tbuckley/cabot-search huggingface dataset:
Abstract 4563: Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma
Authors: Erica L. Carpenter, Elizabeth A. Haglund, Adrian K. Chow, Andrew C. Wood, Lili T. Belcastro, James G. Christensen, Marc Vigny, John M. Maris, Mark A. Lemmon, Yael P. Mosse
Journal: Cancer Research (2011)

Abstract The purpose of this study was to provide the first pre-clinical evidence for antibody targeting of anaplastic lymphoma kinase (ALK) in human neuroblastoma. ALK is a receptor tyrosine kinase expressed by the majority of neuroblastoma tumors. Germline mutations of ALK, shown to account for most cases of familial neuroblastoma, as well as somatically acquired ALK aberrations, induce increased auto-phosphorylation and constitutive ALK activation and increased downstream signaling. Antibody targeting of receptor tyrosine kinases, as monotherapy or together with small-molecule inhibitors, is highly effective in other cancers such as breast and lung cancer. While antibody-mediated immunotherapy targeting of disialoganglioside GD2 has recently been reported to significantly increase 2-year survival in high-risk neuroblastoma patients, over half the patients receiving this therapy ultimately succumb to their disease and therapeutic alternatives are urgently needed to improve survival rates of this devastating pediatric cancer. Therefore, we hypothesized that antibody targeting of ALK in neuroblastoma was a therapeutically appropriate strategy. To first confirm the potential of anti-ALK antibody-mediated immunotherapy, we used in vitro assays to demonstrate enhanced immune-cell induced cytotoxicity of antibody-treated human neuroblastoma-derived cell lines. We next showed that in vitro antibody treatment of neuroblastoma cell lines expressing activated ALK led to growth inhibition and cell death. These effects were enhanced by treatment with PF-02341066, an orally available small-molecule inhibitor of the ALK tyrosine kinase. To identify the mechanism behind this enhanced combined effect, we used flow cytometry to show that PF-02341066 sensitizes cells to antibody treatment by inducing accumulation of cell-surface ALK, thus increasing the accessibility of antigen for antibody binding. Finally, to further predict in vivo cytotoxic mechanisms of dual ALK targeting, we used flow cytometry to demonstrate enhanced apoptosis and proliferation inhibition resulting from combined antibody and inhibitor treatment as compared to either drug alone. Taken together, these findings provide strong evidence for the therapeutic relevance of antibody targeting of ALK in neuroblastoma and argue for the rapid development and further testing of a clinical grade anti-ALK antibody. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4563. doi:10.1158/1538-7445.AM2011-4563
Burkitt cell leukemia following therapy for hodgkin disease
Authors: Victor H. Nassar, Julian Jacobs, Suzanne S. Mirra, Kishan J. Pandya, Sheldon Schwartz, John M. Bennett
Journal: American Journal of Hematology (1982)

Abstract Two adults with advanced Hodgkin disease — one treated with combination chemotherapy, and one with chemotherapy and radiation therapy — developed Burkitt cell leukemia four and seven years after diagnosis, proved by cytochemical and ultrastructural study. Acute lymphocytic leukemia must be considered in the evaluation of therapy‐related leukemias.
Intravenous Aminophylline Dosage
Authors: Miles W. Weinberger
Journal: JAMA (1976)

A practical method for monitoring serum theophylline concentrations has been used to investigate intravenous aminophylline dosage requirements. Initial serum theophylline concentrations were found to vary widely and correlate poorly with drug history. Aminophylline loading doses determined from these values more frequently resulted in drug concentrations in the therapeutic range (10μg to 20μg/ml) than when therapy was given without knowledge of serum theophylline concentrations. Continuous intravenous aminophylline therapy administered in a standardized dosage (0.9 mg/kg/hr in adults and 1.0 mg/kg/hr in children) produced variable and often excessive serum concentrations. This resulted from variable drug clearance rates, which in adults averaged 0.64±0.38 ml/kg/min (mean±SD), only half that previously reported. These observations suggest that it is not possible to achieve optimal therapeutic aminophylline dosage without monitoring serum theophylline concentrations. (<i>JAMA</i>235:2110-2113, 1976)
NHS in England needs new strategy to avoid 30bn shortfall, say health chiefs
Authors: Z. Kmietowicz
Journal: BMJ (2013)

A simple passive haemmagglutination assay (PHA) was developed to detect Vi antibodies, to improve the diagnosis of typhoid fever by small laboratories. The Vi capsular antigen of Salmonella typhi was extracted by alternate alcohol and acetone precipitation. Formalin fixed, sheep red blood cells treated with chromium chloride were sensitised with this Vi antigen and antibodies detected and measured by PHA. The test had a sensitivity of 83.3% among 30 cases of typhoid fever confirmed by culture. The specificity of the test was 94%, making it suitable for use in laboratories without facilities for IFAT or ELISA.
In vitro mutagenesis of HLA-B27. Substitution of an unpaired cysteine residue in the alpha 1 domain causes loss of antibody-defined epitopes.
Authors: J D Taurog, F A el-Zaatari
Journal: Journal of Clinical Investigation (1988)

The HLA class I molecules identified serologically as HLA-B27 are highly associated with ankylosing spondylitis and related human disorders. All known HLA-B27 amino acid sequences contain a cysteine residue at position 67; no other published HLA class I sequence contains a cysteine within the hypervariable region of the alpha 1 domain, which extends from amino acid residues 63-84. To investigate the role of this cysteine residue in the antigenic structure of HLA-B27, we isolated a genomic clone encoding a molecule of the HLA-B27.1 subtype and performed oligonucleotide-directed mutagenesis to convert the cysteine at position 67 to a tyrosine. When transfected into mouse L cells, both the wild-type and Cys67----Tyr67 mutant B27 genes directed the synthesis and surface expression of molecules reactive with the monomorphic anti-HLA class I antibody W6/32. However, only the L cells transfected with the wild-type B27 gene reacted with the anti-B27 antibody ME1; L cells transfected with the mutant B27 were completely unreactive with this antibody. Experiments with hybrid exons created from the HLA-B27 and HLA-A2 genes yielded results consistent with the mapping of the ME1 epitope to the B27 alpha 1 domain. A second anti-B27 antibody, GS145.2, also showed markedly reduced binding to the Cys67----Tyr67 mutant. These studies document the importance of the unique Cys67 residue in the antigenic structure of HLA-B27.
Pulmonary sarcoidosis: alterations in bronchoalveolar lymphocytes and T cell subsets.
Authors: A P Greening, P Nunn, N Dobson, M Rudolf, A D Rees
Journal: Thorax (1985)

Peripheral blood and bronchoalveolar lavage lymphocyte subpopulations have been evaluated in 14 patients with pulmonary sarcoidosis and eight normal subjects, monoclonal antibodies of the leu series being used. No significant alterations of T lymphocyte subpopulations were found in the peripheral blood of sarcoidosis patients. There was, however, a significantly greater proportion of T suppressor-cytotoxic cells (36.0 (SD 17.6%] in the bronchoalveolar lavage fluid of patients than of normal subjects (15% (5.6%); p less than 0.01), but a decrease in the proportion of T helper-inducer cells (51.1% (18%) v 79.3% (9%). These changes correlated with the duration of the disease but not with other clinical, radiological, physiological, or biochemical criteria. Patients were followed up for six to 20 months and five patients had a repeat bronchoalveolar lavage and lymphocyte subpopulation evaluation after three to 14 months. The initial pulmonary T lymphocyte subset proportions were not predictive of clinical, physiological, or radiological alterations during follow up. There was also no consistent pattern in the relationship between change in T subset proportions and change in clinical physiological, and radiological features in the five patients having a repeat lavage. Lymphocyte surface marker studies may indicate immunopathogenetic mechanisms in sarcoidosis but do not appear to be good predictors of clinical outcome.
Analgesic effect of somatostatin analogue (octreotide) in headache associated with pituitary tumours.
Authors: G Williams, J A Ball, R A Lawson, G F Joplin, S R Bloom, M R Maskill
Journal: BMJ (1987)

The COVID19 pandemic, caused by SARS-CoV-2, has infected more than 100 million people worldwide. Due to the rapid spreading of SARS-CoV-2 and its impact, it is paramount to find effective treatments against it. Human neutralizing antibodies are an effective method to fight viral infection. However, the recent discovery of new strains that substantially change the S-protein sequence has raised concern about vaccines and antibodies' effectiveness. Here, we investigated the binding mechanisms between the S-protein and several antibodies. Multiple mutations were included to understand the strategies for antibody escape in new variants. We found that the combination of mutations K417N and E484K produced higher binding energy to ACE2 than the wild type, suggesting higher efficiency to enter host cells. The mutations' effect depends on the antibody class. While Class I enhances the binding avidity in the presence of N501Y mutation, class II antibodies showed a sharp decline in the binding affinity. Our simulations suggest that Class I antibodies will remain effective against the new strains. In contrast, Class II antibodies will have less affinity to the S-protein, potentially affecting these antibodies' efficiency.
Electrocardiographic Response to Exercise in Patients with Mitral Stenosis
Authors: LLOYD H. RAMSEY, JOHN BEEBLE
Journal: Circulation (1959)

On the assumption that a positive Master 2 step exercise test is good evidence for the existence of myocardial ischemia, the coronary circulation of 40 patients with rheumatic heart disease and isolated mitral stenosis has been tested by this means. The findings in patients of classes I to III are discussed regarding factors that might be responsible and the relationship of the findings to symptomatology in patients with mitral stenosis.
JAMA Student Body: High School to Postdoctoral
Authors: Phil Gunby
Journal: JAMA (1987)

IT ISN'T LISTED among the nation's colleges and universities, and no team wearing its colors will appear on a foot-ball field this fall, but in pursuit of its educational missionTHE JOURNALhas a student body of its own. There is the Morris Fishbein Fellowship in Medical Journalism, a one-year program for physicians of working with<i>JAMA</i>'s editorial and production staff in Chicago.<i>JAMA</i>'s tenth Fishbein Fellow will be named next March 15 for the July 1, 1988, through June 30, 1989, fellowship year. Applications must be received no later than Jan 15. Then there is the senior elective program for medical students, who work with the<i>JAMA</i>staff for two or more months. The most recent to complete the program came from Houston and Philadelphia, and two more reported to work this month. Interested students may write to George D. Lundberg, MD, the editor, indicating when they
Female urinary incontinence.
Authors: N W Harrison, P Paterson
Journal: BMJ (1969)

MEDITJSHRNAL 619 close links with general practitioners and the local community.We cannot foresee general practitioners acting as efficient substitutes for junior hospital staff without a complete re- organization of their present duties.Those who live close enough to the hospitals to be of any help at all would not be able to offer sufficient hours unless their practices were able to recruit extra help.There is no evi- dence that this is possible, and, in fact, no evidence that the general practitioners wish to help except with occasional clinics.We also wish to observe that the report's plans for the redeployment of registrars and its suggestion that some consultant posts should only be temporary would be very likely to interfere with the further development of postgraduate education and research which is so important in the periphery.-Weare, etc.,
What's the Matter? White Matter?
Authors: Thomas Zeffiro, Guinevere Eden
Journal: Neuron (2000)

Although many children acquire reading skills rapidly with some formal training, for others learning to read is among the most difficult challenges they face in the first few years at school. The reasons for these large individual differences in skill acquisition are still obscure, with the relative contribution of biological and environmental factors vigorously debated. As the social and economic consequences of widespread illiteracy can be profound, better understanding of the brain mechanisms responsible for the acquisition of reading skills has become a national priority (Lyon 1995).
Subpopulations of B cells distinguished by cell surface expression of Ia antigens. Correlation of Ia and idiotype during activation by cloned Ia-restricted T cells.
Authors: K Bottomly, B Jones, J Kaye, F Jones
Journal: The Journal of Experimental Medicine (1983)

We have investigated in vitro the induction of antibody responses to phosphorylcholine (PC) by cloned T helper (Th) cell lines. The cloned Th cells are antigen specific, in this case ovalbumin (OVA), self-Ia recognizing, and induce antibody secretion only if the hapten, PC, is physically linked to the carrier (OVA) molecule. The plaque-forming cell (PFC) response generated in the presence of cloned Th cells is idiotypically diverse with 5-40% of the secreting B cells bearing the TEPC-15 (T15) idiotype. The interaction of the cloned Th cells and unprimed B cells requires recognition of B cell surface Ia glycoproteins for all B cells activated to secrete anti-PC antibody, whether they be T15-bearing or not. More importantly, however, effective interaction between a cloned Th cell and a B cell is determined by the quantity of B cell surface Ia glycoproteins. Our results indicate that quantitative differences in B cell surface Ia antigens are directly related to B cell activation by the cloned Th cell. The high Ia density B cells are most easily activated by cloned Th cells, and these appear to be mainly non-T15-bearing. These data suggest that the failure of cloned Th cells to effectively activate T15-bearing B cells in vitro may be due to the lower relative Ia density of these B cells and therefore to their inability to interact effectively with cloned Ia-recognizing Th cells. These results imply that monoclonal T cells may distinguish between T15-bearing and non-T15-bearing B cells based on their Ia density.
Baghdad's hospitals struggle to cope with war wounded
Authors: O. Dyer
Journal: BMJ (2003)

As the BMJ went to press on Tuesday, reports from Baghdad's hospitals suggested that they were no longer able to cope with the flow of people wounded in the war. An American armoured foray into the city centre on 6 April brought the heaviest casualties to date in Baghdad, and the Yarmouk Hospital—one of five in the city able to treat war wounded—was receiving 100 new casualties an hour, according to the International Committee of the Red Cross.

Despite the power cut that has affected much of the city since 3 April, the hospitals had electric power from backup generators. They were often plunged into darkness, however, when the generators were shut down to prevent overheating.

Problems were most severe in the south of the city, the Red Cross said, because a damaged bridge and continued fighting were preventing the wounded from reaching the city centre, where the main hospitals are located.

Many hospital staff could not reach work, with the result that doctors were performing nurses' duties and even pushing trolleys. Medical supplies were holding up in Baghdad, but in some hospitals the …
Genetic modification of the vessel wall. Comparison of surgical and catheter-based techniques for delivery of recombinant adenovirus.
Authors: J E Willard, C Landau, D B Glamann, D Burns, M E Jessen, M J Pirwitz, R D Gerard, R S Meidell
Journal: Circulation (1994)

BACKGROUND Gene transfer can potentially alter vessel wall biology and intervene in the pathogenesis of human disease. Although several methods for vector delivery have been described, systematic comparisons of these methods are unavailable. Therefore, this study compared three catheter-based strategies and a surgical technique to assess efficient and selective gene transfer to the vascular wall. METHODS AND RESULTS The common carotid arteries and internal jugular veins of New Zealand White rabbits were infected with recombinant adenovirus encoding either firefly luciferase or a nuclear-localizing variant of beta-galactosidase. Delivery of recombinant virus was achieved by one of four methods: (1) instillation within a surgically isolated vessel segment (dwell), (2) a double-balloon catheter, (3) a perforated balloon catheter (Wolinsky), or (4) an angioplasty balloon catheter coated with a hydrophilic adsorbent polymer (Hydrogel). Vessel segments were analyzed 4 days after infection for luciferase and beta-galactosidase activity and for the extent of injury to the vessel wall. Luciferase activity in vessels infected using the double-balloon method was substantially greater than that achieved by catheter-based methods (P &lt; .05). The dwell and double-balloon methods yielded selective expression in intimal cells, whereas arteries infected using perforated or Hydrogel-coated balloon catheters demonstrated expression primarily in medial cells. Tissue injury was most pronounced with the perforated balloon catheter. CONCLUSIONS Prototype catheters permit relatively efficient direct gene transfer to vascular endothelium; however, delivery methods for targeting the medial cells are inefficient. Modifications are needed to optimize direct gene transfer and minimize tissue injury.
In Vitro Translation and Assembly of a Complete T Cell Receptor–CD3 Complex
Authors: Johannes B. Huppa, Hidde L. Ploegh
Journal: The Journal of Experimental Medicine (1997)

The T cell receptor for antigen (TCR) is a multisubunit complex that consists of at least seven polypeptides: the clonotypic, disulfide-linked α/β heterodimer that is noncovalently associated with the invariant polypeptides of the CD3 complex (CD3-γ, -δ, -ε) and ζ, a disulfide-linked homodimer. We achieved the complete assembly of the human TCR in an in vitro transcription/translation system supplemented with dog pancreas microsomes by simultaneous translation of the messenger RNAs encoding the TCR-α, -β and CD3-γ, -δ, -ε, and -ζ subunits. CD3-ε, one of the subunits that initiates the assembly of the TCR in living cells, forms misfolded, disulfide-linked homooligomers when translated alone. However, co-translation of one of its first binding partners in the course of assembly, CD3-γ or -δ, led to the expression of mainly monomeric and correctly folded ε subunits, the only form we could detect as part of a properly assembled TCR complex. In the absence of these subunits, the ER-resident chaperone calnexin interacted with oligomeric, i.e. misfolded, structures of CD3-ε in a glycan-independent manner. A glycan-dependent interaction between CD3-ε and calnexin was mediated by CD3-γ and concerned only monomeric CD3-ε complexed with CD3-γ, but was dispensable for proper folding of CD3-ε. We suggest that in addition to its signaling function, CD3-ε serves as a monitor for proper subunit assembly of the TCR.
Risk of gastrointestinal effects with COX-2 inhibitors and NSAIDs: Why were patients at major risk excluded?
Authors: Luca Puccetti
Journal: BMJ (2005)

Rationing in response to NHS deficits: rural patients are likely to be affected most See News, p 1426Editor-News that pressing financial problems have caused NHS trusts in Suffolk to set new "thresholds" to treatments such as joint replacements reinforces concerns raised by a recent BMA survey of medical directors of trusts in which over a third of respondents anticipated reductions of key services in response to funding shortfalls. 1 2 What has hitherto escaped comment is how cuts in services are far more likely to be felt in some parts of the country than others.Deficits in the NHS are invariably presented as a problem of financial mismanagement, but the pattern of deficits shows that the current resource allocation model discriminates against particular communities.According to the recently published accounts for 2004-5, 3 89 out of 303 (30%) English primary care trusts ended the year in deficit.The table shows how 301 of these trusts are distributed accorded to fifths of deprivation and rurality.Primary care trusts serving populations that are in both the most rural and the least deprived fifth were most likely to be in financial difficulties.Seventeen of the 25 (68%) in this category were in deficit.These trusts received the lowest funding allocation per head (£995).By contrast, only 3% (one of 34) of the primary care trusts serving populations that are in both the most urban and the most deprived fifths failed to break even in 2004-5.These trusts received the highest funding allocations per head (£1405).This shows that poor financial management can at best only partly explain why some trusts are in deficit.The pattern of deficits implies that NHS funding provides insufficient resources for rural areas, for comparatively affluent areas, and, most particularly, for areas that are both rural and affluent.The risk is that such measures will result in NHS services being subject to a new postcode lottery, in which rural residents are more likely to lose out.
Cellular Immunity to Sperm in Infertile Women
Authors: Gilbert G. Haas
Journal: JAMA (1986)

<h3>To the Editor.—</h3> The interesting article by McShane et al,<sup>1</sup>"Cellular Immunity to Sperm in Infertile Women," supports the contention that cellular immunity to sperm may produce infertility in some women. Close inspection of the sperm antigen preparation technique shows that a whole ejaculate was used to prepare the stimulating antigen. Unfortunately, seminal cells other than spermatozoa are present in an ejaculate and must be separated by "swim-up" techniques or other methods. The possibility that nonsperm cells stimulate lymphocyte cultures has been supported by Rodriguez-Cordoba and Arnaiz-Villena.<sup>2</sup> The article is well written, but I am cautious in interpreting the results.
Alterations in the Interactome of Serine/Threonine Protein Phosphatase Type-1 in Atrial Fibrillation Patients
Authors: David Y. Chiang, Nicolas Lebesgue, David L. Beavers, Katherina M. Alsina, J. Mirjam A. Damen, Niels Voigt, Dobromir Dobrev, Xander H.T. Wehrens, Arjen Scholten
Journal: Journal of the American College of Cardiology (2015)