tbuckley/cabot-search huggingface dataset:
Potential Therapeutic Effect of Glycogen Synthase Kinase 3β Inhibition against Human Glioblastoma
Authors: Katsuyoshi Miyashita, Kazuyuki Kawakami, Mitsutoshi Nakada, Wei Mai, Abbas Shakoori, Hironori Fujisawa, Yutaka Hayashi, Jun-ichiro Hamada, Toshinari Minamoto
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Glioblastoma represents the malignant brain tumor that is most refractory to treatment and in which the identification of molecular target(s) is urgently required. We investigated the expression, activity, and putative pathologic role of glycogen synthase kinase 3β (GSK3β), an emerging therapeutic target for neurodegenerative diseases, in human glioblastoma. Experimental Design: The active fraction of GSK3β that is phosphorylated at the tyrosine 216 residue (pGSK3βY216) was identified in glioblastoma cell lines. GSK3β activity for phosphorylating its substrate was detected in these cells by nonradioisotopic in vitro kinase assay. Results: Higher expression levels of GSK3β and pGSK3βY216 were frequently detected in glioblastomas compared with nonneoplastic brain tissues. Inhibition of GSK3β activity by escalating doses of a small-molecule inhibitor (AR-A014418) or inhibition of its expression by RNA interference induced the apoptosis and attenuated the survival and proliferation of glioblastoma cells in vitro. Inhibition of GSK3β was associated with increased expression of p53 and p21 in glioblastoma cells with wild-type p53 and with decreased Rb phosphorylation and expression of cyclin-dependent kinase 6 in all glioblastoma cell lines. Administration of AR-A014418 at a low dose significantly sensitized glioblastoma cells to temozolomide and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea, chemotherapeutic agents used in the clinical setting, as well as to ionizing radiation. Conclusion: These results indicate that GSK3β exerts a pathologic role by promoting the survival and proliferation of glioblastoma cells and by protecting them from apoptosis via the inactivation of p53- and/or Rb-mediated pathways. Consequently, we propose that GSK3β provides a potential therapeutic target in glioblastoma.
Response to: ‘Overweight/obesity and vitamin D deficiency contribute to the global burden of low back pain’ by Professor Grant
Authors: Damian Hoy, Lyn March, Peter Brooks, Fiona Blyth, Anthony Woolf, Emma Smith, Rachelle Buchbinder
Journal: Annals of the Rheumatic Diseases (2014)

We would like to thank William B Grant for his letter1 on our paper ‘The global burden of low back pain: estimates from the Global Burden of Disease 2010 study’.2 We fully agree with Professor …
Cardiac Troponin Assays
Authors: Stacy E.F. Melanson, Milenko J. Tanasijevic, Petr Jarolim
Journal: Circulation (2007)

M any clinical chemistry laborato- ries perform troponin testing to aid in the diagnosis of acute coronary syndrome (ACS).Laboratories must interact with clinicians to establish diagnostic cut points, achieve acceptable assay performance, and troubleshoot questionable findings.Here we present 3 hypothetical scenarios related to troponin testing in the clinical chemistry laboratory. Troponin: Its Utility in Acute Coronary SyndromeCase Presentation 1: J.P. is an obese 55-year-old male with a history of gastroesophageal reflux disease who presents to the emergency department with substernal chest pain that he attributes to a "large meal."J.P. is pale and diaphoretic.An ECG shows tachycardia with normal sinus rhythm.J.P.'s troponin levels (decision limit Ͼ0.04 g/L) at presentation and at 6 and 12 hours after presentation are 0.09, 4.41, and 19.62 g/L, respectively.
ATR Affecting Cell Radiosensitivity Is Dependent on Homologous Recombination Repair but Independent of Nonhomologous End Joining
Authors: Hongyan Wang, Huichen Wang, Simon N. Powell, George Iliakis, Ya Wang
Journal: Cancer Research (2004)

Abstract ATR is one of the most important checkpoint proteins in mammalian cells responding to DNA damage. Cells defective in normal ATR activity are sensitive to ionizing radiation (IR). The mechanism by which ATR protects the cells from IR-induced killing remains unclear. DNA double-strand breaks (DSBs) induced by IR are critical lesions for cell survival. Two major DNA DSB repair pathways exist in mammalian cells: homologous recombination repair (HRR) and nonhomologous end joining (NHEJ). We show that the doxycycline (dox)-induced ATR kinase dead (ATRkd) cells have the similar inductions and rejoining rates of DNA DSBs compared with cells without dox induction, although the dox-induced ATRkd cells are more sensitive to IR and have the deficient S and G2 checkpoints. We also show that the dox-induced ATRkd cells have a lower HRR efficiency compared with the cells without dox induction. These results indicate that the effects of ATR on cell radiosensitivity are independent of NHEJ but are linked to HRR that may be affected by the deficient S and G2 checkpoints.
All milk products should be heat treated
Authors: D M Campbell, J M Cowden, G Morris, W J Reilly, S J O'Brien
Journal: BMJ (1996)

products....Although Stalin had a sophisticated propaganda machine for its time, the tobacco industry is using the most advanced technology available to produce a 21st-century propaganda effort.Stalin's methods were perceived as cold and calculating, but those of the tobacco industry are smooth and subtle.The marketing plans are prospective, with the result of pervasively infiltrating all facets of Russian life."2I find Hurt's analogy entirely apt, and I urge Cambridge most earnestly to deny BAT an honour which will lower the esteem in which Cambridge is held throughout the world.
The association between ICU level of care and mortality in the Netherlands
Authors: Georg Heinrich Kluge, Sylvia Brinkman, Giel van Berkel, Johannes van der Hoeven, Crétien Jacobs, Yvonne E. M. Snel, John P. W. Vogelaar, Nicolette F. de Keizer, Emiel S. Boon
Journal: Intensive Care Medicine (2015)
Epistatic Rescue of Nkx2.5 Adult Cardiac Conduction Disease Phenotypes by Prospero-Related Homeobox Protein 1 and HDAC3
Authors: Catherine A. Risebro, Louisa K. Petchey, Nicola Smart, John Gomes, James Clark, Joaquim M. Vieira, Joseph Yanni, Halina Dobrzynski, Sean Davidson, Zia Zuberi, Andrew Tinker, Bo Shui, Yvonne I. Tallini, Michael I. Kotlikoff, Lucile Miquerol, Robert J. Schwartz, Paul R. Riley
Journal: Circulation Research (2012)

Nkx2.5 is one of the most widely studied cardiac-specific transcription factors, conserved from flies to man, with multiple essential roles in both the developing and adult heart. Specific dominant mutations in NKX2.5 have been identified in adult congenital heart disease patients presenting with conduction system anomalies and recent genome-wide association studies implicate the NKX2.5 locus, as causative for lethal arrhythmias ("sudden cardiac death") that occur at a frequency in the population of 1 in 1000 per annum worldwide. Haploinsufficiency for Nkx2.5 in the mouse phenocopies human conduction disease pathology yet the phenotypes, described in both mouse and man, are highly pleiotropic, implicit of unknown modifiers and/or factors acting in epistasis with Nkx2.5/NKX2.5.To identify bone fide upstream genetic modifier(s) of Nkx2.5/NKX2.5 function and to determine epistatic effects relevant to the manifestation of NKX2.5-dependent adult congenital heart disease.A study of cardiac function in prospero-related homeobox protein 1 (Prox1) heterozygous mice, using pressure-volume loop and micromannometry, revealed rescue of hemodynamic parameters in Nkx2.5(Cre/+); Prox1(loxP/+) animals versus Nkx2.5(Cre/+) controls. Anatomic studies, on a Cx40(EGFP) background, revealed Cre-mediated knock-down of Prox1 restored the anatomy of the atrioventricular node and His-Purkinje network both of which were severely hypoplastic in Nkx2.5(Cre/+) littermates. Steady state surface electrocardiography recordings and high-speed multiphoton imaging, to assess Ca(2+) handling, revealed atrioventricular conduction and excitation-contraction were also normalized by Prox1 haploinsufficiency, as was expression of conduction genes thought to act downstream of Nkx2.5. Chromatin immunoprecipitation on adult hearts, in combination with both gain and loss-of-function reporter assays in vitro, revealed that Prox1 recruits the corepressor HDAC3 to directly repress Nkx2.5 via a proximal upstream enhancer as a mechanism for regulating Nkx2.5 function in adult cardiac conduction.Here we identify Prox1 as a direct upstream modifier of Nkx2.5 in the maintenance of the adult conduction system and rescue of Nkx2.5 conduction disease phenotypes. This study is the first example of rescue of Nkx2.5 function and establishes a model for ensuring electrophysiological function within the adult heart alongside insight into a novel Prox1-HDAC3-Nkx2.5 signaling pathway for therapeutic targeting in conduction disease.
Physical activity habits of doctors and medical students influence their counselling practices
Authors: F Lobelo, J Duperly, E Frank
Journal: British Journal of Sports Medicine (2008)

Doctors are well positioned to provide physical activity (PA) counselling to patients. They are a respected source of health-related information and can provide continuing preventive counselling feedback and follow-up; they may have ethical obligations to prescribe PA. Several barriers to PA counselling exist, including insufficient training and motivation of doctors and improvable, personal PA habits. Rates of exercise counselling by doctors remain low; only 34% of US adults report exercise counselling at their last medical visit. In view of this gap, one of the US health objectives for 2010 is increasing the proportion of patients appropriately counselled about health behaviours, including exercise/PA. Research shows that clinical providers who themselves act on the advice they give provide better counselling and motivation of their patients to adopt such health advice. In summary, there is compelling evidence that the health of doctors matters and that doctors' own PA practices influence their clinical attitudes towards PA. Medical schools need to increase the proportion of students adopting and maintaining regular PA habits to increase the rates and quality of future PA counselling delivered by doctors.
Exercise Treadmill Testing
Authors: Tamar S. Polonsky, Ron Blankstein
Journal: JAMA (2015)

A53-year-oldmanwithchestpainwas referred toundergoanexercise treadmill test (ETT). He reported substernal chest pain, lasting less than 5minutes, which sometimes occurred if he ranmore than 2miles. He had no other symptoms. The patient's medical history included hypertension (controlled with lisinopril and hydrochlorothiazide), a low-density lipoprotein level of 155mg/dL, andahigh-density lipoprotein level of44mg/dL.Hedidnot smokeorhave familyhistoryofprematurecoronaryarterydisease(CAD).Thepatient’sphysicalexaminationresultswereunremarkable,bloodpressurewas 134/80mmHg, bodymass indexwas 26 (calculated asweight in kilogramsdivided byheight inmeters squared), and resting electrocardiogram (ECG) resultswere normal. The patient had no chest pain during ETT. Results are reported in the Table.
Hard metal asthma: cross immunological and respiratory reactivity between cobalt and nickel?
Authors: T Shirakawa, Y Kusaka, N Fujimura, M Kato, S Heki, K Morimoto
Journal: Thorax (1990)

Eight asthmatic patients with hard metal asthma due to cobalt underwent bronchial provocation challenge with nickel sulphate. Seven patients developed a fall in FEV1 of 20% or more after inhaling nickel sulphate, four showing an immediate response and three a late response. Eight control subjects, including six asthmatic patients, with no history of hard metal exposure, showed no bronchoconstriction in response to a provocation challenge with nickel sulphate. Specific antibodies to nickel conjugated human serum albumin were present in four of the eight patients with sensitivity to cobalt conjugated human serum albumin but were absent from the serum of 60 unexposed asthmatic patients and 25 exposed symptom free workers. These results suggest that nickel as well as cobalt sensitivity plays a part in hard metal asthma.
Successful treatment of refractory anemia with high‐dose methylprednisolone
Authors: Toshiko Motoji, Masanao Teramura, Masatomo Takahashi, Kazuo Oshimi, Michiko Okada, Kiyoko Kusakabe, Hideaki Mizoguchi
Journal: American Journal of Hematology (1990)

Abstract Five patients with refractory anemia were treated with high‐dose methylprednisolone. An immediate and long‐lasting hematological improvement without serious side effects was achieved in two of the patients, although chromosomal abnormalities persisted in both. The clinical course and laboratory data of these two patients are described. Restoration of normal hematopoiesis was achieved regardless of the enhancement of colony formation of granulocyte progenitor cells by the simultaneous addition of hydrocortisone in vitro. The same treatment was given to six patients who had refractory anemia with an excess of myeloblasts (RAEB), but no improvement was observed in any of these patients. It appears that high‐dose methylprednisolone can be valuable in the treatment of refractory anemia, but is not useful for RAEB.
Aleukemic leukemia cutis with extensive bone involvement
Authors: Maria Maroto Iitani, Riichiro Abe, Teruki Yanagi, Asuka Hamasaka, Yasuki Tateishi, Yukiko Abe, Miki Ito, Takeshi Kondo, Kanako Kubota, Hiroshi Shimizu
Journal: Journal of the American Academy of Dermatology (2010)
Transabdominal bowel sonography for the detection of intestinal complications in Crohn’s disease
Authors: C Gasche, G Moser, K Turetschek, E Schober, P Moeschl, G Oberhuber
Journal: Gut (1999)

Background The course of Crohn’s disease is characterised by the occurrence of intestinal complications such as strictures, intra-abdominal fistulas, or abscesses. Standard diagnostic procedures may fail to show these complications, in particular fistulas. Aims To test the value of transabdominal bowel sonography (TABS) for the detection of intestinal complications in Crohn’s disease. Methods TABS was prospectively performed in 213 patients with Crohn’s disease in a university based inflammatory bowel disease referral centre. Thirty three underwent resective bowel surgery and were included in this study. The accuracy of TABS to detect strictures, intra-abdominal fistulas, or abscesses was compared with surgical and pathological findings. Results TABS was able to identify strictures in 22/22 patients and to exclude it in 10/11 patients (100% sensitivity, 91% specificity). Fistulas were correctly identified in 20/23 patients and excluded in 9/10 patients (87% sensitivity, 90% specificity). Intra-abdominal abscesses were correctly detected in 9/9 patients and excluded in 22/24 patients (100% sensitivity, 92% specificity). Conclusions In experienced hands TABS is an accurate method for the detection of intestinal complications in Crohn’s disease. TABS is thus recommended as a primary investigative method for evaluation of severe Crohn’s disease.
Performance of Different Microsatellite Marker Panels for Detection of Mismatch Repair–Deficient Colorectal Tumors
Authors: Rosa M. Xicola, Xavier Llor, Elisenda Pons, Antoni Castells, Cristina Alenda, Virgínia Piñol, Montserrat Andreu, Sergi Castellví-Bel, Artemio Payá, Rodrigo Jover, Xavier Bessa, Anna Girós, José M. Duque, David Nicolás-Pérez, Ana M. Garcia, Joaquin Rigau, Miquel A. Gassull
Journal: JNCI Journal of the National Cancer Institute (2007)

Colorectal tumors caused by failure of the DNA mismatch repair system commonly show microsatellite instability. Our goals were to compare the performance of two panels of markers (a panel previously recommended by the National Cancer Institute [NCI] and a pentaplex of mononucleotide repeats) and to devise the simplest diagnostic strategy for identification of patients with colorectal cancer characterized by defects in mismatch repair.We recruited 1058 patients who were newly diagnosed with colorectal cancer. DNA from fresh-frozen and paraffin-embedded tumors was tested for microsatellite instability, using the NCI-recommended panel of microsatellite markers and the pentaplex panel of mononucleotide repeats, respectively, as templates for polymerase chain reactions (PCRs). Microsatellite instability in fresh-frozen tumors was also assessed using the pentaplex panel of mononucleotides in a crossover analysis. The expression of mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) in the tumors was determined immunohistochemically. The sensitivity and specificity with which the marker panels identified tumors with deficiencies in the expression of mismatch repair proteins were calculated. All statistical tests were two-sided.The sensitivity and positive predictive value of the NCI panel were 76.5% (95% confidence interval [CI] = 61% to 92%) and 65.0% (95% CI = 49% to 81%), respectively; corresponding values for the mononucleotide pentaplex panel were 95.8% (95% CI = 89% to 103%) and 88.5% (95% CI = 79% to 98%), respectively. A panel consisting of the mononucleotide repeat markers BAT26 and NR24 alone had the same predictive value as the pentaplex panel of mononucleotide repeats.The pentaplex panel of mononucleotide repeats performs better than the NCI panel for the detection of mismatch repair-deficient tumors. Simultaneous assessment of the instability of BAT26 and NR24 is as effective as use of the pentaplex panel for diagnosing mismatch repair deficiency.
Inhaled NO as a therapeutic agent
Authors: K BLOCH, F ICHINOSE, J ROBERTSJR, W ZAPOL
Journal: Cardiovascular Research (2007)

In 1991, Frostell and colleagues reported that breathing low concentrations of nitric oxide (NO) decreased pulmonary artery pressure (PAP) in awake lambs with experimental pulmonary hypertension (PH) [Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991;83:2038–47]. Subsequently, efforts of multiple research groups studying animals and patients led to approval of inhaled NO by the US Food and Drug Administration in 1999 and the European Medicine Evaluation Agency and European Commission in 2001. Inhaled NO is currently indicated for the treatment of term and near-term neonates with hypoxemia and PH. Since regulatory approval, several studies have suggested that NO inhalation can prevent chronic lung disease in premature infants. In addition, unanticipated systemic effects of inhaled NO may lead to treatments for a variety of disorders including ischemia-reperfusion injury. This review summarizes the pharmacology and physiological effects of breathing NO. The application of inhaled NO to hypoxemic neonates with PH is discussed including recent studies exploring the use of inhaled NO to prevent bronchopulmonary dysplasia in premature infants. This review also highlights the application of inhaled NO to treat adults with cardiopulmonary disease, strategies to augment the efficacy of inhaled NO, and potential applications of the systemic effects of the gas.
Spontaneous diminution of basal-cell carcinoma
Authors: G. H. V. Clarke
Journal: British Journal of Dermatology (1967)

Journal Article Spontaneous diminution of basal‐cell carcinoma Get access G. H. V. Clarke G. H. V. Clarke Manchester and Salford Hospital for Skin Diseases, Quay Street, Manchester, 2 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 79, Issue 7, 1 July 1967, Page 425, https://doi.org/10.1111/j.1365-2133.1967.tb11525.x Published: 01 July 1967
Thymus Independent T Cell Development and Selection in the Intestinal Epithelium
Authors: P Poussier, M Julius
Journal: Annual Review of Immunology (1994)

The presence of intestinal intra-epithelial lymphocytes (IEL) has been appreciated for over 100 years. However, until recently, the IEL were thought to be simply another specialized component of the gut-associated lymphoid tissue (GALT), sharing the same origin as lymphocytes found in other GALT compartments such as the lamina propria, the Peyer's patches, and the mesenteric lymph nodes. While the IEL remain functionally enigmatic, over the last ten years increasing evidence, originally based on the phenotypic complexity of IEL, has led to the conclusion that the intestinal epithelium comprises a distinct and unique lymphoid compartment within the organism. The recent discovery that the intestinal epithelium is a primary T lymphopoietic organ provides obvious potential explanations for the phenotypic peculiarities of IEL. The following discussion reviews the experiments that established that the intestinal epithelium is a site of T cell development and selection, and the discussion correlates phenotypic and functional heterogeneity of IEL within this context.
Coronary angioplasty and rotablator for atherectomy trial (CARAT): immediate and late results of a prospective multicenter randomized trial
Authors: R.D. Salian, T. Feldman, D.W.M. Muller, D. Mason, T. Schrelber, B. Halk, M. Mooney, W.W. O'Neil
Journal: Journal of the American College of Cardiology (1998)
Screening for Bronchial Hyperresponsiveness Using Methacholine and Adenosine Monophosphate
Authors: STEPHEN J. FOWLER, OWEN J. DEMPSEY, ERIKA J. SIMS, BRIAN J. LIPWORTH
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Bronchial hyperresponsiveness (BHR) is a key feature of asthma and may be measured by direct methacholine challenge or indirect adenosine monophosphate (AMP) challenge. We performed a retrospective analysis of our database (n = 487) of patients with asthma with the aim first, to compare methacholine and AMP challenge as screening tools, and second, to identify any relationships between BHR and disease severity markers or β2-adrenoceptor genotype. Of these subjects, 258 had a methacholine challenge, 259 an AMP challenge and 185 both. Of subjects having both, 140 (76%) were methacholine responsive with PD20 < 500 μ g (PC20 < 5 mg/ml) and 92 (50%) were AMP responsive with PC20 < 200 mg/ ml. For those who were AMP unresponsive 57% were methacholine responsive, whereas for the methacholine nonresponders 11% were AMP responsive. Methacholine (but not AMP)-responsive patients had a significantly (p < 0.05) lower % predicted FEV1 and FEF25–75 and higher inhaled corticosteroid dose than unresponsive patients. Finally, subjects with a glycine allele at codon 16 had significantly (p < 0.05) increased BHR to methacholine but not AMP. Our results suggest that methacholine is a more appropriate screening tool for BHR than AMP as it was more sensitive in our population and was also related to asthma severity. In addition, we have demonstrated an association between the glycine allele (codon 16) and increased BHR to methacholine.