tbuckley/cabot-search huggingface dataset:
V599EB-RAF is an Oncogene in Melanocytes
Authors: Claudia Wellbrock, Lesley Ogilvie, Douglas Hedley, Maria Karasarides, Jan Martin, Dan Niculescu-Duvaz, Caroline J. Springer, Richard Marais
Journal: Cancer Research (2004)

Abstract The oncogenic version of B-RAF, V599EB-RAF, is found in approximately 70% of human melanomas. However, the role that this oncogene plays in melanoma is unclear because V559EB-RAF is also found in approximately 80% of benign nevi. We have examined the role of oncogenic B-RAF in the early stages of melanoma by expressing V599EB-RAF in cultured melanocytes. In these cells, V599EB-RAF induced constitutive mitogen activated ERK-activating kinase (MEK) and extracellular signal-regulated kinase (ERK) signaling, 12-O-tetradecanoylphorbol-13-acetate-independent growth, and tumorigenicity in nude mice. Intriguingly, in RAS-transformed melanocytes, B-RAF depletion did not block MEK-ERK signaling or cell cycle progression. Similarly, B-RAF depletion blocked MEK-ERK signaling in human melanoma cells harboring oncogenic B-RAF, but not in melanoma cells harboring oncogenic RAS. Thus, although B-RAF can act as a potent oncogene in the early stages of melanoma by signaling through MEK and ERK, it is not required for this signaling in RAS-transformed melanocytes due to innate redundancy within the pathway. These findings have important implications for future therapeutic strategies.
Difference in clinical features between Japanese and German patients with refractory anemia in myelodysplastic syndromes
Authors: Akira Matsuda, Ulrich Germing, Itsuro Jinnai, Motohiro Misumi, Andrea Kuendgen, Sabine Knipp, Manuel Aivado, Masako Iwanaga, Yasushi Miyazaki, Hideki Tsushima, Mari Sakai, Masami Bessho, Masao Tomonaga
Journal: Blood (2005)
Two-Pore Domain K Channel, TASK-1, in Pulmonary Artery Smooth Muscle Cells
Authors: A.M. Gurney, O.N. Osipenko, D. MacMillan, K.M. McFarlane, R.J. Tate, F.E.J. Kempsill
Journal: Circulation Research (2003)

Pulmonary vascular tone is strongly influenced by the resting membrane potential of smooth muscle cells, depolarization promoting Ca2+ influx, and contraction. The resting potential is determined largely by the activity of K+-selective ion channels, the molecular nature of which has been debated for some time. In this study, we provide strong evidence that the two-pore domain K+ channel, TASK-1, mediates a noninactivating, background K+ current (IKN), which sets the resting membrane potential in rabbit pulmonary artery smooth muscle cells (PASMCs). TASK-1 mRNA was found to be present in PASMCs, and the membranes of PASMCs contained TASK-1 protein. Both IKN and the resting potential were found to be exquisitely sensitive to extracellular pH, acidosis inhibiting the current and causing depolarization. Moreover, IKN and the resting potential were enhanced by halothane (1 mmol/L), inhibited by Zn2+ (100 to 200 micromol/L) and anandamide (10 micromol/L), but insensitive to cytoplasmic Ca2+. These properties are all diagnostic of TASK-1 channels and add to previously identified features of IKN that are shared with TASK-1, such as inhibition by hypoxia, low sensitivity to 4-aminopyridine and quinine and insensitivity to tetraethylammonium ions. It is therefore concluded that TASK-1 channels are major contributors to the resting potential in pulmonary artery smooth muscle. They are likely to play an important role in mediating pulmonary vascular responses to changes in extracellular pH, and they could be responsible for the modulatory effects of pH on hypoxic pulmonary vasoconstriction.
Tricyclic Antidepressants for Peripheral Neuropathy
Authors: E. Wayne Massey
Journal: JAMA (1980)

To the Editor.—  In their article Medical Management of Chronic Cancer Pain, Shimm et al (241:2408, 1979) speculate that the tricyclic antidepressant drugs imipramine hydrochloride and amitriptyline hydrochloride may be helpful for chronic pain because of causing direct analgesic effects, potentiating other drugs, or simply by relieving depression.  We are confident that tricyclic compounds are helpful for pain and paresthesias caused by peripheral neuropathy. Although a controlled study is still in formulation, we believe that amitriptyline has been particularly helpful for patients with diabetic neuropathy.  Perhaps a fourth mechanism for effects of tricyclics in treating chronic pain or neuropathy consists of affecting neuronal or axonal transmission. Such a mechanism might especially be important for pain from cancer, which may cause a painful neuropathy, and from other causes of peripheral neuropathy, like diabetes.
TISSUE CULTURE STUDIES ON BACTERIAL HYPERSENSITIVITY
Authors: Johannes K. Moen, Homer F. Swift
Journal: The Journal of Experimental Medicine (1936)

1. A high degree of cellular sensitivity to tuberculin toxicity was demonstrated when explants from tuberculous animals were grown in media containing that substance. 2. Similar degrees of sensitivity were noted in cells derived from animals infected with either virulent or relatively lowly virulent strains of tubercle bacilli. 3. The specificity of the tuberculin cytotoxicity was proven by testing with other bacterial cytotoxic materials. 4. Tuberculin sensitive cells grown in vitro in normal media showed, when tested with tuberculin, persistence of this cellular sensitivity through several transplantations during which time many new generations of cells developed. 5. There was a depression of the initial growth energy of explants from animals during the toxic phase of the disease. During the healing stage the initial growth energy returned to normal although marked sensitivity to tuberculin persisted. 6. The degree of cellular sensitivity to tuberculin in vitro did no parallel the acuity of the infectious process but represented a more or less permanent acquired characteristic impressed on the cell as a result of the infection.
Transmural distribution of myocardial blood flow during systole in the awake dog.
Authors: D S Hess, R J Bache
Journal: Circulation Research (1976)

This study was designed to quantitate transmural myocardial blood flow when coronary arterial inflow was limited to systole and during the subsequent reactive hyperemic response. Studies were performed in 10 awake dogs chronically prepared with electromagnetic flowmeters and pneumatic occluders on the left circumflex coronary artery. Intermittent coronary perfusion, confined to the interval of left ventricular systole or an equivalent period during diastole, was effected by an R wave-triggered solenoid valve connected to the occluder. To measure regional myocardial blood flow we injected radionuclide-labeled microspheres, 7-10 mum in diameter, into the left atrium. When arterial inflow was limited to systole, flow was normal in the subepicardial layers and was decreased as a linear function of tissue depth in the subendocardial layers. When coronary arterial inflow was limited to an equivalent interval in diastole, the transmural distribution of flow was uniform. When coronary flow was confirmed to systole for more than 20 seconds, the blood flow debt incurred elicited a reactive hyperemia similar to that following a total occlusion of equivalent blood flow debt. However, regional myocardial blood flow during the peak of reactive hyperemia following systolic perfusion was preferentially directed to the subendocardium, where underperfusion was most marked, whereas reactive hyperemia flow following a total occlusion of equivalent blood flow debt was distributed more evenly across the left ventricular wall. Thus, when coronary inflow was limited to systole, ventricular contraction produced a transmural gradient in myocardial blood flow resulting in subendocardial underperfusion.
Effect of thoracotomy and lung resection on exercise capacity in patients with lung cancer
Authors: A-M Nugent, I C Steele, A M Carragher, K McManus, J A McGuigan, J R P Gibbons, M S Riley, D P Nicholls
Journal: Thorax (1999)

Resection is the treatment of choice for lung cancer, but may cause impaired cardiopulmonary function with an adverse effect on quality of life. Few studies have considered the effects of thoracotomy alone on lung function, and whether the operation itself can impair subsequent exercise capacity.Patients being considered for lung resection (n = 106) underwent full static and dynamic pulmonary function testing which was repeated 3-6 months after surgery (n = 53).Thoracotomy alone (n = 13) produced a reduction in forced expiratory volume in one second (FEV1; mean (SE) 2.10 (0.16) versus 1.87 (0.15) l; p<0.05). Wedge resection (n = 13) produced a non-significant reduction in total lung capacity (TLC) only. Lobectomy (n = 14) reduced forced vital capacity (FVC), TLC, and carbon monoxide transfer factor but exercise capacity was unchanged. Only pneumonectomy (n = 13) reduced exercise capacity by 28% (PVO2 23.9 (1.5) versus 17.2 (1.7) ml/min/kg; difference (95% CI) 6.72 (3.15 to 10.28); p<0.01) and three patients changed from a cardiac limitation to exercise before pneumonectomy to pulmonary limitation afterwards.Neither thoracotomy alone nor limited lung resection has a significant effect on exercise capacity. Only pneumonectomy is associated with impaired exercise performance, and then perhaps not as much as might be expected.
Effects of vaporized perfluorohexane and partial liquid ventilation on regional distribution of alveolar damage in experimental lung injury
Authors: Peter M. Spieth, Lilla Knels, Michael Kasper, André Domingues Quelhas, Bärbel Wiedemann, Amelie Lupp, Matthias Hübler, Antonio Gianella Neto, Thea Koch, Marcelo Gama de Abreu
Journal: Intensive Care Medicine (2006)
E-cigarette vapour could damage health of non-smokers
Authors: I. Torjesen
Journal: BMJ (2014)

Particles in secondhand vapour from e-cigarettes have the potential to damage the health of non-smokers, a study by environmental scientists presented at the e-cigarette summit in London on 13 November has found.

Researchers presented the first results from chamber experiments that measured the concentration, size, and composition of particles in e-cigarette vapour, and how these parameters changed over time, to determine their potential effects on non-smokers.

Roy Harrison, professor of environmental health and risk management at the University of Birmingham, and Gordon McFiggans, professor of atmospheric multiphase processes at the University of Manchester, presented the results. Harrison said that although the data were preliminary, they “provide evidence for a possible exposure risk to passive smokers in …
Risks of health reform are branded "unacceptably high," as wave of opposition breaks over health secretary's head
Authors: A. O'Dowd
Journal: BMJ (2010)

Opposition to the government’s reforms of the NHS reached a crescendo in the second half of December as doctors, politicians, and health policy analysts all went on the offensive.

The wisdom of the changes—to replace primary care trusts with GP led commissioning consortiums and to have the new bodies operating by April 2013—was questioned by numerous diverse sources. The criticisms came in the same week that the government published its response to the consultation on its white paper Equity and Excellence: Liberating the NHS by declaring that the reforms would go ahead with minimal change.

More than 200 clinicians signed a joint letter published in the Times on 13 December warning that the government’s plans would “destroy” the NHS ( BMJ 2010;341:c7224, doi:10.1136/bmj.c7224).

The letter, signed by 206 medical professionals, said that the desire of England’s health secretary, Andrew Lansley, to put patients at the heart of care and involve clinicians in decisions about service provision could be achieved without the “massive structural upheaval” …
Common and Overlapping Oncogenic Pathways Contribute to the Evolution of Acute Myeloid Leukemias
Authors: Brynn T. Kvinlaug, Wai-In Chan, Lars Bullinger, Mukundhan Ramaswami, Christopher Sears, Donna Foster, Stanley E. Lazic, Rachel Okabe, Axel Benner, Benjamin H. Lee, Inusha De Silva, Peter J.M. Valk, Ruud Delwel, Scott A. Armstrong, Hartmut Döhner, D. Gary Gilliland, Brian J.P. Huntly
Journal: Cancer Research (2011)

Fusion oncogenes in acute myeloid leukemia (AML) promote self-renewal from committed progenitors, thereby linking transformation and self-renewal pathways. Like most cancers, AML is a genetically and biologically heterogeneous disease, but it is unclear whether transformation results from common or overlapping genetic programs acting downstream of multiple mutations or by the engagement of unique genetic programs acting cooperatively downstream of individual mutations. This distinction is important, because the involvement of common programs would imply the existence of common molecular targets to treat AML, no matter which oncogenes are involved. Here we show that the ability to promote self-renewal is a generalized property of leukemia-associated oncogenes. Disparate oncogenes initiated overlapping transformation and self-renewal gene expression programs, the common elements of which were defined in established leukemic stem cells from an animal model as well as from a large cohort of patients with differing AML subtypes, where they strongly predicted pathobiological character. Notably, individual genes commonly activated in these programs could partially phenocopy the self-renewal function of leukemia-associated oncogenes in committed murine progenitors. Furthermore, they could generate AML following expression in murine bone marrow. In summary, our findings reveal the operation of common programs of self-renewal and transformation downstream of leukemia-associated oncogenes, suggesting that mechanistically common therapeutic approaches to AML are likely to be possible, regardless of the identity of the driver oncogene involved.
Altering the antibody repertoire via transgene homologous recombination: evidence for global and clone-autonomous regulation of antigen-driven B cell differentiation.
Authors: K A Vora, T Manser
Journal: The Journal of Experimental Medicine (1995)

Antibody VH transgenes containing small amounts of natural 5' and 3' flanking DNA undergo nonreciprocal homologous recombination with the endogenous Igh locus in B cells. The resulting "hybrid" heavy chain loci are generated at a low frequency but are fully functional, undergoing somatic hypermutation and isotype class switching. We have used this recombination pathway to introduce a somatically mutated variable (V) region with an unusually high affinity for the hapten p-azophenylarsonate (Ars) into the preimmune antibody repertoire. The affinity of this V region for Ars is 100-fold higher than any unmutated anti-Ars antibody previously characterized. Expression of the transgene-encoded V region did not affect many aspects of antigen-driven B cell differentiation, including somatic hypermutation, in either Ars-specific transgene- or endogenous V gene-expressing clones. Thus, the regulation of these processes appears to operate in a "global" fashion, in that the mechanisms involved are imperceptive of the relative affinities for antigen of the antibodies expressed by B cell clones participating in the immune response. In contrast, the selection of V region mutants leading to affinity maturation and memory cell formation was found to be strongly influenced by the transgenic V region, but only in clones expressing this V region. Hybridomas derived from transgene- and endogenous V region-expressing memory cells were isolated at similar frequencies from individual transgenic mice. The V regions expressed by hybridomas in both of these groups had 2- to 30-fold greater affinity for Ars than their unmutated precursors, despite the fact that the transgene-encoded precursors had 100-fold higher affinity than their endogenous counterparts. These results show that the criterion for entry into the memory compartment is established not by the affinity of a B cell's V region relative to all other V regions expressed during the response, but by the affinity of this V region relative to its unmutated precursor. Thus, the development of B cell memory is regulated in a "clone-autonomous" fashion.
ADF/Cofilin-Mediated Actin Retrograde Flow Directs Neurite Formation in the Developing Brain
Authors: Kevin C. Flynn, Farida Hellal, Dorothee Neukirchen, Sonja Jacob, Sabina Tahirovic, Sebastian Dupraz, Sina Stern, Boyan K. Garvalov, Christine Gurniak, Alisa E. Shaw, Liane Meyn, Roland Wedlich-Söldner, James R. Bamburg, J. Victor Small, Walter Witke, Frank Bradke
Journal: Neuron (2012)
Effect of Peroxisome Proliferator–Activated Receptor γ Agonist Treatment on Subclinical Atherosclerosis in Patients With Insulin-Requiring Type 2 Diabetes
Authors: Howard N. Hodis, Wendy J. Mack, Ling Zheng, Yanjie Li, Mina Torres, Diego Sevilla, Yolanda Stewart, Barbara Hollen, Karla Garcia, Petar Alaupovic, Thomas A. Buchanan
Journal: Diabetes Care (2006)

To determine the effect of thiazolidinedione treatment on subclinical atherosclerosis progression in insulin-requiring patients with clinical characteristics suggesting type 2 diabetes.Eligible participants (n = 299) were randomized within strata of baseline common carotid artery (CCA) intima-media thickness (IMT) (<0.8 mm, >or=0.8 mm) to 400 mg troglitazone daily or placebo for 2 years. A general linear mixed-effects model was used to compare the rate of change in CCA-IMT between treatment groups.Overall, average rates of CCA-IMT change were not significantly different between troglitazone- and placebo-treated subjects (0.0030 +/- 0.021 vs. 0.0066 +/- 0.021 mm/year; P = 0.17). In the stratum of subjects with CCA-IMT >or=0.8 mm, troglitazone significantly reduced the progression of CCA-IMT relative to placebo (0.0013 +/- 0.022 vs. 0.0084 +/- 0.023 mm/year; P = 0.03). Fasting glucose, insulin, and HbA(1c) were significantly lower in troglitazone- versus placebo-treated subjects (P < 0.01). Whereas blood pressure significantly differed between treatment groups in the >or=0.8-mm stratum, there was no difference between treatment groups in the <0.8-mm stratum.Insulin sensitization and reduction in blood pressure may be contributory mechanisms by which troglitazone reduced subclinical atherosclerosis progression in this cohort of well-controlled insulin-dependent patients with clinical characteristics suggesting type 2 diabetes.
Induced sputum for the diagnosis of paediatric pulmonary TB
Authors: M Wijesinghe
Journal: Thorax (2005)

▴ Zar HJ, Hanslo D, Apolles P, et al. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. Lancet2005;365:130–4. [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Sputum induction in adults is a well recognised method of diagnosing pulmonary tuberculosis (TB). However, in children this technique is not regarded as feasible since young children tend to swallow their sputum and do not expectorate. Gastric lavage has been … [1]: {openurl}?query=rft.jtitle%253DLancet%26rft.stitle%253DLancet%26rft.aulast%253DZar%26rft.auinit1%253DH.%2BJ.%26rft.volume%253D365%26rft.issue%253D9454%26rft.spage%253D130%26rft.epage%253D134%26rft.atitle%253DInduced%2Bsputum%2Bversus%2Bgastric%2Blavage%2Bfor%2Bmicrobiological%2Bconfirmation%2Bof%2Bpulmonary%2Btuberculosis%2Bin%2Binfants%2Band%2Byoung%2Bchildren%253A%2Ba%2Bprospective%2Bstudy.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0140-6736%252805%252917702-2%26rft_id%253Dinfo%253Apmid%252F15639294%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1016/S0140-6736(05)17702-2&link_type=DOI [3]: /lookup/external-ref?access_num=15639294&link_type=MED&atom=%2Fthoraxjnl%2F60%2F4%2F300.atom [4]: /lookup/external-ref?access_num=000226170700027&link_type=ISI
SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production
Authors: Reiko Takahashi, Shuhei Nishimoto, Go Muto, Takashi Sekiya, Taiga Tamiya, Akihiro Kimura, Rimpei Morita, Mayako Asakawa, Takatoshi Chinen, Akihiko Yoshimura
Journal: The Journal of Experimental Medicine (2011)

Regulatory T cells (Treg cells) maintain immune homeostasis by limiting inflammatory responses. SOCS1 (suppressor of cytokine signaling 1), a negative regulator of cytokine signaling, is necessary for the suppressor functions of Treg cells in vivo, yet detailed mechanisms remain to be clarified. We found that Socs1−/− Treg cells produced high levels of IFN-γ and rapidly lost Foxp3 when transferred into Rag2−/− mice or cultured in vitro, even though the CNS2 (conserved noncoding DNA sequence 2) in the Foxp3 enhancer region was fully demethylated. Socs1−/− Treg cells showed hyperactivation of STAT1 and STAT3. Because Foxp3 expression was stable and STAT1 activation was at normal levels in Ifnγ−/−Socs1−/− Treg cells, the restriction of IFN-γ–STAT1 signaling by SOCS1 is suggested to be necessary for stable Foxp3 expression. However, Ifnγ−/−Socs1−/− Treg cells had hyperactivated STAT3 and higher IL-17A (IL-17) production compared with Ifnγ−/−Socs1+/+ Treg cells and could not suppress colitis induced by naive T cells in Rag2−/− mice. In vitro experiments suggested that cytokines produced by Socs1−/− Treg cells and Ifnγ−/−Socs1−/− Treg cells modulated antigen-presenting cells for preferential Th1 and Th17 induction, respectively. We propose that SOCS1 plays important roles in Treg cell integrity and function by maintaining Foxp3 expression and by suppressing IFN-γ and IL-17 production driven by STAT1 and STAT3, respectively.
The diagnosis of longstanding groin pain: a prospective clinical cohort study
Authors: C J Bradshaw, M Bundy, E Falvey
Journal: British Journal of Sports Medicine (2008)

Background: Longstanding groin pain is a difficult diagnostic challenge for sports physicians, and the lack of consensus on diagnostic criteria and taxonomy makes comparison of published studies difficult. Aim: To determine the usefulness and validity of the clinical classification proposed by Holmich et al in a primary care sports medicine population. Design: Prospective cohort study. Setting: Private sports medicine clinic in London, UK. Participants: 218 consecutive cases presenting with longstanding groin pain. Interventions: Clinical assessment, diagnostic investigations and follow-up. Results: Groin pain patients (173 men, 45 women) presented from 23 sporting codes from professional athletes to the recreational exerciser. Men most commonly played soccer (football) (22%) and rugby (21%), while women were most often runners (40%). 12 month follow-up was successful in 65% of cases; an accurate diagnosis was made in 89% of cases. Hip pathology (50.4%) was the most common form of injury, with pubic pathology seen in 21% of cases. Pubic pathology was most often seen in kicking sports (58%), and straight line activities most often resulted in hip pathology (39%). Those patients diagnosed with hip pathology were less likely to return to pre-morbid levels of activity than those diagnosed with pubic pathology (28% vs 15%). Conclusion: This series shows a different breakdown of injuries in a sporting population presenting with groin pain than previously reported. This reflects diagnostic difficulties in the area. The high incidence of hip pathology and the poor prognosis which this confers are worthy of note.
A nice little interest
Authors: Eleanor Lewis
Journal: BMJ (2005)

As I struggle to combine bringing up a family of three young children with flexible training in anaesthesia, the date of my completion of specialist training seems almost as distant as that of my final repayment on my 25 year mortgage. With my eldest child now attending morning nursery, my days on maternity leave are punctuated by the school run. One of the other mothers chatting at the school gate asked me …