tbuckley/cabot-search huggingface dataset:
A Comprehensive, High-Resolution Map of a Gene’s Fitness Landscape
Authors: Elad Firnberg, Jason W. Labonte, Jeffrey J. Gray, Marc Ostermeier
Journal: Molecular Biology and Evolution (2014)

Mutations are central to evolution, providing the genetic variation upon which selection acts. A mutation's effect on the suitability of a gene to perform a particular function (gene fitness) can be positive, negative, or neutral. Knowledge of the distribution of fitness effects (DFE) of mutations is fundamental for understanding evolutionary dynamics, molecular-level genetic variation, complex genetic disease, the accumulation of deleterious mutations, and the molecular clock. We present comprehensive DFEs for point and codon mutants of the Escherichia coli TEM-1 β-lactamase gene and missense mutations in the TEM-1 protein. These DFEs provide insight into the inherent benefits of the genetic code's architecture, support for the hypothesis that mRNA stability dictates codon usage at the beginning of genes, an extensive framework for understanding protein mutational tolerance, and evidence that mutational effects on protein thermodynamic stability shape the DFE. Contrary to prevailing expectations, we find that deleterious effects of mutation primarily arise from a decrease in specific protein activity and not cellular protein levels.
Long-term efficacy and toxicity of ciclosporin A in combination with methotrexate in poor prognosis rheumatoid arthritis: Table 1
Authors: V Bejarano, P G Conaghan, S M Proudman, M H Buch, A K Brown, P Emery
Journal: Annals of the Rheumatic Diseases (2009)

Whereas the optimum therapy for early rheumatoid arthritis (RA) has not been established, there is still interest in combination therapy with existing disease-modifying antirheumatic drugs, due to the cost and toxicity of biological agents. We previously reported a 24-month open-label, randomised study comparing a methotrexate and ciclosporin A combination with sulfasalazine monotherapy in 82 early, poor-prognosis RA patients (n  =  40 combination, n  =  42 sulfasalazine).1 In the combination arm, first ciclosporin A then methotrexate doses were optimised. After 24 months all patients were treated according to standard clinical care. The aim of this report is to present long-term efficacy and toxicity data.

At 12 months there was no difference in …
A COMPARISON OF CUTANEOUS SENSITIZATION AND ANTIBODY FORMATION IN RABBITS IMMUNIZED BY INTRAVENOUS OR INTRADERMAL INJECTIONS OF INDIFFERENT OR HEMOLYTIC STREPTOCOCCI AND PNEUMOCOCCI
Authors: D. Murray Angevine
Journal: The Journal of Experimental Medicine (1941)

1. Rabbits that had received repeated intravenous injections of heat-killed indifferent streptococci with no resulting sensitization were subsequently made skin-sensitive to them by repeated intracutaneous injection of heat-killed vaccine. 2. Serum agglutinins and precipitins developed earlier in rabbits that had received repeated intravenous injections of killed streptococci and pneumococci than in those injected intracutaneously. However, when such injections were continued over a longer period, the antibodies in both groups of animals reached a similar level. 3. Species specific agglutinins reached about the same level after either intracutaneous or intravenous injections of heat-killed Type I(S) pneumococcus vaccine. Type specific agglutinins were present only in the intravenously injected animals after 33 days but were present in all the animals after 63 days although the titres were somewhat lower in those injected intradermally. Both groups developed precipitins which were only slightly less in the intradermally injected rabbits. 4. These experiments indicate that rabbits intravenously injected with heat-killed streptococci can be made highly skin-sensitive in the same manner as animals injected intracutaneously and that they are not immune or refractory to skin sensitization. When antigen was injected either intracutaneously or intravenously into rabbits for a fairly long time, the amount of circulating antibody in both groups was approximately equal.
Rapid Decrease in Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy: Implications for Scheduling of Anti-Angiogenic Drugs
Authors: Astrid A.M. Van der Veldt, Mark Lubberink, Idris Bahce, Maudy Walraven, Michiel P. de Boer, Henri N.J.M. Greuter, N. Harry Hendrikse, Jonas Eriksson, Albert D. Windhorst, Pieter E. Postmus, Henk M. Verheul, Erik H. Serné, Adriaan A. Lammertsma, Egbert F. Smit
Journal: Cancer Cell (2012)

Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in cancer patients. It is assumed that anti-angiogenic drugs, such as bevacizumab, transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy. To investigate this concept, a study was performed in non-small cell lung cancer (NSCLC) patients using positron emission tomography (PET) and radiolabeled docetaxel ([11C]docetaxel). In NSCLC, bevacizumab reduced both perfusion and net influx rate of [11C]docetaxel within 5 hr. These effects persisted after 4 days. The clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors. These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of anti-angiogenic drugs.
Molecular Genetics of Chronic Granulomatous Disease
Authors: M C Dinauer, S H Orkin
Journal: Annual Review of Immunology (1989)

Chronic granulomatous disease is an inherited disorder characterized by the failure of phagocytic cells to produce superoxide upon the ingestion of microorganisms due to a lesion in a membrane-associated NADPH-oxidase. The components of the oxidase have been incompletely characterized by standard biochemical approaches. A genetic strategy has recently led to the identification of the gene affected in the common X-linked form of CGD without reference to its protein product. The X-CGD gene, assigned to chromosome position Xp21.1, encodes a phagocyte-specific RNA transcript that is mutated in patients with X-CGD. Antisera directed toward the predicted protein product of the X-CGD gene recognize a 90 kD membrane glycoprotein, which corresponds to the larger subunit of the phagocyte b-cytochrome heterodimer. The recent genetic and biochemical findings provide an explanation for the consistent absence of the b-cytochrome spectrum in X-CGD, and establish this cytochrome as an essential component of the phagocyte oxidase. The primary amino acid sequence of both the 90 kD b-cytochrome subunit and the 22 kD subunit (cloned as the cDNA using a specific antisera) have no significant similarity to other proteins, including previously studied cytochromes. As both subunits of the b-cytochrome heterodimer are absent in X-CGD, despite a genetic deficiency of only the larger polypeptide, a close interaction between the two subunits may be important for b-cytochrome stability and function. Expression of the b-cytochrome large subunit mRNA is increased by interferon-gamma, an important macrophage activator. Partial or complete restoration of oxidase activity in some X-CGD patients treated with interferon-gamma suggests new therapeutic approaches in the management of this disorder. Molecular reagents prepared from the cloned X-CGD cDNA or gene may prove to be clinically useful in prenatal diagnosis and may provide a basis for somatic gene therapy in future.
DNA Microarrays in Clinical Oncology
Authors: Sridhar Ramaswamy, Todd R. Golub
Journal: Journal of Clinical Oncology (2002)

ABSTRACT: Aberrant gene expression is critical for tumor initiation and progression. However, we lack a comprehensive understanding of all genes that are aberrantly expressed in human cancer. Recently, DNA microarrays have been used to obtain global views of human cancer gene expression and to identify genetic markers that might be important for diagnosis and therapy. We review clinical applications of these novel tools, discuss some important recent studies, identify promising avenues of research in this emerging field of study, and discuss the likely impact that expression profiling will have on clinical oncology.
Ethics, Economics, and the Use of Primaquine to Reduce Falciparum Malaria Transmission in Asymptomatic Populations
Authors: Yoel Lubell, Lisa White, Sheila Varadan, Tom Drake, Shunmay Yeung, Phaik Yeong Cheah, Richard J. Maude, Arjen Dondorp, Nicholas P. J. Day, Nicholas J. White, Michael Parker
Journal: PLoS Medicine (2014)

Yoel Lubell and colleagues consider ethical and economic perspectives on mass drug administration of primaquine to limit transmission of P. falciparum malaria. Please see later in the article for the Editors' Summary
Nontuberculous mycobacteria in non‐HIV patients: epidemiology, treatment and response
Authors: M.T. Henry, L. Inamdar, D. O'Riordain, M. Schweiger, J.P. Watson
Journal: European Respiratory Journal (2004)

Recent international guidelines published in 1997 and 1999 have proposed diagnostic and treatment criteria for disease caused by nontuberculous mycobacteria (NTM). In this paper, the epidemiological data, diagnostic criteria, treatment regimens and outcomes from 117 HIV‐negative patients who had a positive culture for NTM between 1995–1999 are reviewed. The authors wished to identify factors associated with improved outcome in these patients. A total of 71 patients were believed to have a clinical disease caused by NTM, as defined by international criteria. A total of 72% patients were found to have had pulmonary disease. There was a rise in infections between 1995–1999, with a peak in infections in 1997. The most striking rise was in Mycobacterium avium intracellulare complex infections (1995: 33% infections; 1996: 36% infections; 1997: 41% infections; 1998: 61% infections; 1999: 57% infections). There was a link between deprivation and number of positive NTM isolates (34.4% isolates occurred in the areas of lowest Carstairs deprivation index versus 20.6% isolates from areas of least deprivation). There was a significant association between appropriate therapy, defined by American Thoracic Society and British Thoracic Society guidelines, and successful outcome (74%) in contrast to those who received inappropriate treatment prior to the publication of these guidelines. Nontuberculous mycobacteria infections remain a significant problem in non‐HIV patients. Adherence to published guidelines may improve patient outcomes.
Aromatase Inhibitors in the Treatment of Breast Cancer
Authors: Robert W. Brueggemeier, John C. Hackett, Edgar S. Diaz-Cruz
Journal: Endocrine Reviews (2005)

Estradiol, the most potent endogenous estrogen, is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is present in breast tissue, and intratumoral aromatase is the source of local estrogen production in breast cancer tissues. Inhibition of aromatase is an important approach for reducing growth-stimulatory effects of estrogens in estrogen-dependent breast cancer. Steroidal inhibitors that have been developed to date build upon the basic androstenedione nucleus and incorporate chemical substituents at varying positions on the steroid. Nonsteroidal aromatase inhibitors can be divided into three classes: aminoglutethimide-like molecules, imidazole/triazole derivatives, and flavonoid analogs. Mechanism-based aromatase inhibitors are steroidal inhibitors that mimic the substrate, are converted by the enzyme to a reactive intermediate, and result in the inactivation of aromatase. Both steroidal and nonsteroidal aromatase inhibitors have shown clinical efficacy in the treatment of breast cancer. The potent and selective third-generation aromatase inhibitors, anastrozole, letrozole, and exemestane, were introduced into the market as endocrine therapy in postmenopausal patients failing antiestrogen therapy alone or multiple hormonal therapies. These agents are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic estrogen-dependent breast cancer. Several clinical studies of aromatase inhibitors are currently focusing on the use of these agents in the adjuvant setting for the treatment of early breast cancer. Use of an aromatase inhibitor as initial therapy or after treatment with tamoxifen is now recommended as adjuvant hormonal therapy for a postmenopausal woman with hormone-dependent breast cancer.
National, regional, and worldwide estimates of stillbirth rates in 2015, with trends from 2000: a systematic analysis
Authors: Hannah Blencowe, Simon Cousens, Fiorella Bianchi Jassir, Lale Say, Doris Chou, Colin Mathers, Dan Hogan, Suhail Shiekh, Zeshan U Qureshi, Danzhen You, Joy E Lawn, Jun Zhu, Juan Liang, Yi Mu, Xiaohong Li, Anthony Costello, Tim Colbourn, Edward Fottrell, Audrey Prost, David Osrin, Carina King, Melissa Neuman, Neena Shah More, Kishwar Azad, Dharma Manandhar, Nirmala Nair, Prasanta Tripathy, Rajesh Kumar, Ariarathinam Newtonraj, Manmeet Kaur, Madhu Gupta, LK Dhaliwal, Neelam Aggarwal, None Venkateshashan, Deepak Chawla, Anju Hurja, Poonam Shivkumar, Manish Jain, Geeta Gathwala, Smiti Nanda, Shashi Gupta, Sangeeta Singal, Raj Kumar, Sujata Sharma, Manjit Mohi, Santish Minhas, Rajendra Prasad, Suresh Verma, Neena Raina, Aimable Musafi Li, Beena Varghese, Robert Pattison, Jane Hirst, Peter Waiswa, Daniel Kadobera, Sanni Kujala, Anna Bergstrom, Tambosi Phiri, Jennifer A Hall, Louise T Day, Stacy L Saha, Shafi Ul Alam, Anisur Rahman, Shams El-Arifeen, Sayed Rubayet, Ahmed Ali Hassan, Lucy Smith, Bradley N Manktelow, Elizabeth S Draper, Nanbert Zhong, Jans Langhoff-Roos, Vicki Flenady, Kärt Allvee, Mika Gissler, Nicholas Lack, Sonam Wangdi, Jan Cap, Zuzana Podmanicka, Katarzyna Szamotulska, Chantal Hukkelhoven, Joyce Dijs-Elsinga, Theopisti Kyprianou, Kari Klungsøyr, Flor de Maria Herandez, Ala Curteanu, Henrique Barros, Sofia Correia, Shorena Tsiklauri, Ellen Lundqvist, Tinga Fulbert Ilboudo, Abdouli Bah, Lamin Jawara, Jennifer Zeitlin, Jelena Isakova, Olav Poppe
Journal: The Lancet Global Health (2016)

Previous estimates have highlighted a large global burden of stillbirths, with an absence of reliable data from regions where most stillbirths occur. The Every Newborn Action Plan (ENAP) targets national stillbirth rates (SBRs) of 12 or fewer stillbirths per 1000 births by 2030. We estimate SBRs and numbers for 195 countries, including trends from 2000 to 2015.
Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial
Authors: Paul M Ridker, Eleanor Danielson, Francisco AH Fonseca, Jacques Genest, Antonio M Gotto, John JP Kastelein, Wolfgang Koenig, Peter Libby, Alberto J Lorenzatti, Jean G MacFadyen, Børge G Nordestgaard, James Shepherd, James T Willerson, Robert J Glynn
Journal: The Lancet (2009)
Quality of Life and Cognitive Function in Patients with Pituitary Insufficiency
Authors: Pia Burman, Jan Berend Deijen
Journal: Psychotherapy and Psychosomatics (1998)

This review is concerned with the psychosocial functioning and the quality of life in patients with pituitary insufficiency who are receiving conventional hormone replacement therapy. The possible negative effects of pituitary surgery, treatment with irradiation, and suboptimal replacement regimens with hormones other than growth hormone on mood, behaviour and cognitive functioning are discussed. The influence of growth hormone deficiency per se, and the outcome of growth hormone therapy in adult patients are addressed in detail. A possible mechanism for a direct effect of growth hormone on the brain is presented.
Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration
Authors: Önder Alpdogan, Vanessa M. Hubbard, Odette M. Smith, Neel Patel, Sydney Lu, Gabrielle L. Goldberg, Daniel H. Gray, Jared Feinman, Adam A. Kochman, Jeffrey M. Eng, David Suh, Stephanie J. Muriglan, Richard L. Boyd, Marcel R. M. van den Brink
Journal: Blood (2005)
EORTC 26083 phase I/II trial of dasatinib in combination with CCNU in patients with recurrent glioblastoma
Authors: E. Franceschi, R. Stupp, M. J. van den Bent, C. van Herpen, F. Laigle Donadey, T. Gorlia, M. Hegi, B. Lhermitte, L. C. Strauss, A. Allgeier, D. Lacombe, A. A. Brandes
Journal: Neuro-Oncology (2012)

The treatment of patients with recurrent glioblastoma remains a major oncologic problem, with median survival after progression of 7-9 months. To determine the maximum tolerated dose and dose-limiting toxicity (DLT), the combination of dasatinib and cyclonexyl-chloroethyl-nitrosourea (CCNU) was investigated in this setting. The study was designed as multicenter, randomized phase II trial, preceded by a lead-in safety phase. The safety component reported here, which also investigated pharmacokinetics and preliminary clinical activity, required expansion and is therefore considered a phase I part to establish a recommended dosing regimen of the combination of CCNU (90-110 mg/m(2)) and dasatinib (100-200 mg daily). Overall, 28 patients were screened, and 26 patients were enrolled. Five dose levels were explored. DLTs, mainly myelosuppression, occurred in 10 patients. Grade 3 or 4 neutropenia was recorded in 7 patients (26.9%) and thrombocytopenia in 11 patients (42.3%). No significant effect of CCNU coadministration on dasatinib pharmacokinetics was found. Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2-1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents.
Participation of Central Serotonergic Neurons in the Control of the Circulation of the Unanesthetized Rabbit
Authors: LINDON M. H. Wing, JOHN P. CHALMERS
Journal: Circulation Research (1974)

The role of central serotonergic neurons in circulatory control was studied in rabbits given intracisternal injections of 5, 6-dihydroxytryptamine (5, 6-DHT, 300 µg/kg) to cause degeneration of central serotonergic nerve terminals and depletion of central serotonin stores. In normal rabbits, intracisternally administered 5.6-DHT produced decreases in mean arterial blood pressure (11%, P &lt; 0.001) and heart rate (9%, P &lt; 0.001) that were maximum 1 week after injection. Central serotonin levels were reduced to less than 50% in the spinal cords of the rabbits treated with 5, 6-DHT compared with the levels in vehicle-injected controls. Pretreatment with intracisternally administered 5, 6-DHT completely prevented the sustained increases in mean arterial blood pressure and heart rate seen after sinoaortic denervation in control rabbits. In rabbits with neurogenic hypertension following sinoaortic denervation, treatment with intracisternally administered 5, 6-DHT caused a prompt, persistent reduction in mean arterial blood pressure and heart rate. Intracisternally administered 5, 6-DHT failed to interfere with the development or the maintenance of the hypertension that follows bilateral wrapping of the kidneys with cellophane. This study suggests that central serotonergic neurons participate in the baroreceptor reflex arc, possibly at the bulbospinal level. The integrity of these neurons appears to be necessary for the development of sustained neurogenic hypertension following sinoaortic denervation but to be of minimum importance in experimental renal hypertension in the rabbit.
Changes in cardiac transcapillary exchange with metabolic coronary vasodilation in the intact dog.
Authors: D Cousineau, C P Rose, D Lamoureux, C A Goresky
Journal: Circulation Research (1983)

The effects of metabolic coronary vasodilation on transcapillary exchange in the heart were examined in anesthetized dogs by use of the multiple indicator dilution technique. Animals were studied under basal conditions and during coronary sinus pacing. To obviate adrenal medullary stimulation, catheters were placed in coronary artery and coronary sinus in a closed chest preparation. Plasma catecholamine concentrations were determined to provide an index of the level of sympathetic tone. Labeled albumin and sucrose were injected into the coronary artery, and outflow dilution curves were secured. Analysis of these, with a model incorporating throughput and returning components, and heterogeneity of capillary transit times, provided parameters reflecting flow, permeability-surface product for sucrose, and capillary heterogeneity. Coronary sinus pacing increased both heart rate and plasma norepinephrine values; in response, myocardial oxygen consumption increased, metabolic vasodilation occurred, and coronary flow increased. The capillary permeability-surface product for sucrose increased with the flow but tended to plateau at higher values, showing a saturation phenomenon. Capillary heterogeneity, present in control animals with low sympathetic tone, was grossly decreased during cardiac metabolic activation. The Crone-Renkin approximation formula for the permeability-surface product yielded values that were too low at low flows and values approaching those from the complete model at high flows. The findings indicate an integrated pattern of circulatory response to cardiac metabolic activation characterized by decreased resistance, increased flow, increased permeability-surface product, and reduced heterogeneity. The last two effects amplify the capacity of increased flow to deliver substrates to heart muscle cells.
Effect of a Leukemia Virus on Erythropoiesis&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: I Brodsky, S B Kahn
Journal: JNCI Journal of the National Cancer Institute (1969)

A prominent manifestation of the prelymphoid leukemic phase of Rauscher virus infection is anemia. Mice given injections of high closes of virus showed a progressive anemia and died within 6–8 weeks after infection, whereas those infected with lower doses eventually stabilized their hemoglobin concentration and packed cell volume, but at lower than normal levels. The anemia initially was due to a combination of relative bone marrow failure and hemolysis, as indicated by a decreased red blood cell (RBC) survival. However, within 3–6 weeks the bone marrow recovered, as indicated by a return to normal of the59Fe reappearance and the development of reticulocytosis, but the hemolysis persisted. The anemia and severity of bone marrow suppression were potentiated by splenectomy. Rauscher virus infection caused increased osmotic fragility, autohemolysis, and adenosine triphosphate (ATP) instability of the RBC. The increased autohemolysis and ATP instability were prevented by the addition of glucose to the RBC suspensions. Young and old cells were equally susceptible to hemolysis. The data indicate that the shortened RBC survival was probably due to a direct effect of the virus on the RBC membrane. The altered crythropoiesis was a non-neoplastic manifestation of Rauscher virus infection.
Revealing the diagnosis of androgen insensitivity syndrome in adulthood
Authors: Jennifer Conn, Lynn Gillam, Gerard S Conway
Journal: BMJ (2005)

<h3>Abstract</h3> Ganglioside-monosialic acid (GM1) gangliosidosis, a rare autosomal recessive disorder, is frequently caused by deleterious single nucleotide variants (SNVs) in <i>GLB1</i> gene. These variants result in reduced β-galactosidase (β-gal) activity, leading to neurodegeneration associated with premature death. Currently, no effective therapy for GM1 gangliosidosis is available. Three ongoing clinical trials aim to deliver a functional copy of the <i>GLB1</i> gene to stop disease progression. Here, we show that 41% of <i>GLB1</i> pathogenic SNVs might be cured by adenine base editors (ABEs). Our results demonstrate that ABE efficiently corrects the pathogenic allele in patient-derived fibroblasts, restoring a therapeutic level of β-gal activity. Unbiased off-target DNA analysis did not detect off-target editing activity in treated patient’s cells except a bystander edit without consequences on β-gal activity. Altogether our results suggest that gene editing is an alternative strategy to cure GM1 gangliosidosis, by correcting the root cause of disease and avoiding repetitive adeno-associated virus injections.