tbuckley/cabot-search huggingface dataset:
Wit hdrawing artificial feeding from children with brain damage
Authors: P E Shannon
Journal: BMJ (1995)

These are not sufficient arguments for an editorial in the BMJ to recommend one class of ,3 blockade and should be accompanied by the proviso that measurements of blood pressure are only a sur- rogate: it is the prevention of cerebrovascular accidents and myocardial infarctions that matters.As a doctor treating patients with hypertension or ischaemic heart disease most days of the week, I tend to use low doses of the most j3I selective lipophilic agent, bisoprolol, for hypertension and the highest affinity non-selective agent, timolol, for ischaemic heart disease.These drugs have been selected on the basis of theoretical arguments and surrogate measures on which Cleophas and Kalmansohn and I agree.As a clinical pharmacologist unhappy at such evidence, I set up the East Anglian comparison of the two classes of drug in ischaemic heart disease that I mentioned in my editorial and included them in a long term randomised comparison of antihypertensive drugs that started in 1986.
Multiple Loci Modulate Opioid Therapy Response for Cancer Pain
Authors: Antonella Galvan, Frank Skorpen, Pål Klepstad, Anne Kari Knudsen, Torill Fladvad, Felicia S. Falvella, Alessandra Pigni, Cinzia Brunelli, Augusto Caraceni, Stein Kaasa, Tommaso A. Dragani
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Patients treated with opioid drugs for cancer pain experience different relief responses, raising the possibility that genetic factors play a role in opioid therapy outcome. In this study, we tested the hypothesis that genetic variations may control individual response to opioid drugs in cancer patients. Experimental Design: We tested 1 million single-nucleotide polymorphisms (SNP) in European cancer patients, selected in a first series, for extremely poor (pain relief ≤40%; n = 145) or good (pain relief ≥90%; n = 293) responses to opioid therapy using a DNA-pooling approach. Candidate SNPs identified by SNP-array were genotyped in individual samples constituting DNA pools as well as in a second series of 570 patients. Results: Association analysis in 1,008 cancer patients identified eight SNPs significantly associated with pain relief at a statistical threshold of P &amp;lt; 1.0 × 10−3, with rs12948783, upstream of the RHBDF2 gene, showing the best statistical association (P = 8.1 × 10−9). Functional annotation analysis of SNP-tagged genes suggested the involvement of genes acting on processes of the neurologic system. Conclusion: Our results indicate that the identified SNP panel can modulate the response of cancer patients to opioid therapy and may provide a new tool for personalized therapy of cancer pain. Clin Cancer Res; 17(13); 4581–7. ©2011 AACR.
First-in-Human Phase I Study of Pictilisib (GDC-0941), a Potent Pan–Class I Phosphatidylinositol-3-Kinase (PI3K) Inhibitor, in Patients with Advanced Solid Tumors
Authors: Debashis Sarker, Joo Ern Ang, Richard Baird, Rebecca Kristeleit, Krunal Shah, Victor Moreno, Paul A. Clarke, Florence I. Raynaud, Gallia Levy, Joseph A. Ware, Kathryn Mazina, Ray Lin, Jenny Wu, Jill Fredrickson, Jill M. Spoerke, Mark R. Lackner, Yibing Yan, Lori S. Friedman, Stan B. Kaye, Mika K. Derynck, Paul Workman, Johann S. de Bono
Journal: Clinical Cancer Research (2014)

Abstract Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). Patients and Methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. Results: Pictilisib was well tolerated. The most common toxicities were grade 1–2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed &amp;gt;90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC &amp;gt;20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and &amp;gt;25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF–mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Conclusion: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. Clin Cancer Res; 21(1); 77–86. ©2014 AACR.
The intraluminal pressure patterns in diverticulosis of the colon: Part I Resting patterns of pressure
Authors: N. S. Painter, S. C. Truelove
Journal: Gut (1964)

EDITORIAL SYNOPSIS It might be anticipated that patients with diverticulosis might have increased intraluminal colonic pressures but this could not be demonstrated under basal conditions (Part 1).With morphine there is an increased intraluminar pressure, particularly in the affected part of on November 22, 2023 by guest.
A FURTHER CONTRIBUTION ON THE STERILIZATION OF THE SKIN OF OPERATION AREAS
Authors: J. L. Stretton
Journal: BMJ (1910)

will do its work, and the other will, at any rate, do no harm.The number of ceses we give is, we think, sufficient to justify, at any rate, a provisional opinion on the subject, and we have no hesitation in using this reaction ourselves, and recommending it to the profession as a simple and harmless method of obtaining accurate information, which we have found to be of great value in many obscure cases.
Correlation between DNA Repair Capacity in Lymphocytes and Acute Side Effects to Skin during Radiotherapy in Nasopharyngeal Cancer Patients
Authors: Wei-dong Wang, Zheng-tang Chen, De-zhi Li, Zheng-huai Cao, Shi-liang Sun, Ping Pu, Xiao-pin Chen
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Repair of radiation-induced DNA damage plays a critical role for both the susceptibility of patients to side effects after radiotherapy and their subsequent cancer risk. The study objective was to evaluate whether DNA repair data determined in vitro are correlated with the occurrence of acute side effects during radiotherapy. Experimental Design: Nasopharyngeal cancer patients receiving radiation therapy were recruited in a prospective epidemiologic study. As an indicator for clinical radiosensitivity, adverse reactions of the skin were recorded. Cryopreserved lymphocytes from 100 study participants were γ-irradiated with 5 Gy in vitro and analyzed using the alkaline comet assay. Reproducibility of the assay was determined by repeated analysis (n = 22) of cells from a healthy donor. A coefficient of variation of 0.24 was calculated. Results: The various parameters determined to characterize the individual DNA repair capacity showed large differences between patients. Twenty-one patients were identified with considerably enhanced DNA damage induction, and 19 patients exhibited severely reduced DNA repair capacity after 15 and 30 minutes. Eight patients were considered as clinically radiosensitive, indicated by moist desquamation of the skin after a total radiation dose of 70 Gy. Conclusions: Using the alkaline comet assay as described here, nasopharyngeal cancer patients were identified showing abnormal cellular radiation effects, but this repair deficiency corresponded only at a very limited extent to the acute radiation sensitivity of the skin.
The cancer-testis antigens CT7 (MAGE-C1) and MAGE-A3/6 are commonly expressed in multiple myeloma and correlate with plasma-cell proliferation
Authors: Achim A. Jungbluth, Scott Ely, Maurizio DiLiberto, Ruben Niesvizky, Barbara Williamson, Denise Frosina, Yao-Tseng Chen, Nina Bhardwaj, Selina Chen-Kiang, Lloyd J. Old, Hearn Jay Cho
Journal: Blood (2005)
The Expression of Three Genes in Primary Non–Small Cell Lung Cancer Is Associated with Metastatic Spread to the Brain
Authors: Helena Grinberg-Rashi, Efrat Ofek, Marina Perelman, Jozef Skarda, Pnina Yaron, Marián Hajdúch, Jasmin Jacob-Hirsch, Ninette Amariglio, Meir Krupsky, David A. Simansky, Zvi Ram, Raphael Pfeffer, Ilana Galernter, David M. Steinberg, Issachar Ben-Dov, Gideon Rechavi, Shai Izraeli
Journal: Clinical Cancer Research (2009)

Brain metastases affect 25% of patients with non-small cell lung cancer (NSCLC). We hypothesized that the expression of genes in primary NSCLC tumors could predict brain metastasis and be used for identification of high-risk patients, who may benefit from prophylactic therapy.The expression of 12 genes was measured by real-time quantitative reverse transcriptase PCR in 142 frozen NSCLC tissue samples. Univariate and multivariate Cox regression analysis was used to analyze the correlation between gene expression and the occurrence of brain metastasis. Immunohistochemistry on independent samples was used to verify the findings.A score based on the expression levels of three genes, CDH2 (N-cadherin), KIFC1, and FALZ, was highly predictive of brain metastasis in early and advanced lung cancer. The probability of remaining brain metastasis-free at 2 years after diagnosis was 90.0+/-9.5% for patients with stage I/stage II tumors and low score compared with 62.7+/-12% for patients with high score (P<0.01). In patients with more advanced lung cancer, the brain metastasis-free survival at 24 months was 89% for patients with low score compared with only 37% in patients with high score (P<0.02). These results were confirmed by immunohistochemical detection of N-cadherin in independent cohort of primary NSCLC.The expression levels of three genes in primary NSCLC tumors may be used to identify patients at high risk for brain metastasis who may benefit from prophylactic therapy to the central nervous system.
Dicer-dependent microRNA pathway safeguards regulatory T cell function
Authors: Adrian Liston, Li-Fan Lu, Donal O'Carroll, Alexander Tarakhovsky, Alexander Y. Rudensky
Journal: The Journal of Experimental Medicine (2008)

Regulatory T (T reg) cells are indispensable for preventing autoimmunity. Incumbent to this role is the ability of T reg cells to exert their suppressor function under inflammatory conditions. We found that T reg cell–mediated tolerance is critically dependent on the Dicer-controlled microRNA (miRNA) pathway. Depletion of miRNA within the T reg cell lineage resulted in fatal autoimmunity indistinguishable from that in T reg cell–deficient mice. In disease-free mice lacking Dicer in all T cells or harboring both Dicer-deficient and -sufficient T reg cells, Dicer-deficient T reg cells were suppressive, albeit to a lesser degree, whereas their homeostatic potential was diminished as compared with their Dicer-sufficient counterparts. However, in diseased mice, Dicer-deficient T reg cells completely lost suppressor capacity. Thus, miRNA preserve the T reg cell functional program under inflammatory conditions.
Pulmonary hypertension, interstitial lung fibrosis, and lung iron deposition in thalassaemia major
Authors: E Zakynthinos, T Vassilakopoulos, P Kaltsas, E Malagari, Z Daniil, C Roussos, S G Zakynthinos
Journal: Thorax (2001)

Although restrictive lung disease is the predominant abnormality of pulmonary function in patients with thalassaemia major (TM), its aetiology and its association with pulmonary hypertension (PH) detected in some patients with TM remains unknown.We report a patient with TM, iron overload, frequent pulmonary infections, and progressive severe precapillary PH over the previous 5 years.A severe restrictive pattern and interstitial lung fibrosis were revealed by pulmonary function tests and high resolution computed tomography, respectively.This presentation suggests that interstitial fibrosis may complicate lung involvement in TM and can significantly contribute to the development of PH.
Induction of autoreactive B cells allows priming of autoreactive T cells.
Authors: R H Lin, M J Mamula, J A Hardin, C A Janeway
Journal: The Journal of Experimental Medicine (1991)

A novel mechanism for breaking T cell self tolerance is described. B cells induced to make autoantibody by immunization of mice with the non-self protein human cytochrome c can present the self protein mouse cytochrome c to autoreactive T cells in immunogenic form. This mechanism of breaking T cell self tolerance could account for the role of foreign antigens in breaking not only B cell but also T cell self tolerance, leading to sustained autoantibody production in the absence of the foreign antigen.
Loss of B-Cell Translocation Gene-2 in Estrogen Receptor–Positive Breast Carcinoma Is Associated with Tumor Grade and Overexpression of Cyclin D1 Protein
Authors: Hirofumi Kawakubo, Elena Brachtel, Tetsu Hayashida, Giminna Yeo, Joshua Kish, Alona Muzikansky, Paul D. Walden, Shyamala Maheswaran
Journal: Cancer Research (2006)

The B-cell translocation gene-2 (BTG2) is present in the nuclei of epithelial cells in many tissues, including the mammary gland where its expression is regulated during glandular proliferation and differentiation in pregnancy. In immortalized mammary epithelial cells and breast cancer cells, BTG2 protein localized predominantly to the nucleus and cytoplasm, respectively. The highly conserved domains (BTG boxes A, B, and C) were required for regulating localization, suppression of cyclin D1 and growth inhibitory function of BTG2. Expression analysis of BTG2 protein in human breast carcinoma (n = 148) revealed the loss of nuclear expression in 46% of tumors, whereas it was readily detectable in the nuclei of adjacent normal glands. Loss of nuclear BTG2 expression in estrogen receptor-alpha (ERalpha)-positive breast tumors correlated significantly with increased histologic grade and tumor size. Consistent with its ability to suppress cyclin D1 transcription, loss of nuclear BTG2 expression in ER-positive breast carcinomas showed a significant correlation with cyclin D1 protein overexpression, suggesting that loss of BTG2 may be a factor involved in deregulating cyclin D1 expression in human breast cancer.
Who benefits from medical interventions?
Authors: G D Smith, M Egger
Journal: BMJ (1994)

The pharmacokinetics, pharmacodynamics, and platelet binding of 7E3, an anti-glycoprotein IIb/IIIa (GPIIb/IIIa) monoclonal antibody, were studied in the rat in an attempt to develop a quantitative animal model of immune thrombocytopenia (ITP). 7E3, a murine IgG<sub>1</sub> antibody developed against human GPIIb/IIIa, demonstrated cross-reactivity with rat platelets by flow cytometry and via enzyme-linked immunosorbent assay. The apparent affinity (<i>K</i><sub>A</sub>) of 7E3-rat platelet binding was 1.2 ± 0.2 × 10<sup>7</sup> M<sup>−1</sup>, with 3.3 ± 0.3 × 10<sup>4</sup> binding sites per platelet. Following intravenous 7E3 administration (0.8, 4, and 8 mg/kg), plasma concentrations declined in a bi-exponential manner, with a terminal half-life of 61 ± 5 h and a steady-state volume of distribution of 62 ± 15 ml/kg. Clearance was dose-dependent, with values ranging from 0.64 ± 0.08 ml/h/kg (8 mg/kg) to 1.01 ± 0.08 ml/h/kg (0.8 mg/kg). 7E3 induced a reproducible, severe thrombocytopenia in rats and extended bleeding in a manner consistent with human ITP. Nadir platelet counts were 79 ± 33, 25 ± 6, and 17 ± 2 × 10<sup>6</sup>/ml, for 7E3 doses of 0.8, 4, and 8 mg/kg, respectively. Bleeding times after a 10-mm tail incision ranged from 5 ± 3 min in control animals to 15 ± 0 min (the maximum allowed time in this study) in animals receiving 8 mg/kg. Blood volumes lost during bleeding experiments ranged from 30 ± 24 μl (control) to 349 ± 358 μl (8 mg/kg). A reproducible, quantitative rat model of ITP has been created; this model is expected to facilitate the evaluation of new treatments for this disease.
Lung fibrosis induced by Thorotrast.
Authors: P De Vuyst, P Dumortier, P Ketelbant, J Flament-Durand, J Henderson, J C Yernault
Journal: Thorax (1990)

A 63 year old woman developed progressive shortness of breath, pulmonary hypertension, and respiratory failure and died from pulmonary fibrosis 45 years after thoracic fistulography with Thorotrast. Bouts of acute respiratory failure occurred with features of noncardiogenic pulmonary oedema. Lung tissue obtained by biopsy and at necropsy showed abundant radioactive particles of thorium dioxide in the lungs. The particles were congregated in the walls of blood vessels and in perivascular fibrous zones, consistent with a causal role of Thorotrast in the development of lung fibrosis. It is suggested that the fibrosis was due to the combined effects of alpha radiation on the interstitial perivascular zones and of recurrent pulmonary oedema due to endothelial damage.
Anaesthetists are younger than other doctors
Authors: C. McManus
Journal: BMJ (1997)

Editor—D J M Wright and A P Roberts are on difficult ground if they persist with their claim that some groups of doctors, particularly anaesthetists and those from the Indian subcontinent, die earlier than others.1 Kay-Tee Khaw has emphasised their classic error of using the unknown denominator.2 The authors say, in reply, that they “know no source” for “a valid denominator” and that in particular they “are not sure why Professor McManus regards …
Uncoupling protein 3 mediates H2O2 preconditioning-afforded cardioprotection through the inhibition of MPTP opening
Authors: Yixiong Chen, Jinlong Liu, Yanjun Zheng, Jinxi Wang, Zhihua Wang, Shanshan Gu, Jiliang Tan, Qing Jing, Huangtian Yang
Journal: Cardiovascular Research (2014)

Uncoupling protein 3 (UCP3), located in the mitochondrial inner membrane, is cardioprotective, but its mechanisms of preserving mitochondrial function during ischaemia/reperfusion (I/R) are not fully understood. This study investigated whether UCP3 mediates/mimics the cardioprotection of H2O2 preconditioning (H2O2PC) against I/R injury and the downstream pathway that mediates H2O2PC- and UCP3-afforded cardioprotection. H2O2PC at 20 µM for 5 min significantly improved post-ischaemic functional recovery and reduced lactate dehydrogenase (LDH) release and infarct size with concurrently up-regulated UCP3 expressions in perfused rat hearts subjected to global no-flow I/R. These protections were blocked by UCP3 knockdown with short hairpin RNA but mimicked by UCP3 overexpression. Consistently, H2O2PC-attenuated I/R-induced cytosolic and mitochondrial Ca2+ overload, Ca2+ transient suppression, mitochondrial reactive oxygen species burst, and loss of mitochondrial inner membrane potential were reversed by UCP3 knockdown but mimicked by UCP3 overexpression. Moreover, co-immunoprecipitation assay revealed an interaction of UCP3 with the mitochondrial permeability transition pore (mPTP) component, adenine nucleotide translocator (ANT), while the cardioprotection induced by H2O2PC- and UCP3 overexpression in mitochondria, cardiac function, and cell survival was abolished by atractyloside, a mPTP opener binding to ANT, and partially inhibited by a PI3K/Akt inhibitor wortmannin. Furthermore, H2O2PC up-regulated the phosphorylation of Akt, and glycogen synthase kinase 3β was blocked by UCP3 knockdown but mimicked by UCP3 overexpression. UCP3 mediates the cardioprotection of H2O2PC against I/R injury by preserving the mitochondrial function through inhibiting mPTP opening via the interaction with ANT and the PI3K/Akt pathway. Our findings reveal novel mechanisms of UCP3 in the cardioprotection.
Genetic Factors That Might Lead to Different Responses in Individuals Exposed to Perchlorate
Authors: Franco Scinicariello, H. Edward Murray, Lester Smith, Sharon Wilbur, Bruce A. Fowler
Journal: Environmental Health Perspectives (2005)

Perchlorate has been detected in groundwater in many parts of the United States, and recent detection in vegetable and dairy food products indicates that contamination by perchlorate is more widespread than previously thought. Perchlorate is a competitive inhibitor of the sodium iodide symporter, the thyroid cell-surface protein responsible for transporting iodide from the plasma into the thyroid. An estimated 4.3% of the U.S. population is subclinically hypothyroid, and 6.9% of pregnant women may have low iodine intake. Congenital hypothyroidism affects 1 in 3,000 to 1 in 4,000 infants, and 15% of these cases have been attributed to genetic defects. Our objective in this review is to identify genetic biomarkers that would help define subpopulations sensitive to environmental perchlorate exposure. We review the literature to identify genetic defects involved in the iodination process of the thyroid hormone synthesis, particularly defects in iodide transport from circulation into the thyroid cell, defects in iodide transport from the thyroid cell to the follicular lumen (Pendred syndrome), and defects of iodide organification. Furthermore, we summarize relevant studies of perchlorate in humans. Because of perchlorate inhibition of iodide uptake, it is biologically plausible that chronic ingestion of perchlorate through contaminated sources may cause some degree of iodine discharge in populations that are genetically susceptible to defects in the iodination process of the thyroid hormone synthesis, thus deteriorating their conditions. We conclude that future studies linking human disease and environmental perchlorate exposure should consider the genetic makeup of the participants, actual perchlorate exposure levels, and individual iodine intake/excretion levels.
Application of Molecular Ultrasound for Imaging Integrin Expression
Authors: Fabian Kiessling, Jessica Gaetjens, Moritz Palmowski
Journal: Theranostics (2011)

Stabilized microbubbles with a size between 1-5 µm are used as ultrasound contrast agents in the clinical routine. They have shown convincing results for the vascular characterization of tissues as well as in echocardiography. Due to their size, microbubbles strictly remain intravascular where they can be detected with high sensitivity and specificity. This qualifies them for intravascular molecular imaging. Many studies have been published reporting on the successful use of microbubbles conjugated to specific ligands for target identification in vivo. Among them, there are several promising examples on how to use molecular ultrasound for the imaging of integrin expression. This review provides an overview on the composition of ultrasound contrast agents that can be used for molecular imaging and their detection by ultrasound using destructive and non destructive methods. Furthermore, concrete examples are given on the use of molecular ultrasound to characterize integrin expression on vessels. These cover oncological applications where integrin targeted microbubbles were used to identify and characterize tumor angiogenesis and to assess tumor response to antiangiogenic drugs as well as to radiotherapy. In addition, increased accumulation of integrin targeted microbubbles was found during vascular reformation in ischemic tissues as well as in vulnerable atherosclerotic plaques. In summary, there is clear evidence from preclinical studies that integrin targeted ultrasound imaging is a valuable tool for the characterization of a broad spectrum of diseases. Thus, more efforts should be put into translating this promising technology into the clinics.