tbuckley/cabot-search huggingface dataset:
Dendritic Cell Vaccines for Cancer Immunotherapy
Authors: John M. Timmerman, MD, Ronald Levy, MD
Journal: Annual Review of Medicine (1999)

Human tumors express a number of protein antigens that can be recognized by T cells, thus providing potential targets for cancer immunotherapy. Dendritic cells (DCs) are rare leukocytes that are uniquely potent in their ability to present antigens to T cells, and this property has prompted their recent application to therapeutic cancer vaccines. Isolated DCs loaded with tumor antigen ex vivo and administered as a cellular vaccine have been found to induce protective and therapeutic anti-tumor immunity in experimental animals. In pilot clinical trials of DC vaccination for patients with non-Hodgkin's lymphoma and melanoma, induction of anti-tumor immune responses and tumor regressions have been observed. Additional trials of DC vaccination for a variety of human cancers are under way, and methods for targeting tumor antigens to DCs in vivo are also being explored. Exploitation of the antigen-presenting properties of DCs thus offers promise for the development of effective cancer immunotherapies.
Challenges and Key Considerations of the Enhanced Permeability and Retention Effect for Nanomedicine Drug Delivery in Oncology
Authors: Uma Prabhakar, Hiroshi Maeda, Rakesh K. Jain, Eva M. Sevick-Muraca, William Zamboni, Omid C. Farokhzad, Simon T. Barry, Alberto Gabizon, Piotr Grodzinski, David C. Blakey
Journal: Cancer Research (2013)

Enhanced permeability of the tumor vasculature allows macromolecules to enter the tumor interstitial space, whereas the suppressed lymphatic filtration allows them to stay there. This phenomenon, enhanced permeability and retention (EPR), has been the basis of nanotechnology platforms to deliver drugs to tumors. However, progress in developing effective drugs using this approach has been hampered by heterogeneity of EPR effect in different tumors and limited experimental data from patients on effectiveness of this mechanism as related to enhanced drug accumulation. This report summarizes the workshop discussions on key issues of the EPR effect and major gaps that need to be addressed to effectively advance nanoparticle-based drug delivery.
Conservative non-pharmacological treatment for chronic low back pain
Authors: M. van Tulder
Journal: BMJ (2008)

Supervised exercise is effective, if tailored to patients’ preferences and expectations

Low back pain is a major health problem in developed countries, and it is most commonly treated in primary healthcare settings. Lifetime prevalence ranges from 49% to 70% and point prevalence from 12% to 30%.1 The management of patients with chronic low back pain varies considerably within and between countries, and within and between healthcare professions.1 In the linked randomised controlled trial (doi: 10.1136/bmj.a884), Little and colleagues compare the Alexander technique, exercise, and massage for people with chronic and recurrent back pain in 64 English general practices.2

One systematic review found that exercise therapy significantly reduces pain and improves function in adults with chronic low back pain, particularly in patients visiting primary care providers because of back pain.3 However, prescription of home exercises alone is not effective for chronic back pain. Subgroup analysis found that exercise consisting of individually …
Differentiation of Effector/Memory Vδ2 T Cells and Migratory Routes in Lymph Nodes or Inflammatory Sites
Authors: Francesco Dieli, Fabrizio Poccia, Martin Lipp, Guido Sireci, Nadia Caccamo, Caterina Di Sano, Alfredo Salerno
Journal: The Journal of Experimental Medicine (2003)

Vδ2 T lymphocytes recognize nonpeptidic antigens without presentation by MHC molecules and mount both immediate effector functions and memory responses after microbial infection. However, how Vδ2 T cells mediate different facets of a memory response remains unknown. Here, we show that the expression of CD45RA and CD27 antigens defines four subsets of human Vδ2 T cells with distinctive compartmentalization routes. Naive CD45RA+CD27+ and memory CD45RA−CD27+ cells express lymph node homing receptors, abound in lymph nodes, and lack immediate effector functions. Conversely, memory CD45RA−CD27− and terminally differentiated CD45RA+CD27− cells, which express receptors for homing to inflamed tissues, are poorly represented in the lymph nodes while abounding at sites of inflammation, and display immediate effector functions. These observations and additional in vitro experiments indicate a lineage differentiation pattern for human Vδ2 T cells that generates naive cells circulating in lymph nodes, effector/memory cells patrolling the blood, and terminally differentiated effector cells residing in inflamed tissues.
Delayed gas filling imaged in asthma patients using hyperpolarised 3He MRI
Authors: Felix Horn, Helen Marshall, Juan Parra-Robles, Chris Brightling, Jim Wild
Journal: European Respiratory Journal (2014)

Introduction:Delayed ventilation imaging with hyperpolarized  3 He MRI has revealed delayed ventilation pathways in the lungs of COPD patients[1]. The sensitivity of this method to partial airways obstruction and narrowing make it a potentially useful technique in asthma.  Objectives:To investigate presence and repeatability of delayed filling in asthma patients.  Methods:In 9 asthma patients (49±9 years) two 3D lung images were acquired during a single breath-hold with a gap of 5s. Imaging was repeated 12 weeks later. To quantify the effect of delayed ventilation voxels with a signal increase from 1st to 2nd image were counted. Repeatability of delayed gas filling was qualitatively compared between visits.  Results:The figure shows an example of reproducible delayed gas filling in the lower left lung, and an example of reversible delayed-ventilation in the upper right lung (arrows). Delayed ventilation was observed in all patients. An average delayed filling volume of 142ml(SD=171ml) was found over all experiments. In 5/9 cases the delayed gas filling of at least in one defect was found to be reproducible.  Conclusions:This study confirms, as suggested before[2], that some persisting ventilation defects, seen using conventional ventilation imaging, fill with a delay. These persistent regions of delayed-ventilation might explain why lung defects in asthma don9t undergo atelectasis.  [1] Marshall,Thorax,[67],613-7;[2]deLange,Radiology,[250],567-75.
Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial of Patients with Type 2 Diabetes and Overt Nephropathy
Authors: Tomas Berl, Lawrence G. Hunsicker, Julia B. Lewis, Marc A. Pfeffer, Jerome G. Porush, Jean Lucien Rouleau, Paul L. Drury, Enric Esmatjes, Donald E Hricik, Chirag R. Parikh, Itamar Raz, Philippe Vanhille, Thomas B. Wiegmann, Bernard M. Wolfe, Francesco Locatelli, Samuel Z. Goldhaber, Edmund J. Lewis
Journal: Annals of Internal Medicine (2003)

Background: Patients with diabetes have increased risk for adverse cardiovascular events. Angiotensin-converting enzyme inhibitors are protective in type 1 diabetes. However, no definitive studies have examined the use of angiotensin-receptor blockers in patients with type 2 diabetes and overt nephropathy. The primary outcomes of the Irbesartan Diabetic Nephropathy Trial were doubling of serum creatinine levels, end-stage renal disease, and death from any cause. Objective: To compare rates of cardiovascular events among patients with type 2 diabetic nephropathy who received conventional antihypertensive therapy with an angiotensin-receptor blocker (irbesartan) or a calcium-channel blocker (amlodipine), or placebo. Design: Randomized double-blind, placebo-controlled trial with a median follow-up of 2.6 years. A time event analysis was used. Setting: 209 centers in the Americas, Europe, Israel, and Australasia. Participants: 1715 adults with type 2 diabetic nephropathy and hypertension; serum creatinine levels of 89 mol/L (1.0 mg/dL) to 266 mol/L (3.0 mg/dL) in women and 106 mol/L (1.2 mg/dL) to 266 mol/L (3.0 mg/dL) in men; and urinary protein excretion rates of at least 900 mg/d. Intervention: Treatment with irbesartan, amlodipine, or placebo. Measurements: Time to cardiovascular death, myocardial infarction, congestive heart failure, strokes, and coronary revascularization. Results: The three groups were not statistically different in the composite of cardiovascular events. Among the components of the composite, there was a trend toward a decrease in strokes in patients receiving amlodipine versus those receiving placebo (hazard ratio, 0.65 [95% CI, 0.35 to 1.22]; P = 0.18). Likewise, patients receiving amlodipine had a significantly lower rate of myocardial infarction when compared with placebo recipients (hazard ratio, 0.58 [CI, 0.37 to 0.92]; P = 0.02). In contrast, patients receiving irbesartan had a significantly lower incidence of congestive heart failure when compared with placebo recipients (hazard ratio, 0.72 [CI, 0.52 to 1.00]; P = 0.048) or amlodipine recipients (hazard ratio, 0.65 [CI, 0.48 to 0.87]; P = 0.004). Conclusion: The composite cardiovascular event rate did not differ in patients with type 2 diabetes and overt nephropathy treated with irbesartan, amlodipine, or placebo in addition to conventional antihypertensive therapy. *For members of the Collaborative Study Group, see the Appendix.
Subchronic Pulmonary Pathology, Iron Overload, and Transcriptional Activity after Libby Amphibole Exposure in Rat Models of Cardiovascular Disease
Authors: Jonathan H. Shannahan, Abraham Nyska, Mark Cesta, Mette C.J. Schladweiler, Beena D. Vallant, William O. Ward, Andrew J. Ghio, Stephen H. Gavett, Urmila P. Kodavanti
Journal: Environmental Health Perspectives (2011)

Surface-available iron (Fe) is proposed to contribute to asbestos-induced toxicity through the production of reactive oxygen species.Our goal was to evaluate the hypothesis that rat models of cardiovascular disease with coexistent Fe overload would be increasingly sensitive to Libby amphibole (LA)-induced subchronic lung injury.Male healthy Wistar Kyoto (WKY), spontaneously hypertensive (SH), and SH heart failure (SHHF) rats were intratracheally instilled with 0.0, 0.25, or 1.0 mg LA (with saline as the vehicle). We examined bronchoalveolar lavage fluid (BALF) and histological lung sections after 1 week, 1 month, or 3 months for pulmonary biomarkers and pathology. SHHF rats were also assessed at 6 months for pathological changes.All animals developed concentration- and time-dependent interstitial fibrosis. Time-dependent Fe accumulation occurred in LA-laden macrophages in all strains but was exacerbated in SHHF rats. LA-exposed SHHF rats developed atypical hyperplastic lesions of bronchiolar epithelial cell origin at 3 and 6 months. Strain-related baseline differences existed in gene expression at 3 months, with persistent LA effects in WKY but not SH or SHHF rats. LA exposure altered genes for a number of pathways, including inflammation, immune regulation, and cell-cycle control. Cell-cycle control genes were inhibited after LA exposure in SH and SHHF but not WKY rats, whereas tumor suppressor genes were induced only in WKY rats. The inflammatory gene expression also was apparent only in WKY rats.These data show that in Fe-overload conditions, progressive Fe accumulation occurs in fiber-laden macrophages within LA-induced lesions. Fe overload does not appear to contribute to chronic inflammation, and its role in hyperplastic lesion development requires further examination.
Transcatheter Implantation of Homologous “Off-the-Shelf” Tissue-Engineered Heart Valves With Self-Repair Capacity
Authors: Anita Driessen-Mol, Maximilian Y. Emmert, Petra E. Dijkman, Laura Frese, Bart Sanders, Benedikt Weber, Nikola Cesarovic, Michele Sidler, Jori Leenders, Rolf Jenni, Jürg Grünenfelder, Volkmar Falk, Frank P.T. Baaijens, Simon P. Hoerstrup
Journal: Journal of the American College of Cardiology (2013)
14-3-3 Binding Sites in the Snail Protein Are Essential for Snail-Mediated Transcriptional Repression and Epithelial-Mesenchymal Differentiation
Authors: Zhaoyuan Hou, Hongzhuang Peng, David E. White, Pu Wang, Paul M. Lieberman, Thanos Halazonetis, Frank J. Rauscher
Journal: Cancer Research (2010)

The Snail transcription factor is a repressor and a master regulator of epithelial-mesenchymal transition (EMT) events in normal embryonic development and during tumor metastases. Snail directly regulates genes affecting cell adhesion, motility, and polarity. Invasive tumor cells express high levels of Snail, which is a marker for aggressive disease and poor prognosis. Transcriptional repression and EMT induction by Snail requires binding to its obligate corepressor, the LIM protein Ajuba. It is unclear how this complex is assembled and maintained on Snail target genes. Here we define functional 14-3-3 binding motifs in Snail and Ajuba, which selectively bind 14-3-3 protein isoforms. In Snail, an NH(2)-terminal motif in the repression domain cooperates with a COOH-terminal, high-affinity motif for binding to 14-3-3 proteins. Coordinate mutation of both motifs abolishes 14-3-3 binding and inhibits Snail-mediated gene repression and EMT differentiation. Snail, 14-3-3 proteins, and Ajuba form a ternary complex that is readily detected through chromatin immunoprecipitation at the endogenous E-cadherin promoter. Collectively, these data show that 14-3-3 proteins are new components of the Snail transcriptional repression machinery and mediate its important biological functions.
Elevated Blood Pressure Linked to Primary Hyperaldosteronism and Impaired Vasodilation in BK Channel–Deficient Mice
Authors: Matthias Sausbier, Claudia Arntz, Iancu Bucurenciu, Hong Zhao, Xiao-Bo Zhou, Ulrike Sausbier, Susanne Feil, Simone Kamm, Kyrill Essin, Claudia A. Sailer, Usamah Abdullah, Peter Krippeit-Drews, Robert Feil, Franz Hofmann, Hans-Günther Knaus, Chris Kenyon, Michael J. Shipston, Johan F. Storm, Winfried Neuhuber, Michael Korth, Rudolf Schubert, Maik Gollasch, Peter Ruth
Journal: Circulation (2005)

Background— Abnormally elevated blood pressure is the most prevalent risk factor for cardiovascular disease. The large-conductance, voltage- and Ca 2+ -dependent K + (BK) channel has been proposed as an important effector in the control of vascular tone by linking membrane depolarization and local increases in cytosolic Ca 2+ to hyperpolarizing K + outward currents. However, the BK channel may also affect blood pressure by regulating salt and fluid homeostasis, particularly by adjusting the renin-angiotensin-aldosterone system. Methods and Results— Here we report that deletion of the pore-forming BK channel α subunit leads to a significant blood pressure elevation resulting from hyperaldosteronism accompanied by decreased serum K + levels as well as increased vascular tone in small arteries. In smooth muscle from small arteries, deletion of the BK channel leads to a depolarized membrane potential, a complete lack of membrane hyperpolarizing spontaneous K + outward currents, and an attenuated cGMP vasorelaxation associated with a reduced suppression of Ca 2+ transients by cGMP. The high level of BK channel expression observed in wild-type adrenal glomerulosa cells, together with unaltered serum renin activities and corticotropin levels in mutant mice, suggests that the hyperaldosteronism results from abnormal adrenal cortical function in BK −/− mice. Conclusions— These results identify previously unknown roles of BK channels in blood pressure regulation and raise the possibility that BK channel dysfunction may underlie specific forms of hyperaldosteronism.
Airway impedance entropy and exacerbations in severe asthma
Authors: Sherif Gonem, Imraan Umar, Daniel Burke, Dhananjay Desai, Steven Corkill, John Owers-Bradley, Christopher E. Brightling, Salman Siddiqui
Journal: European Respiratory Journal (2012)

Variability of peak flow measurements has been related to clinical outcomes in asthma. We hypothesised that the entropy, or information content, of airway impedance over short time scales may predict asthma exacerbation frequency. 66 patients with severe asthma and 30 healthy control subjects underwent impulse oscillometry at baseline and following bronchodilator administration. On each occasion, airway impedance parameters were measured at 0.2-s intervals for 150 s, yielding a time series that was then subjected to sample entropy (SampEn) analysis. Airway impedance and SampEn of impedance were increased in asthmatic patients compared with healthy controls. In a logistic regression model, SampEn of the resistance at 5 Hz minus the resistance at 20 Hz, a marker of the fluctuation of the heterogeneity of airway constriction over time, was the variable most strongly associated with the frequent exacerbation phenotype (OR 3.23 for every 0.1 increase in SampEn). Increased airway impedance and SampEn of impedance are associated with the frequent exacerbation phenotype. Prospective studies are required to assess their predictive value.
4-Hydroxytamoxifen Induces Autophagic Death through K-Ras Degradation
Authors: Latika Kohli, Niroop Kaza, Tatjana Coric, Stephanie J. Byer, Nicole M. Brossier, Barbara J. Klocke, Mary-Ann Bjornsti, Steven L. Carroll, Kevin A. Roth
Journal: Cancer Research (2013)

Tamoxifen is widely used to treat estrogen receptor-positive breast cancer. Recent findings that tamoxifen and its derivative 4-hydroxytamoxifen (OHT) can exert estrogen receptor-independent cytotoxic effects have prompted the initiation of clinical trials to evaluate its use in estrogen receptor-negative malignancies. For example, tamoxifen and OHT exert cytotoxic effects in malignant peripheral nerve sheath tumors (MPNST) where estrogen is not involved. In this study, we gained insights into the estrogen receptor-independent cytotoxic effects of OHT by studying how it kills MPNST cells. Although caspases were activated following OHT treatment, caspase inhibition provided no protection from OHT-induced death. Rather, OHT-induced death in MPNST cells was associated with autophagic induction and attenuated by genetic inhibition of autophagic vacuole formation. Mechanistic investigations revealed that OHT stimulated autophagic degradation of K-Ras, which is critical for survival of MPNST cells. Similarly, we found that OHT induced K-Ras degradation in breast, colon, glioma, and pancreatic cancer cells. Our findings describe a novel mechanism of autophagic death triggered by OHT in tumor cells that may be more broadly useful clinically in cancer treatment.
Treatment With Dietary <i>trans</i>10<i>cis</i>12 Conjugated Linoleic Acid Causes Isomer-Specific Insulin Resistance in Obese Men With the Metabolic Syndrome
Authors: Ulf Risérus, Peter Arner, Kerstin Brismar, Bengt Vessby
Journal: Diabetes Care (2002)

OBJECTIVE—Conjugated linoleic acid (CLA) is a group of dietary fatty acids with antiobesity and antidiabetic effects in some animals. The trans10cis12 (t10c12) CLA isomer seems to cause these effects, including improved insulin sensitivity. Whether such isomer-specific effects occur in humans is unknown. The aim of this study was to investigate whether t10c12 CLA or a commercial CLA mixture could improve insulin sensitivity, lipid metabolism, or body composition in obese men with signs of the metabolic syndrome. RESEARCH DESIGN AND METHODS—In a randomized, double-blind controlled trial, abdominally obese men (n = 60) were treated with 3.4 g/day CLA (isomer mixture), purified t10c12 CLA, or placebo. Euglycemic-hyperinsulinemic clamp, serum hormones, lipids, and anthropometry were assessed before and after 12 weeks of treatment. RESULTS—Baseline metabolic status was similar between groups. Unexpectedly, t10c12 CLA increased insulin resistance (19%; P &amp;lt; 0.01) and glycemia (4%; P &amp;lt; 0.001) and reduced HDL cholesterol (−4%; P &amp;lt; 0.01) compared with placebo, whereas body fat, sagittal abdominal diameter, and weight decreased versus baseline, but the difference was not significantly different from placebo. The CLA mixture did not change glucose metabolism, body composition, or weight compared with placebo but lowered HDL cholesterol (−2%; P &amp;lt; 0.05). CONCLUSIONS—These results reveal important isomer-specific metabolic actions of CLA in abdominally obese humans. A CLA-induced insulin resistance has previously been described only in lipodystrophic mice. Considering the use of CLA-supplements among obese individuals, it is important to clarify the clinical consequences of these results, but they also provide physiological insights into the role of specific dietary fatty acids as modulators of insulin resistance in humans.
Poliovirus-specific CD4+ Th1 clones with both cytotoxic and helper activity mediate protective humoral immunity against a lethal poliovirus infection in transgenic mice expressing the human poliovirus receptor.
Authors: B P Mahon, K Katrak, A Nomoto, A J Macadam, P D Minor, K H Mills
Journal: The Journal of Experimental Medicine (1995)

The current understanding of the function of CD4+ T helper (Th) cells in immunity to infectious diseases is that Th1 cells, which secrete interleukin (IL)-2 and interferon-gamma, induce cellular immune responses, whereas Th2 cells, which secrete IL-4, IL-5, IL-6, and IL-10, provide helper function for humoral immunity. We have used a panel of poliovirus-specific murine CD4+ T cell clones and mice transgenic for the human poliovirus receptor to evaluate the role of Th cell subpopulations in protective immunity to poliovirus. The majority of T cell clones, as well as polyclonal T cells generated from mice infected or immunized with poliovirus, secreted IL-2 and interferon-gamma, but not IL-4, IL-5, or IL-10, a profile typical of Th1 cells. The Th1 clones displayed major histocompatibility complex class II-restricted cytotoxic T lymphocyte activity against specific poliovirus peptide-pulsed target cells, but also provided help for antipoliovirus neutralizing antibody production. To examine the mechanism of immunity in vivo, we have used poliovirus receptor-transgenic mice on a BALB/c (H-2d) background. These animals developed a poliomyelitis-like disease when challenged intravenously with a virulent wild-type strain of poliovirus, but not with an attenuated vaccine strain. Furthermore, mice immunized with the vaccine strain were protected against a subsequent challenge with wild-type virus. Using an adoptive transfer technique, we demonstrated that it was possible to confer protection with primed B cells in the presence of polyclonal poliovirus-specific T cells, but not when transgenic mice received either B cells or T cells alone. Furthermore, protection was observed when mice received primed B cells in the presence of a VP4-specific Th1 clone. The findings demonstrate that Th1 cells can mediate a protective immune response against poliovirus infection in vivo through helper activity for humoral immunity and that CD4+ T cells, specific for the internal poliovirus capsid protein, VP4, can provide effective help for a protective antibody response directed against surface capsid proteins.