tbuckley/cabot-search huggingface dataset:
Abstract PD02-01: Her2 expression measured by AQUA analysis on BCIRG-005 and BCIRG-006 predicts the benefit of Herceptin therapy
Authors: J Christiansen, N Barakat, D Murphy, DL Rimm, B Dabbas, M Nerenberg, S Beruti, E Quinaux, J Hall, M Press, D Slamon
Journal: Cancer Research (2012)

Abstract Introduction: There have been disparate results reported in breast cancer testing for HER2 assessment as measured by protein expression or DNA amplification, yet both tests are routinely used to prescribe the drug Herceptin (trastuzumab, Genentech, So San Francisco, CA). Typically, immunohistochemistry (IHC) staining intensity of 3+ or FISH copy ratio of ≥2.0 are used to establish the cutoff between a negative and a positive result. However, it is unclear whether positivity is correlated with differential response to therapy. We used Automated Quantitative Analysis (AQUA) and a fluorescent immunohistochemical assay to measure HER2 expression in cases scored by central laboratory FISH and also receiving Herceptin therapy. The intentions of the study were two-fold: first, to provide further validation of the AQUA technology as applied to the clinical measurement of HER2 expression in breast cancer and second, to examine the potential of drug response stratification within those patients that are considered positive. Methods: AQUA fluorescence IHC staining was performed on a multi-cohort tissue microarray (TMA) set. The assay was constructed in the Genoptix CLIA laboratory per ASCO/CAP guidelines and with a cutpoint that was validated against IHC (with FISH reflex). The trial specimens tested were from the BCIRG-005/006 studies. BCIRG-005 had n=1544 cases all assessed as FISH- while the 006 cohort had n=1477 cases all assessed as FISH+. Disease free survival (DFS) was used as the variable in subsequent modeling and analysis. Results: The BCIRG 005 and 006 cohorts, examined in aggregate, allowed for an initial examination of agreement relationships between HER2 levels as assessed by AQUA scoring and HER2 levels as assessed by central lab FISH. Results indicated a 77% negative agreement, a 97% positive agreement and an 87% overall concordance agreement for a total of n=3021 cases. Additional Cox modeling of the patients that were enrolled as FISH+ and stratified for those who did or did not receive Herceptin treatment demonstrated a significant overall hazard ratio (HR = 0.75, CI=0.60,0.93) and when stratified for response to Herceptin, cases determined to be positive by AQUA showed significant benefit from treatment (HR = 0.66, CI = 0.52,0.85) in contrast to those who were scored as negative by AQUA that did demonstrate benefit from therapy (HR = 1.19, CI=0.71,1.97). Conclusions: Analysis of the cases in this study originally determined to be HER2+ by FISH indicates that AQUA may improve predictions of which patients will benefit from Herceptin therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD02-01.
A conversation with Bruce Beutler
Authors: Ushma S. Neill
Journal: Journal of Clinical Investigation (2013)

A legend within the field of innate immunity, Dr. Bruce Beutler (Figure ​(Figure1)1) of the University of Texas Southwestern Medical School is best known for two seminal discoveries: identifying mouse tumor necrosis factor and discovering Toll-like receptor 4, the receptor for lipopolysaccharide. With this discovery, later rewarded with the 2011 Nobel Prize in Medicine, we finally understood how immune cells could recognize and react to bacteria. The full interview, with many more stories on developing etanercept, searching landfills for sequencers, and falling in love with genetics can be seen on the JCI website, http://www.jci.org/kiosk/cgm.
A Novel Solid Lipid Nanoparticle Formulation for Active Targeting to Tumor α<sub>v</sub>β<sub>3</sub> Integrin Receptors Reveals Cyclic RGD as A Double‐Edged Sword
Authors: Adam J. Shuhendler, Preethy Prasad, Michael Leung, Andrew M. Rauth, Ralph S. DaCosta, Xiao Yu Wu
Journal: Advanced Healthcare Materials (2012)

Abstract The overexpression of α v β 3 integrin receptors on tumor cells and tumor vascular endothelium makes it a useful target for imaging, chemotherapy and anti‐angiogenic therapy. However integrin‐targeted delivery of therapeutics by nanoparticles have provided only marginal, if any, enhancement of therapeutic effect. This work was thus focused on the development of novel α v β 3 ‐targeted near infrared light‐emitting solid lipid nanoparticles (SLN) through conjugation to the α v β 3 integrin‐specific ligand cyclic Arg‐Gly‐Asp (cRGD), and the assessment of the effects of α v β 3 targeting on nanoparticle biodistribution. Since our previously developed non‐targeted “stealth” SLN showed little hepatic accumulation, unlike most reported liposomes and micelles, they served as a reference for quantifying the effects of cRGD‐conjugation on tumor uptake and whole animal biodistribution of SLN. Non‐targeted SLN, actively targeted (RGD‐SLN) and blocked RGD‐SLN were prepared to contain near infrared quantum dots for live animal imaging. They were injected intravenously to nude mice bearing xenograft orthotopic human breast tumors or dorsal window chamber breast tumors. Tumor micropharmacokinetics of various SLN formulations were determined using intravital microscopy, and whole animal biodistribution was followed over time by optical imaging. The active tumor targeting with cRGD was found to be a “double‐edged sword”: while the specificity of RGD‐SLN accumulation in tumor blood vessels and their tumor residence time increased, their distribution in the liver, spleen, and kidneys was significantly greater than the non‐targeted SLN, leaving a smaller amount of nanoparticles in the tumor tissue. Nevertheless the enhanced specificity and retention of RGD‐SLN in tumor neovasculature could make this novel formulation useful for tumor neovascular‐specific therapies and imaging applications.
GW25-e0861 Danhong Injection Antagonizes Adriamycin-Induced Cardiotoxicity from Oxidative Stress: Mechanism in vivo and in vitro
Authors: Jiang Xiaoqing, Wang Ting, Lv Bin, Li Pan, Gao Xiumei, Wang Xiaoying
Journal: Journal of the American College of Cardiology (2014)
Specific immunotherapy with a standardized latex extract versus placebo in allergic healthcare workers
Authors: Francisque Leynadier, Denis Herman, Daniel Vervloet, Claude Andre
Journal: Journal of Allergy and Clinical Immunology (2000)

<h2>Abstract</h2> <b>Background:</b> The prevalence of allergy to natural rubber latex proteins has increased over recent years among healthcare professionals but also in children undergoing multiple operations. Exposure to the antigen mainly occurs through the respiratory mucosa and the percutaneous route. Clinical manifestations range from urticaria to angioedema, rhinoconjunctivitis, bronchial asthma, or anaphylactic shock. Preventive measures have been proposed to reduce the risk of sensitization by using only powder-free or synthetic gloves and latex-free material in operating units, but this is not always possible. <b>Objective:</b> The aim of this study was to investigate the efficacy and safety of specific immunotherapy in sensitized workers. <b>Methods:</b> Seventeen patients with latex skin allergy and rhinitis (9 of whom also had asthma) were included in this randomized, double-blind, placebo-controlled trial (9 in the active group and 8 in the placebo group) for 1 year. Treatment started with a 2-day course of rush immunotherapy in hospital. Treatment efficacy was assessed after 6 and 12 months by means of symptom and medication scores recorded on diary cards. Conjunctival provocation tests were also performed. <b>Results:</b> Patients in the active treatment group had a significantly lower total rhinitis score after 6 (<i>P</i> < .04) and 12 months (<i>P</i> < .05), conjunctivitis score after 6 months (<i>P</i> < .02), and cutaneous score after 12 months (<i>P</i> < .03) than in the placebo group. Asthma symptoms after 6 or 12 months of treatment were not significantly different between the two groups after adjustment for baseline values. The global medication score was markedly decreased in the latex-treated group. A significant difference in conjunctival reactivity was observed in favor of the active group: the number of patients for whom the threshold dose was increased after 12 months of treatment was significantly greater in the active group than in the placebo group (<i>P</i> < .02). Most injections were well tolerated, but several adverse effects, including hypotension, urticaria, wheezing, and pharyngeal edema, were observed. <b>Conclusion:</b> The clinical benefits observed during the present study included a significant improvement of rhinitis, conjunctivitis, and cutaneous symptoms. Immunotherapy also decreased allergen-specific conjunctival reactivity. Latex-specific immunotherapy may allow sensitized personnel to remain at work, but further trials need to be conducted in a larger number of patients. (J Allergy Clin Immunol 2000;106:585-90.)
The presence of β2 microglobulin on the membrane of the keratinocyte in premalignant skin disorders
Authors: H.R.KORTHALS ALTES-LEVY VINNINGHE, H.A.M. NEUMANN
Journal: British Journal of Dermatology (1981)

Beta2 Microglobulin, the invariable light chain of the histocompatibility antigen, has proved to be absent on the cell surface of basal cell carcinoma. In actinically damaged skin and in patients with a past history of arsenic ingestion changes can be observed on the epidermal cell membrane which can predict malignancy before cell dysregulation is visible. The epidermis in the basal cell naevus syndrome behaves in this respect as normal epidermis and the spontaneous tumour growth cannot be explained by a predisposing defect in the HLA-antigens of the epidermal cell surface.
Repeatability of ventilatory function measurements in a population survey of 7 year old children.
Authors: D P Strachan
Journal: Thorax (1989)

The within subject variability of forced vital capacity (FVC), forced expiratory volumes in one second (FEV1) and half a second (FEV0.5), peak expiratory flow (PEF), and flow rates at 25-75%, 75-85%, 25%, 50%, and 75% of expired FVC were assessed among 7 year old children from the general population. Within occasion variability in 232 children was lowest for FVC (coefficient of variation (CV) 5%) and FEV1 (CV 4%), and greatest for end expiratory flow rates. The precision of measurement for FEV1 supports its use for bronchial provocation tests, particularly those using a graded challenge. In this context the value of PEF (CV 7%) and mid expiratory flow rates (CV 11%) is limited by their poorer repeatability. Between occasion variability was assessed in 171 children tested at an interval of one to four weeks. The difference between the variances between occasions and within occasions was attributed to biological variation; this accounted for a substantial component of the between occasion variance in all indices, particularly FEV1 (73%) and PEF (66%). Together, within subject variability, sex, and height accounted for about half of the measured variance between subjects for all indices except FVC (68%). These results have implications for epidemiological studies.
Abstract P5-08-04: Overexpression of CXCR-4 confers trastuzumab resistance in human breast cancer cell lines
Authors: A Mehta, GK Wang-Kolodji, D Tripathy
Journal: Cancer Research (2013)

Abstract Background: Trastuzumab significantly improves survival in patients with HER2 positive breast cancer; however, de novo or acquired resistance ensues in the advanced setting. We have identified differentially expression genes in acquired trastuzumab resistance cell line models following long-term trastuzumab exposure and have demonstrated consistent overexpression of CXCR-4 at the mRNA and protein levels. The interaction between the cognate ligand CXCL-12 and its receptor CXCR-4 is known to promote malignant cell proliferation and angiogenesis via activation of Akt and MAPK pathways. CXCR-4 shows no to low expression in normal breast epithelium while its expression sequentially increases from precancerous lesions to carcinomas. CXCR-4 overexpression in human breast cancer is also associated with a worse outcome in small studies. We sought to explore the role of CXCR-4 expression on trastuzumab drug responsiveness. Methods: Trastuzumab-resistant cell lines were generated by serial passaging of HER+ cells lines BT-474 and SKBR-3 for 1 year with continual exposure to 200 μg/ml of trastuzumab. For these resistant cell lines, termed BtRT and SkRT, CXCR-4 mRNA was quantified using qRT-PCR, and CXCR-4 protein expression was quantified by Western blot. Stable clones overexpressing CXCR-4 receptor were selected by transfecting CXCR-4 sequence-containing lentivirus into sensitive parental sensitive BT-474 and SKBR3 cells. Expression of CXCR-4 receptor was assessed by Western blot assay and by flow cytometry. MTT cell viability analysis was performed on these transfected cell lines to characterize trastuzumab dose responsiveness with parental cells as control. Results: Trastuzumab-resistant cell line BtRT demonstrated a 100-fold increase in IC50 to trastuzumab treatment when compared to parental BT-474 cells and also exhibited a 3-fold further increase in CXCR-4 mRNA and a corresponding increase in CXCR-4 protein. CXCR-4-transfected sensitive BT474 cell lines showed a greater than 100 fold increase in the IC50 value on MTT assay after treatment with trastuzumab as compared to the parental cell line. Semi-quantitative analysis by Western-blot confirmed a 5-fold increase in CXCR-4 expression in CXCR-4-transfected cells as compared to parental cells. CXCR-4 expression in HER2+ human breast tumors and responsiveness in patients treated with neoadjuvant trastuzumab-based therapy will be presented. Conclusion: CXCR-4 overexpression and activation of the CXCR-4/CXCL-12 pathway contributes to trastuzumab resistance in human breast cancer cell lines. CXCR-4 targeting may represent a therapeutic strategy to improve the efficacy of trastuzumab in HER2-positive breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-04.
Anti-CD3 preconditioning separates GVL from GVHD via modulating host dendritic cell and donor T-cell migration in recipients conditioned with TBI
Authors: Nainong Li, Ying Chen, Wei He, Tangsheng Yi, Dongchang Zhao, Chunyan Zhang, Chia-Lei Lin, Ivan Todorov, Fouad Kandeel, Stephen Forman, Defu Zeng
Journal: Blood (2008)
Thrombin generation and secretion of platelet Factor 4 during blood clotting.
Authors: M A Shuman, S P Levine
Journal: Journal of Clinical Investigation (1978)

We have studied the platelet release reaction and thrombin generation during the spontaneous clotting of whole blood in vitro. Both thrombin formation and secretion of platelet Factor 4 were detected at least 12 min before clotting (clotting time, 22--26 min). Initially, at low thrombin concentrations (2--5 ng/ml), there is a small increase in plasma platelet Factor 4 (less than 1% of the amount present in serum). This is followed by a gradual increase in both platelet Factor 4 and thrombin concentrations over a 12 to 20-min interval. Finally, 5 min 5 before clotting, there is a rapid increase in both thrombin generation and platelet secretion. Thus, we have shown that the release of platelet Factor 4 is a prolonged reactoin and the extent to which it occurs parallel thrombin generation. It is only when thrombin concentrations are high (45--90) ng/ml)--during the period of clot formation--that the major part of platelet Factor 4 secretion occurs. Release of platelet Factor 4, like fibrin formation, occurs in the last step of in vitro coagulation.
Pitfall in Diagnosis of Diabetic "Cord Bladder"
Authors: Jack P. Whisnant
Journal: JAMA (1960)

This is a report of a case in which urinary and fecal incontinence were thought initially to be due to diabetic "cord bladder" but proved to be caused by an intraspinal tumor compressing the conus medullaris. The patient also had a peripheral neuritis which undoubtedly was related to his diabetes. Urinary and fecal incontinence are uncommon complications of diabetes. That they do exist as apparent complications is attested to by two published autopsy reports and other individual but unconfirmed reports. When clinical doubt exists in such instances of incontinence, radiologic contrast studies are usually necessary.
Hypervariable region sequence in cryoglobulin-associated hepatitis C virus in sera of patients with chronic hepatitis C: Relationship to antibody response against hypervariable region genom
Authors: T Aiyama, K Yoshioka, A Okumura, M Takayanagi, K Iwata, T Ishikawa, S Kakumu
Journal: Hepatology (1996)

Essential mixed cryoglobulinemia is frequently associated with hepatitis C virus (HCV) infection, with the formation of HCV antigen/antibody complexes. The hypervariable region (HVR) of the HCV E2/NS1 region is thought to include epitopes for neutralizing antibodies, but it remains uncertain whether cryoglobulins (CGs) contain such antibody-bound HCV. Thus, we studied HVR clones isolated from cryoprecipitate and supernatant in the sera of four chronic hepatitis C patients with cryoglobulinemia, and expressed as fusion proteins with glutathione S-transferase (GST). Patients' sera were tested for antibody binding to the proteins. The rate of anti-HVR antibody-positive clones was significantly higher in cryoprecipitate (89% +/- 13%, P < .05) than in supernatant (41% +/- 25%). Both HCV RNA and anti-HVR antibody were more concentrated in cryoprecipitates compared with those of serum and supernatant in two patients tested. Anti-HVR antibody-positive clones in cryoprecipitate showed common amino acid (aa) sequences in each of the four patients. Similarly, all the antibody-positive clones in supernatant showed the same aa sequences for three of the four patients. When aa sequences were compared with those of reported isolates with genotype 1b, the mean percentage of aa difference was greater in the clones from supernatant and in anti-HVR antibody-negative clones than in the clones from cryoprecipitate and in the antibody-positive clones, respectively. These findings indicate that serum CG contains anti-HVR antibody-bound HCV in patients with chronic hepatitis C. Anti-HVR antibody-free individual clones, which were more frequently noted in supernatant, showed closely related sequences, but which were of a heterogeneous quasispecies nature.
Evaluation of free and peptide bound collagen crosslink excretion in different skeletal diseases
Authors: A Muller
Journal: Annals of the Rheumatic Diseases (2002)

To investigate urinary fractions of free and peptide forms of collagen crosslinks in patients with rheumatoid arthritis (n=50), osteoarthrosis (n=38), psoriatic arthritis (n=38) and in healthy volunteers (33 adults, 17 children).Pyridinoline (PYD) and deoxypyridinoline (DPD) were measured by high performance liquid chromatography.In rheumatoid arthritis (RA) all fractions of PYD and DPD were significantly raised compared with osteoarthritis, psoriatic arthritis, and healthy controls. PYD and DPD correlated with disease activity in RA. In RA the collagen degradation resulted in primarily peptide bound forms.The correlation between total peptide bound or free collagen crosslinks in different chronic joint diseases varies; however, this variation does not allow for a reliable differentiation between inflammatory and degenerative joint diseases.
Trends in staffing an academic department of surgery in a tropical hospital: past, present, any future?
Authors: P T Nmadu
Journal: BMJ (1996)

<h3>Abstract</h3> <b>Objective</b>: To evaluate the effect of staff mobility on student teaching, the training of young surgeons, and the volume of research in an academic department of surgery of a tropical teaching hospital. <b>Design</b>: Retrospective study of academic staffing in the department of surgery of the Ahmadu Bello University Teaching Hospital between 1975 and 1993. <b>Setting</b>: Zaria, Nigeria. <b>Subjects</b>: 42 academic staff, 1190 medical students, and 110 registrars (trainee surgeons). <b>Main outcome measures</b>: Number of academic staff in post, medical students, and registrars; number of research papers in latter years of the study. <b>Results</b>: In 19 years, 42 academic staff worked for varying periods (1-15 years) in the university department of surgery in Zaria. These included six professors, 12 senior lecturers, and 24 lecturers. Although staff numbers diminished, numbers of students and registrars increased year by year. Average number of publications dropped from a peak of 14.4 to 7.4 a year. <b>Conclusion</b>: Staffing of the department has fallen steadily over the years and has adversely affected the department9s primary responsibility of teaching students and training young surgeons.
Contrast Radiographic Demonstration of a Lymph Node Metastasis
Authors: Harry W. Fischer
Journal: JAMA (1961)

INFORMATION on the number and extent of metastases—particularly early metastases prior to treatment or surgical exposure of malignant tumors—has always been desired. In our present state of knowledge, metastatic tumor in lymph nodes is diagnosed clinically by a considerable increase in node size, by the enlarged nodes exerting pressure on adjacent structures, or by lymphedema. In each of these instances, metastases can be assumed to be extensive and the prognosis generally unfavorable. Contrast lymphography offers some hope for solution to the problem of early diagnosis of metastases in the intact patient. Tjernberg<sup>1</sup>first demonstrated artificially implanted tumor in the nodes of rabbits. Fischer and Zimmerman<sup>2</sup>produced simulated metastases and clearly demonstrated discrete filling defects in otherwise normal popliteal nodes of dogs. From these animal experiments, the possibility of demonstrating discrete node metastases has gained support. We are presenting a case of a metastasis in a lymph node
1121-51 SU11218, a platelet-derived growth factor receptor and vascular endothelial growth factor receptor 2 inhibitor blocks adventitial angiogenesis and prevents intimal hyperplasia after coronary stenting in a porcine model
Authors: Asim N Cheema, Tony S Hong, Jennifer Dietrich, David Holdsworth, Ken Lipson, Bradley H Strauss
Journal: Journal of the American College of Cardiology (2004)