibitors for cancer immunotherapy have been shown to unleash a subdued endogenous T-cell response against mutated tumor antigens, so-called neoepitopes. However, tumors with a low burden of non-synonymous mutations - including gliomas - are poorly presented to the immune system, and therefore unlikely to respond to checkpoint inhibition alone. It is therefore important to identify the signature of relevant immunogenic neoepitopes and the T cell receptors (TCRs) recognizing these epitopes to employ a more specific immunotherapy. Limited availability of tumor-infiltrating lymphocytes (TILs) in turn prompts the identification of neoepitope-specific T-cells in peripheral blood. Aim: This study aimed at establishing a platform for the identification of immunogenic neoepitopes and corresponding neoepitope-specific T cells in the peripheral blood of glioma patients. Methods and Results: Putative neoepitopes were predicted from next generation sequencing mutanome data of tumor samples from three glioma patients. Patient-specific neoepitopes were synthesized as codon-optimized tandem mini gene vector (TMG) optimized for neoepitope presentation, with up to 10 neoeptiopes per TMG. Autologous PBMC-derived dendritic cells were transfected with in vitro transcribed TMG RNA or loaded with peptides to test T-cell neoepitope-reactivity in co-culture assays. On probing the reactivity of T-cells from peripheral blood, we found patient-specific reactivity against neoepitopes. Conclusion and scope: We investigated the T-cell reactivity towards patient specific neoepitopes in the peripheral blood of 3 glioma patients and the phenotypic identity of these neoepitope-reactive T-cells. We are currently probing CD8+ T-cell subpopulations to characterize the neoepitope-reactive T-cell phenotype. Ongoing studies aim to further characterize the neoepitope-specific T-cells with respect to their TCR sequences and expand this platform to a larger cohort of glioma patients to provide a proof-of-principle for a minimally invasive approach to identify tumor-reactive T-cells for personalized glioma immunotherapy.
Abstract P209: MyD88 Mediated Inflammatory Signaling Involved in Post-MI CaMKII Activation and Cardiac Hypertrophy
Authors: Madhu V Singh, Paari D Swaminathan, Beixin J He, Elizabeth E Luczak, William Kutschke, Mark E Anderson
Journal: Circulation Research (2011)

Toll-like receptors (TLRs) and calmodulin kinase II (CaMKII) participate in pathological responses to myocardial infarction (MI), including activation of nuclear factor kappa B (NF-κB) transcription and complement factor B expression (Singh JCI 2009). We tested the effect of MyD88 deficiency on the adverse cardiac outcome after MI. MyD88 knock out (MyD88-/-) hearts had significantly reduced hypertrophy, hypertrophic gene expression, and inflammatory gene expression compared to WT control hearts. Cultured cardiomyocytes from expressing MyD88 and a NF-κB reporter demonstrated robust induction of NF-κB upon TLR induction by bacterial lipopolysaccharides (LPS). In contrast, cardiomyocytes from MyD88-/- mice failed to induce NF-κB upon LPS treatment. An alternative MyD88-independent pathway for NF-κB remained functional in WT and MyD88-/- cells. Both LPS treatment and MI increased a Ca2+/calmodulin independet activated form of CaMKII (CaMKIIox) in cultured cardiomyocytes and mouse hearts, respectively. MyD88-/- hearts, however, did not display increased CaMKIIox upon MI. Taken together, we interpret these results to show that: (1) MyD88 participates in MI mediated hypertrophic and inflammatory gene expression, (2) CaMKII enhances NF-kB activation in cardiomyocytes by a MyD88-dependent mechanism, and (3) CaMKIIox plays a role in MyD88 dependent signaling to induce expression of proinflammatory genes in post-MI hearts.
Bridging the translational innovation gap through good biomarker practice
Authors: Alain J. van Gool, Florence Bietrix, Eric Caldenhoven, Kurt Zatloukal, Andreas Scherer, Jan-Eric Litton, Gerrit Meijer, Niklas Blomberg, Andy Smith, Barend Mons, Jaap Heringa, Wim-Jan Koot, Martin J. Smit, Marian Hajduch, Ton Rijnders, Anton Ussi
Journal: Nature Reviews Drug Discovery (2017)
Genome-Wide Association Studies of Chemotherapeutic Toxicities: Genomics of Inequality
Authors: Brandon Mapes, Omar El Charif, Shereen Al-Sawwaf, M. Eileen Dolan
Journal: Clinical Cancer Research (2017)

Abstract With an estimated global population of cancer survivors exceeding 32 million and growing, there is a heightened awareness of the long-term toxicities resulting from cancer treatments and their impact on quality of life. Unexplained heterogeneity in the persistence and development of toxicities, as well as an incomplete understanding of their mechanisms, have generated a growing need for the identification of predictive pharmacogenomic markers. Early studies addressing this need used a candidate gene approach; however, over the last decade, unbiased and comprehensive genome-wide association studies (GWAS) have provided markers of phenotypic risk and potential targets to explore the mechanistic and regulatory pathways of biological functions associated with chemotherapeutic toxicity. In this review, we provide the current status of GWAS of chemotherapeutic toxicities with an emphasis on examining the ancestral diversity of the representative cohorts within these studies. Persistent calls to incorporate both ancestrally diverse and/or admixed populations into genomic efforts resulted in a recent rise in the number of studies utilizing cohorts of East Asian descent; however, few pharmacogenomic studies to date include cohorts of African, Indigenous American, Southwest Asian, and admixed populations. Through comprehensively evaluating sample size, composition by ancestry, genome-wide significant variants, and population-specific minor allele frequencies as reported by HapMap/dbSNP using NCBI PubMed and the NHGRI-EBI GWAS Catalog, we illustrate how allele frequencies and effect sizes tend to vary among individuals of differing ancestries. In an era of personalized medicine, the lack of diversity in genome-wide studies of anticancer agent toxicity may contribute to the health disparity gap. Clin Cancer Res; 23(15); 4010–9. ©2017 AACR.
Address to the 11th European Conference on Psychosomatic Research
Authors: Chase Patterson Kimball, Margaret Thaler Singer, Harley C. Shands, P.-B. Schneider, Peter E. Sifneos, Roberta Apfel-Savitz, Fred H. Frankel, Heinz H. Wolff, George Spyros Philippopoulos, Louis A. Gottschalk, M. von Rad, L. Lalucat, F. Lolas, R. Vogt, G. Bürckstümmer, L. Ernst, K. Meyer, M. von Rad, W. Bräutigam, M. von Rad, G. Overbeck, Graeme J. Taylor, John C. Nemiah, Paul D. MacLean, Astrid Heiberg, Arvid Heiberg, Johannes Cremerius, Helm Stierlin, M. Wirsching, W. Knauss, E.M. Waring, Renata Gaddini, M. Mitscherlich, S. Zepf, Jan Bastiaans, H. Becker, Hellmuth Freyberger, S. Stephanos, U. Auhagen, A. Sellschopp-Rüppell, M. von Rad, Karola Brede, Frode Larsen, Truls-Eirik Mogstad, B. Waysfeld, M. Le Barzic, P. Aimez, B. Guy-Grand, John G. Flannery, Klaus D. Hoppe, Joseph E. Bogen, R. Pierloot, J. Vinck, John C. Nemiah, Peter E. Sifneos, Roberta Apfel-Savitz, Fred H. Frankel, Roberta Apfel-Savitz, John C. Nemiah, Peter E. Sifneos, Murray Jackson, R. Liedtke, H. Freyberger, S. Zepf, R. Borens, E. Grosse-Schulte, W. Jaensch, K.-H. Kortemme, Charles V. Ford, Kahlila D. Long, J.P. Roberts, A. Sellschopp-Rüppell, Roberta Apfel-Savitz, Daniel Silverman, Michael I. Bennett, H.H. Wolff
Journal: Psychotherapy and Psychosomatics (1977)