tbuckley/cabot-search huggingface dataset:
Exosome-Mediated Transfer of microRNAs Within the Tumor Microenvironment and Neuroblastoma Resistance to Chemotherapy
Authors: Kishore B. Challagundla, Petra M. Wise, Paolo Neviani, Haritha Chava, Mariam Murtadha, Tong Xu, Rebekah Kennedy, Cristina Ivan, Xinna Zhang, Ivan Vannini, Francesca Fanini, Dino Amadori, George A. Calin, Michael Hadjidaniel, Hiroyuki Shimada, Ambrose Jong, Robert C. Seeger, Shahab Asgharzadeh, Amir Goldkorn, Muller Fabbri
Journal: JNCI Journal of the National Cancer Institute (2015)

How exosomic microRNAs (miRNAs) contribute to the development of drug resistance in the context of the tumor microenvironment has not been previously described in neuroblastoma (NBL). Coculture experiments were performed to assess exosomic transfer of miR-21 from NBL cells to human monocytes and miR-155 from human monocytes to NBL cells. Luciferase reporter assays were performed to assess miR-155 targeting of TERF1 in NBL cells. Tumor growth was measured in NBL xenografts treated with Cisplatin and peritumoral exosomic miR-155 (n = 6 mice per group) CD163, miR-155, and TERF1 levels were assessed in 20 NBL primary tissues by Human Exon Arrays and quantitative real-time polymerase chain reaction. Student’s t test was used to evaluate the differences between treatment groups. All statistical tests were two-sided. miR-21 mean fold change (f.c.) was 12.08±0.30 (P < .001) in human monocytes treated with NBL derived exosomes for 48 hours, and miR-155 mean f.c. was 4.51±0.25 (P < .001) in NBL cells cocultured with human monocytes for 48 hours. TERF1 mean luciferase activity in miR-155 transfected NBL cells normalized to scrambled was 0.36 ± 0.05 (P <.001). Mean tumor volumes in Dotap-miR-155 compared with Dotap-scrambled were 322.80±120mm3 and 76.00±39.3mm3, P = .002 at day 24, respectively. Patients with high CD163 infiltrating NBLs had statistically significantly higher intratumoral levels of miR-155 (P = .04) and lower levels of TERF1 mRNA (P = .02). These data indicate a unique role of exosomic miR-21 and miR-155 in the cross-talk between NBL cells and human monocytes in the resistance to chemotherapy, through a novel exosomic miR-21/TLR8-NF-кB/exosomic miR-155/TERF1 signaling pathway.
Antibody to mouse interferon alpha/beta abrogates resistance to the multiplication of Friend erythroleukemia cells in the livers of allogeneic mice.
Authors: I Gresser, C Maury, F Vignaux, O Haller, F Belardelli, M G Tovey
Journal: The Journal of Experimental Medicine (1988)

Friend erythroleukemia cells (FLC) (H-2d) injected intravenously into adult syngeneic DBA/2 or allogeneic C57B1/6 (H-2b) or C3H (H-2k) mice lodge in the liver but only multiply in the liver of syngeneic mice. Our results indicated that endogenous IFN-alpha/beta was a crucial factor in preventing the multiplication of FLC in the liver of adult allogeneic mice. (a) Treatment of allogeneic adult C57B1/6 or C3H mice with polyclonal antibody to mouse IFN-alpha/beta (but not antibody to IFN-gamma) completely abrogated the resistance to the multiplication of FLC in the liver and 87% of tumor-injected, antibody-treated C57B1/6 mice died with extensive tumor involvement of the liver. In contrast, after intravenous inoculation FLC do not multiply at all (or very rarely) in the liver of adult C57B1/6 mice left untreated or treated with a variety of control globulins, and no deaths occurred. (b) 8 h after intravenous inoculation of FLC, poly(A)+ RNA hybridizable with specific DNA probes for mouse IFN-alpha or -beta (but not -gamma) was present in the liver of injected C57B1/6 mice. Using the expression of the Mx protein as an indicator of the presence of IFN-alpha/beta, we showed that Mx+ congenic C57B1/6 mice injected with FLC exhibited a marked increase in the expression of the Mx protein in the liver, spleen, kidney and lung, and this increase was blocked by treatment of mice with antibody to IFN-alpha/beta. The possibility that different host mechanisms are elicited depending on the site of tumor growth in allogeneic mice is discussed. IFN-alpha/beta appears to be of particular importance in determining the resistance of the liver to FLC in allogeneic mice.
A phase III randomized trial of 5-fluorouracil, doxorubicin,and mitomycin C versus 5-fluorouracil and mitomycin C versus 5-fluorouracil alone in curatively resected gastric cancer
Authors: H.M. Chang, K.H. Jung, T.-Y. Kim, W.S. Kim, H.-K. Yang, K.U. Lee, K.J. Choe, D.S. Heo, Y.-J. Bang, N.K. Kim
Journal: Annals of Oncology (2002)
Perceptual cues in the regulation of exercise performance – physical sensations of exercise and awareness of effort interact as separate cues
Authors: Jeroen Swart, Timothy Robert Lindsay, Michael Ian Lambert, James Craig Brown, Timothy David Noakes
Journal: British Journal of Sports Medicine (2011)

It has been argued that the physical sensations induced by exercise, measured as the ratings of perceived exertion (RPE), are distinct from the sense of effort. This study aimed to determine whether a new measure of task effort – the Task Effort and Awareness (TEA) score – is able to measure sensations distinct from those included in the conventional RPE scale. Seven well-trained cyclists completed a maximal effort 100 km time trial (TT) and a submaximal trial at 70% of the power sustained during the TT (70% TT). Five maximal 1 km sprints were included in both trials. Both the RPE related solely to physical sensation (P-RPE) and the TEA score increased during the TT and were linearly related. During the 70% TT, both P-RPE and TEA scores increased, but TEA increased significantly less than P-RPE (p&lt;0.001). TEA scores reached maximal values in all 1 km sprints in both the maximal TT and 70% TT, whereas the RPE increased progressively, reaching a maximal value only in the final 1 km sprints in both the TT and the 70% TT. These results indicate that the physical sensations of effort measured as the P-RPE act as the template regulating performance during exercise and that deviation from that template produces an increase in the sense of effort measured by the TEA score. Together, these controls ensure that the chosen exercise intensity does not threaten bodily homeostasis. Our findings also explain why submaximal exercise conducted within the constraints of the template P-RPE does not produce any conscious awareness of effort.
Natural history of liver disease in cystic fibrosis
Authors: Anders Lindblad, Hans Glaumann, Birgitta Strandvik
Journal: Hepatology (1999)

The median age of the population with cystic fibrosis (CF) has increased worldwide, which has led to the suggestion that the prevalence of liver disease would increase. The aim of this study was to evaluate the natural history of CF-associated liver disease over a 15-year period in a well-controlled population of patients with CF. During the years 1976 through 1993, 124 patients were followed up by yearly liver function tests (LFTs). Fifteen patients were followed up with liver biopsies throughout the whole study period. More than 50% of the patients had pathological LFTs in infancy, later being normalized. Approximately 25% of children 4 years of age or older had biochemical markers of liver disease during the study period. In about 10% of the patients, cirrhosis or advanced fibrosis was confirmed at biopsy and 4% of patients had cirrhosis with clinical liver disease. Severe liver disease developed mainly during prepuberty and puberty. Of the 15 patients prospectively followed up with liver biopsies, only 3 had progressive fibrosis. No specific risk factor was identified, but deficiency of essential fatty acids was found more often in patients with marked steatosis ( P &lt; .05). No patient developed clinical liver disease in adulthood and the histological changes in the liver biopsies were usually not progressive. Liver disease was no more frequent at the end of the study period although the median age of the patient population had increased. Modern treatment might positively influence liver disease because it seemed less common, less progressive, and less serious than previously reported.
Activated Protein C Inhibits Local Coagulation after Intrapulmonary Delivery of Endotoxin in Humans
Authors: Tom van der Poll, Marcel Levi, Jerry A. Nick, Edward Abraham
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: Acute lung injury and pneumonia are associated with pulmonary activation of coagulation and suppression of fibrinolysis, resulting in fibrin deposition in the lung. Activated protein C (APC) has systemic anticoagulant effects in patients with sepsis. Objective: To determine the effect of systemic administration of recombinant human APC on endotoxin-induced hemostatic alterations in the bronchoalveolar space in humans. Methods: Healthy humans received intravenous APC (24 μg/kg/hour; n = 8) or vehicle (n = 7); all subjects were administered saline in one lung subsegment and endotoxin (4 ng/kg) into the contralateral lung. Bronchoalveolar lavage was performed 16 hours after saline and endotoxin administration. Measurements and Main Results: Endotoxin induced local activation of coagulation, as reflected by elevated levels of thrombin–antithrombin complexes (1.9 ± 0.1 ng/ml) and soluble tissue factor (15.0 ± 0.6 pg/ml) in bronchoalveolar lavage fluid, which was inhibited by APC (1.4 ± 0.1 ng/ml and 12.3 ± 0.4 pg/ml, respectively; both p < 0.01). Concurrently, endotoxin suppressed fibrinolysis, as indicated by reduced bronchoalveolar levels of plasminogen activator activity accompanied by elevated levels of plasminogen activator inhibitor type I activity. APC diminished the rise in plasminogen activator inhibitor type I activity (from 3.9 ± 0.1 to 3.0 ± 0.2 ng/ml, p = 0.002), while not significantly influencing plasminogen activator activity levels. Endotoxin reduced bronchoalveolar protein C concentrations, which was prevented by APC. Protein C did not influence the endotoxin-induced rise in local soluble thrombomodulin levels. Conclusion: APC exerts an anticoagulant effect in the human lung challenged with endotoxin.
Aggressive Medical Care at the End of Life
Authors: J. Randall Curtis
Journal: JAMA (1997)

The quality of medical care at the end of life is receiving increased attention in both the popular press<sup>1</sup>and professional journals.<sup>2,3</sup>This interest has developed in part because of the perception that people die with ineffective, painful, expensive, and unwanted medical interventions that deprive them of their dignity, personal interactions, and family savings. This perception is not wholly unfounded. Approximately 60% of Americans die in hospitals.<sup>4</sup>Among the deaths of hospitalized patients in the SUPPORT study,<sup>5</sup>half died after receiving mechanical ventilation for more than 1 week. Many families of dying patients report that their loved ones experience moderate to severe pain during most or all of the loved ones' last few days. Many of the families of dying patients experience severe caregiving and financial burdens.<sup>6</sup>Efforts to improve the quality of end-of-life care through advance directives, education, and more accurate prognostic information have
Cystic fibrosis in Europe: patients live longer but are we ready?
Authors: Carsten Schwarz, Dominik Hartl
Journal: European Respiratory Journal (2015)

Having passed the 25th anniversary of discovering the cystic fibrosis transmembrane conductance regulator (CFTR) gene, let's take a look forward to the next 25 years. Newborn screening, animal models, biomarkers, innovative drugs (prototypical CFTR modulators), and advances in lung transplantation have moved the field forward, probably faster than for any other lung disease in recent years [1–5]. As a consequence, the mean survival of patients with cystic fibrosis (CF) is steadily increasing and now exceeds 40 years of age in most European countries [6, 7] and beyond [8]. This study highlights the future challenge to deal with an ageing CF population and innovative, but expensive drugs <http://ow.ly/JRCnx>
Selective Suppression of Endothelial Cell Apoptosis by the High Molecular Weight Form of Adiponectin
Authors: Hideki Kobayashi, Noriyuki Ouchi, Shinji Kihara, Kenneth Walsh, Masahiro Kumada, Yuki Abe, Tohru Funahashi, Yuji Matsuzawa
Journal: Circulation Research (2004)

Adiponectin is an adipocyte-derived, antiatherogenic protein that is present in serum as three isoforms. Total adiponectin levels are decreased in obese or diabetic humans or animal models. This study was designed to elucidate the relative isoform distribution of adiponectin in human disease states and identify the active form of adiponectin toward vascular endothelial cells. The percentage of high molecular weight form (HMW) per total adiponectin was significantly lower in patients with coronary artery disease than control subjects, whereas the hexamer form was similar and the trimer form was significantly higher. During weight reduction in obese subjects, the HMW form increased and the trimer and hexamer forms decreased. Recombinant adiponectin dose-dependently suppressed apoptosis and caspase-3 activity in human umbilical vein endothelial cells (HUVECs). Transduction with dominant-negative AMP-activated protein kinase (AMPK) abolished the suppressive effect of adiponectin on HUVECs. Gel filtration chromatography was used to separate the adiponectin isoforms, and the antiapoptotic effect toward HUVECs was only observed with the HMW form. These data suggest that HMW adiponectin specifically confers the vascular-protective activities of this adipocytokine. The full text of this article is available online at http://circres.ahajournals.org.
Multi-Institutional Randomized Phase II Trial of the Epothilone B Analog Ixabepilone (BMS-247550) With or Without Estramustine Phosphate in Patients With Progressive Castrate Metastatic Prostate Cancer
Authors: Matthew D. Galsky, Eric J. Small, William K. Oh, Isan Chen, David C. Smith, A. Dimitrios Colevas, Lou Martone, Tracy Curley, Anthony DeLaCruz, Howard I. Scher, W. Kevin Kelly
Journal: Journal of Clinical Oncology (2005)

To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer.Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5.Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm.Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.
Supporting individuals with disabling multiple sclerosis
Authors: J C Gibson, A O Frank
Journal: Journal of the Royal Society of Medicine (2003)

People with disabling multiple sclerosis (MS) can lead rewarding and fulfilling lives. To this end, they will do best if they adjust early to the diagnosis and its implications, if disabling symptoms are kept to a minimum and if they get all possible support (including the use of assistive technology) from both professional and voluntary sectors. Support may be needed by those whose disability is static, those who have relapsed and those whose course is progressive. This review explores how this can sometimes be achieved.

The diagnosis of MS is a devastating event for individuals, their families and friends1,2. Its unpredictable course creates difficulties for psychological adjustment and for planning appropriate support3. The development of new disease-modifying drugs seems to have reduced relapse rates for some but may not alter long-term disability. Advice regarding the use of disease-modifying agents is beyond the scope of this review but has recently been distributed in the UK4. Only a small proportion of people with MS proceed to severe disability, many remaining independent 20 years or longer after diagnosis. However, subsequent progression to more severe disabilities is the experience of many. Rehabilitation is effective in reducing ‘disability and handicap’5 and ‘disability’6 and is an essential part of management1.

Living with MS typically is complicated by3:



Initial difficulty in making the diagnosis


Uncertainty of relapse, remission and progression


Absence of cure


Diversity of symptoms and disabilities


Many family doctors having little experience of the disease


Neurologists having inadequate time with individuals initially and for follow-up


Complex co-morbidity—e.g. depression and pain.






As traditional medicine aims to provide ‘disease intervention’, many doctors feel ill equipped to help those with an incurable disease3. Much, however, can be done to help; and, because of the diversity of cognitive, physical, psychological and social problems experienced, rehabilitation requires a coordinated multiagency approach by health and social services3,7 including:



Acute general hospital (diagnostic and support teams, e.g. urology)


Inpatient rehabilitation services linked to


Community rehabilitation teams


Daycare or domiciliary respite (e.g. crossroad care attendants)


Residential respite care.






Consequently, matching the individual's needs to relevant services is crucial to the success of rehabilitation with different services needed, for example, to restore function after a relapse, to facilitate living with a chronic disability, to respond quickly when there is rapid deterioration and to provide assistive technology (e.g. wheelchairs). Each function should be part of a coherent service7.
Vascular Endothelial Growth Factor Is Required for Coronary Collateral Growth in the Rat
Authors: Eiji Toyota, David C. Warltier, Tommy Brock, Erik Ritman, Christopher Kolz, Peter O’Malley, Petra Rocic, Marta Focardi, William M. Chilian
Journal: Circulation (2005)

Background— The goal of this study was to determine whether the expression of vascular endothelial growth factor (VEGF) is critical for coronary collateral growth. Previous studies have provided an association between coronary collateral growth and VEGF, but none have allowed determination of a causal role. Methods and Results— We measured coronary collateral growth in rats subjected to repetitive episodes of myocardial ischemia (RI; one 40-second occlusion every 20 minutes for 2 hours 40 minutes, followed by 5 hours 20 minutes of rest, with this 8-hour cycle repeated 3 times per day for 10 days). Collateral growth was measured from blood flow (radioactive microspheres), visualization of arterial-arterial anastomoses (x-ray micro-CT), and maintenance of function during complete coronary occlusion in 3 groups of animals: sham (received instrumentation but no RI), experimental (subjected to RI), and anti–vascular endothelial growth factor (RI+anti-VEGF 0.6 mg/100 g per day) to block the endogenous actions of VEGF. In the 3 groups, native collateral flow (measurement for RI or sham protocol) averaged 0.2 to 0.3 mL · min −1 · g −1 of tissue. In the sham group, collateral flow did not increase during the protocol. Collateral flow in the control RI group increased by ≈6-fold to 1.63 mL · min −1 · g −1 tissue, but in the anti-VEGF group, collateral flow did not increase after the RI protocol (0.22 mL · min −1 · g −1 ). In acute experiments, collateral flow was unchanged during vasodilation with dipyridamole, indicating the increases in collateral flow are due to collateral growth and not vasodilation. X-ray micro-CT analysis revealed a 3-fold increase (versus sham group) in the number of arterial-arterial anastomoses per heart after RI, which was prevented by treatment with anti-VEGF. The growth of the collateral circulation was functional in the RI group because complete coronary occlusion did not induce any untoward effects on hemodynamics or arrhythmias. In the sham or anti-VEGF groups, coronary occlusion at the end of the protocol induced many arrhythmias and deterioration of function. Conclusions— From these results, we conclude that the expression of VEGF is critical to the growth of coronary collaterals.
Coarctation of the aorta
Authors: J. D. Wisheart
Journal: Thorax (1970)

In a series of 70 patients who had surgical correction of coarctation of the aorta between 1952 and 1969, the operative mortality was 7% and the complication rate was 14%. The mortality was particularly high in adult males over 30, with pre-operative evidence of left ventricular ischaemia. Simple surgical procedures had satisfactory results, but the use of prostheses carried a high risk, and turning down the left subclavian artery failed to lower the blood pressure. The blood pressure score fell by 68% after operation, and by a further 8% following discharge from hospital. This result was maintained up to 17 years after operation, and may be expected in all groups of patients.
Relationship Between Sunlight Exposure and a Key Genetic Alteration in Basal Cell Carcinoma
Authors: M R Gailani, D J Leffell, A Ziegler, E G Gross, D E Brash, A E Bale
Journal: JNCI Journal of the National Cancer Institute (1996)

Background:Basal cell carcinoma (BCC) of the skin is the most common cancer in humans. Epidemiologic studies implicate sunlight exposure as one risk factor, but the limited association between BCCs and UVB radiation (i.e., UV radiation of a wavelength of 280–320 nm) suggests that additional factors must be involved. At the molecular level, not much is known about the role of specific environmental agents in the pathogenesis of BCCs. Point mutations of the types produced by UVB radiation are seen in the p53 gene (also known as TP53; chromosome 17p) of 40%–56% of BCCs. Loss of heterozygosity (LOH) on chromosome 9q22, however, is the most frequent genetic alteration in these tumors, and its causative agent is unknown.
Deceived by metaphor
Authors: John A. Barnden
Journal: Behavioral and Brain Sciences (1997)

The views of self-deception that Mele attacks are thoroughly metaphorical, and should never have purported to imply the existence of real internal acts of deception. Research on self-deception, including Mele's appealing account, could be enriched and constrained by a broader investigation of the prevalent use of metaphor in thinking and talking about the mind.