tbuckley/cabot-search huggingface dataset:
Clinical and Immunologic Responses to Active Specific Cancer Vaccines in Human Colorectal Cancer
Authors: Dirk Nagorsen, Eckhard Thiel
Journal: Clinical Cancer Research (2006)

Abstract Colorectal cancer is a common malignant disease, which, despite some progress, still requires improved therapeutic options. Several clinical studies have used active specific immunotherapy (i.e., vaccination) in colorectal cancer. However, the literature still lacks a comprehensive meta-analysis of this approach in advanced colorectal cancer. We did a systematic review with a meta-analysis of clinical studies to evaluate the objective clinical and immunologic response to active specific immunotherapy in patients with colorectal cancer. We conducted a search of Medline and the Web of Science, manually reviewed the literature, and consulted with experts. Criteria for including studies were colorectal cancer patients, active specific immunotherapy to induce a response directed against cancer or cancer antigens, an evaluable tumor burden (i.e., advanced or metastatic colorectal cancer), and precise classification of the patient, disease, and response. Response rates were assessed according to WHO criteria. Primary end points were the objective clinical response rate and the rate of immunologic responses. The secondary end point was the distribution of immune and clinical responses in relation to the route of vaccination and the type of vaccine. Thirty-two phase I/II studies reporting on 527 patients with advanced or metastatic colorectal cancer met all inclusion criteria. Pooled analysis showed an overall response rate (complete response + partial response) of 0.9% for advanced/metastatic colorectal cancer patients who underwent active specific immunization with a broad variety of substances (e.g., autologous tumor cells, peptide vaccine, dendritic cells, idiotypic antibody, and virus-based vaccine). Humoral immune responses were reported in 59%, and cellular ones were reported in 44% of the cases. Mixed or minor responses and disease stabilization are described in 1.9% and 8.3% of colorectal cancer patients, respectively. Pooled results of clinical trials reveal a very weak clinical response rate of &amp;lt;1% for active specific immunization procedures currently available for advanced colorectal cancer. Immune response induction is described in approximately half the patients.
Validity of an automated telephonic system to assess COPD exacerbation rates
Authors: Erik W.M.A. Bischoff, Lonneke M. Boer, Johan Molema, Reinier Akkermans, Chris van Weel, Jan H. Vercoulen, Tjard R.J. Schermer
Journal: European Respiratory Journal (2011)

Current tools for recording chronic obstructive pulmonary disease (COPD) exacerbations are limited and often lack validity testing. We assessed the validity of an automated telephonic exacerbation assessment system (TEXAS) and compared its outcomes with existing tools. Over 12 months, 86 COPD patients (22.1% females; mean age 66.5 yrs; mean post-bronchodilator forced expiratory volume in 1 s 53.4% predicted) were called once every 2 weeks by TEXAS to record changes in respiratory symptoms, unscheduled healthcare utilisation and use of respiratory medication. The responses to TEXAS were validated against exacerbation-related information collected by observations made by trained research assistants during home visits. No care assistance was provided in any way. Diagnostic test characteristics were estimated using commonly used definitions of exacerbation. Detection rates, compliance and patient preference were assessed, and compared with paper diary cards and medical record review. A total of 1,824 successful calls were recorded, of which 292 were verified by home visits (median four calls per patient, interquartile range three to five calls per patient). Independent of the exacerbation definition used, validity was high, with sensitivities and specificities between 66% and 98%. Detection rates and compliance differed extensively between the different tools, but were highest with TEXAS. Patient preference did not differ. TEXAS is a valid tool to assess COPD exacerbation rates in prospective clinical studies. Using different tools to record exacerbations strongly affects exacerbation occurrence rates.
Genetic analysis of salt-sensitive hypertension in Dahl rats reveals a link between cardiac fibrosis and high cholesterol
Authors: N. Wendt, A. Schulz, F. Qadri, J. Bolbrinker, P. Kossmehl, K. Winkler, M. Stoll, R. Vetter, R. Kreutz
Journal: Cardiovascular Research (2008)

Previously we confirmed an important role of rat chromosome 19 (RNO19) for salt-sensitive hypertension and target organ damage in male Dahl salt-sensitive rats (SS rats). The aim of this study was to further analyse the basis of left ventricular (LV) fibrosis development in both male and female rats in this model. To this end we utilized a consomic SS-19(SHR) rat strain in which RNO19 was transferred from spontaneously hypertensive rats (SHR) into the susceptible background of SS.We compared the effects of low- (0.2% NaCl) and high-salt (4% NaCl) diet on the development of hypertension, blood lipids and LV fibrosis in male and female SS, SHR, and SS-19(SHR) rats. Systolic blood pressure was significantly lower in male and female SS-19(SHR) compared with SS under both diets (P < 0.001). Relative LV weight was similarly reduced in SS-19(SHR) compared with SS in either sex. Plasma cholesterol concentrations were significantly elevated in high-salt fed male and female SS (141 +/- 6 and 110 +/- 7 mg/dL) compared with SHR (47 +/- 2 and 62 +/- 8 mg/dL, P < 0.001) and were significantly lowered in male and female consomic rats (100 +/- 7 and 87 +/- 3 mg/dL). Both LV interstitial fibrosis (LVIF) and perivascular fibrosis (LVPF) were significantly reduced in high-salt male and female SS-19(SHR). A significant correlation between cholesterol concentrations and LVPF (r = 0.464) and LVIF (r = 0.401, P < 0.0001, respectively) was detected. Fibrosis parameters demonstrated no correlation with blood pressure, LV weight or plasma triglycerides concentrations. LV immunohistochemistry analysis showed a significant higher number of ED-1 positive cells in SS compared with SS-19(SHR). Depositions of collagen I and fibronectin were also greater in LV tissue of SS compared with SS-19(SHR).Our findings point to a link between hypercholesterolemia and LV fibrosis in salt-sensitive hypertension of SS rats which is genetically modulated by RNO19.
Chronic Kidney Disease at High Altitude
Authors: Andrew M. Luks, Richard J. Johnson, Erik R. Swenson
Journal: Journal of the American Society of Nephrology (2008)

With a prevalence of 10 to 11% in the general population, it is likely that many patients with chronic kidney disease will visit or reside in mountainous areas. Little is known, however, about whether short- or long-duration, high-altitude exposure poses a risk in this patient population. Given that many areas of the kidney are marginally oxygenated even at sea level and that kidney disease may result in further renal hypoxia and hypoxia-associated renal injury, there is concern that high altitude may accelerate the progression of chronic kidney disease. In this review, we address how chronic kidney disease and its management is affected at high altitude. We postulate that arterial hypoxemia at high altitude poses a risk of faster disease progression in those with preexisting kidney disease. In addition, we consider the risks of developing acute altitude illness in patients with chronic kidney disease and the appropriate use of medications for the prevention and treatment of these problems.
Effect of Adenovirus-Mediated Expression of Sonic Hedgehog Gene on Hair Regrowth in Mice With Chemotherapy-Induced Alopecia
Authors: N. Sato, P. L. Leopold, R. G. Crystal
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: The Sonic hedgehog (Shh) gene is involved in the initiation of hair growth. We have shown that localized, transient, enhanced expression of the Shh gene in mouse skin mediated by an adenovirus (AdShh) vector accelerates initiation of the anagen (i.e., growth) phase of hair follicle development. Because hair regrowth in chemotherapy-induced alopecia is associated with follicle cell proliferation and active melanogenesis similar to that observed in the anagen phase of normal hair growth, we examined whether AdShh-mediated Shh expression would accelerate hair regrowth in the skin of mice with chemotherapy-induced alopecia. Methods: After establishment of cyclophosphamide-induced alopecia, in either 3- or 7-week-old mice, AdShh or a control vector (AdNull) was delivered to dorsal skin by intradermal injection. Hair regrowth and melanogenesis were assessed by histology and gross morphology. Fisher's exact test was used to compare differences in outcomes between AdShh-treated and control (AdNull-treated or not injected with any vector [naive]) mice. All statistical tests were two-sided. Results: Northern blot analysis confirmed enhanced Shh expression after AdShh administration in 7-week-old mice. Two weeks after AdShh administration, the injection site (all of five mice) showed large, anagen-phase hair follicles with a normal distribution of melanin. In contrast, both skin treated with AdNull (all of five mice) and skin from naive mice (all of five mice) showed dystrophic hair follicles with irregular distribution of melanin (P<.001 in both comparisons). Gross morphologic observations confirmed that AdShh-treated mice, but not naive mice or AdNull-treated mice, showed skin darkening at the injection site indicative of entry into anagen phase (P<.001 in both comparisons). AdShh treatment of 3-week-old mice with cyclophosphamide-induced alopecia was followed by accelerated hair follicle recovery (19 of 22 mice); such recovery was not observed at this rate in AdNull-treated or naive skin (P<.001 for both comparisons). Conclusion: Localized, transient, enhanced expression of Shh gene in skin, mediated by an adenovirus vector, might be a future strategy to accelerate hair follicle regrowth after chemotherapy-induced alopecia.
Lung Cancer Promotion by -Carotene and Tobacco Smoke: Relationship to Suppression of Retinoic Acid Receptor- and Increased Activator Protein-1?
Authors: R. Lotan
Journal: JNCI Journal of the National Cancer Institute (1999)

tene-supplemented animals, and this increase was enhanced further by tobacco smoke. The concentrations of b-carotene and retinoic acid and the levels of RARb in lung tissue were lower in animals supplemented with high-dose b-carotene, exposed to tobacco smoke, or both compared with control animals. Furthermore, ferrets on combined treatment showed a severalfold increase in the expression of c-Jun and c-Fos proteins. Often induced by mitogenic stimuli and tumor-promoting agents, these proteins can form a heterodimer that binds an activator protein-1 (AP-1) site on DNA and enhances gene transcription (15). Wang et al. (14) concluded that the enhanced lung tumorigenesis after high-dose supplementation with b-carotene and exposure to tobacco smoke is the result of RARb suppression and overexpression of c-jun and c-fos genes. The presumed sequence of events is as follows: An increase in b-carotene in the presence of tobacco smoke in the ferret’s lung results in an increase in P450 enzymes. This effect enhances the formation of b-carotene oxidative metabolites such as b-apo-carotenals, which further increase the level of P450 enzymes and may abrogate retinoid signaling. Consequently, b-carotene and retinoic acid levels decrease further. The decrease in retinoic acid may lead to a decrease in the expression of RARb and an increase in the expression of c-fos and c-jun. The decrease in RARb may in turn facilitate the development of squamous metaplasia, and the increase in AP-1 may lead to hyperproliferation and an increase in PCNA. Wang et al. (14) propose that these changes may eventually enhance lung tumorigenesis.
Calcium-Channel Blocker–Clarithromycin Drug Interactions and Acute Kidney Injury
Authors: Sonja Gandhi, Jamie L. Fleet, David G. Bailey, Eric McArthur, Ron Wald, Faisal Rehman, Amit X. Garg
Journal: JAMA (2013)

Calcium-channel blockers are metabolized by the cytochrome P450 3A4 (CYP3A4; EC 1.14.13.97) enzyme. Blood concentrations of these drugs may rise to harmful levels when CYP3A4 activity is inhibited. Clarithromycin is an inhibitor of CYP3A4 and azithromycin is not, which makes comparisons between these 2 macrolide antibiotics useful in assessing clinically important drug interactions.To characterize the risk of acute adverse events following coprescription of clarithromycin compared with azithromycin in older adults taking a calcium-channel blocker.Population-based retrospective cohort study in Ontario, Canada, from 2003 through 2012 of older adults (mean age, 76 years) who were newly coprescribed clarithromycin (n = 96,226) or azithromycin (n = 94,083) while taking a calcium-channel blocker (amlodipine, felodipine, nifedipine, diltiazem, or verapamil).Hospitalization with acute kidney injury (primary outcome) and hospitalization with hypotension and all-cause mortality (secondary outcomes examined separately). Outcomes were assessed within 30 days of a new coprescription.There were no differences in measured baseline characteristics between the clarithromycin and azithromycin groups. Amlodipine was the most commonly prescribed calcium-channel blocker (more than 50% of patients). Coprescribing clarithromycin vs azithromycin with a calcium-channel blocker was associated with a higher risk of hospitalization with acute kidney injury (420 patients of 96,226 taking clarithromycin [0.44%] vs 208 patients of 94,083 taking azithromycin [0.22%]; absolute risk increase, 0.22% [95% CI, 0.16%-0.27%]; odds ratio [OR], 1.98 [95% CI, 1.68-2.34]). In a subgroup analysis, the risk was highest with dihydropyridines, particularly nifedipine (OR, 5.33 [95% CI, 3.39-8.38]; absolute risk increase, 0.63% [95% CI, 0.49%-0.78%]). Coprescription with clarithromycin was also associated with a higher risk of hospitalization with hypotension (111 patients of 96,226 taking clarithromycin [0.12%] vs 68 patients of 94,083 taking azithromycin [0.07%]; absolute risk increase, 0.04% [95% CI, 0.02%-0.07%]; OR, 1.60 [95% CI, 1.18-2.16]) and all-cause mortality (984 patients of 96,226 taking clarithromycin [1.02%] vs 555 patients of 94,083 taking azithromycin [0.59%]; absolute risk increase, 0.43% [95% CI, 0.35%-0.51%]; OR, 1.74 [95% CI, 1.57-1.93]).Among older adults taking a calcium-channel blocker, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically significant greater 30-day risk of hospitalization with acute kidney injury. These findings support current safety warnings regarding concurrent use of CYP3A4 inhibitors and calcium-channel blockers.
Immunoglobulin M Monoclonal Gammopathies of Undetermined Significance and Indolent Waldenström's Macroglobulinemia Recognize the Same Determinants of Evolution Into Symptomatic Lymphoid Disorders: Proposal for a Common Prognostic Scoring System
Authors: Luca Baldini, Maria Goldaniga, Andrea Guffanti, Chiara Broglia, Sergio Cortelazzo, Andrea Rossi, Enrica Morra, Mariangela Colombi, Vincenzo Callea, Enrico Pogliani, Fiorella Ilariucci, Stefano Luminari, Pierre Morel, Giampaolo Merlini, Paolo Gobbi
Journal: Journal of Clinical Oncology (2005)

Purpose To evaluate the clinicohematologic variables at diagnosis that are prognostically related to neoplastic progression in patients with immunoglobulin M (IgM) monoclonal gammopathies of undetermined significance (MGUS), and indolent Waldenström's macroglobulinemia (IWM), and propose a scoring system to identify subsets of patients at different risk. Patients and Methods We evaluated 217 patients with IgM MGUS and 201 with IWM (male-female ratio, 131:86 and 117:84; mean age, 63.7 and 63.6 years, respectively) diagnosed on the basis of serum monoclonal component (MC) levels and bone marrow lymphoplasmacytic infiltration degree. The variables selected by univariate analyses were multivariately investigated; on the basis of their individual relative hazards, a scoring system was devised to identify subsets of patients at different risk of evolution. Results After a median follow-up of 56.1 and 60.2 months, 15 of 217 MGUS and 45 of 201 IWM patients, respectively, required chemotherapy for symptomatic WM (13 and 36), non-Hodgkin's lymphoma (2 and 6) and amyloidosis (0 and 3). The median time to evolution (TTE) was not reached for MGUS and was 141.5 months for IWM. The variables adversely related to evolution were qualitatively the same in both groups: MC levels, Hb concentrations and sex. A scoring system based on these parameters identified three risk groups with highly significant differences in TTE in both groups (P &lt; .0001). Conclusion MGUS and IWM identify disease entities with different propensities for symptomatic neoplastic evolution. As both have the same prognostic determinants of progression, we propose a practical scoring system that, identifying different risks of malignant evolution, may allow an individualized clinical approach.
Endogenous Lentiviral Elements in the Weasel Family (Mustelidae)
Authors: G.-Z. Han, M. Worobey
Journal: Molecular Biology and Evolution (2012)

Endogenous retroviruses provide molecular fossils for studying the ancient evolutionary history of retroviruses. Here, we report our independent discovery and analysis of endogenous lentiviral insertions (Mustelidae endogenous lentivirus [MELV]) within the genomes of weasel family (Mustelidae). Genome-scale screening identified MELV elements in the domestic ferret (Mustela putorius furo) genome (MELVmpf). MELVmpf exhibits a typical lentiviral genomic organization. Phylogenetic analyses position MELVmpf basal to either primate lentiviruses or feline immunodeficiency virus. Moreover, we verified the presence of MELV insertions in the genomes of several species of the Lutrinae and Mustelinae subfamilies but not the Martinae subfamily, suggesting that the invasion of MELV into the Mustelidae genomes likely took place between 8.8 and 11.8 Ma. The discovery of MELV in weasel genomes extends the host range of lentiviruses to the Caniformia (order Carnivora) and provides important insights into the prehistoric diversity of lentiviruses.
Human health effects of dioxins: cancer, reproductive and endocrine system effects
Authors: M. Kogevinas
Journal: Human Reproduction Update (2001)

Polychlorinated dioxins, furans and polychlorinated benzene constitute a family of toxic persistent environmental pollutants. In Europe, environmental concentrations increased slowly throughout this century until the late 1980s. Dioxins have been shown to be carcinogenic in animals and humans. In humans, excess risks were observed for all cancers, without any specific cancer predominating. In specific cohorts, excess risks were observed for reproductive cancers (breast female, endometrium, breast male, testis) but, overall, the pattern is inconsistent. In animals, endocrine, reproductive and developmental effects are among the most sensitive to dioxin exposure. Decreased sperm counts in rats and endometriosis in rhesus monkeys occur at concentrations 10 times higher than current human exposure. In humans, results are inconsistent regarding changes in concentrations of reproductive hormones. A modification of the sex ratio at birth was described in Seveso. There exist no data on effects such as endometriosis or time-to-pregnancy. Small alterations in thyroid function have occasionally been found. Increased risk for diabetes was seen in Seveso and a herbicide applicators cohort but, overall, results were inconsistent. Experimental data indicate that endocrine and reproductive effects should be among the most sensitive effects in both animals and humans. Epidemiological studies have evaluated only a few of these effects.
Role of Antigen-Presenting Cells in Mediating Tolerance and Autoimmunity
Authors: Kristine M. Garza, Steven M. Chan, Rakesh Suri, Linh T. Nguyen, Bernhard Odermatt, Stephen P. Schoenberger, Pamela S. Ohashi
Journal: The Journal of Experimental Medicine (1999)

The mechanisms that determine whether receptor stimulation leads to lymphocyte tolerance versus activation remain poorly understood. We have used rat insulin promoter (RIP)-gp/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic β-islet cells together with T cells expressing an LCMV-gp–specific T cell receptor to assess the requirements for the induction of autoimmunity. Our studies have shown that administration of the gp peptide gp33 leads to the activation of P14-transgenic T cells, as measured by the upregulation of activation markers and the induction of effector cytotoxic activity. This treatment also leads to expansion and deletion of P14 T cells. Despite the induction of cytotoxic T lymphocyte activity, peptide administration is not sufficient to induce diabetes. However, the administration of gp peptide together with an activating anti-CD40 antibody rapidly induces diabetes. These findings suggest that the induction of tolerance versus autoimmunity is determined by resting versus activated antigen-presenting cells.
Age determination by magnetic resonance imaging of the wrist in adolescent male football players
Authors: Jiri Dvorak, John George, Astrid Junge, Juerg Hodler
Journal: British Journal of Sports Medicine (2006)

Background: In football there are established age-related tournaments for males and females to guarantee equal chances within the game for all the different age groups. To prevent participation in the incorrect age group, and owing to the fact that in some Asian and African countries registration at birth is not compulsory, other methods of age determination need to be available. Standard radiographs of the left wrist have been used for assessment of skeletal age for many years. This is, however, not ethical in the sporting environment. Aim: To study the possible use of magnetic resonance imaging (MRI), which has no radiation risk, in estimating the age of healthy adolescent football players. Methods: The examination protocol was applied in four countries using, their respective MRI equipment using a 1-T or 1.5-T magnet and a wrist coil. 496 healthy male adolescent football players between the ages of 14 and 19 years from Switzerland, Malaysia, Algeria and Argentina were selected for the study. The degree of fusion of the left distal radial physis was determined by three independent raters by a newly developed grading system which can be used in future MRI epiphysial fusion grading studies. Results: The inter-rater reliability for grading was high (r = 0.91 and 0.92); all correlations were highly significant (p&lt;0.001). The average age increased with a higher grading of fusion, and the correlation between age and grade of fusion was highly significant (r = 0.69, p&lt;0.001). Only one player (0.8%) in the 16-year-old age group was graded as completely fused. Conclusion: MRI of the wrist offers an alternative as a non-invasive method of age determination in 14–19-year-old male adolescents. The grading system presented here clearly identifies the skeletal maturity by complete fusion in all MRI slices, which eliminates any risk associated with standard radiographic rating as determined by the International Atomic Energy Agency.