tbuckley/cabot-search huggingface dataset:
What do you think should be the political priorities for the NHS?
Authors: R. Coombes
Journal: BMJ (2015)

The frontal lobes are essential for human volition and goal-directed behavior, yet their function remains unclear. While various models have highlighted working memory, reinforcement learning, and cognitive control as key functions, a single framework for interpreting the range of effects observed in prefrontal cortex has yet to emerge. Here we show that a simple computational motif based on predictive coding can be stacked hierarchically to learn and perform arbitrarily complex goal-directed behavior. The resulting Hierarchical Error Representation (HER) model simulates a wide array of findings from fMRI, ERP, single-units, and neuropsychological studies of both lateral and medial prefrontal cortex. Additionally, the model compares favorably with current machine learning approaches, learning more rapidly and with comparable performance, while self-organizing representations into efficient hierarchical groups and managing working memory storage. By reconceptualizing lateral prefrontal activity as anticipating prediction errors, the HER model provides a novel unifying account of prefrontal cortex function with broad implications both for understanding the frontal cortex and building more powerful machine learning applications.
Polymorphisms in DNA Base Excision Repair Genes <i>ADPRT</i> and <i>XRCC1</i> and Risk of Lung Cancer
Authors: Xuemei Zhang, Xiaoping Miao, Gang Liang, Bingtao Hao, Yonggang Wang, Wen Tan, Yi Li, Yongli Guo, Fuchu He, Qingyi Wei, Dongxin Lin
Journal: Cancer Research (2005)

Adenosine diphosphate ribosyl transferase (ADPRT) and X-ray repair cross-complementing 1 (XRCC1) are two major DNA base excision repair (BER) proteins and act interactively in stimulating and executing BER processes. Polymorphisms of ADPRT Val762Ala and XRCC1 Arg399Gln have been associated with altered protein function and BER activity. This case-control study examined the contribution of these two polymorphisms, alone and in combination, or in interaction with smoking, to the risk of developing lung cancer. We estimated the risk of lung cancer associated with these polymorphisms in 1,000 cases and 1,000 cancer-free controls using logistic regression models. Subjects having the ADPRT Ala/Ala genotype had an odds ratio (OR) of 1.68 [95% confidence interval (95% CI), 1.27-2.23] compared with those having the Val/Val genotype. A greater than multiplicative joint effect between the ADPRT polymorphism and smoking was observed. The ORs (95% CI) of the Ala/Ala genotype for nonsmokers and smokers who smoked < or =16, 16 to 28, or >28 pack-years were 1.13 (0.79-1.62), 1.35 (0.68-2.70), 2.46 (1.35-4.51) or 17.09 (8.15-35.83), respectively (P trend test < 0.001). Gene-gene interaction of ADPRT and XRCC1 polymorphisms increased risk of lung cancer in a supermultiplicative manner (OR for the presence of both ADPRT 762Ala/Ala and XRCC1 399Gln/Gln genotypes, 5.91; 95% CI, 2.09-16.72), although the XRCC1 polymorphism itself was not associated with the risk. In conclusion, the ADPRT Val762Ala polymorphism plays an important role in smoking-related lung cancer and the XRCC1 Arg399Gln polymorphism may serve as a risk modifier.
<i>IDH1</i>and<i>IDH2</i>Mutations in Gliomas
Authors: Hai Yan, D. Williams Parsons, Genglin Jin, Roger McLendon, B. Ahmed Rasheed, Weishi Yuan, Ivan Kos, Ines Batinic-Haberle, Siân Jones, Gregory J. Riggins, Henry Friedman, Allan Friedman, David Reardon, James Herndon, Kenneth W. Kinzler, Victor E. Velculescu, Bert Vogelstein, Darell D. Bigner
Journal: New England Journal of Medicine (2009)

A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas).We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes.We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein.Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.
COMPONENTS OF GUINEA PIG COMPLEMENT
Authors: Kusuya Nishioka, William D. Linscott
Journal: The Journal of Experimental Medicine (1963)

Employing sheep erythrocytes sensitized by antibody and the first and fourth components of complement (EAC'1,4), in such a manner as to prevent the development of immune adherence (I-A) reactivity during preparation, four separate substances required for the conversion of EAC'1,4,2 to the final damaged state (E*) were identified in whole guinea pig serum by cellulose chromatography, and tentatively termed C'3c, C'3b, C'3a, and C'3d. I-A reactivity was induced in EAC'1,4,2 after interaction with only one of these four substances, C'3c. A detailed comparison of the effects of heat, hydrazine, low pH, freezing, absorption by immune complexes, and elution from cellulose columns indicated that this same substance which was capable of imparting I-A reactivity to EAC'1,4,2 was also essential for immune hemolysis. Other experiments showed that I-A-reactive cells prepared either by treating EA with different concentrations of whole C' at 0 degrees C, or by treating EAC'1,4,2 with C'3c, underwent lysis by C'2 + C'3b + a + d in proportion to the amount of whole C' or of C'3c used to make the cells reactive in I-A. These data provide strong evidence that a single factor, C'3c, is required both for the conversion of EAC'1,4,2 to an I-A-reactive complex (EAC'1,4,2,3c) and for the lysis of EAC'1,4,2 by C'3b + a + d. C'3c is the only one of the components studied which can induce I-A reactivity, and is the first to react with EAC'1,4,2. Formation of EAC'1,4,2,3c proceeds even at 0 degrees C, but is much more rapid at elevated temperatures, showing a maximum in from 5 to 15 minutes at 37 degrees or 30 degrees C respectively. Prolonged incubation at these temperatures results in a decline in hemolytic reactivity without a noticeable effect on I-A. This loss was resolved into three phenomena: (a) a rapid loss of ability of SAC'1,4,2,3c to react with C'3b, presumably as a result of decay of the C'2 moiety in the complex, which is readily reversed by addition of fresh C'2; (b) a slow, irreversible spontaneous inactivation of SAC'1,4,2,3c; (c) a moderately rapid, irreversible inactivation of SAC'1,4,2,3c by some factor present in C'3c preparations.
Focal adhesion kinase is required for neural crest cell morphogenesis during mouse cardiovascular development
Authors: Ainara Vallejo-Illarramendi, Keling Zang, Louis F. Reichardt
Journal: Journal of Clinical Investigation (2009)

Neural crest cells (NCCs) participate in the remodeling of the cardiac outflow tract and pharyngeal arch arteries during cardiovascular development. Focal adhesion kinase (FAK) mediates signal transduction by integrin and growth factor receptors, each of which is important for normal cardiovascular development. To investigate the role of FAK in NCC morphogenesis, we deleted it in murine NCCs using Wnt1cre, yielding craniofacial and cardiovascular malformations resembling those observed in individuals with DiGeorge syndrome. In these mice, we observed normal cardiac NCC migration but reduced differentiation into smooth muscle within the aortic arch arteries and impaired cardiac outflow tract rotation, which resulted in a dextroposed aortic root. Moreover, within the conotruncal cushions, Fak-deficient NCCs formed a less organized mesenchyme, with reduced expression of perlecan and semaphorin 3C, and exhibited disorganized F-actin stress fibers within the aorticopulmonary septum. Additionally, absence of Fak resulted in reduced in vivo phosphorylation of Crkl and Erk1/2, components of a signaling pathway essential for NCC development. Consistent with this, both TGF-β and FGF induced FAK and Crkl phosphorylation in control but not Fak-deficient NCCs in vitro. Our results indicate that FAK plays an essential role in cardiac outflow tract development by promoting the activation of molecules such as Crkl and Erk1/2.
STUDIES ON BLOOD CELL METABOLISM
Authors: Geo. A. Harrop, E. S. Guzman Barron
Journal: The Journal of Experimental Medicine (1928)

1. The respiratory metabolism of non-nucleated mammalian erythrocytes is enormously accelerated and approaches the magnitude of the metabolism of the nucleated erythrocytes of birds on the addition of methylene blue (and certain other dyes), to a final concentration of 0.005-0.0005 per cent. 2. In the presence of methylene blue the respiration is accelerated even when M/1000 KCN is also present. 3. The accelerated respiration due to methylene blue occurs at room temperature but it is most active at 38 degrees . 4. Methylene blue in the above concentration accelerates the respiration of avian (goose) erythrocytes to a much smaller extent than it does the respiration of the erythrocytes of mammalian blood, while the effect upon anemic goose blood seems to be less than it is upon cells of normal goose blood. 5. Owing to a rather large initial carbon dioxide formation in defibrinated blood on incubation, which may not be related to the immediate respiratory process, proper respiratory quotients cannot be obtained in whole blood. When the cells are separated from the serum and suspended in Locke's solution, respiratory quotients are obtained upon incubation comparable to those of other resting mammalian cells, as well as of the actively respiring erythrocytes of birds. 6. The hypothesis is advanced that methylene blue acts in the rôle of an oxygen carrier, supplying a substance which has disappeared from adult mammalian non-nucleated erythrocytes and restoring their metabolic activity to an extent comparable to that of the young immature forms, or to that of the actively respiring avian (goose) blood.
HOXA13 Promotes Cancer Cell Growth and Predicts Poor Survival of Patients with Esophageal Squamous Cell Carcinoma
Authors: Zhen-Dong Gu, Lu-Yan Shen, Hua Wang, Xiao-Mei Chen, Yong Li, Tao Ning, Ke-Neng Chen
Journal: Cancer Research (2009)

Abstract Homeobox genes are known to be classic examples of the intimate relationship between embryogenesis and tumorigenesis. Here, we investigated whether inhibition of HOXA13, a member of the homeobox genes, was sufficient to affect the proliferation of esophageal cancer cells in vitro and in vivo, and studied the association between HOXA13 expression and survival of patients with esophageal squamous cell carcinoma (ESCC). HOXA13 expression was permanently knocked down using an RNA interference technique, and cell strain with stable knockdown of HOXA13 protein was established. Colony formation assay showed that the number of colonies in HOXA13 protein–deficient cells was significantly less than that of control cells (P &amp;lt; 0.01). Tumor growth in nude mice showed that the weight and volume of tumors from the HOXA13 knockdown cells was significantly less than that from the control cells (P &amp;lt; 0.01). Then, HOXA13 expression in ESCC specimens and paired noncancerous mucosa was detected by immunohistochemistry, and overexpression of HOXA13 was found to be more pronounced in ESCCs than paired noncancerous mucosa (P &amp;lt; 0.05). Furthermore, the association of HOXA13 expression and disease-free survival time was analyzed in 155 ESCC cases. The median survival time of patients expressing HOXA13 was significantly shorter than HOXA13-negative patients (P = 0.0006). Multivariate analysis indicated that tumor-node-metastasis (TNM) stage and HOXA13 expression were independent predictors of disease-free survival time of patients with ESCC. Our results showed that HOXA13 expression enhanced tumor growth in vitro and in vivo, and was a negative independent predictor of disease-free survival of patients with ESCC. [Cancer Res 2009;69(12):4969–73]
Down-regulation of CD46 by Piliated <i>Neisseria gonorrhoeae </i>
Authors: Darcy B. Gill, Michael Koomey, Janne G. Cannon, John P. Atkinson
Journal: The Journal of Experimental Medicine (2003)

Human membrane cofactor protein (CD46) protects host cells against complement attack and may function as a receptor for pathogenic Neisseriae. We assessed CD46 expression in the human cervical cell line ME-180 after exposure to Neisseria gonorrhoeae. Piliated but not nonpiliated gonococci adhered to cells and produced up to an 80% reduction in CD46 surface expression by 6 h that persisted for at least 24 h. This response required a minimum multiplicity of infection of 10 and was not prevented by antibodies to CD46. CD46 down-regulation was not attributable to intracellular retention or a global or specific shutdown of mRNA or protein synthesis. Substantial quantities of CD46 were found in the supernatants, indicating a specific shedding of this protein. Adherent gonococci lacking the pilus retraction protein PilT did not down-regulate CD46 but de-repression of pilT expression restored CD46 down-regulation. After experimental infection of human volunteers with a gonococcal variant incapable of inducing CD46 down-regulation, variants of this strain were reisolated that exhibited CD46 down-regulation. Pilus-mediated interactions of gonococci with human epithelial cells results in a pathogen-induced manipulation of the host cell environment in which a membrane protein is removed from epithelial cells by liberation into the surrounding milieu.
Nongenomic Vascular Action of Aldosterone in the Glomerular Microcirculation
Authors: Shuji Arima, Kentaro Kohagura, Hong-Lan Xu, Akira Sugawara, Takaaki Abe, Fumitoshi Satoh, Kazuhisa Takeuchi, Sadayoshi Ito
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Aldosterone (Aldo) accelerates hypertension, proteinuria, and glomerulosclerosis in animal models of malignant hypertension or chronic renal failure. Aldo may exert these deleterious renal effects by elevating renal vascular resistance and glomerular capillary pressure. To test this possibility, directly examined were the action of Aldo on the afferent (Af) and efferent (Ef) arterioles (Arts). Examined were the effect of Aldo added to both the bath and lumen on the intraluminal diameter (measured at the most responsive point) of rabbits. Aldo caused dose-dependent constriction in both arterioles with a higher sensitivity in Ef-Arts. Vasoconstrictor action of Aldo was not affected by a mineralocorticoid receptor antagonist spironolactone and was reproduced by membrane-impermeable albumin-conjugated Aldo, suggesting that the vasoconstrictor actions are nongenomic. Pretreatment with neomycin (a specific inhibitor of phospholipase C) abolished the vasoconstrictor action of Aldo in both arterioles. In addition, the vasoconstrictor action of Aldo on Af-Arts was inhibited by both nifedipine and efonidipine, whereas that on Ef-Arts was inhibited by efonidipine but not nifedipine. The results demonstrate that Aldo causes nongenomic vasoconstriction by activating phospholipase C with a subsequent calcium mobilization thorough L- or T-type voltage-dependent calcium channels in Af- or Ef-Arts, respectively. These vasoconstrictor actions on the glomerular microcirculation may play an important role in the pathophysiology and progression of renal diseases by elevating renal vascular resistance and glomerular capillary pressure. E-mail: shuarima@mail.cc.tohoku.ac.jp
Phase I Trial of TGF-β2 Antisense GM-CSF Gene-Modified Autologous Tumor Cell (TAG) Vaccine
Authors: Jairo Olivares, Padmasini Kumar, Yang Yu, Phillip B. Maples, Neil Senzer, Cynthia Bedell, Minal Barve, Alex Tong, Beena O. Pappen, Joseph Kuhn, Mitchell Magee, Gladice Wallraven, John Nemunaitis
Journal: Clinical Cancer Research (2011)

Abstract Purpose: On the basis of the hypothesis that the combined expression of immunostimulatory granulocyte macrophage colony stimulating factor (GM-CSF) and antitumor suppressor TGF-β2 antisense (AS) transgenes can break tolerance and stimulate immune responses to cancer-associated antigens, we constructed an expression plasmid [the tumor-associated glycoprotein (TAG) plasmid] that coexpresses GM-CSF and TGF-β2 AS nucleotide sequences and which was incorporated into an autologous whole-cell vaccine. Experimental Design: Patients undergoing resection were enrolled. Freshly harvested autologous tumor cells were mechanically and enzymatically disaggregated, then electroporated with the TAG vector. The resulting vaccine was irradiated, then aliquoted and cryopreserved until the time of injection. Patients received a minimum of 5 to a maximum of 12 monthly intradermal injections. Immune function was monitored at baseline and at months 3 and 6. Results: Vaccine manufacturing efficiency was 84% (32/38). Twenty-three patients received at least 1 vaccination. There were no grade 3 or 4 toxicities, and grade 1 and 2 events were local in nature. Seventeen of 21 patients had stable disease (SD) at month 2 or later as their best response, and 1 patient with stage IVa malignant melanoma achieved a complete response (CR) following 11 vaccinations and remains without evidence of disease 2 years following initiation of therapy. Six of 13 patients displayed a positive enzyme-linked immunospot (ELISPOT) response to autologous TAG vaccine at week 12 including 3 patients with prolonged SD or CR. The 3 other patients survived through week 24, as compared with none of the 7 ELISPOT-negative patients. Conclusions: On the basis of safety and clinical and immunologic results, further evaluation of bifunctional vaccines is warranted. Clin Cancer Res; 17(1); 183–92. ©2011 AACR.
Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer
Authors: Giovanna Vona, Laurence Estepa, Christophe Béroud, Diane Damotte, Frédérique Capron, Bertrand Nalpas, Alexandra Mineur, Dominique Franco, Bernard Lacour, Stanislas Pol, Christian Bréchot, Patrizia Paterlini-Bréchot
Journal: Hepatology (2004)

The clinical impact of circulating tumor cell (CTC) detection is controversial, mainly due to drawbacks of molecular approaches applied to this field. We sought to determine if the specific identification and counting of circulating tumor cells by cytomorphologic analysis has clinical usefulness. Peripheral blood (6 mL), treated using isolation by size of epithelial tumor cells, was obtained from 44 patients with primary liver cancer (PLC) and without metastases, 30 patients with chronic active hepatitis, 39 with liver cirrhosis, and 38 healthy individuals, and followed up for a mean period of 1 year. We searched for β-catenin mutations in 60 single microdissected CTCs. One patient with liver cancer developed extrahepatic metastases during follow-up. CTCs and microemboli were found in 23 of the 44 patients with liver cancer and in none of the patients with chronic active hepatitis, patients with cirrhosis, or healthy subjects. Their presence was significantly associated with tumor diffusion ( P = .0001) and portal tumor thrombosis ( P = .006). Both the presence ( P = .01) and number ( P = .02) of CTCs and microemboli were significantly associated with a shorter survival. β-Catenin mutations were found in 3 of 60 CTCs, arguing against their impact on the initial step of tumor cell invasion. In conclusion, the highly sensitive and specific detection of CTCs and microemboli may have clinical implications for cancer staging and outcome prediction. We also show the feasibility of molecular studies of individual circulating tumor cells, aimed at identifying gene mutations involved in tumor invasion. (Hepatology 2004;39:792-797.)
Meiotic Gene Evolution: Can You Teach a New Dog New Tricks?
Authors: Andrew H. Lloyd, Marion Ranoux, Sonia Vautrin, Natasha Glover, Joelle Fourment, Delphine Charif, Frederic Choulet, Gilles Lassalle, William Marande, Joseph Tran, Fabienne Granier, Lise Pingault, Arnaud Remay, Catherine Marquis, Harry Belcram, Boulos Chalhoub, Catherine Feuillet, Hélène Bergès, Pierre Sourdille, Eric Jenczewski
Journal: Molecular Biology and Evolution (2014)

Meiosis, the basis of sex, evolved through iterative gene duplications. To understand whether subsequent duplications have further enriched the core meiotic "tool-kit," we investigated the fate of meiotic gene duplicates following whole genome duplication (WGD), a common occurrence in eukaryotes. We show that meiotic genes return to a single copy more rapidly than genome-wide average in angiosperms, one of the lineages in which WGD is most vividly exemplified. The rate at which duplicates are lost decreases through time, a tendency that is also observed genome-wide and may thus prove to be a general trend post-WGD. The sharpest decline is observed for the subset of genes mediating meiotic recombination; however, we found no evidence that the presence of these duplicates is counterselected in two recent polyploid crops selected for fertility. We therefore propose that their loss is passive, highlighting how quickly WGDs are resolved in the absence of selective duplicate retention.
Two cycles of escalated BEACOPP followed by four cycles of ABVD utilizing early-interim PET/CT scan is an effective regimen for advanced high-risk Hodgkin's lymphoma
Authors: A. Avigdor, S. Bulvik, I. Levi, E.J. Dann, N. Shemtov, G. Perez-Avraham, A. Shimoni, A. Nagler, I. Ben-Bassat, A. Polliack
Journal: Annals of Oncology (2009)
Efficacy of azathioprine versus mesalazine in postoperative Crohn's disease
Authors: Alexander C Ford
Journal: Gut (2010)

I read the study performed by Reinisch and colleagues with interest.1 As the authors state, the optimum strategy for the treatment of Crohn's disease following intestinal resection remains uncertain, with conflicting evidence for use of mesalazine,2 3 and only limited data to suggest that 6-mercaptopurine (6-MP) or azathioprine are more effective than placebo4 5 in terms of the prevention of either clinical or endoscopic relapse of disease activity.

Reinisch et al are therefore …
Naturally occurring autologous anti-idiotypic antibodies. Participation in immune complex formation in selective IgA deficiency.
Authors: C Cunningham-Rundles
Journal: The Journal of Experimental Medicine (1982)

50% of individuals of selective IgA deficiency have high serum titers of antibody to bovine proteins, and high levels of circulating immune complexes that contain bovine antigens. Because in animal studies, immunization with antigen-antibody complexes is a very effective means of producing anti-idiotypic antibodies, we sought such autoantibodies in two sera known to have large amounts of anticasein. After IgG isolation and two-stage affinity chromatography, IgG-like material (molecular weights of H and L chains on SDS-PAGE), with binding activity for the F(ab')2 of anticasein were isolated from both sera. Pooled human gamma globulin or IgG myeloma proteins did not inhibit binding of specific anti-anticaseins to the corresponding anticasein, but sodium caseinate did block this binding (by 80 and 95%) indicating that most of these autoantibodies have affinity for the casein-binding site. Naturally occurring anti-idiotypic antibodies have been difficult to conclusively demonstrate in human sera; consequently, these experiments provide evidence of a unique model which may be used to explore the network theory of immunoglobulin regulation in humans.