tbuckley/cabot-search huggingface dataset:
HIV Protease Inhibitors Block Akt Signaling and Radiosensitize Tumor Cells Both <i>In vitro</i> and <i>In vivo</i>
Authors: Anjali K. Gupta, George J. Cerniglia, Rosemarie Mick, W. Gillies McKenna, Ruth J. Muschel
Journal: Cancer Research (2005)

Abstract In tumor cells with mutations in epidermal growth factor receptor (SQ20B), H-Ras (T24), or K-Ras (MIAPACA2 and A549), the inhibition of Akt phosphorylation increases radiation sensitivity in clonogenic assays, suggesting that Akt is a potential molecular target when combined with therapeutic radiation. Insulin resistance and diabetes are recognized side effects of HIV protease inhibitors (HPIs), suggesting that these agents may inhibit Akt signaling. Because activation of the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is common in human cancers, we hypothesized that HPIs can inhibit Akt activity resulting in increased tumor cell sensitivity to ionizing radiation–induced cell death. Five first-generation HPIs were subsequently tested and three of the five (amprenavir, nelfinavir, and saquinavir but not ritonavir or indinavir) inhibited Akt phosphorylation at Ser473 at serum concentrations routinely achieved in HIV patients. In both tumor cell colony formation assays and tumor regrowth delay experiments, combinations of drug and radiation exerted synergistic effects compared with either modality alone. In addition, in vivo, doses of amprenavir or nelfinavir comparable with the therapeutic levels achieved in HIV patients were sufficient to down-regulate phosphorylation of Akt in SQ20B and T24 xenografts. Finally, overexpression of active PI3K in cells without activation of Akt resulted in radiation resistance that could be inhibited with HPIs. Because there is abundant safety data on HPIs accumulated in thousands of HIV patients over the last 5 years, these agents are excellent candidates to be tested as radiation sensitizers in clinical trials.
Advances in cell kinetics.
Authors: D A Rew, G D Wilson
Journal: BMJ (1991)

conventional unfractionated heparin given twice or three times a day.These three agents have not yet been compared directly in a single study.What is needed is the most effective drug with the simplest method of administration and control and the smallest risk of adverse effects.In these days of cost effectiveness the modest cost of prophylactic treatment must be measured against the considerable risk of thromboembolic complications of hip surgery if no prophylaxis is given, with the cost of the increased length of stay in hospital, morbidity, and mortality.How long anticoagulants should be continued postoperatively has not been determined; most series have recorded late presentations of thromboembolic complications after dis- charge from hospital.What is inescapable is the need for prophylaxis.
“HER Majesty's a Pretty Nice Girl but She Changes From Day to Day”
Authors: Pierre Bohanes, Fotios Loupakis, Melissa J. Labonte, Takeru Wakatsuki, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2011)

We thank Opdam et al 1 for their letter regarding our study 2 on dextromethorphan as a phenotyping test for endoxifen exposure.The preliminary results of their study confirm our conclusion that dextromethorphan is a promising probe drug for the prediction of endoxifen exposure in patients with breast cancer receiving tamoxifen treatment.After ingestion of carbon isotope-labeled dextromethrophan and measurement of two breath samples, 1 they showed a correlation (r ϭ 0.52) between endoxifen trough levels and delta-over-baseline 13 CO 2 / 12 CO 2 ratio.We share the opinion that phenotyping has potential advantages over genotyping in individualized treatment with many anticancer drugs, including tamoxifen, because it incorporates genetic and environmental factors, which may affect the activity of metabolizing enzymes. 3 As mentioned by Opdam et al, 1 we observed several patients in our study with large discrepancies between CYP2D6 genotype and phenotype (ie, endoxifen steady-state concentration before dosing).Opdam et al suggested that this discrepancy might be caused by increased levels of cytokines, as seen in patients with metastatic disease.If so, patients with metastatic disease would have had a lowered phase I metabolism, leading to lower concentrations of endoxifen than patients treated with tamoxifen in the adjuvant setting.However, as shown in Figure 1, in our study there was no difference in endoxifen (log) steady-state concentration before dosing between these two groups of patients (adjuvant therapy: mean, 1.17 nmol/L v metastatic disease: mean, 1.26 nmol/L; P ϭ .38),making this hypothesis less likely.Although the value of phenotyping in treatment with tamoxifen becomes increasingly apparent, the challenge remains to develop a phenotyping method that is accurate and feasible to implement in daily clinical practice.Although the dextromethorphan breath test has the advantage of rapid measurement, a single sample taken within 1 hour could make the test sensitive to variations among patients in absorption and first-pass metabolism in the GI tract. 4 This could partly explain the lower correlation between this dextromethorphan breath test and endoxifen pharmacokinetics in comparison with our study results.Future studies will, it is hoped, reveal whether a dextromethorphan blood test, breath test, or possibly urinary test 5 is the most optimal test for tailored treatment with tamoxifen.In the meantime, we are refining and simplifying the methods of our test.Currently, we are developing a population pharmacokinetic model from the available data, which should ultimately lead to a limited sampling strategy, requiring only one sample (or a few samples) to predict endoxifen exposure.
Ultrasound integrated backscatter tissue characterization of remote myocardial infarction in human subjects
Authors: Zvi Vered, G.A. Mohr, Benico Barzilai, Carl J. Gessler, Samuel A. Wickline, Keith A. Wear, Thomas A. Shoup, Alan N. Weiss, Burton E. Sobel, James G. Miller, Julio E. Perez
Journal: Journal of the American College of Cardiology (1989)
Benzodiazepine withdrawal: an unfinished story.
Authors: H Ashton
Journal: BMJ (1984)

It can be a very frightening place until my mind becomes adjusted to its colours, noises, and pictures once more."Someone once wrote 'Tranquillisers are the anaesthetics of the emotions'; this is true.When used properly, they are a 'must' in medicine, but used over the long term they poison the body and destroy the mind.One day doctors will realise the extent of tranquilliser withdrawal syndrome but until then it is going to be a hard battle, but in the end, we sincerely hope, worth it."
Which species are in your feces?
Authors: Colby Zaph
Journal: Journal of Clinical Investigation (2010)

Nosocomial infections (i.e., infections acquired as a result of treatment in a hospital or health care unit) result in approximately 100,000 deaths and cost more than 25 billion dollars per year in the US alone. These infections are caused primarily by bacteria and affect mainly immunosuppressed patients. However, not all patients acquire infections, and the events leading up to infection are unclear. In this issue of the JCI, Ubeda et al. report how acquisition of one such infection, vancomycin-resistant Enterococcus faecium (VRE), is linked to a shift in the microbial flora following antibiotic treatment. This study highlights the potential for high-throughput sequencing of intestinal microbiota as a means to identify high-risk populations.
Binding of YY1 and Oct1 to a novel element that downregulates expression of IL-5 in human T cells
Authors: Viatcheslav A. Mordvinov, Gretchen T.F. Schwenger, Régis Fournier, Monica L. De Boer, Susanne E. Peroni, Anish D. Singh, Stéphane Karlen, John W. Holland, Colin J. Sanderson
Journal: Journal of Allergy and Clinical Immunology (1999)
The Latest Victim of Tobacco Trade Sanctions
Authors: Prakit Vateesatokit
Journal: JAMA (1990)

When American colleagues visit me here in Bangkok, beyond the famous golden palaces and ancient temples, they see a modern city with its share of tall buildings, well-heeled businessmen, fancy boutiques, exclusive restaurants, and world-class hotels. This is deceptive. Thailand is an impoverished and underdeveloped agricultural country. Here construction workers labor 7 days a week earning $3.50 a day. Only 6 years of education are required. Thirty percent of Thai people who become ill enough to require medical attention never receive it. There are no motor vehicle emissions control testing or drunk driving laws so the air on a sunny day is a foul leaden black and accidents are the country's number one cause of death. Thai people have been smoking cigarettes for some time, and the number of tobacco-associated illnesses is accelerating. In 1987, the estimated incidence and prevalence rates of coronary heart disease were 10 to 49 and
Treatment of gastric ulceration with carbenoxolone sodium: clinical and radiological evaluation.
Authors: L. Horwich, R. Galloway
Journal: BMJ (1965)

Treatment was started with the trial tablets within five days of the barium-meal examination demonstrating the ulcer crater.The patient took the trial tablets for two weeks, the first week's dosage being two tablets thrice daily, the second week's one tablet three times daily.Patient's were asked to take a normal diet, alkalis were not routinely prescribed, and no instructions were given about smoking and drinking.After two weeks' treatment the patient attended for a restricted barium-meal examination.If the ulcer showed signs of healing, as demonstrated by reduction in size, the trial tablets were continued, but if the ulcer was unchanged in size, or larger, the patient was given known carbenoxolone tablets 50 mg.three times daily until the ulcer was radiologically healed.Patients attended at two-weekly intervals for restricted barium-meal examinations until the ulcer crater was healed.
Surviving Burns Does Early Wound Closure Help?
Authors: Carlotta M. Rinke
Journal: JAMA (1983)

Does early grafting of full-thickness (FT) burn wounds improve survival among  severely burned? Wolfe and colleagues present, in this issue ofThe Journal(p 763), an elegant mathematical model as evidence that early grafting is associated with improved survival. They have collected information on 12,000 patients entered from 11 national burn treatment centers, reporting burned body surface area, treatment, and outcome for each case.  Like mathematical architects, Wolfe and associates generate two bodies of data and then correlate them. Phase 1 explicates computation of  standard mortality rate (SMR). From their burn registry data bank,  authors formulate a multiple logistic regression model to predict mortality in burn patients by assigning probabilities to several variables—burn wound size, age, sex, presence of perineal burn, and year of treatment. The sum of these probabilities in patients treated at one burn center yields the expected number of deaths. The SMR compares
Role of the CS1 adhesion motif of fibronectin in T cell adhesion to synovial membrane and peripheral lymph node endothelium.
Authors: A C van Dinther-Janssen, S T Pals, R J Scheper, C J Meijer
Journal: Annals of the Rheumatic Diseases (1993)

OBJECTIVES--It has previously been shown that the very late antigen-4/vascular cell adhesion molecule-1 (VLA-4/VCAM-1) pathway functions as a receptor/ligand interaction system mediating the recruitment of activated lymphocytes to inflamed synovium of patients with rheumatoid arthritis. This study was performed to determine whether VLA-4 also affects lymphocyte adhesion to inflamed synovium through interaction with the alternatively spliced CS1 domain of fibronectin. METHODS--The effect of the synthetic peptide CS1 on lymphocyte binding to human synovial and peripheral lymph node high endothelial venules (HEVs) was measured in an in vitro frozen section assay. RESULTS--In the presence of the CS1 peptide or antibody to fibronectin, significant inhibition of binding was observed (54 and 51% respectively). Blocking with antibody to VCAM-1 yielded inhibition of binding to 46% of the control value. Maximum inhibition of binding was obtained with a combination of antibody to VCAM-1 and CS1 (65%) and with antibody to VLA-4 alpha (68%). Blocking the classical fibronectin receptor with antibody to VLA-5 alpha gave a slightly lower inhibition at 42%. In normal peripheral lymph nodes, the synthetic peptide CS1 and antibodies to fibronectin and VLA-5 also partially inhibited T cell binding to HEVs (45, 47, and 52% respectively). CONCLUSION--These results show that fibronectin mediates lymphocyte-HEV interactions not only through its classical VLA-5 receptor, but also through its CS1 adhesion motif in inflamed synovium and peripheral lymph nodes.
Micropatterning: Site‐Specific Differentiation of Neural Stem Cell Regulated by Micropatterned Multicomponent Interfaces (Adv. Healthcare Mater. 2/2014)
Authors: Ying Wang, Zhen Xu, Lance C. Kam, Peng Shi
Journal: Advanced Healthcare Materials (2014)

A multicomponent interface with patterns of multiple bio-active proteins is created and used by Peng Shi and team to study the cooperative involvement of cell-matrix interaction and cell–cell signaling in regulating stem cell functions. On page 214, local presentation of notch signaling ligand or cell adhesion molecule effectively modulate the balance between cell–cell and cell–matrix interaction in neural stem cells (NSCs), and significantly change the differentiation toward neuronal or glial lineages.
DNA adducts in peripheral blood lymphocytes from aluminum production plant workers determined by 32P-postlabeling and enzyme-linked immunosorbent assay.
Authors: B Schoket, D H Phillips, M C Poirier, I Vincze
Journal: Environmental Health Perspectives (1993)

32P-Postlabeling analysis and enzyme-linked immunosorbent assay (ELISA) have been used to detect DNA adducts in peripheral blood lymphocytes from primary aluminum production plant workers who were exposed occupationally to a mixture of polycyclic aromatic hydrocarbons (PAHs). Preliminary results reported here are from a comparative study being performed in two aluminum plants. The levels of aromatic DNA adducts have been determined by the 32P-postlabeling assay in samples collected on two occasions, 1 year apart. PAH-DNA adduct levels have also been determined by competitive ELISA in the second set of DNA samples. The results show the necessity of follow-up biomonitoring studies to detect possible alterations in biological effect induced by changing exposures. The comparison of the results obtained by 32P-postlabeling and ELISA may lead to a better understanding of the power and weaknesses of the two methods applied in these studies.
The New Age of Molecular Diagnostics for Microbial Agents
Authors: Richard Whitley
Journal: New England Journal of Medicine (2008)

How, in this era of molecular diagnostic tests, can we best determine whether there is a causal relationship between the presence of a genetic signature of an infectious agent and disease? In recent years, molecular techniques have been applied successfully in the identification of infectious agents such as Borna virus, Kaposi's sarcoma–associated herpesvirus (human herpesvirus 8), West Nile virus, and the severe acute respiratory syndrome (SARS) coronavirus.1 Currently, the majority of surveillance and discovery efforts use methods based on sequences of known agents — namely, competitive polymerase chain reaction (PCR) and microarrays. Such efforts fail, however, when the agents in . . .
Characterization of 1 alpha-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis.
Authors: J S Adams, M A Gacad
Journal: The Journal of Experimental Medicine (1985)

We investigated the 1 alpha-hydroxylation of vitamin D3 sterols by cultured pulmonary alveolar macrophages (PAM) from patients with sarcoidosis with or without clinically abnormal calcium homeostasis. Like the naturally occurring renal 1 alpha-hydroxylase, the PAM 1 alpha-hydroxylation reaction exhibited a high affinity for 25-hydroxyvitamin D3 (25-OH-D3) and a preference for substrates containing a 25-hydroxyl group in the side chain of the sterol. Unlike the renal enzyme, the PAM 1 alpha-hydroxylating mechanism was not accompanied by 24-hydroxylating activity, even after preincubation with 75 nM 1,25-dihydroxyvitamin D3 [1,25-(OH)2-D3] or exposure to high concentrations of substrate (500 nM 25-OH-D3). The PAM 25-OH-D3-1 alpha-hydroxylation reaction was stimulated by gamma interferon and inhibited by exposure to the glucocorticoid dexamethasone. The characteristics of the PAM hydroxylation process in vitro appear to reflect the efficiency of the extrarenal production of 1,25-(OH)2-D3 and the therapeutic efficacy of glucocorticoids in patients with sarcoidosis and disordered calcium metabolism.
The Ankle–Brachial Index for Peripheral Artery Disease Screening and Cardiovascular Disease Prediction Among Asymptomatic Adults: A Systematic Evidence Review for the U.S. Preventive Services Task Force
Authors: Jennifer S. Lin, Carin M. Olson, Eric S. Johnson, Evelyn P. Whitlock
Journal: Annals of Internal Medicine (2013)

Background: Screening for peripheral artery disease (PAD) may reduce morbidity and mortality. Purpose: To review the evidence on the ability of the ankle–brachial index (ABI) to predict cardiovascular disease (CVD) morbidity and mortality independent of Framingham Risk Score (FRS) factors in asymptomatic adults and on the benefits and harms of treating screen-detected adults with PAD. Data Sources: MEDLINE and the Cochrane Central Register of Controlled Trials (1996 to September 2012), clinical trial registries, reference lists, and experts. Study Selection: English-language, population-based prognostic studies evaluating the ABI in addition to the FRS and treatment trials or studies of treatment harms in screen-detected adults with PAD. Data Extraction: Dual quality assessment and abstraction of relevant study details. Data Synthesis: One large meta-analysis (n = 43 919) showed that the ABI could reclassify 10-year risk for coronary artery disease (CAD), but it did not report measures of appropriate reclassification (the net reclassification improvement [NRI]). Four heterogeneous risk prediction studies showed that the magnitude of the NRI was probably small when the ABI was added to the FRS to predict CAD or CVD events. Of 2 treatment trials meeting inclusion criteria, 1 large trial (n = 3350) showed that low-dose aspirin did not prevent CVD events in persons with a screen-detected low ABI but may have increased the risk for major bleeding events. Limitations: Most prognostic studies did not allow for calculation of a bias-corrected NRI. Evidence on treatment benefits and harms was limited to aspirin and was scant. Conclusion: Adding the ABI to the FRS probably has limited value for predicting CAD or CVD. Treatment benefits for asymptomatic individuals with screen-detected PAD are not established. Primary Funding Source: Agency for Healthcare Research and Quality.
Under half of doctors know that antibiotic prophylaxis should be life long
Authors: A A Palejwala, L Y C Hong, D King
Journal: BMJ (1996)

EDITOR,—Despite several articles in the medical press over the past two years, including communications to all doctors from the chief medical officer, we were dismayed to note that several elderly patients admitted to our wards who had had splenectomies years previously had not been given advice on prophylaxis against infection or relevant immunisation. Deodhar et al found that in 184 patients who had had a splenectomy during a 12 year period 58% had not received advice or …
The consequences of parasitic infection for the behavior of the mammalian host.
Authors: P J Donovick, R G Burright
Journal: Environmental Health Perspectives (1987)

As many as one billion people may be infected with animal parasites. The behavioral consequences of such infection, or of illness in general, is poorly understood. This issue is discussed using as an example infection of mice with Toxocara canis, the common roundworm of dogs. Current literature suggests that two-thirds of all dogs have been infected with this parasite, and 7% of all humans have antibodies to T. canis. T. canis completes its life cycle in dogs, but when it infects aberrant mammalian hosts (e.g., humans or mice), larvae migrate through various organ systems including the brain, where they can remain viable and mobile for extended periods of time. Changes in motor activity, sensory reactivity, and learning of mice infected with T. canis have been observed. The pattern of behavioral changes is influenced by the infection regime and exposure to other toxicants such as lead.
Abstract 5278: Superoxide mediated selective tyrosine nitration of protein phosphatase 2A-B56δ stabilizes Bcl-2 phosphorylation and its anti-apoptotic activity
Authors: Ivan C. C. Low, Thomas Loh, David Virshup, Shazib Pervaiz
Journal: Cancer Research (2014)

Abstract Our work over the years has provided strong evidence that an increase in intracellular superoxide anion provides cancer cells with a survival advantage and promotes tumor chemoresistance. The mechanisms underlying superoxide-mediated pro-survival signaling are poorly understood. Here we report that an increase in intracellular superoxide stabilizes the anti-apoptotic activity of Bcl-2 by mechanisms that involve sustained phosphorylation of Bcl-2 at serine 70. Of note, this effect on Bcl-2 S70 phosphorylation is a function of redox-dependent inactivation of Protein Phosphatase 2A (PP2A), which is targeted to Bcl-2 via its B56 subunit; superoxide induces the release of PP2A-AC catalytic core from Bcl-2-bound B56δ, resulting in sustained phosphorylation of Bcl-2 at S70. Dissociation of the PP2A heterotrimer results from the selective nitration (by peroxynitrite derived from the reaction of superoxide with NO) of a conserved tyrosine residue, which we identify as Y289 of B56δ (B56 δY289). Inhibition of B56δY289 nitration blocked the pro-survival effects of superoxide. Furthermore, we provide evidence for clinical relevance of these findings using primary tissue derived from human lymphoma biopsies. Taken together, these data provide evidence for a novel mechanism in which an increase in intracellular superoxide regulates PP2A function via specific B56 subunit tyrosine nitration, and that PP2A-B56 nitration may be a general mechanism for redox-regulated cellular signaling. Citation Format: Ivan C. C. Low, Thomas Loh, David Virshup, Shazib Pervaiz. Superoxide mediated selective tyrosine nitration of protein phosphatase 2A-B56δ stabilizes Bcl-2 phosphorylation and its anti-apoptotic activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5278. doi:10.1158/1538-7445.AM2014-5278