tbuckley/cabot-search huggingface dataset:
Obesity and Breast Cancer: Progress to Understanding the Relationship
Authors: Kristy A. Brown, Evan R. Simpson
Journal: Cancer Research (2009)

Epidemiological evidence supports a correlation between obesity and breast cancer in women. AMP-activated protein kinase (AMPK) is recognized to be a master regulator of energy homeostasis. One of its actions is to phosphorylate and inhibit the actions of cAMP-responsive element binding protein (CREB)-regulated transcription coactivator 2 (CRTC2). In postmenopausal women, the CREB-dependent regulation of aromatase is a crucial determinant of breast tumor formation through local production of estrogens. We report here that the regulation of aromatase expression in the breast by AMPK and CRTC2, in response to the altered adipokine milieu associated with obesity, provides an important link between obesity and breast cancer risk.
Serum Elastase Inhibitor Levels in the Ehlers-Danlos Syndrome
Authors: P. K. Carter, R. L. Walford
Journal: Annals of the Rheumatic Diseases (1963)

Prior studies from this laboratory of the elastin- elastase-serum elastase inhibitor system disclosed, among other findings, a consistent 2-to 3-fold increase in the inhibitor in late pregnancy (Schneider, Walford, and Dignam, 1960).Other disease states, including arteriosclerosis, lupus erythematosus, dermatomyositis, severe liver disease, and nephrotic syndrome, showed mild but inconstant changes in inhibitor levels (Walford and Schneider, 1959).The regular elevation of elastase inhibitor in late preg- nancy is of interest in view of the increased incidence of dissecting aortic aneurysm, which is primarily an elastic tissue disease, in pregnancy (Mandel, Evans, and Walford, 1954).Elastase inhibitor levels might thus reflect changes in the status of elastin or elastase in the body.The investigation reported here was stimulated by the observation (Hall, Keech, Reed, Saxl, Tun- bridge, and Wood, 1955) that the level of elastase inhibitor in a patient with Ehlers-Danlos syndrome was 50 to 100 times higher than normal.Such an elevation would be not only of theoretical and diagnostic importance for this disease state, but might afford a source wherefrom pure inhibitor could be isolated by appropriate techniques.Accordingly we have studied a group of seven patients with classical Ehlers-Danlos syndrome or certain features thereof.In addition to measurement of inhibition of elastolysis by elastase inhibitor, inhibition of casein proteolysis by the enzyme was determined. Clinical DataCase 1, a 7-year-old girl, had shown extreme elasticity of skin, marked hypermobility of all joints, and marked bruisability since the age of 6 months or earlier.Many cutaneous scars.No subcutaneous masses.No record of relatives (adopted child).Skin biopsy showed mild acanthosis and increase in dermal elastic tissue.
THE ROÔLE OF CARBOHYDRATES IN BIOLOGICAL OXIDATIONS AND REDUCTIONS. EXPERIMENTS WITH PNEUMOCOCCUS
Authors: René Dubos
Journal: The Journal of Experimental Medicine (1929)

The reducing power of plain broth cultures of Pneumococcus is largely dependent upon the presence in the medium at the time when the reduction test is performed of certain metabolites. The washed cells of Pneumococcus are able to reduce the various indicators of oxidation-reduction potentials in the presence of glucose. The relative velocity of reduction of these indicators is determined by the number of cells used in the test, the concentration of the dyes, and their position in the oxidation reduction scale. Oxidized thiol compounds (glutathione, cystine, oxidized thioglycollic acid) are likewise rapidly reduced by glucose in the presence of washed cells of Pneumococcus. This Pneumococcus-glucose system is able to form peroxide under aerobic conditions. Those substances which form peroxide in the presence of Pneumococcus cells are also the ones which Cole found to be active in changing hemoglobin into methemoglobin under the same conditions. The power of washed cells of Pneumococcus to reduce methylene blue in the presence of glucose is dependent on at least 2 constituents: one which can be readily removed from the cell by washing. Sugar-free meat infusion will function instead of it. The other is inactivated more slowly by the process of washing and is destroyed by 10 minutes heating at 55 degrees C. The interreaction between the glucose and the cell seems to result in a fundamental reaction in which one molecule of glucose becomes able to reduce rapidly one molecule of methylene blue. The existence of side-reactions often obscures this ratio. The significance of these observations is considered in relation to the nature and mechanism of the "activation" of metabolites, the preparation of synthetic media, the phenomena of growth, and the meaning of the expression "reducing power of a bacterial culture."
Central Photorefractlve Keratectomy for Myopia
Authors: Marguerite B. McDonald, James C. Liu, Thomas J. Byrd, Mohamed Abdelmegeed, Helia Angotti Andrade, Stephen D. Klyce, Ray Varnell, Charles R. Munnerlyn, Terrance N. Clapham, Herbert E. Kaufman
Journal: Ophthalmology (1991)
Maximizing Return on Socioeconomic Investment in Phase II Proof-of-Concept Trials
Authors: Cong Chen, Robert A. Beckman
Journal: Clinical Cancer Research (2014)

Phase II proof-of-concept (POC) trials play a key role in oncology drug development, determining which therapeutic hypotheses will undergo definitive phase III testing according to predefined Go-No Go (GNG) criteria. The number of possible POC hypotheses likely far exceeds available public or private resources. We propose a design strategy for maximizing return on socioeconomic investment in phase II trials that obtains the greatest knowledge with the minimum patient exposure. We compare efficiency using the benefit-cost ratio, defined to be the risk-adjusted number of truly active drugs correctly identified for phase III development divided by the risk-adjusted total sample size in phase II and III development, for different POC trial sizes, powering schemes, and associated GNG criteria. It is most cost-effective to conduct small POC trials and set the corresponding GNG bars high, so that more POC trials can be conducted under socioeconomic constraints. If δ is the minimum treatment effect size of clinical interest in phase II, the study design with the highest benefit-cost ratio has approximately 5% type I error rate and approximately 20% type II error rate (80% power) for detecting an effect size of approximately 1.5δ. A Go decision to phase III is made when the observed effect size is close to δ. With the phenomenal expansion of our knowledge in molecular biology leading to an unprecedented number of new oncology drug targets, conducting more small POC trials and setting high GNG bars maximize the return on socioeconomic investment in phase II POC trials.
The Use of Targeted Mouse Models for Preclinical Testing of Novel Cancer Therapeutics
Authors: Kenneth P. Olive, David A. Tuveson
Journal: Clinical Cancer Research (2006)

Abstract The use of genetically engineered cancer-prone mice as relevant surrogates for patients during the development of pertinent clinical applications is an unproven expectation that awaits direct demonstration. Despite the generally disappointing findings using tumor xenografts and certain early transgenic cancer models to predict therapeutic efficacy in patients, the dramatic progress of mouse models in recent years engenders optimism that the newest generation of mouse models will provide a higher standard of predictive utility in the process of drug development.
ESTRADIOL REDUCES INCORPORATION OF RADIOACTIVE SULFATE INTO CARTILAGE AND AORTAS OF RATS
Authors: Robert E. Priest, R. Marlene Koplitz, Earl P. Benditt
Journal: The Journal of Experimental Medicine (1960)

Estradiol in large amounts reduces the incorporation of radioactive sulfate into cartilage and aortas of rats. This reduction becomes apparent within 3 days for cartilage and 3 weeks for aorta. The effect is not mediated through suppression of testosterone secretion and the hypophysis is not necessary for the effect to be demonstrated. The thoracic segment of aortas from normal rats incorporates more sulfate than does the abdominal segment and this difference is reduced following the administration of estradiol.
A chromosomal region 7p11.2 transcript map: Its development and application to the study of EGFR amplicons in glioblastoma
Authors: Greg D. Eley, Jill L. Reiter, Ajay Pandita, Soyeon Park, Robert B. Jenkins, Nita J. Maihle, C. David James
Journal: Neuro-Oncology (2002)

Cumulative information available about the organization of amplified chromosomal regions in human tumors suggests that the amplification repeat units, or amplicons, can be of a simple or complex nature. For the former, amplified regions generally retain their native chromosomal configuration and involve a single amplification target sequence. For complex amplicons, amplified DNAs usually undergo substantial reorganization relative to the normal chromosomal regions from which they evolve, and the regions subject to amplification may contain multiple target sequences. Previous efforts to characterize the 7p11.2 epidermal growth factor receptor (EGFR) amplicon in glioblastoma have relied primarily on the use of markers positioned by linkage analysis and/or radiation hybrid mapping, both of which are known to have the potential for being inaccurate when attempting to order loci over relatively short (<1 Mb) chromosomal regions. Due to the limited resolution of genetic maps that have been established through the use of these approaches, we have constructed a 2-Mb bacterial and P1-derived artificial chromosome (BAC-PAC) contig for the EGFR region and have applied markers positioned on its associated physical map to the analysis of 7p11.2 amplifications in a series of glioblastomas. Our data indicate that EGFR is the sole amplification target within the mapped region, although there are several additional 7p11.2 genes that can be coamplified and overexpressed with EGFR. Furthermore, these results are consistent with EGFR amplicons retaining the same organization as the native chromosome 7p11.2 region from which they are derived.
Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response.
Authors: L J Ayash, J E Wright, O Tretyakov, R Gonin, A Elias, C Wheeler, J P Eder, A Rosowsky, K Antman, E Frei
Journal: Journal of Clinical Oncology (1992)

Cyclophosphamide, which forms the nucleus for virtually all preparative regimens for autologous bone marrow transplantation (ABMT), is an alkylating agent of which cytotoxicity is not directly caused by the parent compound but by its biologically active metabolites. Its nonmyelosuppressive toxicity in the ABMT setting is cardiomyopathy. We attempted to determine any correlation between plasma levels of total cyclophosphamide and the subsequent development of cardiac dysfunction.Analyses of plasma levels and the derivation of plasma concentration-time curves (area under the curve [AUC]) were performed in 19 women with metastatic breast carcinoma, who received a continuous 96-hour infusion of cyclophosphamide, thiotepa, and carboplatin (CTCb) with ABMT. The assay for total cyclophosphamide measures the inactive parent compound; reliable assays of the active metabolites of cyclophosphamide are not yet available.Six of 19 women developed moderate, but transient, congestive heart failure (CHF) as assessed by clinical and radiologic criteria. These patients had a significantly lower AUC of total cyclophosphamide (median, 2,888 mumol/L/h) than patients who did not develop CHF (median, 6,121 mumol/L/h) (P less than .002). Median duration of tumor response in these patients was also more durable; at least 22 months in patients with lower AUCs versus a median of 5.25 months in those with higher AUCs (P = .008).These pharmacokinetic data support the premise that enhancement of cyclophosphamide activation may lead to both greater tumor cytotoxicity and increased but reversible end-organ toxicity. Early analysis of pharmacokinetic data may allow modulation of cyclophosphamide administration in an attempt to enhance therapeutic efficacy.
Pulmonary Artery Upstroke Time in Pulmonary Stenosis
Authors: F. Camerini, C. Chiemprapha, M. Michaelsson
Journal: Cardiovascular Research (1967)

Journal Article Pulmonary Artery Upstroke Time in Pulmonary Stenosis Get access F. Camerini, F. Camerini * From the Department of Paediatrics, University Hospital, Uppsala, Sweden * Present address: Ospedale Maggiore, Trieste. Search for other works by this author on: Oxford Academic PubMed Google Scholar C. Chiemprapha, C. Chiemprapha † From the Department of Paediatrics, University Hospital, Uppsala, Sweden * Present address: Ospedale Maggiore, Trieste. Search for other works by this author on: Oxford Academic PubMed Google Scholar M. Michaëlsson M. Michaëlsson From the Department of Paediatrics, University Hospital, Uppsala, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 1, Issue 2, April 1967, Pages 184–188, https://doi.org/10.1093/cvr/1.2.184 Published: 01 April 1967 Article history Received: 22 August 1966 Published: 01 April 1967
Peroxiredoxin 1 Controls Prostate Cancer Growth through Toll-Like Receptor 4–Dependent Regulation of Tumor Vasculature
Authors: Jonah R. Riddell, Wiam Bshara, Michael T. Moser, Joseph A. Spernyak, Barbara A. Foster, Sandra O. Gollnick
Journal: Cancer Research (2011)

In recent years a number of studies have implicated chronic inflammation in prostate carcinogenesis. However, mitigating factors of inflammation in the prostate are virtually unknown. Toll-like receptor 4 (TLR4) activity is associated with inflammation and is correlated with progression risk in prostate cancer (CaP). TLR4 ligands include bacterial cell wall proteins, danger signaling proteins, and intracellular proteins such as heat shock proteins and peroxiredoxin 1 (Prx1). Here we show that Prx1 is overexpressed in human CaP specimens and that it regulates prostate tumor growth through TLR4-dependent regulation of prostate tumor vasculature. Inhibiting Prx1 expression in prostate tumor cells reduced tumor vascular formation and function. Furthermore, Prx1 inhibition reduced levels of angiogenic proteins such as VEGF within the tumor microenvironment. Lastly, Prx1-stimulated endothelial cell proliferation, migration, and differentiation in a TLR4- and VEGF-dependent manner. Taken together, these results implicate Prx1 as a tumor-derived inducer of inflammation, providing a mechanistic link between inflammation and TLR4 in prostate carcinogenesis. Our findings implicate Prx1 as a novel therapeutic target for CaP.
Human rRNA Gene Clusters Are Recombinational Hotspots in Cancer
Authors: Dawn M. Stults, Michael W. Killen, Erica P. Williamson, Jon S. Hourigan, H. David Vargas, Susanne M. Arnold, Jeffrey A. Moscow, Andrew J. Pierce
Journal: Cancer Research (2009)

The gene that produces the precursor RNA transcript to the three largest structural rRNA molecules (rDNA) is present in multiple copies and organized into gene clusters. The 10 human rDNA clusters represent <0.5% of the diploid human genome but are critically important for cellular viability. Individual genes within rDNA clusters possess very high levels of sequence identity with respect to each other and are present in high local concentration, making them ideal substrates for genomic rearrangement driven by dysregulated homologous recombination. We recently developed a sensitive physical assay capable of detecting recombination-mediated genomic restructuring in the rDNA by monitoring changes in lengths of the individual clusters. To prove that this dysregulated recombination is a potential driving force of genomic instability in human cancer, we assayed the rDNA for structural rearrangements in prospectively recruited adult patients with either lung or colorectal cancer, and pediatric patients with leukemia. We find that over half of the adult solid tumors show detectable rDNA rearrangements relative to either surrounding nontumor tissue or normal peripheral blood. In contrast, we find a greatly reduced frequency of rDNA alterations in pediatric leukemia. This finding makes rDNA restructuring one of the most common chromosomal alterations in adult solid tumors, illustrates the dynamic plasticity of the human genome, and may prove to have either prognostic or predictive value in disease progression.
Cancer Risk among Children Born after Assisted Conception
Authors: Carrie L. Williams, Kathryn J. Bunch, Charles A. Stiller, Michael F.G. Murphy, Beverley J. Botting, W. Hamish Wallace, Melanie Davies, Alastair G. Sutcliffe
Journal: New England Journal of Medicine (2013)

Accurate population-based data are needed on the incidence of cancer in children born after assisted conception.
Sickle cell anemia as a syndrome: A review of diagnostic features
Authors: Titus H. J. Huisman
Journal: American Journal of Hematology (1979)

Abstract Sickle cell (SS) disease is a complex of various genetic conditions. In some, homozygosity for the β S gene may be present alone or in combination with the heterozygous or homozygous α‐thalassemia‐2 condition. Such combinations might ameliorate the clinical and hematological condition of the patient. The same may be true for the high levels of Hb F and F‐cells observed in many Hb S homozygotes. However, the chemical heterogeneity of Hb F appears not to be related to the clinical status of the Hb S homozygote. Combinations of a Hb S heterozygosity with a heterozygosity for a Hb D‐type of variant, for either one of two types of β‐thalassemia, two types of δβ‐thalassemia, and five types of HPFH are discussed, and data are compared with those obtained for Hb S homozygotes. The use of advanced laboratory procedures and family studies is often necessary for an accurate diagnosis.
A gallon of sweat to make a pint of blood
Authors: Margaret A. Goodell
Journal: The Journal of Experimental Medicine (2014)

In this issue, Canault et al. report for the first time a point mutation in the RAS guanyl-releasing protein 2 (RASGRP2) gene that results in a severe bleeding defect in humans.The study of inherited platelet disorders has shed light on the molecular mechanisms of physiologic thrombosis and hemostasis and led to the development of several therapies to prevent pathologic clotting.The RASGRP2 gene encodes the guanine nucleotide exchange factor (GEF) calcium-and DAG-regulated GEF 1 (CalDAG-GEFI), which is crucial for activation of Rap1, a small GTPase that regulates integrin-mediated activation and granule secretion in platelets and other cells.The function of CalDAG-GEFI has been studied in vitro and in mice-mice lacking CalDAG-GEFI have impaired thrombi formation by platelets as well as a defect in neutrophil function-but to date, no pathological RASGRP2 mutations have been identified in humans.Now, Canault et al. have investigated the cause of an inherited platelet disorder in three siblings from a consanguineous marriage that are all affected by a severe bleeding disorder.Whole genome sequencing was used to identify a mutation (cG742T) in the RASGRP2 gene.This mutation reduces Rac1 GTP binding (secondary to decreased Rap1 activation), impairing the ability of platelets to aggregate in response to a variety of stimuli, to form thrombi under flow, and to undergo normal spreading.Heterozygotes also have platelets that fail to adhere normally under flow and have a spreading defect (see figure) but they do not suffer from bleeding because their platelets aggregate normally.The functional deficiency induced by the mutation was confined to platelets and megakaryocytes with no obvious alteration in leukocytes.This is probably because other GEFs in leukocytes are able to activate Rap1 or, as the authors speculate, that CalDAG-GEFI with this point mutation is still able to function in leukocytes.In fact, even in platelets, the aggregation defects can be overcome by high doses of agonists in vitro, so while CalDAG-GEFI may be the preferred way for platelets to activate Rap1, it is clearly not the only way.Mutations in CalDAG-GEFI had previously been reported to be responsible for leukocyte adhesion deficiency type III, which was later found to be caused by the absence of kindlin-3.To demonstrate that the mutation in CalDAG-GEFI is truly responsible for the phenotype, the authors showed that cells transfected with wild-type RASGRP2 can activate Rap1, whereas those transfected with the mutation found in the affected siblings cannot.Looking at these data from a different perspective, the presence of a single normal allele is sufficient to prevent bleeding, but not platelet adhesion to collagen.This suggests that partial inhibition of CalDAG-GEFI might be a novel and potentially safe therapeutic target to prevent thrombosis without causing bleeding-a holy grail of vascular medicine and surgery.
Iranian national thalassaemia screening programme
Authors: Ashraf Samavat, Bernadette Modell
Journal: BMJ (2004)

Iran's experience shows that genetic screening can be successful in lower resource countries and also provides some lessons for high resource nations Summary pointsIran's thalassaemia programme was implemented in 1997 Linkage to premarital testing within an effective primary care infrastructure has ensured good take up Feedback from the community through systematic evaluation led to national acceptance of prenatal diagnosis Details of the programme's performance are on bmj.com
Na+/K+-ATPase 2-isoform preferentially modulates Ca2+ transients and sarcoplasmic reticulum Ca2+ release in cardiac myocytes
Authors: S. Despa, J. B. Lingrel, D. M. Bers
Journal: Cardiovascular Research (2012)

AimsNa+/K+-ATPase (NKA) is essential in regulating [Na+]i, and thus cardiac myocyte Ca2+ and contractility via Na+/Ca2+ exchange. Different NKA-α subunit isoforms are present in the heart and may differ functionally, depending on specific membrane localization. In smooth muscle and astrocytes, NKA-α2 is located at the junctions with the endo(sarco)plasmic reticulum, where they could regulate local [Na+], and indirectly junctional cleft [Ca2+]. Whether this model holds for cardiac myocytes is unclear.
Phase I Study of Streptozocin- and Carmustine-Sequenced Administration in Patients With Advanced Cancer
Authors: K. C. Micetich, B. Futscher, D. Koch, R. I. Fisher, L. C. Erickson
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article Phase I Study of Streptozocin- and Carmustine-Sequenced Administration in Patients With Advanced Cancer Get access K. C. Micetich, K. C. Micetich * Section of Hematology-Oncology, Stritch School of Medicine, Loyola University of ChicagoMaywood, III *Correspondence to : Kenneth C. Micetich, M.D., Stritch School of Medicine, Loyola University of Chicago, 2160 South First Ave., Maywood, IL 60153. Search for other works by this author on: Oxford Academic PubMed Google Scholar B. Futscher, B. Futscher Section of Hematology-Oncology, Stritch School of Medicine, Loyola University of ChicagoMaywood, III Search for other works by this author on: Oxford Academic PubMed Google Scholar D. Koch, D. Koch Section of Hematology-Oncology, Stritch School of Medicine, Loyola University of ChicagoMaywood, III Search for other works by this author on: Oxford Academic PubMed Google Scholar R. I. Fisher, R. I. Fisher Section of Hematology-Oncology, Stritch School of Medicine, Loyola University of ChicagoMaywood, III Search for other works by this author on: Oxford Academic PubMed Google Scholar L. C. Erickson L. C. Erickson Section of Hematology-Oncology, Stritch School of Medicine, Loyola University of ChicagoMaywood, III Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 4, 19 February 1992, Pages 256–261, https://doi.org/10.1093/jnci/84.4.256 Published: 19 February 1992 Article history Received: 31 May 1991 Revision received: 11 November 1991 Accepted: 27 November 1991 Published: 19 February 1992