tbuckley/cabot-search huggingface dataset:
INDIVIDUAL ANTIGENIC SPECIFICITY OF HUMAN MACROGLOBULINS
Authors: M. Harboe, B. G. Solheim, Johanna Deverill
Journal: The Journal of Experimental Medicine (1969)

The localization of individually specific antigenic determinants on the monoclonal γM Mö was studied in gel diffusion experiments with 19S γM Mö and its 7S subunit. Various types of such determinants were delineated. Some were demonstrable both on the intact macroglobulin molecule and on the subunit. The latter was often unable to precipitate with the corresponding antibody, but combined with it and inhibited precipitation. Immunization of rabbits with purified γMs Mö was the most useful way to obtain antisera demonstrating individually specific antigenic determinants on the subunit by direct precipitation. Still other determinants were apparently destroyed by mild reduction of the γM molecule. Reduction and reassociation of mixtures of two monoclonal γM-globulins resulted in formation of hybrid molecules containing subunits of different origin. Individually specific antisera against the two components were useful for demonstrating hybrid formation. Serological activity, i.e., cold agglutinin activity, was present in the hybrid molecules.
Alternative Strategies to Reduce Maternal Mortality in India: A Cost-Effectiveness Analysis
Authors: Sue J. Goldie, Steve Sweet, Natalie Carvalho, Uma Chandra Mouli Natchu, Delphine Hu
Journal: PLoS Medicine (2010)

A cost-effectiveness study by Sue Goldie and colleagues finds that better family planning, provision of safe abortion, and improved intrapartum and emergency obstetrical care could reduce maternal mortality in India by 75% in 5 years.
Circulating and intra-articular immune complexes in patients with rheumatoid arthritis. Correlation of 125I-Clq binding activity with clinical and biological features of the disease.
Authors: R H Zubler, U Nydegger, L H Perrin, k Fehr, J McCormick, P H Lambert, P A Miescher
Journal: Journal of Clinical Investigation (1976)

The correlation between the incidence and level of immune complexes in serum and synovial fluid and the various clinical and biological manifestations of rheumatoid arthritis has been studied. Immune complexes were quantitated using a sensitive radioimmunoassay, the 125I-Clq binding test, in unheated native sera and synovial fluids from 50 patients with seropositive (RA +) and 45 with seronegative (RA -) rheumatoid arthritis, 17 with other inflammatory arthritis, and 37 with degenerative and post-traumatic joint disease. The following observations were made: (a) when compared to the results from patients with degenerative and post-traumatic joint diseases, the 125I-Clq binding activity (Clq-BA) in synovial fluid was found to be increased (by more than 2 SD) in most of the patients with RA + (80%) and RA - (71%) and in 29% of patients with other inflammatory arthritis; the serum Clq-BA was also frequently increased in both RA + (76%) and RA - (49%) patients, but only exceptionally in patients with other inflammatory arthritis (6%); (b) a significant negative correlation existed between the Clq-BA and the immunochemical C4 level in synovial fluids from patients with RA + and RA -; (c) neither the serum nor the synovial fluid Clq-BA in rheumatoid arthritis significantly correlated with the erythrocyte sedimentation rate, the clinical stage of the disease, or the IgM rheumatoid factor titer; and (d) the serum Clq-BA in patients with rheumatoid arthritis and extra-articular disease manifestations (40 +/- 34% in those with RA +,32 +/- 29% in those with RA -) was significantly increased as compared to the serum Clq-BA in patients with joint disease alone (24 +/- 30% in those with RA +, 10 +/- 13% in those with RA -). Experimental studies were carried out in order to characterize the Clq binding material in rheumatoid arthritis. This material had properties similar to immune complexes: it sedimented in a high molecular weight range on sucrose density gradients (10-30S) and lost the ability to bind Clq after reduction and alkylation, or after acid dissociation at pH 3.8, or after passage through an anti-IgG immunoabsorbant. DNase did not affect the Clq BA. These results support the hypothesis that circulating as well as intra-articular immune complexes may play an important role in some pathogenetic aspects of rheumatoid arthritis. The 125I-Clq binding test may also be of some practical clinical value in detecting patients who have a higher risk of developing vasculitis.
Qualification of a Noninvasive Magnetic Resonance Imaging Biomarker to Assess Tumor Oxygenation
Authors: Florence Colliez, Marie-Aline Neveu, Julie Magat, Thanh Trang Cao Pham, Bernard Gallez, Bénédicte F. Jordan
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Although hypoxia has been long recognized as a crucial factor impairing tumor response in many therapeutic schemes, atraumatic and reliable methods of individually quantifying tumor oxygenation are still lacking in day-to-day clinical practice. The aim of this work was to investigate the potentially quantitative properties of our recently described noninvasive magnetic resonance (MR) technique “MOBILE” (mapping of oxygen by imaging lipids relaxation enhancement) and to qualify this endogenous contrast as a tumor hypoxia marker. Experimental Design: The “MOBILE” technique, which assesses the longitudinal MR relaxation rate, R1, of lipid protons, was benchmarked with the parent technique which assesses the global (or water) R1, in response to a hyperoxic challenge (carbogen breathing) and to a hypoxic challenge (combretastatin A4) in MDA-MB-231 xenografts and in NT2 mammary tumors. Electron paramagnetic resonance (EPR) oximetry was used to quantitatively assess the tumor pO2 in matching tumors longitudinally. Results and Conclusion: Our study evidenced that (i) positive and negative changes in tumor oxygenation can be detected using MOBILE; (ii) a change in the R1 of lipids is positively correlated with a change in the tumor pO2 (P = 0.0217, r = 0.5097); (iii) measured lipid R1 values are positively correlated with absolute pO2 values in both tumor models (P = 0.0275, r = 0.3726); and (iv) changes in the R1 of lipids are more sensitive than changes in the global R1. As this technique presents unique translational properties, it seems promising for the individual longitudinal monitoring of tumor oxygenation in a clinical setting. Clin Cancer Res; 20(21); 5403–11. ©2014 AACR.
Effect of verbal instructions on muscle activity and risk of injury to the anterior cruciate ligament during landing
Authors: E J Cowling, J R Steele, P J McNair
Journal: British Journal of Sports Medicine (2003)

Minimising the likelihood of injury to the anterior cruciate ligament (ACL) during abrupt deceleration requires proper synchrony of the quadriceps and hamstring muscles. However, it is not known whether simple verbal instructions can alter landing muscle activity to protect the knee.To assess the efficacy of verbal instructions to alter landing muscle activity.Twenty four athletes landed abruptly in single limb stance. Sagittal plane motion was recorded with an optoelectric device, and ground reaction force and surface electromyographic data were recorded for the rectus femoris, vastus lateralis, biceps femoris, and semimembranosus muscles. Subjects performed 10 landings per condition: normal landing (N); repeat normal landing (R); landing after instruction to increase knee flexion (K); and landing after instruction to recruit hamstring muscles earlier (M). Muscle bursts immediately before landing were analysed relative to initial foot-ground contact (IC).The K condition resulted in significantly (p</=0.05) greater knee flexion at IC compared with the other conditions. The M condition did not result in earlier hamstring muscle activity, but instead caused significantly (p</=0.05) earlier rectus femoris onset relative to IC, with a similar trend for the vastus lateralis. As these muscles are ACL antagonists, earlier onset times would be detrimental to the ACL.Subjects successfully increased knee flexion during landing following the K condition instruction. However, further research is warranted to establish the efficacy of more extensive lower limb muscle retraining programmes to ensure landings that decrease susceptibility to ACL injury.
Relapsed Classic E-Cadherin (<i>CDH1</i>)–Mutated Invasive Lobular Breast Cancer Shows a High Frequency of<i>HER2</i>(<i>ERBB2</i>) Gene Mutations
Authors: Jeffrey S. Ross, Kai Wang, Christine E. Sheehan, Ann B. Boguniewicz, Geoff Otto, Sean R. Downing, James Sun, Jie He, John A. Curran, Siraj Ali, Roman Yelensky, Doron Lipson, Gary Palmer, Vincent A. Miller, Philip J. Stephens
Journal: Clinical Cancer Research (2013)

We queried whether comprehensive genomic profiling using a next-generation sequencing-based assay could identify novel and unanticipated targets of therapy for patients with relapsed invasive lobular carcinoma (ILC).DNA sequencing (Illumina HiSeq 2000) was conducted for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor-ligated, hybridization-captured libraries using DNA isolated from formalin-fixed paraffin-embedded sections from 22 histologically verified ILC.A total of 75 genomic alterations were identified with an average of 3.4 alterations per tumor (range, 1-6), of which 35 were actionable for an average of 1.59 actionable alterations per patient (range, 0-3). Nineteen of 22 (86%) of the ILC samples harbored at least one actionable alteration. Six (27%) cases featured alterations in ERRB2 including 4 (18%) with ERBB2 mutation, 1 (5%) with an ERBB2 gene fusion, and 1 (5%) with an ERBB2 copy number gain (amplification). The enrichment of ERBB2 mutations/fusion in CDH1-mutated ILC (5 of 22, 23%) compared with the 5 ERBB2 mutations in a series of 286 non-CDH1-mutated breast cancers from which the ILC cases were obtained (5 of 286, 2%) was significant (P = 0.0006).Comprehensive genomic profiling of relapsed CDH1-mutated ILC revealed actionable genomic alterations in 86% of cases, featured a high incidence of ERBB2 alterations, and can reveal actionable alterations that can inform treatment decisions for patients with ILC.
Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates
Authors: Christopher Sundling, Mattias N.E. Forsell, Sijy O'Dell, Yu Feng, Bimal Chakrabarti, Srinivas S. Rao, Karin Loré, John R. Mascola, Richard T. Wyatt, Iyadh Douagi, Gunilla B. Karlsson Hedestam
Journal: The Journal of Experimental Medicine (2010)

Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoproteins (Envs) have proven difficult to elicit by immunization. Therefore, to identify effective Env neutralization targets, efforts are underway to define the specificities of bNAbs in chronically infected individuals. For a prophylactic vaccine, it is equally important to define the immunogenic properties of the heavily glycosylated Env in healthy primates devoid of confounding HIV-induced pathogenic factors. We used rhesus macaques to investigate the magnitude and kinetics of B cell responses stimulated by Env trimers in adjuvant. Robust Env-specific memory B cell responses and high titers of circulating antibodies developed after trimer inoculation. Subsequent immunizations resulted in significant expansion of Env-specific IgG-producing plasma cell populations and circulating Abs that displayed increasing avidity and neutralization capacity. The neutralizing activity elicited with the regimen used was, in most aspects, superior to that elicited by a regimen based on monomeric Env immunization in humans. Despite the potency and breadth of the trimer-elicited response, protection against heterologous rectal simian-HIV (SHIV) challenge was modest, illustrating the challenge of eliciting sufficient titers of cross-reactive protective NAbs in mucosal sites. These data provide important information for the design and evaluation of vaccines aimed at stimulating protective HIV-1 immune responses in humans.
Combined MEK and PI3K Inhibition in a Mouse Model of Pancreatic Cancer
Authors: Brinda Alagesan, Gianmarco Contino, Alexander R. Guimaraes, Ryan B. Corcoran, Vikram Deshpande, Gregory R. Wojtkiewicz, Aram F. Hezel, Kwok-Kin Wong, Massimo Loda, Ralph Weissleder, Cyril Benes, Jeffrey A. Engelman, Nabeel Bardeesy
Journal: Clinical Cancer Research (2014)

Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being used in clinical trials for patients with PDAC, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMM).We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically relevant compounds, including MEK and PI3K inhibitors. We tested the top hit in the screen, the MEK1/2 inhibitor, AZD6244, for efficacy alone or in combination with the PI3K inhibitors, BKM120 or GDC-0941, in a Kras(G12D)-driven GEMM that recapitulates the histopathogenesis of human PDAC.In vitro screens revealed that PDAC cell lines are relatively resistant to single-agent therapies. The response profile to the MEK1/2 inhibitor, AZD6244, was an outlier, showing the highest selective efficacy in PDAC. Although MEK inhibition alone was mainly cytostatic, apoptosis was induced when combined with PI3K inhibitors (BKM120 or GDC-0941). When tested in a PDAC GEMM and compared with the single agents or vehicle controls, the combination delayed tumor formation in the setting of prevention and extended survival when used to treat advanced tumors, although no durable responses were observed.Our studies point to important contributions of MEK and PI3K signaling to PDAC pathogenesis and suggest that dual targeting of these pathways may provide benefit in some patients with PDAC. Clin Cancer Res; 21(2); 396-404. ©2014 AACR.
The Bradford smallpox outbreak in 1962: a personal account
Authors: D. Tovey
Journal: Journal of the Royal Society of Medicine (2004)

Today it is fervently hoped that outbreaks of smallpox such as that which occurred in Bradford in 1962 will never arise again. However, it is unwise to be sure of ‘never’. In 1962, just after I was appointed consultant pathologist in Bradford, isolated cases had been reported in England, but these were amongst people from South East Asia who had recently arrived in the UK. The Bradford outbreak had several unusual features, particularly the events leading up to its discovery.1 Since I am one of the declining number of persons still alive who were heavily involved in the outbreak I am persuaded that my experiences at the time are worth recording.
Inverse Relationship Between Serotonin 5-HT<sub>1A</sub> Receptor Binding and Anxiety: A [<sup>11</sup>C]WAY-100635 PET Investigation in Healthy Volunteers
Authors: J Tauscher, R M Bagby, M Javanmard, B K Christensen, S Kasper, S Kapur
Journal: American Journal of Psychiatry (2001)

The authors investigated the relationship between anxiety--a facet of the Revised NEO Personality Inventory dimension of neuroticism--and serotonin 5-HT(1A) receptor binding potential.Positron emission tomography with [(11)C]WAY-100635 was used to estimate regional 5-HT(1A) binding potential in 19 healthy volunteers who completed the Revised NEO Personality Inventory. Correlation coefficients were calculated to determine the degree of association between 5-HT(1A) binding potential and personality inventory measures.There was a significant negative correlation between 5-HT(1A) binding potential and anxiety in four regions: the dorsolateral prefrontal cortex, anterior cingulate cortex, parietal cortex, and occipital cortex.The inverse relationship between 5-HT(1A) receptor binding potential and anxiety is consistent with 1) animal models that have shown higher anxiety in mice lacking 5-HT(1A) receptors and 2) clinical trial data that have demonstrated antianxiety properties of partial 5-HT(1A) agonists.
Cysteinyl Leukotrienes and Uridine Diphosphate Induce Cytokine Generation by Human Mast Cells Through an Interleukin 4–regulated Pathway that Is Inhibited by Leukotriene Receptor Antagonists
Authors: Elizabeth A. Mellor, K. Frank Austen, Joshua A. Boyce
Journal: The Journal of Experimental Medicine (2002)

We previously reported that interleukin (IL)-4 upregulates the expression of leukotriene C4 synthase (LTC4S) by human cord blood–derived mast cells (hMCs), augments their high-affinity Fc receptor for IgE (FcϵRI)-dependent generation of eicosanoids and cytokines, and induces a calcium flux in response to cysteinyl leukotrienes (cys-LTs) and uridine diphosphate (UDP) that is blocked by cys-LT receptor antagonists. We speculated that this IL-4–dependent, receptor-mediated response to the cys-LTs and UDP might induce cytokine generation by hMCs without concomitant exocytosis. Unlike hMCs maintained in cytoprotective stem cell factor (SCF) alone, hMCs primed for 5 d with IL-4 responded to UDP (1 μM), LTC4 (100 nM), and LTD4 (100 nM) by producing IL-5, tumor necrosis factor (TNF)-α, and especially large quantities of macrophage inflammatory protein (MIP)-1β de novo at 6 h, preceded by the induced expression of the corresponding mRNAs. Cys-LT– and UDP-mediated cytokine production by the primed hMCs occurred without histamine release or PGD2 generation and was inhibited by the CysLT1 receptor antagonist MK571. Additionally, pretreatment of hMCs with MK571 or with the cys-LT biosynthetic inhibitor MK886 decreased IL-5 and TNF-α production in response to IgE receptor cross-linkage, implying a positive feedback by endogenously produced cys-LTs. Cys-LTs and UDP thus orchestrate a novel, IL-4–regulated, non-IgE–dependent hMC activation for cytokine gene induction that could be initiated by microbes, cellular injury, or neurogenic or inflammatory signals; and this pathobiologic event would not be recognized in tissue studies where hMC activation is classically defined by exocytosis.
Uncovering Growth-Suppressive MicroRNAs in Lung Cancer
Authors: Xi Liu, Lorenzo F. Sempere, Fabrizio Galimberti, Sarah J. Freemantle, Candice Black, Konstantin H. Dragnev, Yan Ma, Steven Fiering, Vincent Memoli, Hua Li, James DiRenzo, Murray Korc, Charles N. Cole, Mads Bak, Sakari Kauppinen, Ethan Dmitrovsky
Journal: Clinical Cancer Research (2009)

Abstract Purpose: MicroRNA (miRNA) expression profiles improve classification, diagnosis, and prognostic information of malignancies, including lung cancer. This study uncovered unique growth-suppressive miRNAs in lung cancer. Experimental Design: miRNA arrays were done on normal lung tissues and adenocarcinomas from wild-type and proteasome degradation-resistant cyclin E transgenic mice to reveal repressed miRNAs in lung cancer. Real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays validated these findings. Lung cancer cell lines were derived from each transgenic line (designated as ED-1 and ED-2 cells, respectively). Each highlighted miRNA was independently transfected into these cells. Growth-suppressive mechanisms were explored. Expression of a computationally predicted miRNA target was examined. These miRNAs were studied in a paired normal-malignant human lung tissue bank. Results: miR-34c, miR-145, and miR-142-5p were repressed in transgenic lung cancers. Findings were confirmed by real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays. Similar miRNA profiles occurred in human normal versus malignant lung tissues. Individual overexpression of miR-34c, miR-145, and miR-142-5p in ED-1 and ED-2 cells markedly repressed cell growth. Anti-miR cotransfections antagonized this inhibition. The miR-34c target, cyclin E, was repressed by miR-34c transfection and provided a mechanism for observed growth suppression. Conclusions: miR-34c, miR-145, and miR-142-5p were repressed in murine and human lung cancers. Transfection of each miRNA significantly repressed lung cancer cell growth. Thus, these miRNAs were growth suppressive and are proposed to exert antineoplastic effects in the lung.
Current Progress in Gene Delivery Technology Based on Chemical Methods and Nano-carriers
Authors: Lian Jin, Xin Zeng, Ming Liu, Yan Deng, Nongyue He
Journal: Theranostics (2014)

Gene transfer methods are promising in the field of gene therapy. Current methods for gene transfer include three major groups: viral, physical and chemical methods. This review mainly summarizes development of several types of chemical methods for gene transfer in vitro and in vivo by means of nano-carriers like; calcium phosphates, lipids, and cationic polymers including chitosan, polyethylenimine, polyamidoamine dendrimers, and poly(lactide-co-glycolide). This review also briefly introduces applications of these chemical methods for gene delivery.
Renal Malformations May Be Linked to Mutations in the Hepatocyte Nuclear Factor-1α (MODY3) Gene
Authors: Maciej T. Malecki, Jan Skupien, Sylwia Gorczynska-Kosiorz, Tomasz Klupa, Joanna Nazim, Dariusz K. Moczulski, Jacek Sieradzki
Journal: Diabetes Care (2005)

aturity-onset diabetes of the young (MODY) is an autosomaldominant form of disease characterized by ␤-cell defects and early age of diagnosis.So far, six MODY genes have been identified (1,2).MODY is sometimes accompanied by extrapancreatic features such as developmental malformations and physiological and biochemical abnormalities (3).The most frequent MODY3 subtype is caused by mutations in the hepatocyte nuclear factor (HNF)-1␣ gene, a transcription factor expressed in pancreas, kidney, liver, and gut. RESEARCH DESIGN AND METHODS-To dissect the genetic background and to provide clinical characteristics of this form of diabetes in Poland, the Nationwide Registry was established in 2004 at the Department of Metabolic Diseases, Jagiellonian University Medical College in Krakow.So far, 30 families with the early-onset, autosomaldominant form of diabetes meeting commonly used criteria of MODY (diabetes occurring in at least three generations and at least two individuals diagnosed with diabetes before the age of 25 years) were included in this program.The subjects from those families received a standard questionnaire that contained questions regarding the age of diabetes diagnosis, family history, treatment method, and