tbuckley/cabot-search huggingface dataset:
REQUIREMENTS FOR PROLONGED SUPPRESSION OF AN IDIOTYPIC SPECIFICITY IN ADULT MICE
Authors: Laura L. Pawlak, David A. Hart, Alfred Nisonoff
Journal: The Journal of Experimental Medicine (1973)

The appearance of an idiotypic specificity, present in anti-p-azophenylarsonate (anti-Ar) antibodies of all immunized A/J mice, ran be suppressed in adult mice by prior administration of an IgG fraction of rabbit antiidiotypic (anti-D) antiserum; anti-Ar antibodies arise but are of different idiotype. Prolonged suppression was observed in earlier experiments, but antigen was first administered to adult mice only 2 wk or 9 wk after anti-D antibodies; subsequent escape from idiotypic suppression could have been masked by the capture of antigen by large numbers of memory cells having receptors of a different idiotype. In the present experiments antigen was first administered at intervals up to 22 wk after the antiidiotypic antibody. Suppression was maintained for 6 wk in all mice and for 5 mo in about half the mice tested. It thus appears that suppression of idiotype is less reversible if antigen is administered soon after the antiidiotypic antibody. The data suggest that escape from suppression is attributable to the generation of new precursor cells rather than to reactivation of suppressed cells. The minimum dosage of antiidiotypic IgG required for effective suppression was about 2 mg. The subcutaneous or intraperitoneal routes of inoculation of antiidiotypic IgG were equally effective. When antiidiotypic antibody was administered 3 days after antigen no suppressive effects were observed. There was partial suppression when antiidiotypic antibody was injected on the same day as the antigen. Fab' and F(ab')(2) fragments of antiidiotypic IgG had no suppressive effect. Quantitative measurements revealed no significant differences among control and suppressed mice with respect to total concentration of precipitable anti-Ar antibodies produced.
Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors
Authors: Jason I Herschkowitz, Karl Simin, Victor J Weigman, Igor Mikaelian, Jerry Usary, Zhiyuan Hu, Karen E Rasmussen, Laundette P Jones, Shahin Assefnia, Subhashini Chandrasekharan, Michael G Backlund, Yuzhi Yin, Andrey I Khramtsov, Roy Bastein, John Quackenbush, Robert I Glazer, Powel H Brown, Jeffrey E Green, Levy Kopelovich, Priscilla A Furth, Juan P Palazzo, Olufunmilayo I Olopade, Philip S Bernard, Gary A Churchill, Terry Van Dyke, Charles M Perou
Journal: Genome biology (2007)

Abstract Background Although numerous mouse models of breast carcinomas have been developed, we do not know the extent to which any faithfully represent clinically significant human phenotypes. To address this need, we characterized mammary tumor gene expression profiles from 13 different murine models using DNA microarrays and compared the resulting data to those from human breast tumors. Results Unsupervised hierarchical clustering analysis showed that six models (TgWAP- Myc , TgMMTV- Neu , TgMMTV- PyMT , TgWAP- Int3 , TgWAP- Tag , and TgC3(1)- Tag ) yielded tumors with distinctive and homogeneous expression patterns within each strain. However, in each of four other models (TgWAP- T 121 , TgMMTV- Wnt1 , Brca1 Co / Co ;TgMMTV- Cre ; p53 +/- and DMBA-induced), tumors with a variety of histologies and expression profiles developed. In many models, similarities to human breast tumors were recognized, including proliferation and human breast tumor subtype signatures. Significantly, tumors of several models displayed characteristics of human basal-like breast tumors, including two models with induced Brca1 deficiencies. Tumors of other murine models shared features and trended towards significance of gene enrichment with human luminal tumors; however, these murine tumors lacked expression of estrogen receptor (ER) and ER-regulated genes. TgMMTV- Neu tumors did not have a significant gene overlap with the human HER2+/ER- subtype and were more similar to human luminal tumors. Conclusion Many of the defining characteristics of human subtypes were conserved among the mouse models. Although no single mouse model recapitulated all the expression features of a given human subtype, these shared expression features provide a common framework for an improved integration of murine mammary tumor models with human breast tumors.
FIBROBLAST GROWTH FACTOR-23 IS ASSOCIATED WITH DISEASE SEVERITY AND PROGNOSIS IN CHRONIC HEART FAILURE
Authors: Gerhard Poelzl, Christian Trenkler, Johannes Kliebhan, Philipp Wuertinger, Christoph Seger, Susanne Kaser, Gert Mayer, Markus Pirklbauer, Hanno Ulmer, Andrea Griesmacher
Journal: Journal of the American College of Cardiology (2014)
Epigenetic Inactivation of <b> <i>ID4</i> </b> in Colorectal Carcinomas Correlates with Poor Differentiation and Unfavorable Prognosis
Authors: Naoyuki Umetani, Hiroya Takeuchi, Akihide Fujimoto, Masaru Shinozaki, Anton J. Bilchik, Dave S. B. Hoon
Journal: Clinical Cancer Research (2004)

Abstract Purpose: ID4 gene is a member of the inhibitor of DNA binding (ID) family proteins that inhibit DNA binding of basic helix-loop-helix transcription factors. The epigenetic inactivation of ID4 gene on colorectal cancer (CRC) development and its clinical significance was assessed. Experimental Design: In CRC cell lines, ID4 methylation status of the promoter region was assessed by methylation-specific PCR and bisulfite sequencing. The mRNA expression level was assessed by quantitative real-time reverse transcription-PCR. The methylation status of 9 normal epithelia, 13 adenomas, 92 primary CRCs, and 26 liver metastases was assessed by methylation-specific PCR. ID4 protein expression was assessed by immunohistochemistry analysis of tissue specimen. Results: CRC cell lines were shown to be hypermethylated, and mRNA expression was suppressed and could be restored by 5-aza–cytidine treatment. In clinical specimens from normal epithelia, adenomas, primary CRCs, and liver metastases, the frequency of ID4 hypermethylation was 0 of 9 (0%), 0 of 13 (0%), 49 of 92 (53%), and 19 of 26 (73%), respectively, with a significant elevation according to CRC pathological progression. Methylation status of primary CRCs significantly correlated with histopathological tumor grade (P = 0.028). Immunohistochemistry analysis showed ID4 expression of normal colon epithelia, adenomas, and unmethylated primary CRCs but not hypermethylated CRC specimens. Among 76 American Joint Committee on Cancer stage I to IV patients who had undergone curative surgical resection, overall survival was significantly poorer in patients with hypermethylated ID4 bearing tumors (P = 0.0066). Conclusions: ID4 gene is a potential tumor suppressor gene for which methylation status may play an important role in the CRC progression.
Emergence of Epidermal Growth Factor Receptor T790M Mutation during Chronic Exposure to Gefitinib in a Non–Small Cell Lung Cancer Cell Line
Authors: Atsuko Ogino, Hiroyuki Kitao, Seiki Hirano, Akiko Uchida, Masamichi Ishiai, Toshiyuki Kozuki, Nagio Takigawa, Minoru Takata, Katsuyuki Kiura, Mitsune Tanimoto
Journal: Cancer Research (2007)

Abstract The epidermal growth factor receptor (EGFR)–specific tyrosine kinase inhibitor gefitinib may provide dramatic clinical responses in some patients with pulmonary adenocarcinoma carrying activating mutations of the EGFR. However, prolonged administration of gefitinib may eventually induce acquired resistance in such patients. To gain insight into the mechanisms of this phenomenon, we placed PC-9, a cell line derived from pulmonary adenocarcinoma that has a 15-bp deletion in EGFR exon 19, under the continuous selective pressure of low levels of gefitinib without any mutagen, and established a subline that was able to grow in the presence of 2 μmol/L of gefitinib (designated RPC-9). In this cell line, about half of the reverse transcription-PCR products from mutated EGFR also carried an additional mutation (T790M). In keeping with the proposed role of T790M in abrogating gefitinib binding with EGFR, gefitinib-treated RPC-9 hardly displayed any decrease in the constitutive phosphorylation of EGFR, Akt, or Erk1/2 unlike in PC-9 cells. Interestingly, transfection of the EGFR carrying only a 15-bp deletion reversed the resistance to gefitinib in RPC-9 cells. Thus, the balance of expression levels between gefitinib-sensitive or gefitinib-resistant EGFR may govern the response to gefitinib in lung cancer. [Cancer Res 2007;67(16):7807–14]
Chloralamide as a Hypnotic
Authors: W. H. White
Journal: BMJ (1889)

always produced sleep.CASE \x'.-Carcinoma of the pylorus.A woman sged 56.3gr.always' produced sleep better than morphine.CA-s xvI.-Chronic eczema.A man aged 40.30 gr. caused comfortable sleep.CAsE XvIr -Mitral regurgitstion and floating kidney.A woman aged 50.30 gr. produced sleep, altbough the floating kidney caused much pain.CASE XVITI.-Spasticparaplegia.A woman aged 56.20 gr.caused comfortable sleep.CASE xrx.-Phthisis, aortic disease, saturnine paralyia.A man aged 65. 20 gr.always produced sleep, but it took twelve hoursto act, so that if the medicine were given in tLe evening the pstient did not sleep duriog the night, but he slept all the next CASE ix.-Mitral regurgitation.An adult man.A severe cis'. 30gr. prodtuced comfort.utuesteel,.
First Ebola treatment is approved by WHO
Authors: A. Gulland
Journal: BMJ (2014)

Serum from people who are convalescing from infection with the Ebola virus can be used to treat new patients, the World Health Organization announced last week.

At the end of a two day meeting of around 200 international experts, including regulators, ethicists, virologists, and health workers, WHO approved the use of convalescent serum and whole blood products to treat affected patients in a bid to control the outbreak that has spread through west Africa at an unprecedented rate.1 2 WHO also announced that two promising candidate vaccines, chimpanzee adenovirus vaccine and vesicular stomatitis virus, may be introduced as early as November when safety studies have concluded.

Marie-Paule Kieny, assistant director general of WHO, told a press conference that the infrastructure to develop blood products needed to be put in place in the …
Absence of IFN-γ accelerates thrombus resolution through enhanced MMP-9 and VEGF expression in mice
Authors: Mizuho Nosaka, Yuko Ishida, Akihiko Kimura, Yumi Kuninaka, Masanori Inui, Naofumi Mukaida, Toshikazu Kondo
Journal: Journal of Clinical Investigation (2011)

Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism, a leading cause of death in individuals with DVT. Several lines of evidence indicate proinflammatory cytokines such as TNF-α are involved in thrombus formation and resolution, but the roles of IFN-γ remain unclear. To address this issue, we performed ligation of the inferior vena cava to induce DVT in WT and IFN-γ-deficient (Ifng-/-) mice. In WT mice, intrathrombotic IFN-γ levels were elevated progressively as the postligation interval was extended. Thrombus size was substantially smaller at 10 and 14 days in Ifng-/- mice than in WT mice. Intrathrombotic collagen content was remarkably reduced at more than 10 days after the ligation in Ifng-/- mice compared with WT mice. The expression and activity of MMP-9, but not MMP-2, was higher at the late phase in Ifng-/- mice than in WT mice. Moreover, intrathrombotic recanalization was increased in Ifng-/- mice, with enhanced Vegf gene expression, compared with that in WT mice. Activation of the IFN-γ/Stat1 signal pathway suppressed PMA-induced Mmp9 and Vegf gene expression in peritoneal macrophages. Furthermore, administration of anti-IFN-γ mAbs accelerated thrombus resolution in WT mice. Collectively, these findings indicate that IFN-γ can have detrimental roles in thrombus resolution and may be a good molecular target for the acceleration of thrombus resolution in individuals with DVT.
Randomized Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen Sodium (Bcl-2 antisense) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
Authors: Susan O'Brien, Joseph O. Moore, Thomas E. Boyd, Loree M. Larratt, Aleksander Skotnicki, Benjamin Koziner, Asher A. Chanan-Khan, John F. Seymour, R. Gregory Bociek, Steve Pavletic, Kanti R. Rai
Journal: Journal of Clinical Oncology (2007)

Expression of Bcl-2 protein is associated with chemotherapy resistance and decreased survival in chronic lymphocytic leukemia (CLL). We evaluated whether oblimersen would improve response to chemotherapy in patients with relapsed or refractory CLL.Patients had received at least one prior fludarabine-containing regimen and were stratified on the basis of prior fludarabine response, number of prior regimens, and duration of response to last prior therapy. Patients were randomly assigned to 28-day cycles of fludarabine 25 mg/m2/d plus cyclophosphamide 250 mg/m2/d administered intravenously for 3 days with or without oblimersen 3 mg/kg/d as a 7-day continuous intravenous infusion (beginning 4 days before chemotherapy) for up to six cycles. The primary end point was the proportion of patients who achieved complete response (CR) or nodular partial response (nPR).Of 241 patients randomly assigned, CR/nPR was achieved in 20 (17%) of 120 patients in the oblimersen group and eight (7%) of 121 patients in the chemotherapy-only group (P = .025). Achievement of CR/nPR was correlated with both an extended time to progression and survival (P < .0001). In patients who remained sensitive to fludarabine, oblimersen was associated with a four-fold increase in the CR/nPR rate and a significant survival benefit (P = .05). Oblimersen was frequently associated with thrombocytopenia and, rarely, tumor lysis syndrome and cytokine release reactions; the incidence of opportunistic infections and second malignancies was similar in both groups.The addition of oblimersen to fludarabine plus cyclophosphamide significantly increases the CR/nPR rate in patients with relapsed or refractory CLL (particularly fludarabine-sensitive patients), as well as response duration among patients who achieve CR/nPR.
Receptor of Activated Protein C Promotes Metastasis and Correlates with Clinical Outcome in Lung Adenocarcinoma
Authors: Iker Antón, Eva Molina, Diego Luis-Ravelo, Carolina Zandueta, Karmele Valencia, Cristina Ormazabal, Susana Martínez-Canarias, Naiara Perurena, María José Pajares, Jackeline Agorreta, Luis M. Montuenga, Victor Segura, Ignacio I. Wistuba, Javier De Las Rivas, José Hermida, Fernando Lecanda
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Efficient metastasis requires survival and adaptation of tumor cells to stringent conditions imposed by the extracellular milieu. Identification of critical survival signaling pathways in tumor cells might unveil novel targets relevant in disease progression.To investigate the contribution of activated protein C (APC) and its receptor (endothelial protein C receptor [EPCR]) in animal models of lung cancer metastasis and in patients with lung adenocarcinoma.Signaling pathway triggered by APC/EPCR and its relevance in apoptosis was studied in vitro. Functional significance was assessed by silencing and blocking antibodies in several in vivo models of lung cancer metastasis in athymic nude Foxn1(nu) mice. We examined EPCR levels using a microarray dataset of 107 patients. Immunohistochemical analysis was performed in an independent cohort of 295 patients with lung adenocarcinoma.The effects of APC binding to EPCR rapidly triggered Akt and extracellular signal-regulated kinase signaling pathways, leading to attenuated in vitro apoptosis. In vivo, silencing of EPCR expression or blocking APC/EPCR interaction reduced infiltration in the target organ, resulting in impaired prometastatic activity. Moreover, overexpression of EPCR induced an increased metastatic activity to target organs. Analysis of clinical samples showed a robust association between high EPCR levels and poor prognosis, particularly in stage I patients.EPCR and its ligand APC promote cell survival that contributes to tumor cell endurance to stress favoring prometastatic activity of lung adenocarcinoma. EPCR/APC is a novel target of relevance in the clinical outcome of early-stage lung cancer.
The torch has passed: G Gayle Stephens
Authors: D. Loxterkamp
Journal: BMJ (2014)

G Gayle Stephens helped shape family medicine in the US and was an inspiration to many



Earlier this year, G Gayle Stephens, died in his Alabama home at the age of 85. He was one of the earliest advocates and leading lights for a new specialty called family practice.

In the aftermath of the second world war, England adopted the National Health Service, which secured a future for primary care. Generalists in the United States fared worse. The war accelerated medicine’s technological advance, introduced pay differentials for specialists, and funded rapid expansions in postgraduate medical education. Few medical graduates were choosing general practice, and fewer still settled in areas of greatest need. General practice entered a death spiral.

The 1960s brought a shift in the political winds. Stephens founded a residency program in Wichita, Kansas, two years before the specialty was approved (1969), chaired its major academic organization, became the first dean of a medical school dedicated to primary care, and served as an associate editor for the specialty board’s journal.

But it is as a writer that we got to know him. I was a medical student in the late …
Overcoming Drug-Resistant Cancer by a Newly Developed Copper Chelate through Host-Protective Cytokine-Mediated Apoptosis
Authors: Ananda Mookerjee, Jayati Mookerjee Basu, Pranabananda Dutta, Surajit Majumder, Sankar Bhattacharyya, Jaydip Biswas, Smarajit Pal, Pratima Mukherjee, Sanghamitra Raha, Rathindra N. Baral, Tania Das, Thomas Efferth, Gourisankar Sa, Shyamal Roy, Soumitra K. Choudhuri
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Previously, we have synthesized and characterized a novel Cu(II) complex, copper N-(2-hydroxy acetophenone) glycinate (CuNG). Herein, we have determined the efficacy of CuNG in overcoming multidrug-resistant cancer using drug-resistant murine and human cancer cell lines. Experimental Design: Action of CuNG following single i.m. administration (5 mg/kg body weight) was tested in vivo on doxorubicin-resistant Ehrlich ascites carcinoma (EAC/Dox)–bearing mice and doxorubicin-resistant sarcoma 180–bearing mice. Tumor size, ascitic load, and survival rates were monitored at regular intervals. Apoptosis of cancer cells was determined by cell cycle analysis, confocal microscopy, Annexin V binding, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay ex vivo. IFN-γ and tumor necrosis factor-α were assayed in the culture supernatants of in vivo and in vitro CuNG-treated splenic mononuclear cells from EAC/Dox-bearing mice and their apoptogenic effect was determined. Source of IFN-γ and changes in number of T regulatory marker-bearing cells in the tumor site following CuNG treatment were investigated by flow cytometry. Supernatants of in vitro CuNG-treated cultures of peripheral blood mononuclear cells from different drug-insensitive cancer patients were tested for presence of the apoptogenic cytokine IFN-γ and its involvement in induction of apoptosis of doxorubicin-resistant CEM/ADR5000 cells. Results: CuNG treatment could resolve drug-resistant cancers through induction of apoptogenic cytokines, such as IFN-γ and/or tumor necrosis factor-α, from splenic mononuclear cells or patient peripheral blood mononuclear cells and reduce the number of T regulatory marker-bearing cells while increase infiltration of IFN-γ-producing T cells in the ascetic tumor site. Conclusion: Our results show the potential usefulness of CuNG in immunotherapy of drug-resistant cancers irrespective of multidrug resistance phenotype.
Recovery of mutations of different sizes from a population sample of DNA sequences under variable mutation rates across sites
Authors: H. W. Deng, J. L. Li, J. Li
Journal: Molecular Biology and Evolution (1999)

Mutations may be classified according to their positions of occurrence in the genealogy of the sampled DNA sequences from a population. A mutation is said to be of size i if it has i descendants in the sample. Such classifications for mutations may yield detailed insights into the evolutionary history and properties of the population. Statistical methods based on such classification have been developed and shown to be efficient and powerful. However, the utility of these statistical methods critically depends on reliable and robust recovery of mutations of different sizes. We investigated the distributional changes of mutations of different sizes due to genealogy reconstruction using the unweighted pair-group method with arithmetic mean (UPGMA) and the performance of maximum-parsimony method in inferring mutations of different sizes on a given topology. Genealogy reconstruction by UPGMA was found to change the distribution of mutations of different sizes on constructed topologies. Multiple hits at some nucleotide sites made it difficult to infer mutations of different sizes with the maximum-parsimony method, even when the true topology was designated. These results suggest that while the newly developed statistical methods employing information on mutations of different sites are powerful, they also impose significant new challenges for developing methods to accurately recover mutations of different sizes from population DNA sequence data.
Internalized constraints may function as an emulator
Authors: Margaret Wilson
Journal: Behavioral and Brain Sciences (2001)

Kubovy and Epstein's main quarrel is with the concept of “internalization.” I argue that they underestimate the aptness of this metaphor. In particular, an emulator which predicts unfolding events can be described as an internalization of external structures. Further, an emulator may use motoric as well as perceptual resources, which lends support to Hecht's proposal. [Hecht; Kubovy &amp; Epstein]
Plasma levels of lathosterol and phytosterols in relation to age, sex, anthropometric parameters, plasma lipids, and apolipoprotein E phenotype, in 160 Dutch families
Authors: H.J.M. Kempen, P. de Knijff, D.I. Boomsma, H.A. van der Voort, J.A. Gevers Leuven, L. Havekes
Journal: Metabolism (1991)
Jumper's knee paradox—jumping ability is a risk factor for developing jumper's knee: a 5-year prospective study
Authors: Håvard Visnes, Hans Åge Aandahl, Roald Bahr
Journal: British Journal of Sports Medicine (2012)

Background The ‘jumper's knee paradox’, where symptomatic athletes appear to perform better in a counter movement jump (CMJ) compared to asymptomatic controls in previous case–control studies is not fully understood. Aim The aim was to examine the relationship between jumping ability and change of jumping ability as potential risk factors for developing jumper's knee. Methods A 5-year prospective cohort study among elite volleyball players, aged 16–18. Jump tests were done on a portable force plate at the time of inclusion and semiannually. Jumper's knee was diagnosed based on a standardised clinical examination. Results All 150 students (68 males and 82 females) were included and 28 developed jumper's knee (22 males and 6 females). At the time of inclusion, male athletes who went on to develop jumper's knee had significantly better results in CMJ (38.0±5.8 cm) compared to asymptomatic males (34.6±5.5 cm, p=0.03), while no difference was detected in standing jump (SJ: jumper's knee: 30.3±7.4 cm, asymptomatic: 28.1±6.1 cm, p=0.23). In a multivariate logistic regression analysis corrected for gender and previous volleyball training, the OR was 2.09 (1.03–4.25) per cm difference in CMJ at the time of inclusion. Our results did not reveal any significant differences in the change in jumping ability between the groups, although both groups improved their jump performance. Conclusions Volleyball players with a natural ability for jumping high are at an increased risk for developing jumper's knee.