tbuckley/cabot-search huggingface dataset:
Inhibition of Metastatic Outgrowth from Single Dormant Tumor Cells by Targeting the Cytoskeleton
Authors: Dalit Barkan, Hynda Kleinman, Justin L. Simmons, Holly Asmussen, Anil K. Kamaraju, Mark J. Hoenorhoff, Zi-yao Liu, Sylvain V. Costes, Edward H. Cho, Stephen Lockett, Chand Khanna, Ann F. Chambers, Jeffrey E. Green
Journal: Cancer Research (2008)

Abstract Metastatic breast cancer may emerge from latent tumor cells that remain dormant at disseminated sites for many years. Identifying mechanisms regulating the switch from dormancy to proliferative metastatic growth has been elusive due to the lack of experimental models of tumor cell dormancy. We characterized the in vitro growth characteristics of cells that exhibit either dormant (D2.0R, MCF-7, and K7M2AS1.46) or proliferative (D2A1, MDA-MB-231, and K7M2) metastatic behavior in vivo. Although these cells proliferate readily in two-dimensional culture, we show that when grown in three-dimensional matrix, distinct growth properties of the cells were revealed that correlate to their dormant or proliferative behavior at metastatic sites in vivo. In three-dimensional culture, cells with dormant behavior in vivo remained cell cycle arrested with elevated nuclear expression of p16 and p27. The transition from quiescence to proliferation of D2A1 cells was dependent on fibronectin production and signaling through integrin β1, leading to cytoskeletal reorganization with filamentous actin (F-actin) stress fiber formation. We show that phosphorylation of myosin light chain (MLC) by MLC kinase (MLCK) through integrin β1 is required for actin stress fiber formation and proliferative growth. Inhibition of integrin β1 or MLCK prevents transition from a quiescent to proliferative state in vitro. Inhibition of MLCK significantly reduces metastatic outgrowth in vivo. These studies show that the switch from dormancy to metastatic growth may be regulated, in part, through epigenetic signaling from the microenvironment, leading to changes in the cytoskeletal architecture of dormant cells. Targeting this process may provide therapeutic strategies for inhibition of the dormant-to-proliferative metastatic switch. [Cancer Res 2008;68(15):6241–50]
Long inhalation time is associated with short treatment time when using the I-neb AAD system in target inhalation mode
Authors: Tim Spencer, Alex Black, Nicholas Smith, Kurt Nikander, Tony Dyche
Journal: European Respiratory Journal (2012)

The I-neb Adaptive Aerosol Delivery (AAD) System is designed to emit aerosol only during the inspiratory phase of breathing and can be operated in tidal breathing mode (TBM), in which the user breathes in a normal manner during treatment, or target inhalation mode (TIM), in which the user is guided to longer inhalations via feedback from the I-neb AAD system. The I-neb AAD system is equipped with a patient logging system (PLS) to facilitate the analysis of patient breathing by recording data on treatment time and mean inhalation time per breath per treatment.  Forty nine patients with cystic fibrosis were enrolled in a 13 week handling study; PLS data was analyzed for 43 of these patients. Each patient9s mean treatment (nebulization) time and inhalation time per breath were calculated for treatments taken in TBM or TIM in order to determine the relationship of these variables.  Figure 1. Mean patient treatment times versus mean patient inhalation times  The median of patient mean treatment times for TBM and TIM were 291 and 146 s, respectively. The median of patient mean inhalation times were 2.6 and 6.9 s, respectively. Patients with longer inhalation times generally had shorter treatment times and patients using TIM had shorter treatment times than those using TBM. It might therefore be of benefit for patients using TBM to switch to using TIM.
Mitochondrial DNA of Vitis vinifera and the Issue of Rampant Horizontal Gene Transfer
Authors: V. V. Goremykin, F. Salamini, R. Velasco, R. Viola
Journal: Molecular Biology and Evolution (2008)

The mitochondrial genome of grape (Vitis vinifera), the largest organelle genome sequenced so far, is presented. The genome is 773,279 nt long and has the highest coding capacity among known angiosperm mitochondrial DNAs (mtDNAs). The proportion of promiscuous DNA of plastid origin in the genome is also the largest ever reported for an angiosperm mtDNA, both in absolute and relative terms. In all, 42.4% of chloroplast genome of Vitis has been incorporated into its mitochondrial genome. In order to test if horizontal gene transfer (HGT) has also contributed to the gene content of the grape mtDNA, we built phylogenetic trees with the coding sequences of mitochondrial genes of grape and their homologs from plant mitochondrial genomes. Many incongruent gene tree topologies were obtained. However, the extent of incongruence between these gene trees is not significantly greater than that observed among optimal trees for chloroplast genes, the common ancestry of which has never been in doubt. In both cases, we attribute this incongruence to artifacts of tree reconstruction, insufficient numbers of characters, and gene paralogy. This finding leads us to question the recent phylogenetic interpretation of Bergthorsson et al. (2003, 2004) and Richardson and Palmer (2007) that rampant HGT into the mtDNA of Amborella best explains phylogenetic incongruence between mitochondrial gene trees for angiosperms. The only evidence for HGT into the Vitis mtDNA found involves fragments of two coding sequences stemming from two closteroviruses that cause the leaf roll disease of this plant. We also report that analysis of sequences shared by both chloroplast and mitochondrial genomes provides evidence for a previously unknown gene transfer route from the mitochondrion to the chloroplast.
Nuclear Translocation of the Epidermal Growth Factor Receptor Family Membrane Tyrosine Kinase Receptors
Authors: Shao-Chun Wang, Mien-Chie Hung
Journal: Clinical Cancer Research (2009)

Integral membrane proteins contain a hydrophobic transmembrane domain and mainly locate in the plasma membrane lipid bilayer. The receptor tyrosine kinases (RTK) of the epidermal growth factor receptor (EGFR) superfamily, including ErbB-1, ErbB-2, ErbB-3, and ErbB-4, constitute an important group of such membrane proteins, which have a profound impact on cancer initiation, progression, and patient outcome. Although studies of their functions have conventionally focused on their membrane-associated forms, documented observations of the presence of these membrane receptors and their functioning partners in the nucleus have reshaped the intracellular geography and highlight the need to modify the central dogma. The ErbB proteins in the membrane can translocate to the nucleus through different mechanisms. Nuclear RTKs regulate a variety of cellular functions, such as cell proliferation, DNA damage repair, and signal transduction, both in normal tissues and in human cancer cell. In addition, they play important roles in determining cancer response to cancer therapy. Nuclear presence of these ErbB proteins is emerging as an important marker in human cancers. An integrated picture of the RTK-centered signaling transduction network extending from the membrane-cytoplasm boundary to the nuclear compartment is looming in the foreseeable horizon for clinical application.
Interobserver reliability in musculoskeletal ultrasonography: results from a "Teach the Teachers" rheumatologist course
Authors: E Naredo
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To assess the interobserver reliability of the main periarticular and intra-articular ultrasonographic pathologies and to establish the principal disagreements on scanning technique and diagnostic criteria between a group of experts in musculoskeletal ultrasonography. <b>Methods:</b> The shoulder, wrist/hand, ankle/foot, or knee of 24 patients with rheumatic diseases were evaluated by 23 musculoskeletal ultrasound experts from different European countries randomly assigned to six groups. The participants did not reach consensus on scanning method or diagnostic criteria before the investigation. They were unaware of the patients' clinical and imaging data. The experts from each group undertook a blinded ultrasound examination of the four anatomical regions. The ultrasound investigation included the presence/absence of joint effusion/synovitis, bony cortex abnormalities, tenosynovitis, tendon lesions, bursitis, and power Doppler signal. Afterwards they compared the ultrasound findings and re-examined the patients together while discussing their results. <b>Results:</b> Overall agreements were 91% for joint effusion/synovitis and tendon lesions, 87% for cortical abnormalities, 84% for tenosynovitis, 83.5% for bursitis, and 83% for power Doppler signal; κ values were good for the wrist/hand and knee (0.61 and 0.60) and fair for the shoulder and ankle/foot (0.50 and 0.54). The principal differences in scanning method and diagnostic criteria between experts were related to dynamic examination, definition of tendon lesions, and pathological <i>v</i> physiological fluid within joints, tendon sheaths, and bursae. <b>Conclusions:</b> Musculoskeletal ultrasound has a moderate to good interobserver reliability. Further consensus on standardisation of scanning technique and diagnostic criteria is necessary to improve musculoskeletal ultrasonography reproducibility.
NK cells promote transplant tolerance by killing donor antigen-presenting cells
Authors: Guang Yu, Xuemin Xu, Minh Diem Vu, Elizabeth D. Kilpatrick, Xian Chang Li
Journal: The Journal of Experimental Medicine (2006)

Natural killer (NK) cells are programmed to kill target cells without prior antigen priming. Because of their potent cytolytic activities, NK cells are one of the key cell types involved in dismantling allografts. However, in certain transplant models, NK cells also express potent immunoregulatory properties that promote tolerance induction. The precise mechanism for such striking dichotomy remains unknown. In the present study, we showed in a skin transplant model that the skin allografts contain a subset of antigen-presenting cells (APCs) that can home to the recipient mice. We also showed that such graft-derived APCs are usually destroyed by the host NK cells. But in the absence of NK cells, donor APCs can survive and then migrate to the host lymphoid and extralymphoid sites where they directly stimulate the activation of alloreactive T cells. T cells activated in the absence of NK cells are more resistant to costimulatory blockade treatment, and under such conditions stable skin allograft survival is difficult to achieve. Our study identified a novel role for NK cells in regulating T cell priming in transplant models, and may have important clinical implications in tolerance induction.
The Quotable Osler
Authors: S M Cooper
Journal: Journal of the Royal Society of Medicine (2003)

Sir William Osler (1849-1919), a dedicated and caring physician, was the prolific author of more than 1600 works in his lifetime, including The Principles and Practice of Medicine, one of the first comprehensive medical textbooks. Such was his output, his great personal following and the large number of eponymous signs and diseases he gave rise to, it is unsurprising that his sayings have endured. Many a lecturer has embellished his talk with an Oslerian quote or two. A Canadian by birth, he worked in his native country, the United States and finally in Oxford as the Regius Professor of Medicine, so his influence spanned two continents.

The Quotable Osler is a collection of quotations compiled from his various publications by three American editors. The book is divided into themes such as personal qualities, the art and practice of medicine, diagnosis and science and truth. The selected quotes portray Osler as a deeply moral, committed and enthusiastic doctor whose capacity for hard work was immense. He believed ‘that the practice of medicine is an art, not a trade; a calling, not a business; a calling in which your heart will be exercised equally with your head’. His bedside skills and manner were widely admired by students and colleagues. He was a passionate educator of medical students and advocate of lifetime learning, believing in the value of careful examination of the patient and the study of medical texts. ‘To study the phenomena of disease without the books is to sail an uncharted sea, while to study books without patients is not to go to sea at all’.

The chapter on Men, Women, Aging and History provides some of the most surprising and colourful quotes. Osler's ambivalent views on women in medicine are aired. On the one hand he applauded the decision to allow women entry to medical school but, on the other hand, he considered women more suited to science than to medicine: ‘a larger proportion of women than men are unfit for practice... and what they [women] lack in initiative and independence is counterbalanced by a more delicate technique’. It is easy to criticize 100 years on but Osler's reservations reflected the views of his generation. He had some advice on marriage—‘Choose a freckle-faced girl for a wife: they are invariably more amiable’—and considered it important for a physician to ‘marry well’. Osler possessed some amusing ageist views on ‘the comparative uselessness of men above forty’ and considered that ‘a very large proportion of the evils [of the world] may be traced to sexagenarians’, who account for the greatest political and social mistakes, the worst poems and the worst sermons. Not surprisingly, he felt ‘men above 60 should retire’.

The Quotable Osler is a fascinating insight into the life and beliefs of one of the greatest physicians. It is mainly of value as a historical account rather than of direct relevance to today's practice. Osler enthusiasts will doubtless disagree. This book will enthral retired physicians, and doctors with even the slightest interest in medical history.
Prof. Brian James Whipp, 1937-2011: a master in respiratory and exercise physiology
Authors: P. Palange, R. Casaburi, S.A. Ward
Journal: European Respiratory Journal (2011)

It is with great sadness that we announce to the European Respiratory Society (ERS) community the passing of Professor Brian James Whipp, after a short illness, in Cardiff, UK, on October 20, 2011 at the age of 74. This event represents an immense loss to those who have had the privilege of knowing Brian, who was a talented scientist and a great man. A masterful researcher, he has been a mentor to many young physiologists and physicians from all over the world. He was also known worldwide as a gifted lecturer and teacher. Indeed, he was one of the most appreciated speakers of the ERS School, and this was formally recognised in 2010 through the Jean-Claude Yernault Lectureship Educational Award.

Born in 1937 in Tredegar, UK, Brian gained a Diploma in Physical Education at the prestigious Loughborough College (Loughborough, UK). He subsequently continued his studies in the USA, first at the University of Florida (Gainesville, FL, USA) and then at Stanford University (Stanford, CA, USA) where, as a Danforth Fellow, he gained his PhD in Physiology in 1967, under …
The Targeted Immunocytokine L19-IL2 Efficiently Inhibits the Growth of Orthotopic Pancreatic Cancer
Authors: Karola Wagner, Petra Schulz, Arne Scholz, Bertram Wiedenmann, Andreas Menrad
Journal: Clinical Cancer Research (2008)

Effective control of pancreatic cancer has been hampered primarily by the lack of tumor specificity of current treatment modalities. The highly specific antibody-mediated delivery of therapeutic agents to the tumor microenvironment might overcome this problem. We therefore investigated the therapeutic efficacy of the targeted immunocytokine L19-Interleukin-2 (L19-IL2), consisting of the human single-chain Fv antibody L19, which is highly specific for the extradomain B (ED-B) of fibronectin, and the human cytokine IL-2, in pancreatic cancer.Therapeutic effects of L19-IL-2, IL-2, and gemcitabine on tumor growth and metastasis were evaluated in orthotopic mouse models for pancreatic cancer. Immunohistochemistry was done to define ED-B expression, tumor necrosis, apoptosis, proliferation, and invasion of macrophages and natural killer (NK) cells. NK cells were depleted by i.v. injection of an anti-asialo-GM-1 antibody.ED-B is selectively expressed in human pancreatic cancer and in primary tumors and metastases of the mouse models. L19-IL-2 therapy was clearly superior to untargeted IL-2 or gemcitabine and inhibited tumor growth and metastasis with remarkable long-term tumor control. Therapeutic effects were associated with the induction of extensive tumor necrosis and inhibition of tumor cell proliferation. Immunohistochemistry revealed an increase of macrophages and NK cells in the tumor tissue, suggesting immune-mediated mechanisms. The functional relevance of NK cells for the therapeutic effect of the targeted immunocytokine L19-IL-2 was confirmed by NK cell depletion, which completely abolished its antitumor efficacy.These preclinical results strongly encourage the initiation of clinical studies using L19-IL-2 in pancreatic cancer.
Mechanisms of anti-tumor action of Corynebacterium parvum. II. Potentiated cytolytic T cell response and its tumor-induced suppression.
Authors: C D Mills, R J North, E S Dye
Journal: The Journal of Experimental Medicine (1981)

It was shown that subcutaneous implantation of P815 tumor cells admixed with Corynebacterium parvum resulted in the emergence of a tumor that grew for 9-10 d and then regressed. The onset of tumor aggression was preceded by the substantial generation in the draining lymph node and spleen of T cells capable of specifically lysing P815 target cells in vitro. The finding that the magnitude of this cytolytic response was much greater than the cytolytic response to a control tumor that grew progressively is consistent with the hypothesis that the anti-tumor action of C. parvum is based on its capacity to augment the production of T cells sensitized to tumor-specific transplantation antigens. This adjuvant action of C. parvum was revealed by additional experiments in which irradiated, nonreplicating tumor cells were substituted for living tumor cells in the admixture. The results support the conclusion that the potentiated cytolytic response to subcutaneous injection of an admixture of irradiated tumor cells and C. parvum is responsible for the ability of this admixture to cause the regression of a test tumor growing at a distant site. Finally, it was shown that the failure of the therapeutic admixture to cause the regression of distant test tumors above a certain size was associated with a failure of the admixture to cause a potentiated, anti-tumor cytolytic response. We discussed the possibility that this failure was caused by the presence of a tumor-induced state of immunosuppression.
Oesophagogastrectomy in patients over 70.
Authors: D D Muehrcke, D K Kaplan, R J Donnelly
Journal: Thorax (1989)

Although the results of oesophageal resection for benign and malignant disease are well documented, the risk of operative death and long term survival in patients over the age of 70 is not well defined. The outcome has been reviewed for 46 patients (23 male, 23 female) aged 70 years or more (mean 74 years) undergoing oesophageal resection during a period of seven years; 16 patients were 75 years or over. All resections were performed with the EEA stapler, except for one cervical anastomosis that was stitched by hand. In 42 patients resection was for malignancy. Six patients died within 30 days of operation or during the initial hospital stay, giving an operative mortality of 13%. Only one of the 16 patients aged 75 years or more died. Cardiopulmonary complications accounted for most of the operative deaths. Patients were scored retrospectively by a multifactual risk factor. Patients who left hospital had a mean preoperative score of 3.66, compared with 15.2 for those who died. Use of such a score may help to improve selection for surgery in this age group. It is concluded that oesophagogastrectomy may be performed in selected patients over the age of 70 years with acceptable mortality, morbidity, and length of hospital stay.
A clinical trial and molecular study of photoadaptation in vitiligo
Authors: C.L. Hexsel, B.H. Mahmoud, D. Mitchell, J. Rivard, M. Owen, F.M. Strickland, H.W. Lim, I. Hamzavi
Journal: British Journal of Dermatology (2008)

Photoadaptation to ultraviolet (UV) B phototherapy is due to both pigmentary and nonpigmentary influences.To measure photoadaptation in vitiliginous skin and to compare it with normal pigmented skin.Seventeen patients with Fitzpatrick skin phototypes III-VI with vitiligo received six to nine UVB treatments, two to three times weekly. Minimal erythema dose (MED) testing was done at baseline and after all treatments; the percentage change in MED was analysed as a measure of photoadaptation. The percentage decrease in cyclobutane pyrimidine dimers (CPDs) over 24 h after a single exposure of 1 MED was analysed on vitiliginous and normal skin.The mean +/- SD percentage change in MED from before to after treatments was: treated vitiliginous skin 28.5 +/- 39.9% (P = 0.015), treated normal skin 35.9 +/- 49.9% (P = 0.015), untreated vitiliginous skin 11.9 +/- 22.6% (P =0.070), untreated normal skin 25.1 +/- 41.3% (P = 0.041). Of these patients, two-thirds had a positive percentage change in MED (photoadaptation). The mean amount of CPDs induced per megabase of DNA immediately after exposure was significantly higher in vitiliginous skin. The mean +/- SD percentage decrease in CPDs (rate of repair) in 24 h was 35.7 +/- 26.8% in vitiliginous skin (P = 0.027) and 46.2 +/- 19.5% in normally pigmented skin (P = 0.001); no difference was noted in the repair in vitiliginous skin compared with normal skin (P = 0.4).Photoadaptation in vitiliginous and normal skin was observed in two-thirds of patients. Vitiliginous skin had significantly more CPDs following UVB exposure; the rate of repair of UVB-induced DNA damage was equivalent to that in normal skin.