tbuckley/cabot-search huggingface dataset:
Analgesic effect of sucrose
Authors: D. Barker, N. Rutter
Journal: BMJ (1995)

<h3>ABSTRACT</h3> Many immunoreceptors have cytoplasmic domains that are intrinsically disordered (i.e., have high configurational entropy), have multiple sites of post-translational modification (e.g., tyrosine phosphorylation), and participate in nonlinear signaling pathways (e.g., exhibiting switch-like behavior). Several hypotheses to explain the origin of these nonlinearities fall under the broad hypothesis that modification at one site changes the immunoreceptor's entropy, which in turn changes further modification dynamics. Here we use coarse-grain simulation to study three scenarios, all related to the chains that comprise the T Cell Receptor. We find that, first, if phosphorylation induces local changes in the flexibility of the TCR <i>ζ</i>-chain, this naturally leads to rate enhancements and cooperativity. Second, we find that TCR CD3<i>ϵ</i> can provide a switch by modulating its residence in the plasma membrane. By constraining our model to be consistent with the previous observation that both basic residues and phosphorylation control membrane residence, we find that there is only a moderate rate enhancement of 10% between first and subsequent phosphorylation events. And third, we find that volume constraints do not limit the number of ZAP70s that can bind the TCR, but that entropic penalties lead to a 200-fold decrease in binding rate by the seventh ZAP70, potentially explaining the observation that each TCR has around six ZAP70 molecules bound following receptor triggering. In all three scenarios, our results demonstrate that phenomena that change an immunoreceptor chain's entropy (stiffening, confinement to a membrane, and multiple simultaneous binding) can lead to nonlinearities (rate enhancement, switching, and negative cooperativity) in how the receptor participates in signaling. These polymer-entropy-driven nonlinearities may augment the nonlinearities that arise from, e.g., kinetic proofreading and cluster formation. They also suggest different design strategies for engineered receptors, e.g., whether or not to put signaling modules on one chain or multiple clustered chains. <h3>STATEMENT OF SIGNIFICANCE</h3> Many of the proteins involved in signal processing are both mechanically flexible and have multiple sites of interaction, leading to a combinatorial complexity making them challenging to study. One example is the T Cell Receptor, a key player in immunological decision making. It consists of 6 flexible chains with 20 interaction sites, and exhibits nonlinear responses to signal inputs, although the mechanisms are elusive. By using polymer physics to simulate the T Cell Receptor's chains, this work demonstrates that several of the nonlinear responses observed experimentally emerge naturally due to constraints on the chains that change their entropy. This work points to new avenues to modulate signaling proteins for therapeutics by modulating their mechanical flexibility and spatial extent.
Glucose-Insulin-Potassium Administration in Acute Myocardial Infarction
Authors: C E Rackley, R O Russell, W J Rogers, J A Mantle, H G McDaniel, S E Papapietro
Journal: Annual Review of Medicine (1982)

Physiologic studies spanning fifty years suggest that glucose and insulin can be beneficial to cardiac performance under experimental conditions. In 1926, Visscher & Muller observed the positive inotropic effects of insulin on the isolated beating turtle heart (I). Bayliss et al (2) described in 1928 the action of insulin and sugar on the heart-lung preparation. The marked abnormality in carbohydrate metabolism attending fatal diphtheritic myo­ carditis was reported to respond to dextrose and insulin administration in 1930 (3). In his pioneering studies on coronary blood flow and myocardial metabolism, Bing identified extraction and utilization of glucose, lactate, pyruvate, fatty acids, and ketone bodies (4, 5). In experiments on glucose uptake by the perfused rat heart, Morgan and associates (6) found that anoxia increased glucose uptake, and anoxia plus insulin further accelerated glucose uptake. Brachfe1d & Scheuer (7) ob­ served that myocardial ischemia accelerated glycolysis as evidenced by in­ creased glucose consumption and lactate production. Scheuer & Stezoski (8) demonstrated that elevations in cardiac glycogen increased glycolytic reserve and improved resistance to hypoxia mainly by enhancing glycolytic and anaerobic ATP production.
Language evolution: Patients were sectioned before ever they were consented.
Authors: Naresh D Gandhi, Zeyn W Green-Thompson
Journal: BMJ (2002)

Editor—We write in response to the article by Aronson1 to point out that the apparently contemporary form of passive transformation “she was consented” is pre-dated by the widely prevalent description of the detention of a patient under any section of the Mental Health Act 1983: “s/he was sectioned.”
NRF2 regulates serine biosynthesis in non–small cell lung cancer
Authors: Gina M DeNicola, Pei-Hsuan Chen, Edouard Mullarky, Jessica A Sudderth, Zeping Hu, David Wu, Hao Tang, Yang Xie, John M Asara, Kenneth E Huffman, Ignacio I Wistuba, John D Minna, Ralph J DeBerardinis, Lewis C Cantley
Journal: Nature Genetics (2015)
The Natural History of Congenital Isolated Pulmonic and Aortic Stenosis
Authors: J I E Hoffman
Journal: Annual Review of Medicine (1969)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
A Prospective Investigation of PTEN Loss and ERG Expression in Lethal Prostate Cancer
Authors: Thomas U Ahearn, Andreas Pettersson, Ericka M Ebot, Travis Gerke, Rebecca E Graff, Carlos L Morais, Jessica L Hicks, Kathryn M Wilson, Jennifer R Rider, Howard D Sesso, Michelangelo Fiorentino, Richard Flavin, Stephen Finn, Edward L Giovannucci, Massimo Loda, Meir J Stampfer, Angelo M De Marzo, Lorelei A Mucci, Tamara L Lotan
Journal: JNCI Journal of the National Cancer Institute (2015)

Background: PTEN is a tumor suppressor frequently deleted in prostate cancer that may be a useful prognostic biomarker.However, the association of PTEN loss with lethal disease has not been tested in a large, predominantly surgically treated cohort. Methods:In the Health Professionals Follow-up Study and Physicians' Health Study, we followed 1044 incident prostate cancer cases diagnosed between 1986 and 2009 for cancer-specific and all-cause mortality.A genetically validated PTEN immunohistochemistry (IHC) assay was performed on tissue microarrays (TMAs).TMPRSS2:ERG status was previously assessed in a subset of cases by a genetically validated IHC assay for ERG.Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and clinical or pathologic TNM stage were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association with lethal disease.All statistical tests were two-sided.Results: On average, men were followed 11.7 years, during which there were 81 lethal events.Sixteen percent of cases had complete PTEN loss in all TMA cores and 9% had heterogeneous PTEN loss across cores.After adjustment for clinicalpathologic variables, complete PTEN loss was associated with lethal progression (HR = 1.8, 95% CI = 1.2 to 2.9).The association of PTEN loss (complete or heterogeneous) with lethal progression was only among men with ERG-negative (HR = 3.1, 95% CI = 1.7 to 5.7) but not ERG-positive (HR = 1.2, 95% CI = 0.7 to 2.2) tumors. Conclusions:PTEN loss is independently associated with increased risk of lethal progression, particularly in the ERG fusionnegative subgroup.These validated and inexpensive IHC assays may be useful for risk stratification in prostate cancer.
Toxicology of Thiono-Sulfur Compounds
Authors: R A Neal, J Halpert
Journal: The Annual Review of Pharmacology and Toxicology (1982)

Thiono-sulfur-containing compounds cause a wide variety of toxic effects in mammals. These toxic effects of thiono-sulfur-containing compounds appear to be at least partially the result of their metabolism to reactive intermediates by the cytochrome P-450-containing monooxygenase enzyme systems. Covalent binding of (atomic) sulfur released in the cytochrome P-450 monooxygenase catalyzed metabolism of certain thiono-sulfur compounds appears to be responsible for the inhibition of monooxygenase activity and the loss of cytochrome P-450 seen on administration of these thiono-sulfur compounds in vivo or incubation with cytochrome P-450 monooxygenase enzymes in vitro. Liver necrosis and perhaps the induction of lung edema and neoplasia as well as other effects of thiono-sulfur-containing compounds are more likely the result of the covalent binding of the electrophilic S-oxides or S-dioxides or carbene derivatives of these S-oxides and S-dioxides to tissue macromolecules. The rationale for implicating metabolites of thiono-sulfur compounds other than atomic sulfur in these effects derives from the experiments with thioacetamide and the fact that atomic sulfur is highly reactive and appears to bind predominantly or exclusively to cytochrome P-450. It is difficult to rationalize why binding to and inhibition of cytochrome P-450 would lead to the production of, for examples, liver necrosis.
The future of U.K. dermatology translational research through the Oracle of Delphi
Authors: J. Thomson, E.A. O'Toole
Journal: British Journal of Dermatology (2015)

Journal Article The future of U.K. dermatology translational research through the Oracle of Delphi Get access J. Thomson, J. Thomson Department of Dermatology Royal London Hospital Barts Health NHS Trust London U.K Search for other works by this author on: Oxford Academic Google Scholar E.A. O'Toole E.A. O'Toole Department of Dermatology Royal London Hospital Barts Health NHS Trust London U.KCentre for Cell Biology and Cutaneous Research Blizard Institute Barts and the London School of Medicine and Dentistry London U.K https://orcid.org/0000-0002-4084-4836 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 173, Issue 5, 1 November 2015, Pages 1122–1123, https://doi.org/10.1111/bjd.14194 Published: 01 November 2015
Psychiatric Dilemmas—Surgery and the Mental Health Act (1983)
Authors: Suzi Porter, Chris Williams
Journal: Journal of the Royal Society of Medicine (1997)

Clinicians commonly face an ethical conundrum when the patient declines a treatment they believe to be necessary. The decision, whether to give or to withhold treatment, may also have legal repercussions. Two illustrative cases are presented. Although the Mental Health Act (1983) is concerned with treatment of mental disorder, treatments for physical disorders may be given in certain circumstances if the patient is deemed to lack the competence to understand the issues involved in the decision, and treatment is deemed to be in their best interests.
Noninvasive Fractional Flow Reserve Derived From Coronary CT Angiography
Authors: James K. Min, Charles A. Taylor, Stephan Achenbach, Bon Kwon Koo, Jonathon Leipsic, Bjarne L. Nørgaard, Nico J. Pijls, Bernard De Bruyne
Journal: JACC. Cardiovascular imaging (2015)
Utilization of E-Health Services Among U.S. Adults With Diabetes
Authors: Chiu-Fang Chou, Kai McKeever Bullard, Jinan B. Saaddine, Heather M. Devlin, John Crews, Giuseppina Imperatore, Judith McDivitt, Ann Albright
Journal: Diabetes Care (2015)

Electronic health (e-health) services have become increasingly important as a method to improve access to health care, including online renewal of prescription medications and making appointments. Healthy People 2020 includes objectives related to e-health to improve population health outcomes and to reduce health disparities, particularly to improve shared decision-making processes between patients and health care professionals (1). E-health services have been encouraged as part of the strategy to improve diabetes care and prevention (2,3). The adoption of these services among health care professionals has improved the quality and efficiency of care (4). However, e-health services may be underutilized among patients with diabetes. While research related to e-health services has been conducted in clinical and managed care settings (5), there are no national population estimates or trends for the utilization of e-health …
The <i>Drosophila</i> Neuromuscular Junction: A Model System for Studying Synaptic Development and Function
Authors: Haig Keshishian, Kendal Broadie, Akira Chiba, Michael Bate
Journal: Annual Review of Neuroscience (1996)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms
Authors: D Pietra, E Rumi, V V Ferretti, C A Di Buduo, C Milanesi, C Cavalloni, E Sant'Antonio, V Abbonante, F Moccia, I C Casetti, M Bellini, M C Renna, E Roncoroni, E Fugazza, C Astori, E Boveri, V Rosti, G Barosi, A Balduini, M Cazzola
Journal: Leukemia (2015)

A quarter of patients with essential thrombocythemia or primary myelofibrosis carry a driver mutation of CALR, the calreticulin gene. A 52-bp deletion (type 1) and a 5-bp insertion (type 2 mutation) are the most frequent variants. These indels might differentially impair the calcium binding activity of mutant calreticulin. We studied the relationship between mutation subtype and biological/clinical features of the disease. Thirty-two different types of CALR variants were identified in 311 patients. Based on their predicted effect on calreticulin C-terminal, mutations were classified as: (i) type 1-like (65%); (ii) type 2-like (32%); and (iii) other types (3%). Corresponding CALR mutants had significantly different estimated isoelectric points. Patients with type 1 mutation, but not those with type 2, showed abnormal cytosolic calcium signals in cultured megakaryocytes. Type 1-like mutations were mainly associated with a myelofibrosis phenotype and a significantly higher risk of myelofibrotic transformation in essential thrombocythemia. Type 2-like CALR mutations were preferentially associated with an essential thrombocythemia phenotype, low risk of thrombosis despite very-high platelet counts and indolent clinical course. Thus, mutation subtype contributes to determining clinical phenotype and outcomes in CALR-mutant myeloproliferative neoplasms. CALR variants that markedly impair the calcium binding activity of mutant calreticulin are mainly associated with a myelofibrosis phenotype.
Myelodysplastic syndromes: Contemporary review and how we treat
Authors: Naseema Gangat, Mrinal M. Patnaik, Ayalew Tefferi
Journal: American Journal of Hematology (2015)

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for leukemic transformation. Diagnosis is currently based on the presence of peripheral blood cytopenias, peripheral blood and bone marrow dysplasia/blasts, and clonal cytogenetic abnormalities. With the advent of next generation sequencing, recurrent somatic mutations in genes involved in epigenetic regulation ( TET2, ASXL1, EZH2, DNMT3A, IDH1/2 ), RNA splicing ( SF3B1, SRSF2, U2AF1, ZRSR2 ), DNA damage response ( TP53 ), transcriptional regulation ( RUNX1, BCOR, ETV6 ) and signal transduction ( CBL, NRAS, JAK2 ) have been identified in MDS. Conventional prognostication is by the revised International prognostic scoring system (IPSS‐R) with additional adverse prognosis conferred by presence of ASXL1 , EZH2 , or TP53 mutations. Currently Food and Drug administration (FDA)‐approved drugs for the treatment of MDS are not curative and their effect on survival is limited; they include the hypomethylating agents (HMA) azacitidine and decitabine and lenalidomide for MDS with isolated del(5q). To date, allogeneic stem cell transplant (ASCT) remains the only treatment option for possible cure. Given the current lack of drugs with convincing evidence of favorable effect on survival, we consider ASCT as the treatment of choice for most patients with symptomatic disease, and especially for those with high‐risk disease. For nontransplant candidates, participation in clinical trials is preferred over conventional therapy. There is not one right way of treatment for patients who are not candidates for either ASCT or clinical trials and palliative drugs of choice depend on the clinical problem, such as symptomatic anemia (ESAs, danazol, HMA), thrombocytopenia (HMA), or neutropenia (myeloid growth factors). Conversely, there is no controlled evidence to support the use of iron chelating agents in MDS. Going forward, we believe it is time to incorporate mutation information in clinically derived prognostic models in MDS and encourage development of novel drugs with disease‐modifying activity. Am. J. Hematol. 91:76–89, 2016. © 2015 Wiley Periodicals, Inc.
Retroperitoneal fibrosis following treatment for Hodgkin's disease.
Authors: N Chao, J Levine, S J Horning
Journal: Journal of Clinical Oncology (1987)

With improvement and refinement of therapy, the majority of Hodgkin's disease patients are alive and free of disease at 5 years. As these patients continue to be observed, a variety of late complications have been reported. We describe herein three patients who developed retroperitoneal fibrosis following definitive therapy for Hodgkin's disease. The incidence approaches that seen with methysergide.
Inactivation of the p53–KLF4–CEBPA Axis in Acute Myeloid Leukemia
Authors: Katja Seipel, Miguel Teixera Marques, Marie-Ange Bozzini, Christina Meinken, Beatrice U. Mueller, Thomas Pabst
Journal: Clinical Cancer Research (2015)

Abstract Purpose: In acute myeloid leukemia (AML), the transcription factors CEBPA and KLF4 as well as the universal tumor suppressor p53 are frequently deregulated. Here, we investigated the extent of dysregulation, the molecular interactions, and the mechanisms involved. Experimental Design: One hundred ten AML patient samples were analyzed for protein levels of CEBPA, KLF4, p53, and p53 modulators. Regulation of CEBPA gene expression by KLF4 and p53 or by chemical p53 activators was characterized in AML cell lines. Results: We found that CEBPA gene transcription can be directly activated by p53 and KLF4, suggesting a p53–KLF4–CEBPA axis. In AML patient cells, we observed a prominent loss of p53 function and concomitant reduction of KLF4 and CEBPA protein levels. Assessment of cellular p53 modulator proteins indicated that p53 inactivation in leukemic cells correlated with elevated levels of the nuclear export protein XPO1/CRM1 and increase of the p53 inhibitors MDM2 and CUL9/PARC in the cytoplasm. Finally, restoring p53 function following treatment with cytotoxic chemotherapy compounds and p53 restoring non-genotoxic agents induced CEBPA gene expression, myeloid differentiation, and cell-cycle arrest in AML cells. Conclusions: The p53–KLF4–CEBPA axis is deregulated in AML but can be functionally restored by conventional chemotherapy and novel p53 activating treatments. Clin Cancer Res; 22(3); 746–56. ©2015 AACR.
Pathogenesis of the Postphlebitic Syndrome
Authors: P Jacobs, F R C Path
Journal: Annual Review of Medicine (1983)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis
Authors: Martyn T. Smith, Kathryn Z. Guyton, Catherine F. Gibbons, Jason M. Fritz, Christopher J. Portier, Ivan Rusyn, David M. DeMarini, Jane C. Caldwell, Robert J. Kavlock, Paul F. Lambert, Stephen S. Hecht, John R. Bucher, Bernard W. Stewart, Robert A. Baan, Vincent J. Cogliano, Kurt Straif
Journal: Environmental Health Perspectives (2015)

A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens.
Young People's Experiences of Participation in Clinical Trials: Reasons for Taking Part
Authors: Malou Luchtenberg, Els Maeckelberghe, Louise Locock, Lesley Powell, A.A. Eduard Verhagen
Journal: The American Journal of Bioethics (2015)

Given the lack of knowledge about safety and efficacy of many treatments for children, pediatric clinical trials are important, but recruitment for pediatric research is difficult. Little is known about children's perspective on participating in trials. The purpose of this study was to understand the experiences and motivations of young people who took part in clinical trials. This is a qualitative interview study of 25 young people aged 10-23 who were invited to take part in clinical trials. Interviews were audio or video recorded and analyzed using framework analysis. Young peoples' motivations were both personal benefit and helping others. Both incentives appeared to be more complex than expected. We introduce the terms "network of exchange" and "intergenerational solidarity" to describe these motivations. To improve recruitment, professionals should be more open about research opportunities, provide better information, and give young people feedback after the trial has ended.
Identifying and defining complications of dermatologic surgery to be tracked in the American College of Mohs Surgery (ACMS) Registry
Authors: M. Laurin Council, Murad Alam, Hugh M. Gloster, Jeremy S. Bordeaux, Bryan T. Carroll, Justin J. Leitenberger, Oliver J. Wisco, Ian A. Maher
Journal: Journal of the American Academy of Dermatology (2015)
Specific Pharmacology of Calcium in Myocardium, Cardiac Pacemakers, and Vascular Smooth Muscle
Authors: A Fleckenstein
Journal: The Annual Review of Pharmacology and Toxicology (1977)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non–Clear Cell Renal Cell Carcinoma (ESPN): A Randomized Multicenter Phase 2 Trial
Authors: Nizar M. Tannir, Eric Jonasch, Laurence Albiges, Emre Altinmakas, Chaan S. Ng, Surena F. Matin, Xuemei Wang, Wei Qiao, Zita Dubauskas Lim, Pheroze Tamboli, Priya Rao, Kanishka Sircar, Jose A. Karam, David F. McDermott, Christopher G. Wood, Toni K. Choueiri
Journal: European Urology (2015)
PGE2, Kidney Disease, and Cardiovascular Risk
Authors: Rania Nasrallah, Ramzi Hassouneh, Richard L. Hébert
Journal: Journal of the American Society of Nephrology (2015)

An important measure of cardiovascular health is obtained by evaluating the global cardiovascular risk, which comprises a number of factors, including hypertension and type 2 diabetes, the leading causes of illness and death in the world, as well as the metabolic syndrome. Altered immunity, inflammation, and oxidative stress underlie many of the changes associated with cardiovascular disease, diabetes, and the metabolic syndrome, and recent efforts have begun to elucidate the contribution of PGE2 in these events. This review summarizes the role of PGE2 in kidney disease outcomes that accelerate cardiovascular disease, highlights the role of cyclooxygenase-2/microsomal PGE synthase 1/PGE2 signaling in hypertension and diabetes, and outlines the contribution of PGE2 to other aspects of the metabolic syndrome, particularly abdominal adiposity, dyslipidemia, and atherogenesis. A clearer understanding of the role of PGE2 could lead to new avenues to improve therapeutic options and disease management strategies.