tbuckley/cabot-search huggingface dataset:
Rab25 Regulates Invasion and Metastasis in Head and Neck Cancer
Authors: Panomwat Amornphimoltham, Kamil Rechache, Jamie Thompson, Andrius Masedunskas, Kantima Leelahavanichkul, Vyomesh Patel, Alfredo Molinolo, J. Silvio Gutkind, Roberto Weigert
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common cancers with a 50% five-year survival rate, which has remained unchanged for the past three decades. One of the major reasons for the aggressiveness of this cancer is that HNSCCs readily metastasize to cervical lymph nodes that are abundant in the head and neck region. Hence, discovering new molecules controlling the metastatic process as well as understanding their regulation at the molecular level are essential for effective therapeutic strategies. Experimental Design: Rab25 expression level was analyzed in HNSCC tissue microarray. We used a combination of intravital microscopy in live animals and immunofluorescence in an in vitro invasion assay to study the role of Rab25 in tumor cell migration and invasion. Results: In this study, we identified the small GTPase Rab25 as a key regulator of HNSCC metastasis. We observed that Rab25 is downregulated in HNSCC patients. Next, we determined that reexpression of Rab25 in a metastatic cell line is sufficient to block invasion in a three-dimensional collagen matrix and metastasis to cervical lymph nodes in a mouse model for oral cancer. Specifically, Rab25 affects the organization of F-actin at the cell surface, rather than cell proliferation, apoptosis, or tumor angiogenesis. Conclusion: These findings suggest that Rab25 plays an important role in tumor migration and metastasis, and that understanding its function may lead to the development of new strategies to prevent metastasis in oral cancer patients. Clin Cancer Res; 19(6); 1375–88. ©2013 AACR.
Beneficial effect of high-dose chemotherapy in multiple myeloma patients with unfavorable prognostic features
Authors: H. Kaufmann, J. Ackermann, H. Greinix, T. Nösslinger, H. Gisslinger, A. Keck, H. Ludwig, N. Worel, P. Kalhs, C. Zielinski, J. Drach
Journal: Annals of Oncology (2003)
Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients
Authors: K. Tefs, M. Gueorguieva, J. Klammt, C. M. Allen, D. Aktas, F. Y. Anlar, S. D. Aydogdu, D. Brown, E. Ciftci, P. Contarini, C.-E. Dempfle, M. Dostalek, S. Eisert, A. Gokbuget, O. Gunhan, A. A. Hidayat, B. Hugle, M. Isikoglu, M. Irkec, S. K. Joss, S. Klebe, C. Kneppo, I. Kurtulus, R. P. Mehta, K. Ornek, R. Schneppenheim, S. Seregard, E. Sweeney, S. Turtschi, G. Veres, P. Zeitler, M. Ziegler, V. Schuster
Journal: Blood (2006)
Individualization of Antihypertensive Drug Treatment
Authors: Giuseppe Mancia, Guido Grassi
Journal: Diabetes Care (2013)

Antihypertensive drug classes are usually classified as 1st, 2nd, 3rd, and 4th or 5th choice to help physicians select the drug most suitable for treatment initiation among the very many classes available to lower blood pressure (BP) in patients with a BP elevation. However, this approach was appropriate decades ago when several drugs had inconveniences that made their use in monotherapy inadvisable. An example was the then widely used vasodilator hydralazine whose sodium-retaining and tachycardic effects made its administration recommendable only with a diuretic or a β-blocker, with, thus, a classification as a 2nd- or 3rd-choice drug (1). This is no longer the case because several current antihypertensive drug classes are characterized by a similar BP-lowering effect (2), a good tolerability profile (2), and evidence of cardiovascular protection in prospective randomized trials (3,4). As recently argued in a document of the European Society of Hypertension (5), this implies that rather than classifying drugs as 1st, 2nd, 3rd, and further choice, it might be more appropriate to help physicians select the drug (or drug combination) that might be preferred for treatment initiation in a given patient or a given clinical condition. This article will discuss the factors that may help physicians move toward this more individualized treatment approach.

### Demographic factors

Evidence is available that antihypertensive treatment is protective in either hypertensive males or hypertensive females and that for a similar decrease in BP the reduction of cardiovascular risk is proportionally similar in both sexes (6). Thus, sex does not represent a factor to consider in the choice of antihypertensive treatment except for the need to avoid blockers of the renin-angiotensin system (ACE inhibitors, angiotensin receptor antagonists, and renin inhibitors) in pregnant women because of the suspicion, from animal studies, of teratogenic effects (7).

Although the British guidelines have long maintained …
Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer: A Randomized Multicenter Phase II Trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group
Authors: Jalid Sehouli, Dirk Stengel, Philipp Harter, Christian Kurzeder, Antje Belau, Thomas Bogenrieder, Susanne Markmann, Sven Mahner, Lothar Mueller, Ralf Lorenz, Andreas Nugent, Jochen Wilke, Andreas Kuznik, Gabriele Doering, Arthur Wischnik, Harald Sommer, Hans-Gerd Meerpohl, Willibald Schroeder, Werner Lichtenegger, Guelten Oskay-Oezcelik
Journal: Journal of Clinical Oncology (2010)

Weekly administration of topotecan (Tw) is less toxic and widely considered a better treatment option than conventional 5-day therapy (Tc) in women with platinum-resistant recurrent ovarian cancer. We conducted a randomized phase II trial (TOWER [Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer]) to better define the ratio between benefits and risks with either treatment approach.Patients were randomly assigned to two independent two-stage protocols of Tw (4 mg/m(2)/wk administered on days 1, 8, and 15) or Tc (1.25 mg/m(2)/d on days 1 to 5). We evaluated risk ratios (RRs) for the primary end point of clinical benefit (complete response, partial response, and stable disease), the duration of progression-free survival (PFS) and overall survival (OS), associated hazard ratios (HRs), and RRs of toxicity with 95% CIs.In total, 194 patients were randomly assigned at 54 centers to Tw (n = 97) or Tc (n = 97). Clinical benefit was observed in 36 of 76 (47%; 95% CI, 36% to 59%) Tw and 46 of 80 (58%; 95% CI, 46% to 68%) Tc patients (RR, 1.21; 95% CI, 0.90 to 1.64; P = .205). Patients in the Tw group had a slightly shorter PFS (HR, 1.29; 95% CI, 0.96 to 1.76) but similar OS (HR, 1.04; 95% CI, 0.74 to 1.45) compared with Tc. Tw was associated with significantly lower risks of anemia (RR, 0.35; 95% CI, 0.16 to 0.79), neutropenia (RR, 0.38; 95% CI, 0.23 to 0.65), and thrombocytopenia (RR, 0.23; 95% CI, 0.09 to 0.57).With regard to effectiveness in terms of response and PFS, Tc remains the standard of care in patients with platinum-resistant recurrent ovarian cancer. However, comparable OS rates and a favorable toxicity profile make Tw another viable treatment option in this setting.
Regulation of vascular prostaglandin synthesis by metabolites of arachidonic acid in perfused rabbit aorta.
Authors: R S Kent, S L Diedrich, A R Whorton
Journal: Journal of Clinical Investigation (1983)

To address the hypothesis that metabolites of arachidonic acid are important regulators of prostaglandin (PG) synthesis in intact vascular tissue, we studied arachidonate metabolism in rabbit aortas in response to a continuous infusion of arachidonic acid, 10 micrograms/ml. Prostacyclin (PGI2; measured as 6-keto-PGF1 alpha) production rate accelerated during the first 2 min, reached peak velocity at 2 min, and then progressively decelerated. The velocity profile of PGI2 production was similar to that previously reported for cyclooxygenase holoenzyme assayed in vitro, and was consistent with progressive inactivation of the enzymes leading to PGI2 synthesis. We determined the specific inhibition of cyclooxygenase and prostacyclin synthetase by measuring PGI2 and PGE2 production rates and by infusing cyclic endoperoxides. Our results indicate preferential inactivation of cyclooxygenase during arachidonate metabolism, most likely due to cyclooxygenase-derived oxidative intermediates. This was a dose-dependent response and resulted in a progressive decrease in the 6-keto-PGF1 alpha/PGE2 ratio. Exogenously added 15-hydroperoxy eicosatetraenoic acid, on the other hand, actually stimulated cyclooxygenase activity at low doses, while markedly inhibiting prostacyclin synthetase. This finding, along with the accelerating nature of arachidonate metabolism, is consistent with the concept of "peroxide tone" as a mediator of cyclooxygenase activity in this system. These results demonstrate that arachidonate metabolites regulate PG synthesis in intact blood vessels. The progressive enzymatic inhibition intrinsic to arachidonate metabolism may be a model for similar changes occurring in states of enhanced lipid peroxidation. These metabolic alterations might greatly influence the numerous vascular functions known to involve arachidonic acid metabolism.
Long-Term Control of HIV by<i>CCR5</i>Delta32/Delta32 Stem-Cell Transplantation
Authors: Gero Hütter, Daniel Nowak, Maximilian Mossner, Susanne Ganepola, Arne Müßig, Kristina Allers, Thomas Schneider, Jörg Hofmann, Claudia Kücherer, Olga Blau, Igor W. Blau, Wolf K. Hofmann, Eckhard Thiel
Journal: New England Journal of Medicine (2009)

Infection with the human immunodeficiency virus type 1 (HIV-1) requires the presence of a CD4 receptor and a chemokine receptor, principally chemokine receptor 5 (CCR5). Homozygosity for a 32-bp deletion in the CCR5 allele provides resistance against HIV-1 acquisition. We transplanted stem cells from a donor who was homozygous for CCR5 delta32 in a patient with acute myeloid leukemia and HIV-1 infection. The patient remained without viral rebound 20 months after transplantation and discontinuation of antiretroviral therapy. This outcome demonstrates the critical role CCR5 plays in maintaining HIV-1 infection.
Level of acceptability of EULAR recommendations for the management of knee osteoarthritis by practitioners in different European countries
Authors: B Mazieres
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To evaluate the level of acceptability of the EULAR recommendations for the management of knee osteoarthritis (KOA) in practice. <b>Methods:</b> A questionnaire was sent to general practitioners, rheumatologists, rehabilitators, and orthopaedic surgeons in five European countries (France, Spain, Belgium, Switzerland, Italy). Practitioners were asked to give their opinion on the 10 EULAR recommendations and on 23 treatment modes for KOA. Practitioners' opinions were compared with those of the expert task force involved in the development of these recommendations. <b>Results:</b> The overall response rate was 10.4% (4204 replies). Results were similar across countries and specialties. Of the 23 treatment modes proposed, only joint lavage and intra-articular (IA) corticosteroid injections were more strongly recommended by the expert task force than by the responders as a whole, while the opposite was true for spa therapy. Principal component analysis showed: (1) some practitioners preferred "hard line" treatments (surgery, IA injections, or non-steroidal anti-inflammatory drugs (NSAIDs)); (2) there was a difference between those prescribing pharmacological (paracetamol) or non-pharmacological measures with low iatrogenicity (exercises, sticks, education), and those prescribing less well validated treatments closer to "alternative" medicine; (3) each specialist tended to advocate modes that they were most familiar with: rheumatologists were more likely to recommend IA injections and NSAIDs; orthopaedic surgeons, surgical procedures; rehabilitators, education and all non-pharmacological modes; general practitioners, spa therapy and opioids. <b>Conclusions:</b> A multidisciplinary approach is optimal in the management of this chronic disease with its variable course.
Adrenomedullin: a smart road from pheochromocytoma to treatment of pulmonary hypertension
Authors: M. Westphal
Journal: European Respiratory Journal (2004)

In 1993, Kitamura et al. 1 isolated a new peptide from human pheochromocytoma cells, stimulating cAMP production in human platelets and inducing systemic hypotension in rats. Due to its origin of discovery, i.e. the medulla of the adrenal gland, it was named adrenomedullin 1. Adrenomedullin is a 52-amino acid peptide hormone with structural homology to calcitonin gene-related peptide 2. Together with pro-adrenomedullin N-terminal 20-peptide, adrenomedullin is generated by post-translational splicing from its precursor, pro-adrenomedullin 3. Initially, it was believed that adrenomedullin is only expressed in tumour cells, but subsequent studies revealed that it is a multifunctional peptide, synthesised by a huge variety of mammalian tissues, including myocardium, central nervous system, kidney, and reproductive and digestive organs 2, 4. In addition, adrenomedullin is produced by endothelial and smooth muscle cells of both the systemic and pulmonary circulation 5. Adrenomedullin regulates cardiopulmonary functions and vascular tone as both a circulating hormone and as a local autocrine/paracrine mediator 6.

The haemodynamic effects of adrenomedullin are predominantly mediated by cAMP production resulting from activation of two Gs-protein-coupled plasma membrane receptors of the calcitonin peptide family: the calcitonin receptor-like receptor and the receptor activity-modifiying protein-2 or -3 2. Moreover, adrenomedullin mediates smooth muscle cell hyperpolarisation by activating ATP-sensitive K+ channels 7, stimulates the release of vasodilatory prostaglandins 8, and elicits endothelium-dependent vasorelaxation secondary to nitric oxide (NO) formation 8, 9.

Inasmuch as adrenomedullin reduces pulmonary vascular tone and improves tissue oxygenation 10, supplementation of exogenous adrenomedullin may be a rationale in the …
Which Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease Benefit from Noninvasive Positive-Pressure Ventilation?
Authors: Sean P. Keenan, Tasnim Sinuff, Deborah J. Cook, Nicholas S. Hill
Journal: Annals of Internal Medicine (2003)

Background: Over the past decade, noninvasive positive-pressure ventilation (NPPV) in the setting of acute exacerbations of chronic obstructive pulmonary disease (COPD) has increased in popularity. Although several trials have been published on the relative effectiveness of this treatment, apparent inconsistencies in study results remain. Purpose: To assess the effect of NPPV on rate of endotracheal intubation, length of hospital stay, and in-hospital mortality rate in patients with an acute exacerbation of COPD and to determine the effect of exacerbation severity on these outcomes. Data Sources: MEDLINE (1966 to 2002) and EMBASE (1990 to 2002). Additional data sources included the Cochrane Library, personal files, abstract proceedings, reference lists of selected articles, and expert contact. There were no language restrictions. Study Selection: The researchers selected randomized, controlled trials that 1) examined patients with acute exacerbation of COPD; 2) compared noninvasive ventilation and standard therapy with standard therapy alone; and 3) included need for endotracheal intubation, length of hospital stay, or hospital survival as an outcome. Data Extraction: Methodologic quality and results were abstracted independently and in duplicate. Data Synthesis: The addition of NPPV to standard care in patients with an acute exacerbation of COPD decreased the rate of endotracheal intubation (risk reduction, 28% [95% CI, 15% to 40%]), length of hospital stay (absolute reduction, 4.57 days [CI, 2.30 to 6.83 days]), and in-hospital mortality rate (risk reduction, 10% [CI, 5% to 15%]). However, subgroup analysis showed that these beneficial effects occurred only in patients with severe exacerbations, not in those with milder exacerbations. Conclusions: Patients with severe exacerbations of COPD benefit from the addition of NPPV to standard therapy. However, NPPV has not been shown to benefit hospitalized patients with milder COPD exacerbations.
NHS errors led to more than 800 deaths
Authors: Rebecca Coombes
Journal: BMJ (2005)

More than half a million errors are made in patient care in acute NHS hospitals each year, according to the National Patient Safety Agency. Most incidents resulted in no harm to the patient but in 840 cases the patient died, according to the agency's estimates.

Unintentional injury, such as slips and trips, was the most common incident reported, but drug errors, treatment, and problems with documents were a major problem.

The estimates were drawn from 85 342 incident reports via the National Reporting and Learning System between November 2003 and 31 March 2005. It represents the first public analysis of patient safety data in England and Wales. The agency …
Therapeutic activity of two xanthones in a xenograft murine model of human chronic lymphocytic leukemia
Authors: Séverine Loisel, Karine Le Ster, Michèle Meyer, Christian Berthou, Pierre Youinou, Jean-Pierre Kolb, Christian Billard
Journal: Journal of Hematology & Oncology (2010)

We previously reported that allanxanthone C and macluraxanthone, two xanthones purified from Guttiferae trees, display in vitro antiproliferative and proapoptotic activities in leukemic cells from chronic lymphocytic leukemia (CLL) and leukemia B cell lines.Here, we investigated the in vivo therapeutic effects of the two xanthones in a xenograft murine model of human CLL, developed by engrafting CD5-transfected chronic leukemia B cells into SCID mice. Treatment of the animals with five daily injections of either allanxanthone C or macluraxanthone resulted in a significant prolongation of their survival as compared to control animals injected with the solvent alone (p = 0.0006 and p = 0.0141, respectively). The same treatment of mice which were not xenografted induced no mortality.These data show for the first time the in vivo antileukemic activities of two plant-derived xanthones, and confirm their potential interest for CLL therapy.
Plasmacytoid dendritic cells prime IL-10–producing T regulatory cells by inducible costimulator ligand
Authors: Tomoki Ito, Maria Yang, Yui-Hsi Wang, Roberto Lande, Josh Gregorio, Olivia A Perng, Xiao-Feng Qin, Yong-Jun Liu, Michel Gilliet
Journal: The Journal of Experimental Medicine (2007)

Although there is evidence for distinct roles of myeloid dendritic cells (DCs [mDCs]) and plasmacytoid pre-DCs (pDCs) in regulating T cell-mediated adaptive immunity, the concept of functional DC subsets has been questioned because of the lack of a molecular mechanism to explain these differences. In this study, we provide direct evidence that maturing mDCs and pDCs express different sets of molecules for T cell priming. Although both maturing mDCs and pDCs upregulate the expression of CD80 and CD86, only pDCs upregulate the expression of inducible costimulator ligand (ICOS-L) and maintain high expression levels upon differentiation into mature DCs. High ICOS-L expression endows maturing pDCs with the ability to induce the differentiation of naive CD4 T cells to produce interleukin-10 (IL-10) but not the T helper (Th)2 cytokines IL-4, -5, and -13. These IL-10-producing T cells are T regulatory cells, and their generation by ICOS-L is independent of pDC-driven Th1 and Th2 differentiation, although, in the later condition, some contribution from endogenous IL-4 cannot be completely ruled out. Thus, in contrast to mDCs, pDCs are poised to express ICOS-L upon maturation, which leads to the generation of IL-10-producing T regulatory cells. Our findings demonstrate that mDC and pDCs are intrinsically different in the expression of costimulatory molecules that drive distinct types of T cell responses.
Management of early stage Hodgkin's disease: The role of radiation therapy and/or chemotherapy
Authors: P.M. Mauch
Journal: Annals of Oncology (1996)

Clinical trials in early stage Hodgkin's disease comparing radiation therapy (RT) alone versus chemotherapy (CMT) have indicated fewer relapses in the CMT groups. However, none of the trials have demonstrated an overall survival difference. Risk factors for relapse in early stages include large mediastinal adenopathy, fevers, and weight loss. Ongoing clinical trials might prove less toxic CMT effective in curing occult microscopic disease, perhaps eventually obviating the need for staging laparotomy and splenectomy.
Lysylhydroxylation and non-reducible crosslinking of human supraspinatus tendon collagen: changes with age and in chronic rotator cuff tendinitis
Authors: R. A Bank, J. M TeKoppele, G. Oostingh, B. L Hazleman, G. P Riley
Journal: Annals of the Rheumatic Diseases (1999)

To investigate age related and site specific variations in turnover and chemistry of the collagen network in healthy tendons as well as the role of collagen remodelling in the degeneration of the supraspinatus tendon (ST-D) in rotator cuff tendinitis.Collagen content and the amount of hydroxylysine (Hyl), hydroxy-lysylpyridinoline (HP), lysylpyridinoline (LP), and the degree of non-enzymatic glycation (pentosidine) were investigated in ST-D and in normal human supraspinatus (ST-N) and biceps brachii tendons (BT-N) by high-performance liquid chromatography.In BT-N, tendons that served as control tissue as it shows rarely matrix abnormalities, pentosidine levels rise linearly with age (20-90 years), indicating little tissue remodelling (resulting in an undisturbed accumulation of pentosidine). A similar accumulation was observed in ST-N up to 50 years. At older ages, little pentosidine accumulation was observed and pentosidine levels showed large interindividual variability. This was interpreted as remodelling of collagen in normal ST after age 50 years because of microruptures (thus diluting old collagen with newly synthesised collagen). All degenerate ST samples showed decreased pentosidine levels compared with age matched controls, indicating extensive remodelling in an attempt to repair the tendon defect. Collagen content and the amount of Hyl, HP, and LP of ST-N and BT-N did not change with age. With the exception of collagen content, which did not differ, all parameters were significantly (p < 0.001) lower in BT-N. The ST-D samples had a reduced collagen content and had higher Hyl, HP, and LP levels than ST-N (p < 0.001).Inasmuch as Hyl, HP, and LP levels in ST-N did not change with age, tissue remodelling as a consequence of microruptures does not seem to affect the quality of the tendon collagen. On the other hand, the clearly different profile of post-translational modifications in ST-D indicates that the newly deposited collagen network in degenerated tendons is qualitatively different. It is concluded that in ST-D the previously functional and carefully constructed matrix is replaced by aberrant collagen. This may result in a mechanically less stable tendon; as the supraspinatus is constantly subjected to considerable forces this could explain why tendinitis is mostly of a chronic nature.