tbuckley/cabot-search huggingface dataset:
Pathogenesis and Treatment of Sickle Cell Disease
Authors: H. Franklin Bunn
Journal: New England Journal of Medicine (1997)

In 1949, the discovery that sickle hemoglobin (α2 βS2) has an abnormal electrophoretic mobility prompted Linus Pauling and his colleagues to christen sickle cell anemia "a molecular disease."1 The ensuing five decades have produced a wealth of information on the mechanisms by which a single base substitution in the gene encoding the human β-globin subunit, with the resulting replacement of β6 glutamic acid by valine, leads to the protean and devastating clinical manifestations of sickle cell disease. Until recently there was a disappointing lag in the application of this knowledge to the design of safe and effective . . .
Thymic Uptake of Radiopharmaceuticals
Authors: Leonard P. Connolly, Susan A. Connolly
Journal: Clinical Nuclear Medicine (2003)

The thymus, as the site of T-cell differentiation, plays a critical role in the development of the immune system. The gland increases in weight until puberty and then is slowly replaced by fat. Various radiopharmaceuticals can localize to the thymus before it involutes. This pictorial presentation reviews the appearance and proposed mechanisms of thymic uptake of Ga-67 citrate, F-18 fluorodeoxyglucose, radioiodine, and In-111 pentetreotide.
A novel t(Y;11) translocation with MLL gene rearrangement in a case of acute myelomonocytic leukemia (AML-M4)
Authors: P Bernasconi, PM Cavigliano, M Boni, L Malcovati, S Calatroni, C Astori, M Caresana, C Bernasconi
Journal: Leukemia (1999)
Unusual Pelvic Mass on Bone Scan Caused by a Preserved Cranial Bone Graft
Authors: Viktoriya Paroder, Joseph E. Glaser, Chukwuemeka Onyedika, Kwang J. Chun, Leonard M. Freeman
Journal: Clinical Nuclear Medicine (2012)

A 54-year-old man presented with left-sided weakness and altered mental status. CT demonstrated a large acute right middle cerebral arterial infarct with midline shift and uncal herniation. He underwent right decompressive hemicraniectomy with storage of bone flap in the periumbilical subcutaneous pocket. The patient was referred for whole-body bone scan for evaluation of osseous metastases secondary to newly suspected renal cell carcinoma. It showed increased radiotracer uptake in the right lower quadrant of the abdomen corresponding to the site of implanted bone flap, confirming its viability. The autologous bone flap was subsequently successfully reimplanted in the cranium.
Abstract 822: Withaferin A inhibits breast cancer invasion and metastasis at subcytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation
Authors: Jose T. Thaiparambil, Laura Bender, Thota Ganesh, Erik Kline, Pritty Patel, Yuan Liu, Mourad Tighiouart, Paula M. Vertino, R Donald Harvey, Anapatricia Garcia, Adam Marcus
Journal: Cancer Research (2011)

Abstract Withaferin A (WFA) is purified from the plant Withania somnifera and inhibits the vimentin cytoskeleton. Vimentin overexpression in cancer correlates with metastatic disease, induction of epithelial to mesenchymal transition, and reduced patient survival. Since WFA has significant anti-tumor activity and vimentin functions in cell motility, we wanted to test the hypothesis that WFA inhibits cancer metastasis by disrupting vimentin function. These data show that WFA has weak antiproliferative and apoptotic activity at concentrations less than or equal to 500 nM, but retains potent anti-invasive activity at these low doses. Live cell imaging in breast cancer cell lines revealed that WFA induces perinuclear vimentin bundling followed by rapid vimentin depolymerization. A concomitant induction of vimentin ser56 phosphorylation was observed, which is consistent with vimentin disassembly. Structure activity relationships were established using a set of chemically modified WFA analogs and showed that the predicted vimentin-binding region of WFA is necessary to induce vimentin ser56 phosphorylation and for its anti-invasive activity. Pharmacokinetic studies in mice revealed that WFA reaches peak concentrations up to 2μM in plasma with a half-life of 1.36 hours following a single 4 mg/kg dose. In a breast cancer metastasis mouse model, WFA showed dose-dependent inhibition of metastatic lung nodules and also induced vimentin ser56 phosphorylation, with minimal toxicity to lung tissue. Based upon these studies, we conclude that WFA is a potent breast cancer anti-metastatic agent and the anti-metastatic activity of WFA is, at least in part, mediated through its effects on vimentin and vimentin ser56 phosphorylation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 822. doi:10.1158/1538-7445.AM2011-822
THU0016 The Relationship between Infection and Anti-Phospholipid Syndrome: A Systemic Review of CASE Reports
Authors: N. Abdel-Wahab, M.A. Lopez-Olivo, H.R. Siddhanamatha, M.E. Suarez-Almazor
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The coexistence of infection and anti-phospholipid syndrome (APS) has been increasingly reported in the literature under the assumption that infection may be a triggering factor for the development of APS. <h3>Objectives</h3> To conduct a systematic review of case reports documenting the development of primary APS after a prior infection, and to describe and categorize the clinical and immunological phenotypes in these cases. <h3>Methods</h3> We conducted a comprehensive search in electronic databases from inception through October 2013 (Medline, EMBASE, Web of Science, and CENTRAL). We selected publications of case reports: 1) describing APS development after an infection; and 2) published in English, French, or Spanish. Study selection, quality appraisal, and data extraction were performed by two independent researchers. We extracted data on the potentially putative infection, the cases9 clinical presentation, and their anti-phospholipid antibodies (APL Ab) profiles. <h3>Results</h3> Out of 2,278 citations, only 200 case reports met our inclusion criteria. Two different groups of patients were identified. The first group included patients who presented with specific clinical and immunological findings that fulfilled the diagnostic criteria of primary APS after a definite history with documentation of preceding infection. Various types of bacterial (including spirochetal), viral, parasitic, and fungal infections were reported as preceding or triggering APS. Most commonly reported infections involved Human Immunodeficiency Virus (HIV), hepatitis C virus (HCV) and Mycoplasma pneumonia. Thromboembolic events included neurological, respiratory, and peripheral thrombosis, often with persistent positive APL Ab. The second group included patients who did not fulfil the criteria for diagnosis of APS, but developed transient positive autoimmune APL Ab after an infection. Among this group, 60% developed thromboembolic attacks during the course of the infection, with or without other coagulation disorders. In these latter cases the causal relationship between the development of antibodies and thrombosis was not clearly established, since thrombotic events could also be attributed to the infection itself, or a separate co-existent hypercoagulable state. <h3>Conclusions</h3> This review found many reports of APS or APL Ab occurring after a variety of infections, including bacterial, viral, fungal and parasitic agents. A causal relationship cannot be established with these data, but the evidence supports that further longitudinal studies should be conducted to identify the risk of APS after infection with these agents. <h3>Acknowledgements</h3> Dr. Suarez-Almazor is the recipient of a K24 career award from the National Institute for Musculoskeletal and Skin Disorders. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5229
Abstract 3516: AZD1208 PIM kinase inhibitor - Preliminary evidence of target pathway inhibition in Phase I clinical trials of AML.
Authors: Kristen A. McEachern, Yichen Cao, Rachel DuPont, Lourdes Pablo, Patricia McCoon, Jorge E. Cortes, Daniel J. DeAngelo, Mark D. Minden, Becker Hewes, Jeffrey L. Brown, Carl Barrett
Journal: Cancer Research (2013)

Abstract PIM kinases have been shown to play a key role as downstream effectors of growth factor signalling pathways including Flt3 and the Jak-STAT signalling pathways in AML, NHL and other solid tumors. AZD1208 is a novel, orally bioavailable, highly selective PIM kinase inhibitor with single nanomolar potency against all three PIM kinases and is currently undergoing Phase I testing and dose escalation studies in AML. Here we describe a multiplexed biomarker strategy measuring pBAD, p4EBP1 and p-p70S6K as downstream pharmacodynamic biomarkers for PIM kinase inhibition in clinical trials. Patient bone marrow aspirates and peripheral blood samples were collected pre- and post-AZD1208 treatment in AML patients during the Phase I dose escalation and expansions. Primary patient samples were analyzed for quantitative changes in pBAD, p4EBP1 by NanoPro and MesoScale assay platforms as well as a qualitative evaluation of p-p70S6K and other exploratory endpoints. Preclinical PK-PD modeling data with AZD1208 had suggested that greater than a 50% decrease in the levels of one of these phosphorlyated substrates would be indicative of efficacy and PIM pathway inhibition. Following a single dose of AZD1208 at 120mg, the first dose level, approximately 60-70% inhibition of pBAD, S112 was seen in the bone marrow and peripheral blasts. Taken together, the data presented here provide evidence for single agent AZD1208 activity in AML patients based on quantitative reduction in these biomarkers. Correlations of these biomarker endpoints with Phase I pharmacokinetic data underscore the therapeutic potential of Pim kinase inhibition by AZD1208 for the treatment of AML, and strongly support further investigation of this agent in other indications where PIM signaling may play a role in tumorigenesis and survival. Citation Format: Kristen A. McEachern, Yichen Cao, Rachel DuPont, Lourdes Pablo, Patricia McCoon, Jorge E. Cortes, Daniel J. DeAngelo, Mark D. Minden, Becker Hewes, Jeffrey L. Brown, Carl Barrett. AZD1208 PIM kinase inhibitor - Preliminary evidence of target pathway inhibition in Phase I clinical trials of AML. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3516. doi:10.1158/1538-7445.AM2013-3516
FRI0007 The transcription factor C-MAF plays an essential role in a memory TH-cell dependent model of inflammation
Authors: K. Sato, T. Mimura
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Th17 cells are a recently identified effector T-helper (Th) cell subset, which has been suggested to play an important role in various inflammatory diseases, and thus has gathered considerable attention. Indeed, antibodies to interleukin (IL-)17, a representative cytokine produced by Th17 cells, have been shown to have clinical efficacy against psoriatic arthritis and also are undergoing clinical trials for rheumatoid arthritis (1, 2). We reported in this meeting 2 years ago the following results: (i) The transcription factor c-Maf is highly expressed in Th17 cells. (ii) One of its transcriptional target is Il23r. (iii) Most of the Th cells in c-Maf transgenic mice have an effector-memory phenotype (3). <h3>Objectives</h3> The role c-Maf plays in memory Th cells is scarcely known. Thus, we aim to investigate it. <h3>Methods</h3> As c-Maf-deficient mice are embryonically lethal, it was necessary to make chimeras of T-cell deficient Rag-1 or 2 knockout mice and hematopoietic stem cells derived from c-Maf deficient embryos. We utilized a colitis model in which naïve Th cells were transferred into Rag knockout mice (4) and analyzed the role c-Maf played <i>in vivo</i>. We also sorted human Th cells into naïve, central memory and effector memory cells based on their surface markers, and performed transcriptome analysis to identify the expression pattern of the transcription factors in human naïve and memory Th cells. <h3>Results</h3> Rag-2 knockout mice that received <i>Maf</i><sup>-/-</sup> naïve Th cells exhibited a lesser degree of colitis than control mice that received WT naïve Th cells. In human Th cells, the expression of <i>MAF</i> encoding c-MAF was the highest in effector memory cells and the lowest in naïve cells, demonstrating that the expression of <i>MAF</i> is induced in the course of differentiation from naïve to memory Th cells. <h3>Conclusions</h3> c-Maf plays an important role in the inflammation that is dependent on memory-phenotype Th cells. In human Th cells, too, c-MAF is strongly induced in memory Th cells, suggesting the importance of this transcription factor across species. Further study will be needed to elucidate its function in detail. <h3>References</h3> Genovese, M. C., et al.: Arthritis Rheum, 62: 929-939.2010. Hueber, W., et al.: Sci Transl Med, 2: 52ra72.2010. Sato, K., et al.: J Biol Chem, 286: 14963-14971.2011. Powrie, F., et al.: J Exp Med, 183: 2669-2674.1996. <h3>Disclosure of Interest</h3> None Declared
DR-04 * VALPROIC ACID AND HEDGEHOG PATHWAY: A POSSIBLE DRUG RESISTANCE MECHANISM IN MEDULLOBLASTOMA?
Authors: B. Mascaro-Cordeiro, I. Oliveira, M. T. Alves, N. Saba-Silva, A. Capellano, S. Cavalheiro, P. Dastoli, S. Toledo
Journal: Neuro-Oncology (2014)

BACKGROUND: Medulloblastoma (MB) is a malignant neuroepithelial embryonal tumor of cerebellum. In children, they comprise the most frequent embryonal brain tumor. This study aim to investigate the role of valproic acid (VA) and cisplatin (CDDP) in the cytotoxicity, viability, and expression of hedgehog pathway (HH) in MB DAOY cell line. METHODS: The treatment of DAOY cells was distributed in four groups: (1) VA single, (2) CDDP single, (3) VA sensibilization + CDDP, (4) untreated. Cell viability was measured by Presto Blue assay, qPCR was performed to quantify HH genes and two PTCH1 punctual mutations were investigated by direct sequencing. RESULTS: VA and CDDP affected the viability of DAOY cell line (IC50= 6mM and 10mM, respectively). VA sensibilization followed by CDDP exposure (group 3) caused the most significant reduction of cell viability. Interestingly, we observed higher expression levels of PTCH1, SMO, GLI1 and GLI2 genes in the cells treated with VA (single or combined), than the cells submitted to the others treatments (groups 2 and 4). We identified the presence of H408N mutation, in PTCH1 gene in DAOY cells. CONCLUSIONS: The HH pathway is considered to be crucially involved in the development of MB. Our study showed that MB cells resistant to treatment with VA, single or combined, presented high expression of HH genes. Recent studies have demonstrated that the chronic use of VA is associated with reactivation of AKT pathway, which may be involved in resistance development. Additionally, AKT activates HH pathway in an independent-manner. In this way, we suggest that the resistance of MB cells submitted to VA treatment may be related to the activation of HH pathway via AKT. The MB treatment with VA should be cautious and deserves further investigation about the role of this HDAC inhibitor in the drug resistance development in MB.
MITRAL REGURGITATION SEVERITY IS ASSOCIATED WITH INCREASED DIFFUSE MYOCARDIAL FIBROSIS BY EXTRACELLULAR VOLUME QUANTIFICATION IN NON-ISCHEMIC CARDIOMYOPATHY
Authors: Samornrat Jampates, Srikanth Koneru, Zoran Popovic, Scott Flamm, Wai Hong Tang, Brian Griffin, Deborah Kwon
Journal: Journal of the American College of Cardiology (2016)
Abstract LB-440: Low density array profiling of head and neck squamous cell carcinoma utilizing a 25-gene signature can reliably identify hypoxic tumors
Authors: Amanda Williamson, Guy NJ Betts, Shalini Patiar, Helen R. Valentine, Joely J. Irlam, Anassuya Ramachandran, Ashirwad Merve, Jarrod J. Homer, Carla Moller-Levet, Franscesca M. Buffa, Gillian Hall, Crispin J. Miller, Adrian L. Harris, Catharine ML West
Journal: Cancer Research (2012)

Abstract Purpose: Administering hypoxia modifying therapy to patients with head and neck squamous cell carcinoma (HNSCC) improves outcomes in those with identified hypoxic tumors. As no method for measuring tumor hypoxia has demonstrated clinical utility, this study aimed to validate use of a gene expression signature with a TaqMan Low Density Array (TLDA) platform. Experimental design: Tumor samples (n=201) from 80 HNSCC patients were collected prospectively from two centers. Fifty-three patients received pimonidazole prior to surgery. Hypoxia scores (TLDA HS) were obtained by quantitative real-time PCR (qPCR) using a 25-gene signature and customized TLDA cards. Assay performance was assessed as coefficient of variation (CoV). Relationships with outcome were determined by log-rank analysis. Results: The assay was sensitive with linear reaction efficiencies across a 4log10 range of inputted cDNA (0.001-10 ng/µl). Intra- (CoV=0.5%) and inter- (CoV=0.1%) assay reproducibility were excellent. Intra-tumor heterogeneity was lower for TLDA HS (23.2%) than for pimonidazole (67.2%) or single gene measurements of CA9 (62.2%), VEGFA (45.0%) or HIG2 (39.4%). TLDA HS in HNSCC cell lines increased with decreasing pO2 and was reduced but not completely abrogated in HIF1A silenced cells. TLDA HS correlated with Affymetrix U133 Plus 2.0 microarray HS (p&amp;lt;0.01) and pimonidazole scores (p=0.021). High TLDA HS was associated with worse overall (p=0.037) and recurrence free (p=0.036) survival. Conclusions: Gene expression measurements of hypoxia using a 25-gene signature and TLDA cards are sensitive, reproducible and associated with lower intra-tumor heterogeneity than assaying individual genes or pimonidazole binding. The approach is suitable for application in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-440. doi:1538-7445.AM2012-LB-440
Abstract 621: The importance of antioxidant, antiangiogenesis and immune stimulation in cancer
Authors: Jerry T. Thornthwaite, Henry Respess, Hare Shah, William Peeples, Kyle Thornthwaite, Bonita Thornthwaite, Patrick Kent, Mark Allen
Journal: Cancer Research (2012)

Abstract In our quest over the last nine years to find comprehensive over-the- counter supplements, designed to facilitate current classical treatments in fighting diseases, include antiangiogenic, immune and antioxidant defense systems. These supplements include, in part, Acetyl L-Carnitine (ALC), Alpha Lipoic Acid (ALA), Coenzyme Q10 (CoQ10), Curcumin with Piperine, Genistein, Lentinan, N-AcetylCysteine (NAC), Resveratrol, selenium, Vitamin B Complex, Vitamin C, Vitamin E and zinc. These ingredients have been demonstrated, either individually or collectively, to have antioxidant, anti-angiogenesis, and immune stimulation and antioxidant properties. Furthermore, the scientific literature supports direct cancer cell cytotoxicity for Curcumin, Geinstein and NAC. The dietary supplement activities are supported by over 50,000 references in the scientific literature (PubMed.com) and over 150 clinical trials (clinicaltrials.gov), not including the human-cancer publications (23,000) and clinical trials (2,100) with zinc and the vitamins. From the literature there is evidence that some of the antiangiogenesis components that affect the majority if not all pathways of angiogenesis, such as Curcumin, Genistein and NAC, actually stimulate the in vivo production of natural antiangiogenic compounds that include Angiostatin, Endostatin and Thrombospotin 1. All of the components play a role in serving as either water or lipid soluble (able to cross the blood-brain barrier) antioxidants. Curcumin, Genistein, Resveratrol, Lentinen, NAC, zinc, selenium and the B and C vitamins all stimulate the immune system. Except for ALC and CoQ10, the other components show anti-inflammatory activity. ALC, Resveratrol along with the B and C vitamins are helpful in treating fatigue. The components that help protect the brain and promote nerve regeneration include ALA, CoQ10, Resveratrol, NAC, selenium, zinc and the B/C vitamins. In conclusion, effective prevention and treatment from and for diseases such as cancer, heart disease and immune deficiency will require multiple compounds. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 621. doi:1538-7445.AM2012-621
Penicillin Inhalation Therapy
Authors: Maurice S. Segal, Claire MacIntyre Ryder
Journal: New England Journal of Medicine (1947)

INHALATION therapy has attained amazing prominence since the ancient and empirical practice of inhaling medicated vapors. In a report on the use of oxygen, helium and oxygen mixtures and aerosolized sprays of various therapeutic agents for the maintenance of respiratory function, the use of penicillin aerosol was suggested.1 Barach and his associates2 , 3 first described the technic and the value of continued vaporization of various drugs with oxygen streams. Castex et al.,4 , 5 Krueger et al.6 , 7 and Mutch8 demonstrated that aerosolized substances penetrate to the outermost air sacs of the lungs and to the ends of the bronchial tree.The physiologic rationale . . .