tbuckley/cabot-search huggingface dataset:
The Extraction of Foreign Bodies from the Ear
Authors: J. M. Sims
Journal: BMJ (1878)

rise and become cataleptic, and such was the result ; that a second touch On the same point would reduce the rigidity, and cause it to fall, and such again was proved to be the fact.After a variety of other experiments, every one of which proved precisely as I had predicted, she was aroused.I now applied the ring of my instrument on the third finger of the right hand, from which it was suspended, and told the doctor that when it was so suspended it would send her to sleep.To this he replied, 'It never will', but I again told him that I felt confident that it would send her to sleep.We then were silent, and very speedily she was once more asleep.Having aroused her, I put
Radiotherapy Sensitization by Tumor-Specific <i>TRAIL</i> Gene Targeting Improves Survival of Mice Bearing Human Non–Small Cell Lung Cancer
Authors: Xiaochun Zhang, Rex Min Cheung, Ritsuko Komaki, Bingliang Fang, Joe Y. Chang
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To sensitize non–small cell lung cancer (NSCLC) to radiotherapy by tumor-specific delivery of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) gene. Experimental Design: The TRAIL was delivered to human NSCLC cell lines and normal human bronchial epithelial cells by the replication-defective adenoviral vector Ad/TRAIL-F/RGD using a tumor-specific human telomerase reverse transcriptase promoter. Cancer growth was studied using 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt and clonogenic assays. Activation of the apoptosis pathway was analyzed in a Western blot and sub-G1 DNA accumulation. A xenograft mouse lung cancer model was treated by intratumoral injections of Ad/TRAIL-F/RGD and local radiotherapy; the other groups received one of these treatments alone or a control agent. Apoptosis and TRAIL expression in tumors were also analyzed. Results: Ad/TRAIL-F/RGD specifically targets human NSCLC cells without significant effect in normal human bronchial epithelial cells. The combination of Ad/TRAIL-F/RGD and radiotherapy significantly improved cell-killing effect in all NSCLC cell lines tested (P &amp;lt; 0.05). Expression of TRAIL showed a dose-dependent relationship with Ad/TRAIL-F/RGD, and radiation seemed to increase TRAIL expression. Activation of the apoptosis by TRAIL and radiation was shown by activation of caspase-9, caspase-8, caspase-3, and poly(ADP-ribose) polymerase and increased DNA sub-G1 accumulation. The combination of TRAIL and radiotherapy significantly increased apoptosis in vivo, inhibited tumor growth, and prolonged mean survival in mice bearing human NSCLC to 43.7 days compared with 23.7 days (TRAIL only) and 16.5 days (radiotherapy only; P &amp;lt; 0.05). Conclusions: The combination of Ad/TRAIL-F/RGD and radiotherapy significantly improved therapeutic efficacy in suppressing NSCLC tumor growth and prolonging survival. Ad/TRAIL-F/RGD may improve the therapeutic ratio of radiotherapy in NSCLC.
Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells
Authors: Susumu Goyama, Janet Schibler, Lea Cunningham, Yue Zhang, Yalan Rao, Nahoko Nishimoto, Masahiro Nakagawa, Andre Olsson, Mark Wunderlich, Kevin A. Link, Benjamin Mizukawa, H. Leighton Grimes, Mineo Kurokawa, P. Paul Liu, Gang Huang, James C. Mulloy
Journal: Journal of Clinical Investigation (2013)

RUNX1 is generally considered a tumor suppressor in myeloid neoplasms. Inactivating RUNX1 mutations have frequently been found in patients with myelodysplastic syndrome (MDS) and cytogenetically normal acute myeloid leukemia (AML). However, no somatic RUNX1 alteration was found in AMLs with leukemogenic fusion proteins, such as core-binding factor (CBF) leukemia and MLL fusion leukemia, raising the possibility that RUNX1 could actually promote the growth of these leukemia cells. Using normal human cord blood cells and those expressing leukemogenic fusion proteins, we discovered a dual role of RUNX1 in myeloid leukemogenesis. RUNX1 overexpression inhibited the growth of normal cord blood cells by inducing myeloid differentiation, whereas a certain level of RUNX1 activity was required for the growth of AML1-ETO and MLL-AF9 cells. Using a mouse genetic model, we also showed that the combined loss of Runx1/Cbfb inhibited leukemia development induced by MLL-AF9. RUNX2 could compensate for the loss of RUNX1. The survival effect of RUNX1 was mediated by BCL2 in MLL fusion leukemia. Our study unveiled an unexpected prosurvival role for RUNX1 in myeloid leukemogenesis. Inhibiting RUNX1 activity rather than enhancing it could be a promising therapeutic strategy for AMLs with leukemogenic fusion proteins.
Applying the discovery of the Philadelphia chromosome
Authors: Daniel W. Sherbenou, Brian J. Druker
Journal: Journal of Clinical Investigation (2007)

The identification of the Philadelphia chromosome in cells from individuals with chronic myelogenous leukemia (CML) led to the recognition that the BCR-ABL tyrosine kinase causes CML. This in turn led to the development of imatinib mesylate, a clinically successful inhibitor of the BCR-ABL kinase. Incorporating the use of markers of BCR-ABL kinase inhibition into clinical trials led to the realization that imatinib-resistant kinase domain mutations are the major cause of relapse during imatinib therapy and the subsequent development of new inhibitors to treat CML patients. The development of imatinib validates an emerging paradigm in cancer, in which a tumor is defined by genetic abnormalities and effective therapies are developed that target events critical to the growth and survival of a specific tumor.
Determination of Cellularly Processed HLA-A2402-Restricted Novel CTL Epitopes Derived from Two Cancer Germ Line Genes, <i>MAGE-A4</i> and <i>SAGE</i>
Authors: Yoshihiro Miyahara, Hiroaki Naota, Lijie Wang, Atsunori Hiasa, Megumi Goto, Masato Watanabe, Shigehisa Kitano, Satoshi Okumura, Tetsushi Takemitsu, Atsushi Yuta, Yuichi Majima, François A. Lemonnier, Thierry Boon, Hiroshi Shiku
Journal: Clinical Cancer Research (2005)

Abstract Purpose: For identification of CTL epitopes useful for cancer vaccines, it is crucial to determine whether cognate epitopes are presented on the cell surface of target cancer cells through natural processing of endogenous proteins. For this purpose, we tried to use the cellular machinery of both mice and human to define naturally processed CTL epitopes derived from two “cancer germ line” genes, MAGE-A4 and SAGE. Experimental Design: We vaccinated newly produced HLA-A2402 transgenic mice with DNA plasmids encoding target antigens. Following screening of synthesized peptides by splenic CD8+ T cells of vaccinated mice, we selected candidate epitopes bound to HLA-A2402. We then examined whether human CD8+ T cells sensitized with autologous CD4+ PHA blasts transduced by mRNA for the cognate antigens could react with these selected peptides in an HLA-A2402-restricted manner. Results: After DNA vaccination, murine CD8+ T cells recognizing MAGE-A4143-151 or SAGE715-723 in an HLA-A2402-restricted manner became detectable. Human CTLs specific for these two peptides were generated after sensitization of HLA-A2402-positive CD8+ T cells with autologous CD4+ PHA blasts transduced with respective mRNA. CTL clones were cytotoxic toward tumor cell lines expressing HLA-A2402 and cognate genes. Taken together, these CTL epitopes defined in HLA-A24 transgenic mice are also processed and expressed with HLA-A2402 in human cells. The presence of SAGE715-723-specific precursors was observed in HLA-A2402-positive healthy individuals. Conclusions: Two novel HLA-A2402-restricted CTL epitopes, MAGE-A4143-151 and SAGE715-723, were identified. Our approach assisted by cellular machinery of both mice and human could be widely applicable to identify naturally processed CTL epitopes.
Ciclesonide 80 μg or 160 μg once-daily is as effective as fluticasone propionate 88 μg twice-daily in the treatment of persistent asthma
Authors: H. Magnussen, J. Hofman, B. Novakova, B. Kaczmarek-Czeczotka, T. Koci, P. Staneta, M. Hellwig, R. Engelstätter
Journal: Journal of Allergy and Clinical Immunology (2005)
Differences in Tumor-Associated Protein Levels among Middle-Age Flemish Women in Association with Area of Residence and Exposure to Pollutants
Authors: Nicolas A. van Larebeke, Marc E. Bracke, Vera Nelen, Gudrun Koppen, Greet Schoeters, Herman Van Loon, Robert Vlietinck
Journal: Environmental Health Perspectives (2006)

We measured tumor-associated proteins (TAPs) and pollutants in blood, serum, and urine of 200 nonsmoking women 50–65 years of age, residing in the rural municipality of Peer or in Hoboken or Wilrijk, industrial suburbs of Antwerp, Belgium. Persons with occupational exposures or commuting to other towns were excluded. Residents from Hoboken had significantly higher levels of blood lead and serum zinc and polychlorinated biphenyls. Surprisingly, residents of Peer had significantly higher levels of serum cadmium, dioxin-like activity in blood fat, and urinary 1-hydroxypyrene. For 5 of the 12 TAPs assessed in this study, we observed significant differences in serum levels among residents of the three municipalities after adjusting for personal or lifestyle parameters. Although we found levels of internal exposure to pollutants to be quite homogeneous in Flanders, we found significantly higher levels of TAPs only in the industrial suburbs. In multiple regression with all 29 available personal, lifestyle, and internal exposure parameters, blood lead levels showed a positive association with serum levels of anti-p53, carcino-embryonic antigen (CEA), and tissue polypeptide–specific antigen (TPS) and with an index for mean TAP level (Itap); dioxin-like activity in serum and serum copper showed a positive association with serum CA 125 (cancer antigen 125); and serum zinc showed a positive association with serum levels of c-erbB-2 ectodomain and TPS. An index of internal exposure showed a positive association with serum levels of both CEA and anti-p53 and with Itap. This study provides some evidence that levels of internal exposure such as those present in Flanders, in particular concerning lead, are indeed associated with biologic effects.
HLA-A*02 is associated with a reduced risk and HLA-A*01 with an increased risk of developing EBV+ Hodgkin lymphoma
Authors: Marijke Niens, Ruth F. Jarrett, Bouke Hepkema, Ilja M. Nolte, Arjan Diepstra, Mathieu Platteel, Niels Kouprie, Craig P. Delury, Alice Gallagher, Lydia Visser, Sibrand Poppema, Gerard J. te Meerman, Anke van den Berg
Journal: Blood (2007)
Chloroquine induces human macrophage killing of Histoplasma capsulatum by limiting the availability of intracellular iron and is therapeutic in a murine model of histoplasmosis.
Authors: S L Newman, L Gootee, G Brunner, G S Deepe
Journal: Journal of Clinical Investigation (1994)

We investigated the role of intracellular iron on the capacity of Histoplasma capsulatum (Hc) yeasts to multiply within human macrophages (Mphi). Coculture of Hc-infected Mphi with the iron chelator deferoxamine suppressed the growth of yeasts in a concentration-dependent manner. The effect of deferoxamine was reversed by iron-saturated transferrin (holotransferrin) but not by iron-free transferrin (apotransferrin). Chloroquine, which prevents release of iron from transferrin by raising endocytic and lysosomal pH, induced human Mphi to kill Hc. The effect of chloroquine was reversed by iron nitriloacetate, an iron compound that is soluble at neutral to alkaline pH, but not by holotransferrin, which releases iron only in an acidic environment. Chloroquine (40-120 mg/kg) given intraperitoneally for 6 d to Hc-infected C57BL/6 mice significantly reduced the growth of Hc in a dose-dependent manner. At 120 mg/kg there was a 17- and 15-fold reduction (P < 0.01) in CFU in spleens and livers, respectively. The therapeutic effect of chloroquine also correlated with the length of treatment. As little as 2 d of chloroquine therapy (120 mg/kg), when started at day 5 after infection, reduced CFU in the spleen by 50%. Treatment with chloroquine for 10 d after a lethal inoculum of Hc protected six of nine mice; all control mice were dead by day 11 (P = 0.009). This study demonstrates that: (a) iron is of critical importance to the survival and multiplication of Hc yeasts in human Mphi; (b) in vitro, chloroquine induces Mphi killing of Hc yeasts by restricting the availability of intracellular iron; and (c) in vivo, chloroquine significantly reduces the number of organisms in the spleens and livers of Hc-infected mice and can protect mice from a lethal inoculum of Hc yeasts. Thus, chloroquine may be effective in the treatment of active histoplasmosis and also may be useful in preventing relapse of histoplasmosis in patients with acquired immunodeficiency syndromes.
Clinical, radiographic and functional differences between juvenile-onset and adult–onset ankylosing spondylitis: results from the PSOAS cohort
Authors: L S Gensler, M M Ward, J D Reveille, T J Learch, M H Weisman, J C Davis
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Aims:</h3> Previous data suggests that patients with juvenile-onset ankylosing spondylitis (JoAS) have more severe disease and worse functional outcomes than adult-onset AS (AoAS). The purpose of this study was to evaluate clinical, functional and radiographic differences between patients with JoAS and AoAS in a large cohort of patients with long-standing disease. <h3>Methods:</h3> A total of 402 subjects who met the Modified New York Criteria for definitive AS and had had disease ⩾20 years were enrolled in a multi-centre cross-sectional study (Prospective Study of Outcomes in Ankylosing Spondylitis; PSOAS). JoAS was defined as initial symptoms ⩽16 years of age. A total of 79 subjects with JoAS and 323 subjects with AoAS were identified. An analysis of clinical and demographic comparisons between the two groups was performed including HLA B27 status. Functional outcomes were assessed by Bath AS Functional Index (BASFI) and the Health Assessment Questionnaire modified for the Spondyloarthropathies (HAQS). Radiographic disease severity was assessed by the Bath AS Radiology Index (BASRI). <h3>Results:</h3> With the exception of obvious differences in age at onset and disease duration, demographic and clinical characteristics were similar between the two groups. However, the JoAS group trended towards more women (32.9 vs 22.9%, p = 0.07). Controlling for multiple covariates including disease duration, both the BASRI hip score and the need for total hip arthroplasty (THA) was higher in the JoAS group. The BASRI spine score (including total, lumbar and cervical spine) was significantly lower in the patients with JoAS even after controlling for multiple covariates including disease duration and gender. No difference in function (BASFI or HAQS scores) between groups was identified. <h3>Conclusions:</h3> Compared to AoAS, subjects with JoAS have (1) less severe axial involvement radiographically, (2) similar functional outcomes, (3) more hip involvement with a greater need for THA, and (4) a slightly higher proportion of women.
Biochemical and histological changes in osteoarthritic synovial membrane.
Authors: O Gedikoglu, M T Bayliss, S Y Ali, I Tuncer
Journal: Annals of the Rheumatic Diseases (1986)

In order to investigate the relationship between the synovial inflammatory response and lysosomal enzyme activity in osteoarthritis, synovial specimens obtained from 19 osteoarthritic patients and control specimens from 10 normal joints were analysed for cathepsin D and acid phosphatase enzyme levels. In estimating enzyme activities methods previously developed for quantitative enzyme determination in cartilage were modified and applied to synovial tissues for the first time. In addition, samples of osteoarthritic synovium were histologically graded according to their degree of inflammation. It was found that in osteoarthritic synovium cathepsin D and acid phosphatase, which is a general marker for lysosomal enzyme activity, were significantly increased compared with normal control synovium. No significant relationship was found between the degree of synovial tissue inflammation and lysosomal enzyme activity.
Effectiveness of visits from community pharmacists for patients with heart failure: HeartMed randomised controlled trial
Authors: Richard Holland, Iain Brooksby, Elizabeth Lenaghan, Kate Ashton, Laura Hay, Richard Smith, Lee Shepstone, Alistair Lipp, Clare Daly, Amanda Howe, Roger Hall, Ian Harvey
Journal: BMJ (2007)

<b>Objective</b> To test whether a drug review and symptom self management and lifestyle advice intervention by community pharmacists could reduce hospital admissions or mortality in heart failure patients. <b>Design</b> Randomised controlled trial. <b>Setting</b> Home based intervention in heart failure patients. <b>Participants</b> 293 patients diagnosed with heart failure were included (149 intervention, 144 control) after an emergency admission. <b>Intervention</b> Two home visits by one of 17 community pharmacists within two and eight weeks of discharge. Pharmacists reviewed drugs and gave symptom self management and lifestyle advice. Controls received usual care. <b>Main outcome measures</b> The primary outcome was total hospital readmissions at six months. Secondary outcomes included mortality and quality of life (Minnesota living with heart failure questionnaire and EQ-5D). <b>Results</b> Primary outcome data were available for 291 participants (99%). 136 (91%) intervention patients received one or two visits. 134 admissions occurred in the intervention group compared with 112 in the control group (rate ratio=1.15, 95% confidence interval 0.89 to 1.48; P=0.28, Poisson model). 30 intervention patients died compared with 24 controls (hazard ratio=1.18, 0.69 to 2.03; P=0.54). Although EQ-5D scores favoured the intervention group, Minnesota living with heart failure questionnaire scores favoured controls; neither difference was statistically significant. <b>Conclusion</b> This community pharmacist intervention did not lead to reductions in hospital admissions in contrast to those found in trials of specialist nurse led interventions in heart failure. Given that heart failure accounts for 5% of hospital admissions, these results present a problem for policy makers who are faced with a shortage of specialist provision and have hoped that skilled community pharmacists could produce the same benefits. <b>Trial registration number</b>ISRCTN59427925.
Treatment of Acute Stanford Type B Aortic Dissection With a Novel Cylindrical Balloon Catheter in Dogs
Authors: H Terai, N Tamura, T Nakamura, K Nishimura, N Tsutsui, Y Shimizu, M Komeda
Journal: Circulation (2000)

Despite recent progress in medical and surgical treatment, acute type B aortic dissection still carries a high mortality rate. We have developed a novel cylindrical balloon catheter for less invasive treatment to block the entry of the dissection and induce thrombotic occlusion of the false lumen. The balloon has the shape of a sheet when deflated but a double-cylinder shape when inflated. Therefore, aortic blood flow is maintained through the cylindrical lumen during balloon inflation.Six beagle dogs underwent a left thoracotomy at the 6th intercostal space. An acute dissection of 4-cm length was created surgically on the descending aorta. The balloon catheter was inserted through the distal descending aorta and advanced to the entry site. The balloon catheter was inflated for 6 hours. The blood flow in the descending aorta and the position of the balloon was monitored by color Doppler echovasculography. Four dogs were killed humanely on the following day and 2 dogs 10 days after the surgery. The descending aorta was examined macroscopically and microscopically in all dogs. In all dogs, the false lumen was occluded by thrombi. Although no dog had clinical evidence of distal thromboembolism, 2 of the 4 dogs that were killed on the second postoperative day had fresh mural thrombi in the true lumen.The false lumen of the acute type B aortic dissection was effectively occluded by the novel cylindrical balloon catheter in the canine experimental model. The thrombus formation in the true lumen is the problem to be solved.
Lactulose inhibits endotoxin induced tumour necrosis factor production by monocytes. An in vitro study.
Authors: J W Greve, D J Gouma, P A von Leeuwen, W A Buurman
Journal: Gut (1990)

Preoperative oral treatment with lactulose is used to prevent complications after surgery in patients with obstructive jaundice. The effect is perhaps the result of an inactivation of gut derived endotoxins but the exact mechanism of action is, however, unknown. Tumour necrosis factor is an important mediator of endotoxin toxicity. The cytokine tumour necrosis factor is mainly produced by mononuclear phagocytes. In this study, the effect of lactulose on the endotoxin induced tumour necrosis factor release by monocytes was investigated. The direct effect of lactulose on endotoxin was tested in a chromogenic limulus amoebocyte lysate assay. Polymyxin B a known inactivator of endotoxin was used as control in both experiments. Lactulose has a limited capacity to inactivate endotoxin as measured in the endotoxin assay. In contrast lactulose significantly reduced endotoxin induced tumour necrosis factor production by monocytes. In conclusion lactulose inhibits tumour necrosis factor production by a direct inhibitory effect on monocytes, rather than by inactivation of endotoxin. Because tumour necrosis factor is an important mediator of endotoxin toxicity, this inhibitory effect could explain the beneficial effect of lactulose in obstructive jaundice.
Personalized Medicine in a Phase I Clinical Trials Program: The MD Anderson Cancer Center Initiative
Authors: Apostolia-Maria Tsimberidou, Nancy G. Iskander, David S. Hong, Jennifer J. Wheler, Gerald S. Falchook, Siqing Fu, Sarina Piha-Paul, Aung Naing, Filip Janku, Rajyalakshmi Luthra, Yang Ye, Sijin Wen, Donald Berry, Razelle Kurzrock
Journal: Clinical Cancer Research (2012)

Abstract Purpose: We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations. Patient and Methods: Patients with advanced cancer were treated in the Clinical Center for Targeted Therapy. Molecular analysis was conducted in the MD Anderson Clinical Laboratory Improvement Amendments (CLIA)–certified laboratory. Patients whose tumors had an aberration were treated with matched targeted therapy, when available. Treatment assignment was not randomized. The clinical outcomes of patients with molecular aberrations treated with matched targeted therapy were compared with those of consecutive patients who were not treated with matched targeted therapy. Results: Of 1,144 patients analyzed, 460 (40.2%) had 1 or more aberration. In patients with 1 molecular aberration, matched therapy (n = 175) compared with treatment without matching (n = 116) was associated with a higher overall response rate (27% vs. 5%; P &amp;lt; 0.0001), longer time-to-treatment failure (TTF; median, 5.2 vs. 2.2 months; P &amp;lt; 0.0001), and longer survival (median, 13.4 vs. 9.0 months; P = 0.017). Matched targeted therapy was associated with longer TTF compared with their prior systemic therapy in patients with 1 mutation (5.2 vs. 3.1 months, respectively; P &amp;lt; 0.0001). In multivariate analysis in patients with 1 molecular aberration, matched therapy was an independent factor predicting response (P = 0.001) and TTF (P = 0.0001). Conclusion: Keeping in mind that the study was not randomized and patients had diverse tumor types and a median of 5 prior therapies, our results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials. Clin Cancer Res; 18(22); 6373–83. ©2012 AACR.