tbuckley/cabot-search huggingface dataset:
OP01 * MISMATCH REPAIR DEFICIENCY CONFERS INCREASED SENSITIVITY TO IONISING RADIATION (XR) IN GLIOBLASTOMA
Authors: H. L. Payne, S.-A. Martin, S. C. Short
Journal: Neuro-Oncology (2014)

INTRODUCTION: Combination chemo-radiotherapy, including the alkylating agent temozolomide (TMZ) is standard of care for patients with glioma. Increased TMZ use has lead to sustained interest in the mechanisms underlying acquired resistance. Amongst these, deficiency in mismatch repair (MMR) is best described, with TMZ treatment promoting loss of functional MMR proteins most frequently through point mutations in MSH2/6, which may then lead to a hyper-mutation phenotype. Since patients are increasingly exposed to TMZ as first-line treatment with subsequent radiotherapy we set out to investigate how MMR status may influence response to XR and/or radiosensitising agents. METHOD: Effects of MMR protein deficiency on response to XR in paired isogenic glioma cell lines; U251 (MMR proficient) and U251.TR3 (MMR deficient, TMZ-induced MSH6mut) lines determined by clonogenic assay and immunofluorescence to detect γH2AX foci. MMR proteins were down-regulated by siRNA transfection. MMR protein expression was determined by western blotting and MMR deficient cell lines were further characterised by sequencing. RESULTS: We have shown that U251.TR3 cells (MMR deficient) are more sensitive to radiation-induced cell death than MMR proficient U251 cells in clonogenic assays (surviving fraction at 2Gy 0.41 ± 0.03 and 0.71 ± 0.04 respectively, p < 0.001). This sensitisation is accompanied by an increase in gH2AX foci (28 ± 3 and 50 ± 6 foci per cell in U251 and U251.TR3 cells respectively). On-going work is investigating whether this effect is due to MMR deficiency per se or secondary mutations driven by a hyper-mutation phenotype. CONCLUSION: Detection of MMR proteins following TMZ exposure may serve as a tool to stratify patients for treatment.
Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease
Authors: Jee Hoon Roh, Hong Jiang, Mary Beth Finn, Floy R. Stewart, Thomas E. Mahan, John R. Cirrito, Ashish Heda, B. Joy Snider, Mingjie Li, Masashi Yanagisawa, Luis de Lecea, David M. Holtzman
Journal: The Journal of Experimental Medicine (2014)

Age-related aggregation of amyloid-β (Aβ) is an upstream pathological event in Alzheimer's disease (AD) pathogenesis, and it disrupts the sleep-wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects Aβ aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect Aβ pathology. Amyloid precursor protein (APP)/Presenilin 1 (PS1) transgenic mice, in which the orexin gene is knocked out, showed a marked decrease in the amount of Aβ pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of Aβ pathology. In contrast, sleep deprivation or increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of Aβ pathology in the brain. Collectively, modulation of orexin and its effects on sleep appear to modulate Aβ pathology in the brain.
Prospects for Cancer Control in the 1990s
Authors: C S Muir, A J Sasco
Journal: Annual Review of Public Health (1990)

Around 1618 Thomas Adams wrote He is a better physician that keepes diseases off us than he that cures them being on us; prevention is so much better than healing because it saves the labour of being sick. Where do stand some 370 years later? This review examines the current and possible future world cancer burden identifies the sites of cancer for which a better understanding of etiology is urgently needed (for without knowledge of cause rational prevention is difficult) and sets these topics in the context of cancer prevention today and tomorrow.  (excerpt)
Clinical predictors of time to return to competition and of recurrence following hamstring strain in elite Australian footballers
Authors: Price Warren, Belinda J Gabbe, Michal Schneider-Kolsky, Kim L Bennell
Journal: British Journal of Sports Medicine (2008)

Objective To investigate early clinical predictors of time to return to competition and of recurrence following hamstring strain. Design Prospective observational study. Setting Elite level of Australian football competition. Participant 59 players who suffered a hamstring strain in 2002 season. Predictors Clinical assessment by a physiotherapist and questionnaire. Main outcome measures Time taken to return to play and recurrence of hamstring injury within 3 weeks. Results Players taking more than 1 day to walk pain-free were significantly more likely (p=0.018) to take longer than 3 weeks to return to competition (adjusted odds ratio 4.0; 95% CI 1.3 to 12.6). Nine players (15.2%) experienced an injury recurrence, all involving the biceps femoris. Recurrence was more likely in players who reported a hamstring injury in the past 12 months (adjusted odds ratio 19.6; 95% CI 1.5 to 261.0; p=0.025). Conclusion Time to walk pain-free and previous hamstring injury are predictors of time to return to competition and recurrence, respectively, and should be included in a clinical assessment to aid in prognosis.
Journal Impact Factors for 1999
Authors: J. BRITTON
Journal: Thorax (2000)

The Journal Impact Factors for 1999 have recently been released 1 and indicate that Thorax has again increased its impact factor, from 2.861 in 1998 to 3.437 in 1999.Thorax has thus further consolidated its position as the highest ranking specialist respiratory journal after the two American Thoracic Society publications.The position of Thorax in terms of impact factor relative to other selected specialist journals of similar or complementary interest is shown in the table.We are pleased to see this continued improvement in the international status of the journal, and thank all who have helped to achieve it.The ultimate determinant of the impact factor of the journal is the standard of the papers submitted to us.
Breast Cancers with a<i>BRCA1</i>-like DNA Copy Number Profile Recur Less Often Than Expected after High-Dose Alkylating Chemotherapy
Authors: Philip C. Schouten, Frederik Marmé, Sebastian Aulmann, Hans-Peter Sinn, Hendrik F. van Essen, Bauke Ylstra, Michael Hauptmann, Andreas Schneeweiss, Sabine C. Linn
Journal: Clinical Cancer Research (2014)

Breast cancers in carriers of inactivating mutations of the BRCA1 gene carry a specific DNA copy-number signature ("BRCA1-like"). This signature is shared with cancers that inactivate BRCA1 through other mechanisms. Because BRCA1 is important in repair of DNA double-strand breaks through error-free homologous recombination, patients with a BRCA1-like tumor may benefit from high-dose alkylating (HD) chemotherapy, which induces DNA double-strand breaks.We investigated a single institution cohort of high-risk patients that received tandem HD chemotherapy schedule comprising ifosfamide, epirubicin, and carboplatin or conventional chemotherapy. We classified copy-number profiles to be BRCA1-like or non-BRCA1-like and analyzed clinical associations and performed survival analysis with a treatment by biomarker interaction design.BRCA1-like status associated with high-grade and triple-negative breast cancers. BRCA1-like cases benefitted from the HD compared with a conventional regimen on disease-free survival (DFS): [hazard ratio (HR), 0.05; 95% confidence interval (CI), 0.01-0.38; P = 0.003]; distant DFS (DDFS): (HR, 0.06; 95% CI, 0.01-0.43; P = 0.01); and overall survival (OS; HR, 0.15; 95% CI, 0.03-0.83; P = 0.03) after correction for prognostic factors. No such benefit was observed in the non-BRCA1-like cases on DFS (HR, 0.74; 95% CI, 0.38-1.46; P = 0.39), DDFS (HR, 0.79; 95% CI, 0.41-1.52; P = 0.47), and OS (HR, 0.93; 95% CI, 0.52-1.64; P = 0.79). The P values for interaction were 0.01 (DFS), 0.01 (DDFS), and 0.045 (OS).BRCA1-like tumors recurred significantly less often after HD than conventional chemotherapy. BRCA1-like copy-number profile classification may be a predictive marker for HD alkylating chemotherapy.
Receptor Activator of Nuclear Factor κB Ligand Is a Novel Inducer of Tissue Factor in Macrophages
Authors: Jihye Kim, Jeong-Ki Min, Jeong Ae Park, Hyun-Ju Doh, Yeon-Sook Choi, Jaerang Rho, Young-Myeong Kim, Young-Guen Kwon
Journal: Circulation Research (2010)

Although recent studies have suggested a role for the receptor activator of nuclear factor κB ligand (RANKL) in the late stages of atherosclerosis (eg, plaque destabilization and rupture), the underlying mechanisms and subsequent events are unclear.Because blood clotting is common after plaque rupture, we hypothesized that RANKL influenced tissue factor (TF) expression and activity to initiate the coagulation cascade.RANKL increased the TF mRNA level and procoagulant activity in macrophages, as determined by semiquantitative reverse transcription polymerase chain reaction (semiquantitative RT-PCR) and a chromogenic assay. TF promoter analysis revealed that AP-1 and Egr-1 are responsible for RANKL-induced TF transcription. In addition, RANKL increased phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)1/2. RANKL-induced TF expression was attenuated by JNK- and MEK1-specific inhibitors and by small interfering RNA knockdown of c-Jun and Egr-1.Our results indicate that RANKL induces TF in macrophages mainly through the cooperative action of AP-1 and Egr-1 via JNK and ERK1/2 pathways. These findings provide strong mechanistic support for the role of RANKL in the thrombogenicity of atherosclerotic plaques.
Keeping the right time in space: importance of circadian clock and sleep for physiology and performance of astronauts
Authors: Jin-Hu Guo, Wei-Min Qu, Shan-Guang Chen, Xiao-Ping Chen, Ke Lv, Zhi-Li Huang, Yi-Lan Wu
Journal: Military Medical Research (2014)

The circadian clock and sleep are essential for human physiology and behavior; deregulation of circadian rhythms impairs health and performance. Circadian clocks and sleep evolved to adapt to Earth's environment, which is characterized by a 24-hour light–dark cycle. Changes in gravity load, lighting and work schedules during spaceflight missions can impact circadian clocks and disrupt sleep, in turn jeopardizing the mood, cognition and performance of orbiting astronauts. In this review, we summarize our understanding of both the influence of the space environment on the circadian timing system and sleep and the impact of these changes on astronaut physiology and performance.
Factors Affecting Response and Survival in Patients With Myelodysplasia Treated With Immunosuppressive Therapy
Authors: Elaine M. Sloand, Colin O. Wu, Peter Greenberg, Neal Young, John Barrett
Journal: Journal of Clinical Oncology (2008)

Marrow failure in some patients with myelodysplastic syndrome (MDS) responds to immunosuppressive treatment (IST), but long-term outcome after IST has not been described. We evaluated patients with MDS treated with IST at our institution to determine their clinical course compared with a comparable supportive care only group.One hundred twenty-nine patients with MDS received IST with a median follow-up of 3.0 years (range, 0.03 to 11.3 years), using antithymocyte globulin (ATG) or cyclosporine (CsA) in combination or singly. Variables affecting response and survival were studied and outcomes were compared with those of 816 patients with MDS reported to the International Myelodysplasia Risk Analysis Workshop (IMRAW) who received only supportive care.Thirty-nine (30%) of 129 patients receiving IST responded either completely or partially: 18 (24%) of 74 patients responded to ATG, 20 (48%) of 42 patients responded to ATG plus CsA, and one (8%) of 13 patients responded to CsA. Thirty-one percent (12 of 39) of the responses were complete, resulting in transfusion independence and near-normal blood counts. In multivariate analysis, younger age was the most significant factor favoring response to therapy. Other favorable factors affecting response were HLA-DR15 positivity and combination ATG plus CsA treatment (P = .001 and P = .048, respectively). In multivariate analysis of the combined IMRAW and IST cohorts, younger age, treatment with IST, and intermediate or low International Prognostic Scoring System score significantly favored survival.IST produced significant improvement in the pancytopenia of a substantial proportion of patients with MDS and was associated with improved overall and progression-free survival, especially in younger individuals with lower-risk disease.
Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils.
Authors: P D Ponath, S Qin, T W Post, J Wang, L Wu, N P Gerard, W Newman, C Gerard, C R Mackay
Journal: The Journal of Experimental Medicine (1996)

The chemokine eotaxin is unusual in that it appears to be a highly specific chemoattractant for eosinophils. Ligand-binding studies with radiolabeled eotaxin demonstrated a receptor on eosinophils distinct from the known chemokine receptors CKR-1 and -2. The distinct eotaxin binding site on human eosinophils also bound RANTES (regulated on activation T expressed and secreted) and monocyte chemotactic protein (MCP)3. We have now isolated a cDNA from eosinophils, termed CKR-3, with significant sequence similarity to other well characterized chemokine receptors. Cells transfected with CKR-3 cDNA bound radiolabeled eotaxin specifically and with high affinity, comparable to the binding affinity observed with eosinophils. This receptor also bound RANTES and MCP-3 with high affinity, but not other CC or CXC chemokines. Furthermore, receptor transfectants generated in a murine B cell lymphoma cell line migrated in transwell chemotaxis assays to eotaxin, RANTES, and MCP-3, but not to any other chemokines. A monoclonal antibody recognizing CKR-3 was used to show that eosinophils, but not other leukocyte types, expressed this receptor. This pattern of expression was confirmed by Northern blot with RNA from highly purified leukocyte subsets. The restricted expression of CKR-3 on eosinophils and the fidelity of eotaxin binding to CKR-3, provides a potential mechanism for the selective recruitment and migration of eosinophils within tissues.
EULAR evidence based recommendations for the management of hand osteoarthritis: Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT)
Authors: W Zhang, M Doherty, B F Leeb, L Alekseeva, N K Arden, J W Bijlsma, F Dincer, K Dziedzic, H J Hauselmann, G Herrero-Beaumont, P Kaklamanis, S Lohmander, E Maheu, E Martin-Mola, K Pavelka, L Punzi, S Reiter, J Sautner, J Smolen, G Verbruggen, I Zimmermann-Gorska
Journal: Annals of the Rheumatic Diseases (2006)

To develop evidence based recommendations for the management of hand osteoarthritis (OA).
Psychiatric aspects of civilian disasters.
Authors: J G Edwards
Journal: BMJ (1976)

Every society should have contingency plans for dealing with catastrophes, however unlikely they may be, and every large hospital should have a disaster plan. The overall organisation and administration of this, together with the provision of emergency medical treatment, is clearly of primary importance, but the emotional reactions of the survivors, their loved ones and even of the relief personnel and staff is also of considerable importance. In introducing psychiatry into disaster planning and relief work it should not be seen as yet another example of trying to psychiatrise all the problems of the world but as a means of increasing awareness of and sensitivity to the way people react to extreme environmental stress and as an adjunct to the overall management of survivors.
Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness
Authors: Juerg Schwaller, Pascal Schneider, Paulette Mhawech-Fauceglia, Thomas McKee, Samir Myit, Thomas Matthes, Jurg Tschopp, Olivier Donze, Frederique-Anne Le Gal, Bertrand Huard
Journal: Blood (2006)
Apical wall stress by finite element analysis predicts subsequent left ventricular remodeling in the healing and early afterload reducing trial
Authors: Y. Aikawa, L. Rohde, S. Greaves, P. Ridker, F. Menapace, M. Arnold, J. Rouleau, M. Pfeffer, R. Lee, S. Solomon
Journal: Journal of the American College of Cardiology (1998)
Isotretinoin and serum lipids: studies on fatty acid, apolipoprotein and intermediary metabolism
Authors: M.F. LAKER, C. GREEN, A.K.M.J. BHUIYAN, S. SHUSTER
Journal: British Journal of Dermatology (1987)

Thirteen patients with severe acne were treated for 16 weeks with 1.0 mg/kg/day isotretinoin. There were significant increases in serum cholesterol (P less than 0.02), triglycerides (P less than 0.02) and apolipoprotein B (P less than 0.02). No changes were found in serum apolipoprotein A-1, non-esterified fatty acids (NEFA), carnitine, lactate, pyruvate, glycerol, alanine, beta-hydroxybutyrate, glucose or insulin. We therefore found no evidence that the hyperlipidaemia of isotretinoin therapy is due to increased fluxes of NEFA from adipose tissue to the liver, although we cannot exclude the possibility that there are changes in the proportion of NEFA being esterified to triglyceride or undergoing beta-oxidation. We suggest that the hyperlipidaemia induced by isotretinoin may be due to an increase in circulating lipoprotein from increased production or impaired catabolism.
Do the calmodulin-stimulated adenylyl cyclases play a role in neuroplasticity?
Authors: Zhengui Xia, Eui-Ju Choi, Daniel R. Storm, Christine Blazynski
Journal: Behavioral and Brain Sciences (1995)

Abstract Evidence from invertebrate systems including Aplysia and Drosophila , as well as studies carried out with mammalian brain, suggests that Ca 2+ -sensitive adenylyl cyclases may be important for long-term synaptic changes and learning and memory. Furthermore, some forms of long-term potentiation (LTP) in the hippocampus elevate cyclic AMP (cAMP) signals, and activation of adenylyl cyclases and cAMP-dependent protein kinase may be required for late stages of LTP. We propose that long-term changes in neurons and at synapses may require synergism between the cAMP and Ca 2+ signal transduction systems which regulates transcription and synthesis of specific proteins required for long-term synaptic changes. During LTP, protein kinase C is activated and intraccllular Ca 2+ increases. We hypothesize that the calmodulin (CaM)-regulated adenylyl cyclases may be activated during LTP because of increases in intracellular Ca 2+ , release of free CaM from neuromodulin, activation by protein kinase C, release of neurotransmitters, or a combination of these events. Synergistic activation of CaM-sensitive adenylyl cyclases may produce a robust or prolonged cAMP signal required for transcriptional control. Furthermore, the coupling of the Ca 2+ and cAMP systems may provide positive feedback regulation of Ca 2+ channels by cAMP-dependent protein kinase
Mechanisms of Monoclonal Antibody–Drug Interactions
Authors: Honghui Zhou, Mary Ann Mascelli
Journal: The Annual Review of Pharmacology and Toxicology (2011)

The concept of monoclonal antibodies (mAbs) as pharmacotherapeutics was validated in the mid-1980s with the successful clinical development of the fully murine mAb muromonab-CD3 for prevention of acute organ rejection. However, clinical applications of fully murine mAbs are restricted, owing to the high incidence of serious immune-mediated side effects, particularly upon repeated exposure. The rate and severity of immune-mediated toxicities of these agents were significantly attenuated by the development of mouse/human chimeric, fully human, and humanized mAbs. These refinements in molecular structure allowed repeated, long-term administration, where therapeutically warranted, which, in turn, broadened the scope of indications for this class of therapy. Presently, numerous mAbs are approved or are undergoing clinical evaluation for treatment of oncologic and chronic inflammatory diseases. The current experimental development landscape spans respiratory, metabolic, and central nervous system disorders as well as infectious disease. A consequence of the expanding numbers of mAb indications is concomitant administration of these agents with established small molecule pharmacotherapies, which necessitates a comprehensive understanding of mAb-small molecule drug interactions as well as mAb-mAb interactions. Current knowledge indicates that mAbs do not elicit a direct effect on the metabolic/clearance pathways for small molecular therapeutics. However, the immunomodulatory properties of mAbs can indirectly alter clearance of certain small molecule entities through the attenuation of noncatabolic enzymatic pathways.
Cell-surface expression of CD25, CD26, and CD30 by allergen-specific T cells is intrinsically different in cow's milk allergy
Authors: Rogier P. Schade, Adrie G. Van Ieperen-Van Dijk, Coraline Versluis, Frank C. Van Reijsen, Jan L.L. Kimpen, Carla A.F.M Bruijnzeel-Koomen, Edward F. Knol, Els Van Hoffen
Journal: Journal of Allergy and Clinical Immunology (2002)
High frequency chest wall oscillation (HFCWO) in the treatment of acute pulmonary exacerbation in adult cystic fibrosis (CF) patients
Authors: Stanislav Krasovskij, Elena Amelina, Maria Usacheva, Victor Samoylenko, Natalia Krilova
Journal: European Respiratory Journal (2013)

The aim:  to assess the clinical effect of HFCWO (Vest System) during acute pulmonary exacerbation in adult CF patients .    Materials and methods .31 CF patients admitted for acute pulmonary exacerbation were randomly allocated to receive HFCWO (Vest Hill-RomServices, USA) or conventional physiotherapy (CPT). 15 adult CF patients were in the study group, 16 patients in the comparison group. Clinical, anthropometric, microbiological and functional characteristics in the HFCC group were comparable with CPT group. C-reactive protein (CRP), respiratory function (FVC, FEV 1 , PEF), SpO2, height and weight, exercise tolerance (6-minute walk test) and dyspnoe (MRC scale) were measured. Courses duration were 12-14 days. HFCWO was performed for 15 min. twice a day with 9-12 Hz frequency and amplitude 6-9 bar. CPT was airway clearance technique used by the patient routinely: Active Cycle of Breathing Technique, Flutter, or PEP.   Results.  Significant improvement was seen in both groups. CRP decreased: -15,4±7,3 mg/l vs -11,0±6,9 mg/l, p=0,10, BMI increase in group1: 0,29±0,25 kg/m 2 , did not differ (p=0,74) from group 2 – 0,32±0,28 kg/m 2 . The dyspnoe scale changes and 6-minute walk test changes were equal in the two groups, SpO2 changes were: 3,0±1,0 % vs 3,2±1,2 %, p=0,88.  Significant difference could be seen in FEV 1 changes: 10,0±4,6 % vs 6,9±3,6 % (p= 0,04) and FVC: 9,5±4,8 % vs 5,9±3,8 % (p=0,03) for the study group and comparison group respectively. HFCWO showed no side-effects.   Conclusion.  The study shows that the addition of HFCWO to medical treatment decreases airway obstruction and can benefit CF adults during acute respiratory exacerbation.