tbuckley/cabot-search huggingface dataset:
4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N‐Ras proto‐oncogenes in mice
Authors: Chunmei Wang, Antonio Cigliano, Lijie Jiang, Xiaolei Li, Biao Fan, Maria G. Pilo, Yan Liu, Bing Gui, Marcella Sini, Jeffrey W. Smith, Frank Dombrowski, Diego F. Calvisi, Matthias Evert, Xin Chen
Journal: Hepatology (2014)

Concomitant expression of activated forms of v‐akt murine thymoma viral oncogene homolog (AKT) and Ras in mouse liver (AKT/Ras) leads to rapid tumor development through strong activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. mTORC1 functions by regulating p70S6K/ribosomal protein S6 (RPS6) and eukaryotic translation initiation factor 4E‐binding protein 1/ eukaryotic translation initiation factor 4E (4EBP1/eIF4E) cascades. How these cascades contribute to hepatocarcinogenesis remains unknown. Here, we show that inhibition of the RPS6 pathway by rapamycin effectively suppressed, whereas blockade of the 4EBP1/eIF4E cascade by 4EBP1A4, an unphosphorylatable form of 4EBP1, significantly delayed, AKT/Ras‐induced hepatocarcinogenesis. Combined treatment with rapamycin and 4EBP1A4 completely inhibited AKT/Ras hepatocarcinogenesis. This strong antineoplastic effect was successfully recapitulated by ablating regulatory associated protein of mTORC1, the major subunit of mTORC1, in AKT/Ras‐overexpressing livers. Furthermore, we demonstrate that overexpression of eIF4E, the proto‐oncogene whose activity is specifically inhibited by 4EBP1, resulted in hepatocellular carcinoma (HCC) development in cooperation with activated Ras. Mechanistically, we identified the ectonucleoside triphosphate diphosphohydrolase 5/ adenylate kinase 1/cytidine monophosphate kinase 1 axis and the mitochondrial biogenesis pathway as targets of the 4EBP1/eIF4E cascade in AKT/Ras and Ras/eIF4E livers as well as in human HCC cell lines and tissues. Conclusions : Complete inhibition of mTORC1 is required to suppress liver cancer development induced by AKT and Ras proto‐oncogenes in mice. The mTORC1 effectors, RPS6 and eIF4E, play distinct roles and are both necessary for AKT/Ras hepatocarcinogenesis. These new findings might open the way for innovative therapies against human HCC. (H epatology 2015;61:200–213)
The impact of malaria parasitism: from corpuscles to communities
Authors: Thomas E. Wellems, Karen Hayton, Rick M. Fairhurst
Journal: Journal of Clinical Investigation (2009)

Malaria continues to exert a tremendous health burden on human populations, reflecting astonishingly successful adaptations of the causative Plasmodium parasites. We discuss here how this burden has driven the natural selection of numerous polymorphisms in the genes encoding hemoglobin and other erythrocyte proteins and some effectors of immunity. Plasmodium falciparum, the most deadly parasite species in humans, displays a vigorous system of antigen variation to counter host defenses and families of functionally redundant ligands to invade human cells. Advances in genetics and genomics are providing fresh insights into the nature of these evolutionary adaptations, processes of parasite transmission and infection, and the difficult challenges of malaria control.
The Argument to Support Broader Application of Extracranial Carotid Artery Stent Technology
Authors: Rodney M. Samuelson, Junichi Yamamoto, Elad I. Levy, Adnan H. Siddiqui, L. Nelson Hopkins
Journal: Circulation (2007)

P rimarily on the basis of data derived from the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, 1 the US Food and Drug Administration (FDA) has approved the use of carotid stents (CASs) in high-risk patients.The SAPPHIRE trial was published and much heralded as a randomized trial demonstrating that CASs were not inferior to carotid endarterectomy (CEA).Yet, the more recent Endarterectomy Versus Angioplasty in Patients with Symptomatic Carotid Stenosis randomized trial of CASs compared with CEA had to be stopped because the stroke rate with stents was so high that it triggered the safety guidelines of the study design. 2How can we explain the striking difference in outcome between these 2 studies, and how did it happen that the FDA was so convinced of the quality and validity of the SAPPHIRE trial that it granted approval for CASs?An examination of the SAPPHIRE trial-its conduct, data collection and analysis, the circumstances of publication, the presentation to the FDA Advisory Panel, and its consequent approval-is the primary focus of this article.This is a case study of the flaws in our system for the evaluation and approval of medical devices that warrant serious reflection on our ability to properly create and act on accurate information and live up to our commitment to evidence-based decision making. Response by Samuelson et al p 1601As it now stands, existing studies leave us with the unfortunate but not unreasonable conclusion that no scientific basis exists for the use of CASs as approved by the FDA, and in the absence of change, there is every reason to doubt the capability of our current system to protect the public from unnecessary risk in the future.Although this article focuses on just 1 example of how our systems are flawed at multiple levels to provide a reliable assessment of CASs and other technology, readers seeking further examples can find a wealth of related information.
Respiratory symptoms and atopy in Aberdeen schoolchildren: evidence from two surveys 25 years apart.
Authors: T. K. Ninan, G. Russell
Journal: BMJ (1992)

OBJECTIVE--To estimate changes in the prevalence of respiratory symptoms and the reported diagnoses of asthma, eczema, and hay fever in primary school children in Aberdeen between 1964 and 1989. DESIGN--Determination of incidence prevalence and prevalence from survey data. SETTING--Aberdeen, Scotland. PARTICIPANTS--2743 primary school children (aged 8-13) from 1964 and 4003 [corrected] from 1989. MAIN OUTCOME MEASURES--Survey data on whether, according to the parent or guardian, the child wheezed or was troubled with shortness of breath; the number of episodes of breathlessness in the past year; and whether asthma, eczema, or hay fever had ever been diagnosed. RESULTS--Questionnaires were completed by the parents of 2510 children in 1964 and 3403 children in 1989. The prevalence of wheeze rose from 10.4% in 1964 to 19.8% in 1989, and the prevalence of episodes of shortness of breath increased from 5.4% to 10.0%. In both surveys wheeze and shortness of breath were more prevalent in boys than in girls. The reported diagnosis of asthma rose from 4.1% to 10.2%, hay fever from 3.2% to 11.9%, and eczema from 5.3% to 12%. The proportion of boys suffering from eczema rose from 47.7% to 60.0%. Hay fever showed a similar increase, from 49.4% to 60.1%, in boys over the 25 year period. Though the parents of a higher proportion of children with wheeze were aware of the diagnosis of asthma in 1989, because of the increased prevalence of wheeze the absolute number of parents of wheezy children who were not aware of a diagnosis of asthma increased from 7.4% to 9.6% of the population studied. CONCLUSION--The higher diagnosis rate for asthma is due not simply to changes in diagnostic fashion but reflects an increase over the past 25 years in the prevalence of respiratory symptoms, which in turn may reflect a more general change in the prevalence of atopy, the increase in which was particularly noticeable in boys. This increase explains some of the increase in hospital admission rates for children with asthma.
Regulation of cytokine production by soluble CD23: costimulation of interferon gamma secretion and triggering of tumor necrosis factor alpha release.
Authors: M Armant, H Ishihara, M Rubio, G Delespesse, M Sarfati
Journal: The Journal of Experimental Medicine (1994)

Soluble CD23 (sCD23) has multiple IgE-independent biological activities. In the present study, we examined the regulatory effect of sCD23 on cytokine production by human peripheral blood mononuclear cells (PBMC). We show that sCD23 enhances by about 80-fold the interleukin 2 (IL-2)-induced interferon gamma (IFN-gamma) production and by about 10-fold the response to IL-12. This potentiating activity is time and dose dependent and is not associated with a significant effect on DNA synthesis. The sCD23 costimulatory activity for IFN-gamma synthesis is drastically reduced in monocyte-depleted PBMC, suggesting that monocytes may be the target for sCD23. This hypothesis was supported by the following observations. First, sCD23 alone is a potent inducer of tumor necrosis factor alpha (TNF-alpha) production by PBMC and this effect disappears after monocyte depletion. The triggering of TNF-alpha release is specifically inhibited by neutralizing anti-CD23 monoclonal antibody (mAb). In addition, IL-2 and IL-12 synergize with sCD23 to induce TNF-alpha production. Second, sCD23 triggers the release of other inflammatory mediators such as IL-1 alpha, IL-1 beta, and IL-6. Finally, TNF-alpha production in response to IL-2 and sCD23 precedes IFN-gamma and IFN-gamma secretion is significantly inhibited by anti-TNF-alpha mAb, indicating that the sCD23 costimulatory signal for IFN-gamma production may be partially mediated by TNF-alpha release. It is proposed that sCD23 is a proinflammatory cytokine that, in addition, may play an important role in the control of the immune response via the enhancement of IFN-gamma production.
Socioeconomic and lifestyle factors and melanoma: a systematic review
Authors: A.J. Jiang, P.V. Rambhatla, M.J. Eide
Journal: British Journal of Dermatology (2014)

Evidence of social determinants of disease and awareness of the impact of these factors on outcomes continues to increase. Social determinants include both socioeconomic and lifestyle factors. This review examines the interface between socioeconomic status (SES) and lifestyle and their effects on melanoma incidence and mortality. Lifestyle factors including occupation, occupational exposures, body mass index, marital status, smoking, recreational sun exposure and tanning were explored as they have a known relationship with melanoma. A remarkable association of SES with melanoma incidence and prognosis has been acknowledged worldwide. Melanoma incidence is increased in populations of higher SES, especially among the highly educated, while lower SES populations present with later-stage disease at time of diagnosis and display greater mortality. The aforementioned lifestyle factors are also related to SES, and have been shown internationally to affect melanoma incidence and mortality. This comprehensive systematic review suggests that lifestyle factors including occupation, occupational exposure, obesity, recreational sun exposure and tanning may explain the relationship between SES and melanoma.
Combined Cognitive Remediation and Functional Skills Training for Schizophrenia: Effects on Cognition, Functional Competence, and Real-World Behavior
Authors: Christopher R. Bowie, Susan R. McGurk, Brent Mausbach, Thomas L. Patterson, Philip D. Harvey
Journal: American Journal of Psychiatry (2012)

Cognitive remediation is an efficacious treatment for schizophrenia and, when used within broader psychosocial treatments, improves transfer to real-world behavior change. The authors examined whether cognitive remediation effectively generalizes to functional competence and real-world functioning as a standalone treatment and when combined with a functional skills treatment.Outpatients with schizophrenia (N=107) were randomly assigned to receive cognitive remediation, functional adaptation skills training, or combined treatment, with cognitive remediation preceding functional skills training. Clinical symptoms, neurocognition, social competence, functional competence, and case-manager-rated real-world behavior were assessed at baseline, at end of treatment, and at a 12-week durability assessment.Neurocognition improved, with durable effects, after cognitive remediation but not after functional skills training. Social competence improved both with functional skills training and with combined treatment but not with cognitive remediation alone. Improvements in functional competence were greater and more durable with combined treatment. Cognitive remediation alone did not produce significant improvements in real-world behavior, but when combined with functional skills training, statistically significant improvements from baseline to end of treatment and follow-up were observed in community or household activities and work skills. Number-needed-to-treat analyses suggest that as few as three cases are required for treatment to induce a meaningful improvement in functional skills.In a short intervention, cognitive remediation produced robust improvements in neurocognition. Generalization to functional competence and real-world behavior was more likely when supplemental skills training and cognitive remediation were combined.
Low dose aspirin prevents duodenoesophageal reflux induced mucosal changes in wistar rat esophagus by MAP kinase mediated pathways
Authors: Ben Selvan, Anup Ramachandran, Anu Korula, G. Jayakumar Amirtharaj, Kavithapriya Kettimuthu, Sheila Nair, Aravindan Nair, Prasanna Samuel, George Mathew
Journal: International Journal of Surgery (2011)
UROLOGIC SURGERY IN PEDIATRICS
Authors: Herman L. Kretschmer
Journal: JAMA (1922)

It may be said without fear of contradiction that the urologic study of pediatric cases has not received the consideration that is due so important a subject. This is practically an undeveloped province of medicine, and, as evidence of this statement, attention may be called to the scant references, both in pediatric and in genitourinary literature. In this country, Beer, 1 Hyman, 2 Hinman, 3 Stevens, 4 Thomas and Tanner, 5 and Helmholz and I 6 have made a study of the subject—not a large showing. Hence, it appears to me that this province for clinical study has been decidedly neglected, though the problems and possibilities undoubtedly are many and of great variety. But to achieve gratifying results, the closest cooperation between the pediatrician, general practitioner and genito-urinary surgeon is necessary. This alliance effected, I am ready to admit, without being unduly enthusiastic, that pediatric urology will be the open
Cleavage of mitochondrial antiviral signaling protein in the liver of patients with chronic hepatitis C correlates with a reduced activation of the endogenous interferon system
Authors: Pantxika Bellecave, Magdalena Sarasin‐Filipowicz, Olivier Donzé, Audrey Kennel, Jérôme Gouttenoire, Etienne Meylan, Luigi Terracciano, Jürg Tschopp, Christoph Sarrazin, Thomas Berg, Darius Moradpour, Markus H. Heim
Journal: Hepatology (2009)

Hepatitis C virus (HCV) infection induces the endogenous interferon (IFN) system in the liver in some but not all patients with chronic hepatitis C (CHC). Patients with a pre-activated IFN system are less likely to respond to the current standard therapy with pegylated IFN-α. Mitochondrial antiviral signaling protein (MAVS) is an important adaptor molecule in a signal transduction pathway that senses viral infections and transcriptionally activates IFN-β. The HCV NS3-4A protease can cleave and thereby inactivate MAVS in vitro, and, therefore, might be crucial in determining the activation status of the IFN system in the liver of infected patients. We analyzed liver biopsies from 129 patients with CHC to investigate whether MAVS is cleaved in vivo and whether cleavage prevents the induction of the endogenous IFN system. Cleavage of MAVS was detected in 62 of the 129 samples (48%) and was more extensive in patients with a high HCV viral load. MAVS was cleaved by all HCV genotypes (GTs), but more efficiently by GTs 2 and 3 than by GTs 1 and 4. The IFN-induced Janus kinase (Jak)-signal transducer and activator of transcription protein (STAT) pathway was less frequently activated in patients with cleaved MAVS, and there was a significant inverse correlation between cleavage of MAVS and the expression level of the IFN-stimulated genes IFI44L, Viperin, IFI27, USP18, and STAT1. We conclude that the pre-activation status of the endogenous IFN system in the liver of patients with CHC is in part regulated by cleavage of MAVS. (HEPATOLOGY 2010.)
The Great Banana Hoax
Authors: LOUIS BOZZETTI, STEPHEN GOLDSMITH, J. THOMAS UNGERLEIDER
Journal: American Journal of Psychiatry (1967)

The recent practice of smoking dried banana scrapings to achieve a "psychedelic experience" led the authors to investigate the hallucinogenic properties of bananadine, or "mellow yellow." They conclude that the "active ingredient" in bananadine is the psychic suggestibility of the user in the proper setting.
The Lupus Erythematosus Cell and its Significance
Authors: M. Wilkinson, L. S. Sacker
Journal: BMJ (1957)

While it is accepted that the lupus erythematosus cell (L.E.cell) can be demonstrated in the blood of most patients with systemic lupus erythematosus, it remains uncertain whether L.E. cells can be demonstrated in patients with various other diseases.This report deals with three years' experience of L.E.- cell tests in patients with systemic lupus erythematosus and other diseases.Our results are compared with those of other workers, and various aspects of the literature are reviewed.Methods We have used two techniques for demonstrating the L.E.-cell phenomenon.For the. first, and preferred, method defibrinated blood from the patient is incubated for two and a half hours at 370 C., then centrifuged, and smears are made from the leucocyte layer.The second method is convenient when multiple tests are being run together or when only serum is available.For this test, fresh normal leucocytes are suspended in the patient's serum, incubated for two and a half hours at 370 C., then centrifuged, and smears are made from the leucocyte button.Both of these methods have been fully described by Dacie (1956).With sensitive and easily repeated peripheral-blood techniques available, methods involving marrow biopsy hardly seem justifiable and are probably less sensitive because of the presence of anticoagulant.Certain practical points are worthy of comment.Incubation Time.-TheL.E. cell requires a consider- able interval of time for its formation.By counting the number of L.E. cells per 1,000 polymorphs after varying incubation times we have found two and a half hours to be optimal.After this period the number of L.E. cells is maximal and degenerative changes in the leucocytes are not conspicuous.Effect of Anticoagulants.-Similarcounts of the num- ber of L.E. cells produced in specimens of blood with and without anticoagulants confirm the findings of Zimmer and Hargraves (1952) that anticoagulants depress L.E.-cell formation.Even a moderately positive test with a clotted-blood technique may be matched by negative or weakly positive results when citrate, heparin, oxalate, or sequestrene is present. Interpretation of FilmsIn Romanowsky-stained films the L.E. cell is usually a neutrophil polymorph containing within its cytoplasm the L.E. body, a homogeneous, purple-staining spherical in- clusion of variable size, but usually large enough to dis- place the cell nucleus to the periphery.The L.E. body is completely homogeneous, with no evidence of nuclear struc- *Part of the material in this report was taken from an M.D.
Insensitivity of Paediatric HIV-1 Subtype C Viruses to Broadly Neutralising Monoclonal Antibodies Raised against Subtype B
Authors: Elin Solomonovna Gray, Tammy Meyers, Glenda Gray, David Charles Montefiori, Lynn Morris
Journal: PLoS Medicine (2006)

Background A Phase I clinical trial has been proposed that uses neutralising monoclonal antibodies (MAbs) as passive immunoprophylaxis to prevent mother-to-child transmission of HIV-1 in South Africa. To assess the suitability of such an approach, we determined the sensitivity of paediatric HIV-1 subtype C viruses to the broadly neutralising MAbs IgG1b12, 2G12, 2F5, and 4E10. Methods and Findings The gp160 envelope genes from seven children with HIV-1 subtype C infection were cloned and used to construct Env-pseudotyped viruses that were tested in a single-cycle neutralisation assay. The epitopes defining three of these MAbs were determined from sequence analysis of the envelope genes. None of the seven HIV-1 subtype C pseudovirions was sensitive to 2G12 or 2F5, which correlated with the absence of crucial N-linked glycans that define the 2G12 epitope and substitutions of residues integral to the 2F5 epitope. Four viruses were sensitive to IgG1b12, and all seven viruses were sensitive to 4E10. Conclusions Only 4E10 showed significant activity against HIV-1 subtype C isolates, while 2G12 and 2F5 MAbs were ineffective and IgG1b12 was partly effective. It is therefore recommended that 2G12 and 2F5 MAbs not be used for passive immunization experiments in southern Africa and other regions where HIV-1 subtype C viruses predominate.
Recombinase-Driver Rat Lines: Tools, Techniques, and Optogenetic Application to Dopamine-Mediated Reinforcement
Authors: Ilana B. Witten, Elizabeth E. Steinberg, Soo Yeun Lee, Thomas J. Davidson, Kelly A. Zalocusky, Matthew Brodsky, Ofer Yizhar, Saemi L. Cho, Shiaoching Gong, Charu Ramakrishnan, Garret D. Stuber, Kay M. Tye, Patricia H. Janak, Karl Deisseroth
Journal: Neuron (2011)
Abstract PR14: Lineage labeling elucidates the natural history of metastatic colonization
Authors: Nicole M. Aiello, David L. Bajor, Robert H. Vonderheide, Ben Z. Stanger
Journal: Cancer Research (2013)

Abstract Compared to primary tumor formation and invasion, relatively little is known about later stages of the metastatic cascade, including the seeding and colonization of distal tissues. To visualize these late steps in metastasis, we have generated an autochthonous mouse model of pancreatic ductal adenocarcinoma in which all pancreatic epithelial cells are genetically labeled with yellow fluorescent protein (the KPCY model). This system allows for the detection of single seeded tumor cells in distant organs, as well as micrometastasis and larger lesions. We have assessed the size distribution of metastatic lesions in two frequently colonized organs, the liver and lung, and found that single cells and clusters consisting of less than ten cells represent the majority of lesions in both tissues; however these small lesions only progress to gross metastasis in the liver, not the lung. We have previously used the KPCY model to study the dynamic process of epithelial-mesenchymal transition (EMT) and its involvement in invasion and dissemination from the primary tumor. We have extended these studies to assess the role of EMT and the reverse phenomenon, mesenchymal-epithelial transition (MET), in seeding and colonization at metastatic sites. Our results suggest that while EMT is favored for entry into the circulation, there may be selection for epithelial tumor cells or MET at the metastatic site. Additionally this model allows us to investigate the parallel evolution of metastatic lesions, from single cells to macrometastasis, and the associated metastatic microenvironment. Citation Format: Nicole M. Aiello, David L. Bajor, Robert H. Vonderheide, Ben Z. Stanger. Lineage labeling elucidates the natural history of metastatic colonization. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR14.
Management of ulcerative colitis shows the failings in chronic disease management in the current NHS
Authors: I. L. P. Beales
Journal: BMJ (2013)

Ford and colleagues’ summary of the current management of ulcerative colitis highlights the major failings of chronic disease management in the current purchaser-provider split NHS; this will only get worse with the upcoming changes.1

They rightly highlight the importance of preventing opportunistic infections with immunisations. …