tbuckley/cabot-search huggingface dataset:
An Inhibitor of ADAMs (a Distintegrin and Metalloproteinase) Overcomes HER3-Mediated Resistance to Trastuzumab and Lapatinib.
Authors: P. Scherle, C. Marando, M. Covington, W. Yao, R. Newton, S. Friedman
Journal: Cancer Research (2009)

Abstract Background: Inhibitors of HER-2/neu and EGF receptors such as trastuzumab, lapatinib, and erlotinib have demonstrated clinical efficacy but not all HER-2/neu or EGFR positive tumors respond and many that initially respond develop resistance. Ligand mediated HER-3 signaling results in tumor growth and survival and is a proposed mechanism of resistance to trastuzumab and lapatinib. Proteolytic cleavage of both ErbB ligands and receptors has been shown to be a critical event that results in ErbB pathway activation. Cleavage is necessary for the generation of soluble, functionally active forms of ErbB ligands and in the case of HER-2/neu, cleavage results in a shed extracellular domain (ECD) and a membrane bound fragment (p95) that contains a kinase domain with significant constitutive activity. In addition, it has been shown that the preferential association between HER3 and p95 can further activate the pathway. Both ErbB ligand and HER-2/neu cleavage are mediated by the ADAM family of proteases. Further, we have previously shown that the ADAM protease inhibitor, INCB7839, provides synergistic inhibition of HER2+ breast cancer cell line growth when combined with either trastuzumab or lapatinib. Materials and Methods: The HER-2 overexpressing BT-474 human breast cancer cell line was treated with either lapatinib or trastuzumab in the presence or absence of the HER-3 ligand, heregulin, and the effects on cell growth measured. The effects of the ADAM protease inhibitor INCB7839 in this system were also examined. Results: The addition of heregulin overcame the anti-proliferative effects of both lapatinib and trastuzumab on the growth of the BT-474 cell line in vitro. Addition of INCB7839 synergized with lapatinib or trastuzumab and importantly, restored the anti-proliferative effects of these agents in the presence of heregulin. Further, pretreatment of BT-474 cells with INCB7839 for 6 days, which we have previously shown completely eliminates the presence of the p95 form of HER2, amplified these effects, presumably by eliminating p95 before stimulating the cells with heregulin. Discussion: Together, these results confirm that heregulin can overcome the anti-proliferative effects of both trastuzumab and lapatinib as previously reported. Prevention of p95 formation by ADAM protease inhibitors appears to restore the anti-proliferative effects of both trastuzumab and lapatinib when heregulin/HER3 signaling occurs, negating a proposed mechanism of resistance to these agents in the clinic. These results suggest that combining an ADAM inhibitor with targeted inhibitors of the ErbB family can overcome HER-3-mediated resistance and enhance the clinical efficacy of approved HER2-targeted agents in the clinical setting. INCB7839 is currently under clinical investigation in combination with trastuzumab for women with metastatic breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3138.
Off-the-shelf Adenoviral-mediated Immunotherapy via Bicistronic Expression of Tumor Antigen and iMyD88/CD40 Adjuvant
Authors: Jan Ole Kemnade, Mamatha Seethammagari, Priya Narayanan, Jonathan M Levitt, Alison A McCormick, David M Spencer
Journal: Molecular Therapy (2012)

Recent modest successes in ex vivo dendritic cell (DC) immunotherapy have motivated continued innovation in the area of DC manipulation and activation. Although ex vivo vaccine approaches continue to be proving grounds for new DC manipulation techniques, the intrinsic limits of ex vivo therapy, including high cost, minimal standardization, cumbersome delivery, and poor accessibility, incentivizes the development of vaccines compatible with in vivo DC targeting. We describe here a method to co-deliver both tumor-specific antigen (TSA) and an iMyD88/CD40 adjuvant (iMC), to DCs that combines toll-like receptor (TLR) and CD40 signaling. In this study, we demonstrate that simple TSA delivery via adenoviral vectors results in strong antitumor immunity. Addition of iMC delivered in a separate vector is insufficient to enhance this effect. However, when delivered simultaneously with TSA in a single bicistronic vector (BV), iMC is able to significantly enhance antigen-specific cytotoxic T-cell (CTL) responses and inhibit established tumor growth. This study demonstrates the spatial-temporal importance of concurrent DC activation and TSA presentation. Further, it demonstrates the feasibility of in vivo molecular enhancement of DCs necessary for effective antitumor immune responses.
INTRAMUSCULAR ADMINISTRATION OF BISMUTH
Authors: J. L. Grund
Journal: JAMA (1926)

<h3>To the Editor:</h3> —InThe Journal, January 30, appears an article by Dr. Irwin Sutton, who reports a case of gluteal abscess following the intramuscular administration of a bismuth salt, neotrepol, which was used in the treatment of a patient with syphilis. The impression conveyed is that the phenomenon is rare. During our early experience with neotrepol at the Boston Dispensary several years ago, we encountered at least two similar cases. Following the substitution of potassium bismuth tartrate for the latter drug, we encountered at least ten more. These have occurred for the most part in obese women. In view of the large number of patients receiving bismuth treatment, this forms only a small percentage of the total. Nodes appearing at the site of the injection have been not uncommon and have also made their most frequent appearance in women. An abscess following the injection of bismuth is due as
CONSENSUS DEFINITION-BASED CUTOFFS OF HIGH ON-TREATMENT PLATELET REACTIVITY: VALIDATION BETWEEN LIGHT TRANSMITTANCE AND MULTIPLE ELECTRODE AGGREGOMETRIES
Authors: Yongwhi Park, Young-Hoon Jeong, In-Suk Kim, Jeong Rang Park, Seok-Jae Hwang, Choong Hwan Kwak, Jin-Yong Hwang
Journal: Journal of the American College of Cardiology (2011)
Triplex-Stimulated Intermolecular Recombination at a Single-Copy Genomic Target
Authors: Melissa P. Knauert, Jennifer M. Kalish, Denise C. Hegan, Peter M. Glazer
Journal: Molecular Therapy (2006)

Gene targeting via homologous recombination offers a potential strategy for therapeutic correction of mutations in disease-related human genes. However, there is a need to improve the efficiency of site-specific recombination by transfected donor DNAs. Oligonucleotide-mediated triple helix formation has been shown to constitute a DNA lesion sufficient to provoke DNA repair and thereby stimulate recombination. However, the ability of triplex-forming oligonucleotides (TFOs) to induce recombination between a target locus and a donor DNA has so far been demonstrated only with multicopy episomal targets in mammalian cells. Using cell lines containing the firefly luciferase reporter gene, we have now established the ability of TFOs to induce gene correction by exogenous donor DNAs at a single-copy chromosomal locus. We find that cotransfection of TFOs and short, single-stranded DNA donor molecules into mammalian cells yields gene correction in a dose-dependent manner at frequencies up to 0.1%, which is five- to ninefold above background. We demonstrate both oligonucleotide-specific and target site-specific effects. We also find that recombination can be induced by both parallel and antiparallel triple helix formation. These results provide further support for the development of TFOs as reagents to stimulate site-specific correction of defective human genes.
Ultrastructural studies of human lymphoid cells. mu and J chain expression as a function of B cell differentiation.
Authors: I Hajdu, Z Moldoveanu, M D Cooper, J Mestecky
Journal: The Journal of Experimental Medicine (1983)

J chain expression was examined as a function of the stage in differentiation along the B cell axis in humans. Intracellular distribution of J and mu chains in leukemic HLA-DR+ null and pre-B cells, and in normal B cells stimulated with pokeweed mitogen (PWM) was determined by immunoelectron microscopy and radioimmunoassay (RIA). J chain was detected in leukemic null and pre-B cells on free and membrane-bound ribosomes in the cytoplasm, or on perinuclear cisternae. Mu chain was found on free ribosomes and ribosomal clusters in leukemic pre-B cells but was absent in the leukemic null cells. In pre-B cell lines, mu chain was seen within rough endoplasmic reticulum (RER) and the Golgi apparatus whereas J chain was not detected in these organelles. However, both mu and J chain were detected in RER and the Golgi apparatus of immature and mature plasma cells induced by PWM stimulation of normal peripheral blood lymphocytes. Low levels of J chain were also detected by RIA in lysates of leukemic null and pre-B cells. Most of the intracellular J chain became detectable after reduction and alkylation of cell lysates, and free J chain was not found in the culture supernatants. The amount of intracellular and secreted immunoglobulin-bound J chain increased dramatically after PWM stimulation of peripheral blood lymphocytes. The majority of J chain-positive cells seen over an 8 d culture interval were lymphocytes and lymphoblasts, while mu chain was found primarily in plasma cells. These results suggest that J chain expression precedes mu chain synthesis during B cell differentiation and that a combination of the two chains for secretion is not initiated until the onset of plasma cells maturation.
Media focus on failures of screening programme
Authors: J. Johnson
Journal: BMJ (1997)

Channel 4's recent Dispatches programme on cervical screening focused on one poorly performing laboratory. Dr Jane Johnson says it is important that the whole screening programme is not tarred with the same brush. 

The NHS cervical screening programme is the envy of the world. Since the introduction of the central call and recall system and incentive payments for general practitioners in 1989-90, the percentage of women aged 20-64 being screened in England and Wales has increased from 50-60% to over 80%, and the death rate from the disease is falling steadily at about 7% a year. It has been estimated that the screening programme may save up to 7000 women's lives every year.

The number of new cases of invasive cancer being diagnosed has …
Comparative Efficacy of Insect Repellents against Mosquito Bites
Authors: Mark S. Fradin, John F. Day
Journal: New England Journal of Medicine (2002)

The worldwide threat of arthropod-transmitted diseases, with their associated morbidity and mortality, underscores the need for effective insect repellents. Multiple chemical, botanical, and “alternative” repellent products are marketed to consumers. We sought to determine which products available in the United States provide reliable and prolonged complete protection from mosquito bites.
HL-A antigens in patients with guttate psoriasis
Authors: R.C. WILLIAMS, A.W. McKENZIE, J.H. ROGER, V.C. JOYSEY
Journal: British Journal of Dermatology (1976)

Journal Article HL‐A antigens in patients with guttate psoriasis Get access R.C. WILLIAMS, R.C. WILLIAMS Previously Department of Physical Anthropology, University of Cambridge, Norfolk and Norwich Hospital, Department of Applied Statistics, University of Reading, and Tissue Typing Laboratory, Addenbrooke's Hospital, Cambridge Search for other works by this author on: Oxford Academic Google Scholar A.W. McKENZIE, A.W. McKENZIE Previously Department of Physical Anthropology, University of Cambridge, Norfolk and Norwich Hospital, Department of Applied Statistics, University of Reading, and Tissue Typing Laboratory, Addenbrooke's Hospital, Cambridge Search for other works by this author on: Oxford Academic Google Scholar J.H. ROGER, J.H. ROGER Previously Department of Physical Anthropology, University of Cambridge, Norfolk and Norwich Hospital, Department of Applied Statistics, University of Reading, and Tissue Typing Laboratory, Addenbrooke's Hospital, Cambridge Search for other works by this author on: Oxford Academic Google Scholar V.C. JOYSEY V.C. JOYSEY Previously Department of Physical Anthropology, University of Cambridge, Norfolk and Norwich Hospital, Department of Applied Statistics, University of Reading, and Tissue Typing Laboratory, Addenbrooke's Hospital, Cambridge Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 95, Issue 2, 1 August 1976, Pages 163–167, https://doi.org/10.1111/j.1365-2133.1976.tb00820.x Published: 01 August 1976
A case of intrinsic asthma.
Authors: P J Kingsley
Journal: BMJ (1977)

<h3>Abstract</h3> Influenza viruses have caused disease outbreaks in human societies for a long time. Influenza often has rapid onset and relatively short duration, both in the individual and in the population. The case fatality rate varies for different strains of the virus, as do the effects on total mortality. Outbreaks related to coronavirus infections have recently become a global concern but much less is known about the dynamics of these outbreaks and their effects on mortality. In this work, disease outbreaks in Sweden, in the time period of 1860-2020, are characterized and compared to the currently ongoing COVID-19 outbreak. The focus is on outbreaks with a sharp increase in all-cause mortality. Outbreak onset is defined as the time point when deaths counts starts to increase consistently for a period of 10 days. The duration of the outbreak is defined as the time period in which mortality rates are elevated. Excess mortality is estimated by standard methods. In total there were 15 outbreaks detected in the time period, the first 14 were likely caused by influenza virus infections, the last by SARS-CoV-2. The mortality dynamics of the SARS-CoV-2 outbreak is shown to be similar to outbreaks due to influenza virus, and in terms of the number of excess deaths, it is the worst outbreak in Sweden since the ’Spanish flu’ of 1918-1919.
The birth and re-birth of respiratory medicine notes from the British Thoracic Society Winter Meeting 2006
Authors: J K Quint, R Baghai-Ravary
Journal: Thorax (2007)

The annual Winter British Thoracic Society (BTS) meeting in December 2006 provided us with yet another exciting forum for both scientists and clinicians to share advances in respiratory medicine. The meeting consisted of inspiring, novel and interesting work, presented by students and non-clinicians, as well as world renowned respiratory physicians. Professor Stephen Holgate, in his address as President of the BTS entitled “The birth and re-birth of respiratory medicine”, spoke of changes and shared his visions for the future. Dr Alex Richter and Dr Clare Sander deserve congratulations for their success in the Young Investigator Prizes. In this review we highlight some of the important spoken and abstract sessions from the meeting.

Chronic obstructive pulmonary disease (COPD) was well represented at the meeting this year, with a stimulating symposium focusing on the science and impact of exacerbations. Spoken sessions on a novel in vivo model of human rhinovirus infection1 and application of real-time quantitative polymerase chain reaction for the detection of bacteria2 opened platforms for improved understanding of the infectious mechanisms of exacerbations. There was evidence to suggest that prolonged exacerbation in smokers may be related to impaired neutrophil activation.3 Smoking cannabis was related to greater airflow obstruction than cigarettes,4 re-enforcing the need to address all smoking cessation.

The consequences of depression in COPD, in particular the associations with mental and general fatigue,5 relation to reduced time spent outdoors, health-related quality of life6 and failure to complete pulmonary rehabilitation,7 were discussed in several sessions. Randomised controlled trials are needed to investigate reports of benefit from pulmonary rehabilitation initiated during admission for acute exacerbation8 and in maintenance of weekly supervised exercise sessions.9 An assessment of the national availability, need, cost-effectiveness and outcome of pulmonary rehabilitation10,11 may be facilitated by a …
Hybrid Coronary Revascularization for the Treatment of Multivessel Coronary Artery Disease
Authors: John D. Puskas, Michael E. Halkos, Joseph J. DeRose, Emilia Bagiella, Marissa A. Miller, Jessica Overbey, Johannes Bonatti, V.S. Srinivas, Mark Vesely, Francis Sutter, Janine Lynch, Katherine Kirkwood, Timothy A. Shapiro, Konstantinos D. Boudoulas, Juan Crestanello, Thomas Gehrig, Peter Smith, Michael Ragosta, Steven J. Hoff, David Zhao, Annetine C. Gelijns, Wilson Y. Szeto, Giora Weisz, Michael Argenziano, Thomas Vassiliades, Henry Liberman, William Matthai, Deborah D. Ascheim
Journal: Journal of the American College of Cardiology (2016)
Cysteine-modifying agents: a possible approach for effective anticancer and antiviral drugs.
Authors: Angela Casini, Andrea Scozzafava, Claudiu T Supuran
Journal: Environmental Health Perspectives (2002)

Modification of cysteine residues in proteins, due to a) the participation of the thiol moiety of this amino acid in oxido-reduction reactions, b) its ability to strongly coordinate transition metal ions, or c) its nucleophilic nature and facile reaction with electrophiles, may be critically important for the design of novel types of pharmacological agents. Application of such procedures recently led to the design of novel antivirals, mainly based on the reaction of zinc finger proteins with disulfides and related derivatives. This approach was particularly successful for developing novel antiviral agents for human immunodeficiency virus and human papilloma virus. Several new anticancer therapeutic approaches, mainly targeting tubulin, have also been reported. Thus, this unique amino acid offers very interesting possibilities for developing particularly useful pharmacological agents, which generally possess a completely different mechanism of action compared with classic agents in clinical use, thus avoiding major problems such as multidrug resistance (for antiviral and anticancer agents) or high toxicity.
Knowledge and experience of young people of drug abuse 1969-84.
Authors: J D Wright, L Pearl
Journal: BMJ (1986)

An anonymous questionnaire survey of the knowledge and experience of drug abuse among fourth year pupils in three Wolverhampton secondary schools in 1969, 1974, 1979, and 1984 showed familiarity with the names of drugs but considerable ignorance and misunderstanding about how the drugs were taken and their dangers. The proportion of pupils who knew someone taking illicit drugs almost doubled over the period from 15% in 1969 to 28% in 1984, and the proportion of those who had been offered illicit drugs almost trebled, from 5% in 1969 to 14% in 1984. Television remained the most important source of information about drugs. Peer group and social pressures continued to be the most important reason for starting to take drugs. The results of this study endorse the need for continued evaluation of programmes of education about drugs. Such programmes must be part of a wider programme of health and social education, define clear goals, and be sensitive to culture, locality, and ability.
Changes in Shear Stress–Related Gene Expression After Experimentally Altered Venous Return in the Chicken Embryo
Authors: Bianca C.W. Groenendijk, Beerend P. Hierck, Johannes Vrolijk, Martin Baiker, Mathieu J.B.M. Pourquie, Adriana C. Gittenberger-de Groot, Robert E. Poelmann
Journal: Circulation Research (2005)

Hemodynamics play an important role in cardiovascular development, and changes in blood flow can cause congenital heart malformations. The endothelium and endocardium are subjected to mechanical forces, of which fluid shear stress is correlated to blood flow velocity. The shear stress responsive genes lung Krüppel-like factor (KLF2), endothelin-1 (ET-1), and endothelial nitric oxide synthase (NOS-3) display specific expression patterns in vivo during chicken cardiovascular development. Nonoverlapping patterns of these genes were demonstrated in the endocardium at structural lumen constrictions that are subjected to high blood flow velocities. Previously, we described in chicken embryos a dynamic flow model (the venous clip) in which the venous return to the heart is altered and cardiac blood flow patterns are disturbed, causing the formation of congenital cardiac malformations. In the present study we test the hypothesis that disturbed blood flow can induce altered gene expression. In situ hybridizations indeed show a change in gene expression after venous clip. The level of expression of ET-1 in the heart is locally decreased, whereas KLF2 and NOS-3 are both upregulated. We conclude that venous obstruction results in altered expression patterns of KLF2, ET-1, and NOS-3, suggestive for increased cardiac shear stress.
Abstract P5-05-03: Progesterone receptor antagonists as inhibitors of breast cancer stem cell activity
Authors: D Alferez, RB Clarke, C Cresta, S Mnene, SJ Howell
Journal: Cancer Research (2013)

Abstract Background: Tamoxifen has become the standard of care for premenopausal women with hormone receptor positive breast cancer (BC). However, resistance to Tamoxifen therapy remains a major clinical problem and we have evidence that cancer stem cells (CSCs) may play a role in recurrence in these patients. The progesterone receptor (PR) is a potential therapeutic target in BC but development of steroidal PR antagonists (PRAs) has been halted due to toxicity issues, despite evidence of activity. Recent reports have linked PR activity to the expansion of adult mammary gland stem cells through paracrine effectors such as RANK-L. Methods: To investigate the effects of PR antagonism on CSCs, we have tested 2 non-steroidal PRAs; onapristone (Schering AG/Arno Therapeutics) and AZPRA (AstraZeneca) in 2 hormone receptor positive BC cell lines (MCF-7 &amp; T47D) and 8 patient-derived samples (PDS; from malignant pleural effusions and ascitic fluid), using a low adherence mammosphere assay. Western and gene expression array analysis of PDS samples were performed to identify predictive biomarkers. Results: In the presence of 10nM P4 AZPRA inhibited mammosphere forming efficiency (MFE) in MCF-7 cells by 32% (p&amp;lt;0.0001) and in T47D by 21% (p&amp;lt;0.0001). Similar results were seen with onapristone (34% inhibition in MCF-7 (p&amp;lt;0.002) and 34% in T47D cells (p&amp;lt;0.0002). AZPRA or onapristone significantly reduced MFE in 7 of 8 PDS. Tamoxifen affected MFE in 4/6 PDS samples. In 5 of 7 PDS tested additive effects were seen when AZPRA was combined with tamoxifen (&amp;gt;80% reduction in MFE; p&amp;lt;0.001). A similar effect was seen with onapristone (&amp;gt;70% reduction in MFE (p&amp;lt;0.05)). Data from Western analysis of PR A and B isoforms and gene expression analysis of PDS samples will be presented at the conference. Conclusions: Preliminary data on PR inhibition presented here support the rationale of administration of PRA in the clinic but predictive biomarkers are required to identify which patients are likely to benefit. Combination of PRA with current anti-oestrogen therapies such as Tamoxifen may be a way of overcoming resistance mechanisms by targeting CSCs. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-05-03.
Planning services for the mentally handicapped: a look at Sweden.
Authors: A M Golding
Journal: BMJ (1982)

The modern hospital does credit to latter day civilisation. Physical restraint is no longer practised. Neat dormitories, cosy single rooms, and sitting and dining rooms please the eye. In place of bare walls and floors and curtainless windows are pictures, plants, rugs, birds, curtains and, in many asylums, even the barred windows have been abolished.1 This quotation from the Encyclopaedia Britannica of 1911 is part of an article on the mentally ill and mentally handicapped, which ends with the sentence, But the ideal system is that of the psychopathic hospital and the colony for the insane.