tbuckley/cabot-search huggingface dataset:
Opsonic activity of myeloma immuno‐globulins (mm‐lg)
Authors: Bruce D. Cheson
Journal: American Journal of Hematology (1981)

Abstract Patients with MM are at an increased risk for life‐threatening bacterial infections, primarily by organisms that require opsonization for interaction with granulocytes. In the present study we used a neutrophil chemiluminescence (CL) assay of opsonization to explore the opsonic activity of MM‐lg for zymosan particles. Particles were treated with serum lacking in Ig to explore the contribution of Ig to zymosan opsonization. This serum was found to have 69 ± 2.6% (X̄ ± SEM) of the opsonic activity of normal serum (P &lt; .001). Normal serum concentrations of normal IgG, MM‐IgG, and MM‐IgA all lacked opsonic activity for zymosan. However, when particles were treated with Nl‐IgG, MM‐IgG, or MM‐IgA as well as complement, normal opsonic activity was generated. Increasing the concentration of the Ig to stimulate MM serum did not inhibit this opsonic activity. Thus both MM‐IgG and MM‐IgA can function as normal, nonspecific opsonins.
Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS)
Authors: G.F Watts, B Lewis, E.S Lewis, D.J Coltart, L.D.R Smith, A.V Swan, J.N.H Brunt, J.I Mann
Journal: The Lancet (1992)
Case of Ulcer of Stomach, Penetrating into the Liver
Authors: J. I. MacKenzie
Journal: BMJ (1880)

rapidly " paid" by the finger and thumb into the cavity of the nostril.The solid mass thus formed should be forced along the floor of the nose, first with the little finger, and then with the dressing forceps or a pencil, until it is found to occupy the' posterior nostril, and distinctly felt in it by tlhe finger, hooked rounzd the soft pa/ate.This is far the most important part of 'the entire proceeding, being, as it were, the basis of operations.The second portion should now be paid into the nostril in the same way, and pressed by the finger and forceps into its position-the roof of the nose.The third and last portion should be pushed into the nostril, so as to occupy a position in front of and below the other two, and, being caught within the edge of the alar cartilage, will usually retain its position without trouble.I think it desirable that the material should not be cut, but retained as one continuous piece for the facility of subsequent removal; but"too much care cannot be taken in disposing of the first portion.The nostril being thus perfectly and thoroughly packed, every portion of the lining membrane is steadily and firmly compressed, and the escape' of blood is rendered physically impos- sible.In the course of about forty-eight hours, the plug begins to loosen, the end falling from the nostril.Directions should be given to the nurse or attendant on no account to pull it, but simply cut the pro- jecting part on a level with the nostril, according as it drops, until the pntire plug comes away.For some years past, I have adopted no other mo'de of plugging the nostrils; and many of my professional brethren in Dublin, who have practised it, have found it simple, effective, and satisfactory.There is little fear of the plug remaining too long, as, when the natural secretion is restored, it becomes quickly loosened and unpacked, and falls away through the anterior nostril.
Vaccine-specific T cell responses in delayed-type hypersensitivity biopsies after dendritic cell vaccination correlate with clinical outcome
Authors: A.C.I. Boullart, I.J.M. de Vries, M.R. Bernsen, W.J. Lesterhuis, N.M. Scharenborg, C.G. Figdor, G.J. Adema, C.J.A. Punt
Journal: Annals of Oncology (2005)
Biology of Endoplasmic Reticulum Stress in the Heart
Authors: Jody Groenendyk, Pradeep Kumar Sreenivasaiah, Do Han Kim, Luis B. Agellon, Marek Michalak
Journal: Circulation Research (2010)

The endoplasmic reticulum (ER) is a multifunctional intracellular organelle supporting many processes required by virtually every mammalian cell, including cardiomyocytes. It performs diverse functions, including protein synthesis, translocation across the membrane, integration into the membrane, folding, posttranslational modification including N -linked glycosylation, and synthesis of phospholipids and steroids on the cytoplasmic side of the ER membrane, and regulation of Ca 2+ homeostasis. Perturbation of ER-associated functions results in ER stress via the activation of complex cytoplasmic and nuclear signaling pathways, collectively termed the unfolded protein response (UPR) (also known as misfolded protein response), leading to upregulation of expression of ER resident chaperones, inhibition of protein synthesis and activation of protein degradation. The UPR has been associated with numerous human pathologies, and it may play an important role in the pathophysiology of the heart. ER stress responses, ER Ca 2+ buffering, and protein and lipid turnover impact many cardiac functions, including energy metabolism, cardiogenesis, ischemic/reperfusion, cardiomyopathies, and heart failure. ER proteins and ER stress-associated pathways may play a role in the development of novel UPR-targeted therapies for cardiovascular diseases.
Leukocyte-specific protein 1 interacts with DC-SIGN and mediates transport of HIV to the proteasome in dendritic cells
Authors: Alvin L. Smith, Lakshmanan Ganesh, Kwanyee Leung, Jenny Jongstra-Bilen, Jan Jongstra, Gary J. Nabel
Journal: The Journal of Experimental Medicine (2007)

Dendritic cells (DCs) capture and internalize human immunodeficiency virus (HIV)-1 through C-type lectins, including DC-SIGN. These cells mediate efficient infection of T cells by concentrating the delivery of virus through the infectious synapse, a process dependent on the cytoplasmic domain of DC-SIGN. Here, we identify a cellular protein that binds specifically to the cytoplasmic region of DC-SIGN and directs internalized virus to the proteasome. This cellular protein, leukocyte-specific protein 1 (LSP1), was defined biochemically by immunoprecipitation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. LSP1 is an F-actin binding protein involved in leukocyte motility and found on the cytoplasmic surface of the plasma membrane. LSP1 interacted specifically with DC-SIGN and other C-type lectins, but not the inactive mutant DC-SIGNΔ35, which lacks a cytoplasmic domain and shows altered virus transport in DCs. LSP1 diverts HIV-1 to the proteasome. Down-regulation of LSP1 with specific small interfering RNAs in human DCs enhanced HIV-1 transfer to T cells, and bone marrow DCs from lsp1−/− mice also showed an increase in transfer of HIV-1BaL to a human T cell line. Proteasome inhibitors increased retention of viral proteins in lsp1+/+ DCs, and substantial colocalization of virus to the proteasome was observed in wild-type compared with LSP1-deficient cells. Collectively, these data suggest that LSP1 protein facilitates virus transport into the proteasome after its interaction with DC-SIGN through its interaction with cytoskeletal proteins.
Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma
Authors: Minji Byun, Avinash Abhyankar, Virginie Lelarge, Sabine Plancoulaine, Ayse Palanduz, Leyla Telhan, Bertrand Boisson, Capucine Picard, Scott Dewell, Connie Zhao, Emmanuelle Jouanguy, Stefan Feske, Laurent Abel, Jean-Laurent Casanova
Journal: The Journal of Experimental Medicine (2010)

Classic Kaposi sarcoma (KS) is exceedingly rare in children from the Mediterranean Basin, despite the high prevalence of human herpesvirus-8 (HHV-8) infection in this region. We hypothesized that rare single-gene inborn errors of immunity to HHV-8 may underlie classic KS in childhood. We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age. Whole-exome sequencing in the patient revealed a homozygous splice-site mutation in STIM1, the gene encoding stromal interaction molecule 1, which regulates store-operated Ca2+ entry. STIM1 mRNA splicing, protein production, and Ca2+ influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1. Based on the previous discovery of STIM1 deficiency in a single family with a severe T cell immunodeficiency and the much higher risk of KS in individuals with acquired T cell deficiencies, we conclude that STIM1 T cell deficiency precipitated the development of lethal KS in this child upon infection with HHV-8. Our report provides the first evidence that isolated classic KS in childhood may result from single-gene defects and provides proof-of-principle that whole-exome sequencing in single patients can decipher the genetic basis of rare inborn errors.
A functional map of NFκB signaling identifies novel modulators and multiple system controls
Authors: Thomas A Halsey, Longlong Yang, John R Walker, John B Hogenesch, Russell S Thomas
Journal: Genome biology (2007)

The network of signaling pathways that leads to activation of the NFkappaB transcription factors is a branched structure with different inputs and cross-coupling with other signaling pathways. How these signals are integrated to produce specific, yet diverse responses is not clearly understood. To identify the components and structural features of the NFkappaB network, a series of cell-based, genomic screens was performed using a library of approximately 14,500 full-length genes.A total of 154 positive and 88 negative modulators of NFkappaB signaling were identified. Using a series of dominant-negative constructs and functional assays, these modulators were mapped to the known NFkappaB signaling cascade. Most of the positive modulators acted upstream of the IkappaB kinase complex, supporting previous observations that the IkappaB kinases represent the primary point of convergence in the network. A number of negative modulators were localized downstream of the IkappaB kinase beta (IKBKB) subunit, suggesting that they form an additional layer of negative control within the system. The expression of the modulators at the RNA level was distributed disproportionately across tissues, providing flexibility in network structure, and the number of positive and negative modulators present in a given tissue was highly correlated, suggesting that positive and negative regulation is balanced at the tissue level.The relative locations of the modulators are consistent with an hourglass structure for the NFkappaB network that is characteristic of robust systems. The tissue distribution of the modulators and downstream location of the negative modulators serve as layers of control within the system that allow differential responses to different stimuli.
Police advise GPs to take steps against telephone fraud
Authors: G. Iacobucci
Journal: BMJ (2014)

General practices in the United Kingdom have been warned to take precautionary steps against potential telephone fraud, after a spate of cyber attacks on small businesses.

Fraud experts have reported an upsurge in reports of criminals hacking into telephone systems and then making calls to affiliated premium rate or foreign numbers, resulting in losses of tens of thousands of pounds for the victims. The experts warned that medical centres were increasingly vulnerable to attacks: four surgeries had been targeted over the past three months, compared with just two in the previous seven months.

In a document detailing the crimes, City of London Police’s National Fraud Intelligence Bureau—which is responsible for examining all cyber crime reported to the …
Blockade of p38 Mitogen-Activated Protein Kinase and TGF-β1/Smad Signaling Pathways Rescues Bone Marrow–Derived Peritubular Capillary Endothelial Cells in Adriamycin-Induced Nephrosis
Authors: Jinhua Li, James A. Deane, Naomi V. Campanale, John F. Bertram, Sharon D. Ricardo
Journal: Journal of the American Society of Nephrology (2006)

The peritubular capillary (PTC) network is a component of the tubulointerstitium of the kidney with important roles in renal function and hemodynamics. Bone marrow (BM)-derived cells can contribute to repair of the renal PTC network after ischemic injury. However, the cell fate and the regulation of renal BM-derived cell engraftment in comparison with somatic cells during disease progression are unclear. This study characterized the time course and regulation of PTC endothelial cell injury in adriamycin (ADR)-induced nephropathy in mice, a model of chronic, irreversible, progressive renal disease. Enhanced green fluorescence protein-positive BM cells that coexpressed two endothelial cell markers, von Willebrand factor and CD31, were found to engraft into the PTC of chimeric ADR-injected mice in a time-dependent manner. The number of BM-derived PTC endothelial cells peaked 2 wk after ADR injection, then declined dramatically thereafter. In these mice, apoptosis was evident in BM-derived PTC endothelial cells, and the p38 mitogen-activated protein kinase (MAPK) and TGF-beta1/Smad signaling pathways were activated. Blocking both the p38 MAPK and TGF-beta1/Smad signaling pathways by administration of a p38 MAPK inhibitor (SB203580) and a TGF-beta receptor 1 inhibitor (ALK5I) to ADR-injected mice rescued BM-derived PTC endothelial cells from apoptosis, reduced the loss of PTC, and restored kidney function. Investigation into the signaling pathways that regulate the differentiation and survival of BM-derived cells that engraft into the kidney in the proinflammatory setting of progressive renal disease is vital for the successful development of cell-based therapies to promote renal regeneration and repair.
The Combination of Epidermal Growth Factor Receptor Inhibitors with Gemcitabine and Radiation in Pancreatic Cancer
Authors: Meredith A. Morgan, Leslie A. Parsels, Laura E. Kollar, Daniel P. Normolle, Jonathan Maybaum, Theodore S. Lawrence
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Gemcitabine-radiotherapy is a standard treatment for locally advanced pancreatic cancer. Clinical data have shown that gemcitabine plus erlotinib is superior to gemcitabine alone for advanced pancreatic cancer. Therefore, we investigated the effects of the combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation on a pancreatic cancer model. Experimental Design: EGFR signaling was analyzed by measuring phosphorylated EGFR (pEGFR(Y845), (Y1173)) and AKT (pAKT(S473)) protein levels in pancreatic cancer cell lines and tumors. The effects of scheduling on gemcitabine-mediated cytotoxicity and radiosensitization combined with erlotinib were determined by clonogenic survival. In vivo, the effects of cetuximab or erlotinib in combination with gemcitabine-radiation on the growth of BxPC-3 tumor xenografts were measured. Results: We found in vitro that gemcitabine induced phosphorylation of EGFR at Y845 and Y1173 that was blocked by erlotinib. Treatment of BxPC-3 cells with gemcitabine before erlotinib enhanced gemcitabine-mediated cytotoxicity without abrogating radiosensitization. In vivo, cetuximab or erlotinib in combination with gemcitabine-radiation inhibited growth compared with gemcitabine-radiation (time to tumor doubling: gemcitabine + radiation, 19 ± 3 days; cetuximab + gemcitabine + radiation, 30 ± 3 days; P &amp;lt; 0.05, erlotinib + gemcitabine + radiation 28 ± 3 days; P &amp;lt; 0.1). Cetuximab or erlotinib in combination with gemcitabine-radiation resulted in significant inhibition of pEGFR(Y1173) and pAKT(S473) early in treatment, and pEGFR(Y845), pEGFR(Y1173), and pAKT(S473) by the end of treatment. This study shows a novel difference pEGFR(Y845) and pEGFR(Y1173) in response to EGFR inhibition. Conclusions: These results show that the EGFR inhibitors cetuximab and erlotinib increase the efficacy of gemcitabine-radiation. This work supports the integration of EGFR inhibitors with gemcitabine-radiation in clinical trials for pancreatic cancer.
Low Birth Weight and High Birth Weight Infants Are Both at an Increased Risk to Have Type 2 Diabetes Among Schoolchildren in Taiwan
Authors: Jung-Nan Wei, Fung-Chang Sung, Chung-Yi Li, Chia-Hsuin Chang, Ruey-Shiung Lin, Chau-Ching Lin, Chuan-Chi Chiang, Lee-Ming Chuang
Journal: Diabetes Care (2003)

OBJECTIVE—To study the effect of birth weight on risk of type 2 diabetes in the schoolchildren in Taiwan. RESEARCH DESIGN AND METHODS—From 1992 to 1997, all schoolchildren aged 6–18 years were screened for diabetes in Taiwan Province. This cohort consisted of 1,966 patients with diabetes and 1,780 randomly selected subjects with normal fasting glycemia (NFG). Questionnaire interviewing was designed to classify diabetes. The birth weight was obtained from the Taiwan’s Birth Registry. After merging the data, there were 978 subjects, including 429 with type 2 diabetes and 549 with of NFG enrolled in the present analyses. RESULTS—The odds ratios (95% CI) for type 2 diabetes, after adjusting age, sex, BMI, family history of diabetes, and socioeconomic status, were 2.91 (1.25–6.76) for children with low birth weight (&amp;lt;2,500 g) and 1.78 (1.04–3.06) for those with high birth weight (≥4,000 g) when compared with the referent group (birth weight 3,000–3,499 g). The risk of diabetes was still 64% higher in the high birth weight group [odds ratio (OR) 1.64 (95% CI 0.91–2.96)], even after adjustment for gestational diabetes mellitus (GDM). Patients with type 2 diabetes who were born with high birth weight were more likely to have a higher BMI and diastolic blood pressure as well as a higher family history of diabetes compared with those with low birth weight. CONCLUSIONS—A U-shaped relationship between birth weight and risk of type 2 diabetes was found in the schoolchildren aged 6–18 years in Taiwan. Schoolchildren with type 2 diabetes who were born with low birth weight had different metabolic phenotypes compared with those born with high birth weight.
Evidence for a polygenic contribution to androgenetic alopecia
Authors: S. Heilmann, F.F. Brockschmidt, A.M. Hillmer, S. Hanneken, S. Eigelshoven, K.U. Ludwig, C. Herold, E. Mangold, T. Becker, R. Kruse, M. Knapp, M.M. Nöthen
Journal: British Journal of Dermatology (2013)

Male pattern baldness (androgenetic alopecia, AGA) is a highly heritable trait and the most common form of hair loss in humans. Eight genome-wide significant risk loci for AGA have been identified.To determine whether a polygenic component contributes to the genetic risk for AGA.This study used a German case-control sample for AGA, which comprised 581 severely affected patients and 617 controls, to determine the contribution of polygenic variance to AGA risk. The sample was divided evenly into discovery and test samples. An additive polygenic risk score was calculated from risk alleles with increasingly liberal P-values in the discovery dataset, which was then used to test for the enrichment of AGA risk score alleles in the independent test samples.The polygenic score analysis provided significant evidence for a polygenic contribution to AGA where the amount of variance explained was 1·4-4·5%.This study provides evidence for the specific contribution of a polygenic component to the overall heritable risk for AGA. To some degree, the polygenic architecture of AGA might reflect the complexity of the biological pathways involved. Further analyses and strategies that complement conventional genome-wide association studies are needed to identify these factors. These may include pathway-based analyses, the analysis of functional candidate genes and tests for epistatic effects with known loci.
Distributions of Statistics Used for the Comparison of Models of Sequence Evolution in Phylogenetics
Authors: S. Whelan, N. Goldman
Journal: Molecular Biology and Evolution (1999)

Asymptotic statistical theory suggests that when two nested models are compared by a likelihood ratio test, a 2 distribution, with number of degrees of freedom equal to the difference in numbers of free parameters of the two models, can be used for significance testing.This asymptotic result has been assumed to apply in phylogenetics with the support of only a few studies.In this paper, 12 comparisons among a selection of commonly used models of nucleotide substitution were examined to see whether this assumption is reasonable.The true distributions of likelihood ratio statistics were estimated by computer simulation and compared with the appropriate 2 distributions.It was found that 2 distributions are adequate for significance testing in the comparison of models differing by parameters describing transition/transversion bias and/or unequal base frequencies when these parameters have been estimated by maximum likelihood.The 2 distribution was, however, found to be significantly different from the true distributions in the comparison of models differing by parameters describing rate variation across sites (estimated by maximum likelihood) or unequal base frequencies (estimated as the observed base frequencies in an alignment).These last findings may have important consequences for real-model comparisons and for the construction of increasingly complex and realistic models of nucleotide sequence evolution.
Different Forms of Helper Tolerance to Carcinoembryonic Antigen: Ignorance and Regulation
Authors: Wendy J. Pickford, Angus J.M. Watson, Robert N. Barker
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Understanding the mechanisms of immune tolerance to tumor-associated antigens (TAA) is an important step in the design of cancer immunotherapy. The aim was to determine how T helper (Th) cell tolerance is mediated for a prototypic TAA, carcinoembryonic antigen (CEA). Experimental Design: Peripheral blood mononuclear cells from 50 healthy volunteers were stimulated with CEA, and the type and fine specificity of any Th cell responses were identified. The inhibitory effects of T regulatory (Tr) populations were determined by depleting “natural” CD25+ Tr cells or neutralizing cytokine produced by the “induced” Tr form. Results: Proliferative Th cell responses were consistently induced by CEA in 22 of 50 individuals. Responding cells were drawn from the CD45RA+ “naive” or quiescent population. Depleting the CD25+ fraction did not enhance CEA responsiveness. However, CEA elicited secretion of the Tr cytokine interleukin-10 (IL-10) in 23 of 50 donors, including 20 of 22 where no proliferation was induced. Neutralizing IL-10 revealed previously unseen proliferation to CEA by CD45RO+ “memory” Th cells. Epitope maps revealed differences in the fine specificities of Th cells capable of proliferating or secreting IL-10. Conclusions: There are at least two major forms of CEA tolerance in different individuals. One is “ignorance,” a failure of specific Th cells to respond to antigen presented in vivo. The other, seen when ignorance is lost, is mediated by IL-10–secreting Tr cells that recognize CEA. TAA tolerance, for example to colorectal carcinoma cells expressing CEA, may be overcome by peptide vaccines that exploit the differences in epitopes recognized by effector and Tr responses.