tbuckley/cabot-search huggingface dataset:
Recombinant <b> <i>Listeria</i> </b> Vaccines Containing PEST Sequences Are Potent Immune Adjuvants for the Tumor-Associated Antigen Human Papillomavirus-16 E7
Authors: Duane A. Sewell, Vafa Shahabi, George R. Gunn, Zhen-Kun Pan, Mary E. Dominiecki, Yvonne Paterson
Journal: Cancer Research (2004)

Abstract Previous work in our laboratory has established that the fusion of tumor-associated antigens to a truncated form of the Listeria monocytogenes virulence factor listeriolysin O (LLO) enhances the immunogenicity and antitumor efficacy of the tumor antigen when delivered by Listeria or by vaccinia. LLO contains a PEST sequence at the NH2 terminus. These sequences, which are found in eukaryotic proteins with a short cellular half-life, target proteins for degradation in the ubiquitin-proteosome pathway. To investigate whether the enhanced immunogenicity conferred by LLO is due to the PEST sequence, we constructed new Listeria recombinants that expressed the HPV-16 E7 antigen fused to LLO, which either contained or had been deleted of this sequence. We then compared the antitumor efficacy of this set of vectors and found that Listeria expressing the fusion protein LLO-E7 or PEST-E7 were effective at regressing established macroscopic HPV-16 immortalized tumors in syngeneic mice. In contrast, Listeria recombinants expressing E7 alone or E7 fused to LLO from which the PEST sequence had been genetically removed could only slow tumor growth. Because CD8+ T cell epitopes are generated in the ubiquitin-proteosome pathway, we also investigated the ability of the vaccines to induce E7-specific CD8+ T cells in the spleen and to generate E7-specific tumor-infiltrating lymphocytes. A strong correlation was observed between CD8+ T-cell induction and tumor homing and the antitumor efficacy of the Listeria-E7 vaccines. These findings suggest a strategy for the augmentation of tumor antigen-based immunotherapeutic strategies that may be broadly applicable.
Site and mechanism of leptin action in a rodent form of congenital lipodystrophy
Authors: Esra Asilmaz, Paul Cohen, Makoto Miyazaki, Pawel Dobrzyn, Kohjiro Ueki, Gulnorakhon Fayzikhodjaeva, Alexander A. Soukas, C. Ronald Kahn, James M. Ntambi, Nicholas D. Socci, Jeffrey M. Friedman
Journal: Journal of Clinical Investigation (2004)

Lipodystrophy is characterized by the complete or partial absence of adipose tissue, insulin resistance, hepatic steatosis, and leptin deficiency. Here, we show that low-dose central leptin corrects the insulin resistance and fatty liver of lipodystrophic aP2-nSREBP-1c mice, while the same dose given peripherally does not. Central leptin also repressed stearoyl-CoA desaturase-1 (SCD-1) RNA and enzymatic activity, which were increased in livers of lipodystrophic mice. aP2-nSREBP-1c mice homozygous for an SCD-1 deletion had markedly reduced hepatic steatosis, increased saturated fatty acids, decreased acetyl-CoA carboxylase activity, and decreased malonyl-CoA levels in the liver. Despite the reduction in hepatic steatosis, these mice remained diabetic. A leptin dose-response curve showed that subcutaneous leptin improved hyperglycemia and hyperinsulinemia in aP2-nSREBP-1c mice at doses that did not substantially alter hepatic steatosis or hepatic SCD enzymatic activity. Leptin treatment at this dose improved insulin-stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) phosphorylation, IRS-2-associated PI3K activity, and Akt activity in liver. Together, these data suggest that CNS-mediated repression of SCD-1 contributes to leptin's antisteatotic actions. Intracerebroventricular leptin improves glucose homeostasis by improving insulin signal transduction in liver, but in this case the effect appears to be independent of SCD-1.
IFN-γ– and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers
Authors: Bin Zhang, Theodore Karrison, Donald A. Rowley, Hans Schreiber
Journal: Journal of Clinical Investigation (2008)

Tumors elicit antitumor immune responses, but over time they evolve and can escape immune control through various mechanisms, including the loss of the antigen to which the response is directed. The escape of antigen-loss variants (ALVs) is a major obstacle to T cell–based immunotherapy for cancer. However, cancers can be cured if both the number of CTLs and the expression of antigen are high enough to allow targeting of not only tumor cells, but also the tumor stroma. Here, we showed that IFN-γ and TNF produced by CTLs were crucial for the elimination of established mouse tumors, including ALVs. In addition, both BM- and non-BM–derived stromal cells were required to express TNF receptors and IFN-γ receptors for the elimination of ALVs. Although IFN-γ and TNF were not required by CTLs for perforin-mediated killing of antigen-expressing tumor cells, the strong inference is that tumor antigen–specific CTLs must secrete IFN-γ and TNF for destruction of tumor stroma. Therefore, bystander killing of ALVs may result from IFN-γ and TNF acting on tumor stroma.
Preclinical Evaluation of Imaging Biomarkers for Prostate Cancer Bone Metastasis and Response to Cabozantinib
Authors: Timothy J. Graham, Gary Box, Nina Tunariu, Mateus Crespo, Terry J. Spinks, Susana Miranda, Gerhardt Attard, Johann de Bono, Suzanne A. Eccles, Faith E. Davies, Simon P. Robinson
Journal: JNCI Journal of the National Cancer Institute (2014)

Prostate cancer is incurable once it has metastasized to the bone. Appropriate preclinical models are lacking. The therapeutic efficacy of the multikinase inhibitor cabozantinib was assessed in an orthotopic xenograft model of castration-resistant prostate cancer (CRPC) bone metastasis using noninvasive, multimodality functional imaging. NOD/SCID mice were injected intratibially with luciferase-expressing ERG (v-ets avian erythroblastosis virus E26 oncogene homolog) rearranged VCaP human prostate carcinoma cells. The response of VCaP xenografts (n = 7 per group) to cabozantinib was investigated using bioluminescence imaging and anatomical and diffusion weighted magnetic resonance imaging. This enabled quantitation of tumor volume and apparent diffusion coefficient (ADC). Bone uptake of technetium-methylene diphosphonate ( 99m Tc-MDP) was assessed by single-photon emission computed tomography. Ex vivo micro computed tomography was used to quantify bone volume and correlated with appropriate histopathology. Statistical significance was determined using the two-sided Mann–Whitney test or Wilcoxon signed rank test. VCaP xenografts were predominantly osteosclerotic with some osteolytic activity. Fluorescent in situ hybridization analysis confirmed retention of ERG oncogene rearrangements. Cabozantinib induced a statistically significant 52% reduction in tumor luminance ( P = .02) and stasis in tumor volume after 15 days of treatment. Tumor ADC statistically significantly increased with cabozantinib and was associated with extensive necrosis (after 10 days, mean tumor ADC ± SD = 556±43×10 −6 mm 2 /s vs pretreatment ADC = 485±43×10 −6 mm 2 /s; P = .02 ). Tumor-associated uptake of 99m Tc-MDP was statistically significantly reduced after 3 days of treatment ( P = .02), sustained over 15 days treatment, and associated with a statistically significant ( P = .048) reduction in bone growth on the tibial cortex, yet a highly statistically significant ( P = .001) increase in trabecular bone volume. The intratibial VCaP model faithfully emulates clinical disease. Cabozantinib exerts potent effects on both tumor and tumor-induced bone matrix remodeling, and quantitation of ADC provides a clinically translatable imaging biomarker for early, sensitive assessment of treatment response in CRPC bone metastasis.
Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children
Authors: A. Barbato, T. Frischer, C. E. Kuehni, D. Snijders, I. Azevedo, G. Baktai, L. Bartoloni, E. Eber, A. Escribano, E. Haarman, B. Hesselmar, C. Hogg, M. Jorissen, J. Lucas, K. G. Nielsen, C. O'Callaghan, H. Omran, P. Pohunek, M-P. F. Strippoli, A. Bush
Journal: European Respiratory Journal (2009)

Primary ciliary dyskinesia (PCD) is associated with abnormal ciliary structure and function, which results in retention of mucus and bacteria in the respiratory tract, leading to chronic oto-sino-pulmonary disease, situs abnormalities and abnormal sperm motility. The diagnosis of PCD requires the presence of the characteristic clinical phenotype and either specific ultrastructural ciliary defects identified by transmission electron microscopy or evidence of abnormal ciliary function. Although the management of children affected with PCD remains uncertain and evidence is limited, it remains important to follow-up these patients with an adequate and shared care system in order to prevent future lung damage. This European Respiratory Society consensus statement on the management of children with PCD formulates recommendations regarding diagnostic and therapeutic approaches in order to permit a more accurate approach in these patients. Large well-designed randomised controlled trials, with clear description of patients, are required in order to improve these recommendations on diagnostic and treatment approaches in this disease.
Enhanced Lung Gene Expression After Aerosol Delivery of Concentrated pDNA/PEI Complexes
Authors: Lee A Davies, Gerry McLachlan, Stephanie G Sumner-Jones, David Ferguson, Alison Baker, Peter Tennant, Catherine Gordon, Christina Vrettou, Eilidh Baker, Jie Zhu, Eric WFW Alton, David DS Collie, David J Porteous, Stephen C Hyde, Deborah R Gill
Journal: Molecular Therapy (2008)

A major limitation of many self-assembling nonviral gene transfer formulations is that they are commonly prepared at relatively low component concentrations. While this typically has little impact on their use in cell culture, it can severely limit the progress of in vivo studies. In order to overcome this, we have developed a simple, scalable, pharmaceutically acceptable concentration method that has allowed us to increase the concentration of a commonly used pDNA/PEI formulation from 0.2 to >8 mg/ml plasmid DNA (pDNA). Crucially, the concentration method was found to have only minimal impact on the electrostatic properties or size of the pDNA/PEI particles. When delivered as an aerosol to the mouse lung, the concentrated pDNA/PEI formulations resulted in a 15-fold increase in lung reporter gene expression, with minimal impact in terms of inflammation or toxicity. Importantly, this performance advantage was replicated after aerosol administration to sheep lungs, with reporter gene expression being similarly approximately 15-fold higher than with the conventional pDNA/PEI formulation, and lung inflammation falling to background levels. These findings demonstrate that concentrated pDNA/PEI formulations offer increased aerosol gene transfer with decreased inflammatory sequelae, and represent a promising advance in the field of nonviral lung gene transfer. It seems likely that similar benefits might be achievable with alternative delivery routes and with other nonviral formulations.
Treatment of Hypertension
Authors: A. R. Gilchrist
Journal: BMJ (1956)

In the treatment of hypertensive vascular disease, a great variety of effective remedies are now available-so many, indeed, that considerable discrimination is required in the selection of the therapeutic procedures best adapted to a particular patient.Some are powerful remedies, not easy to administer or regulate, and call for the fullest co-operation between doctor and patient.Others, simple in themselves, demand skill in application to get the best results.Occasionally the justification for recommend- ing a surgical procedure, remedial or palliative, will require careful consideration.With a multiplicity of aetiological factors, and with great variations in tha pattern, course, and intensity of the disease, it is natural that treatment must vary widely from patient to patient and be adapted to the requirements of the particular individual.No single remedy is uniformly successful. General Measures ManagementOf the general measures widely applicable, considera- tion must be given to the judicious and tactful manage- ment of the hypertensive patient.By their manner, attitude, and personality, some doctors are able to accomplish more than others for hypertensive patients.They owe their skill to the confidence they inspire.The first step in successful treatment is therefore the employment of conscious or unconscious psychotherapy.By this means the doctor establishes a relationship of mutual trust of particular advantage to the patient, who is thereby steadied in his outlook, reassured, and encour- aged.The relief of emotional tension promotes a sense of tranquillity, which in itself can set a blood pressure at lower levels.As a general rule, the fears of high blood pressure should be countered at the earliest opportunity, with the explanation that such a condition may persist for years without disagreeable happenings.It may even subside spontaneously, without serious embarrassment or permanent crippling.Doubts and fears can usually be set aside by explaining that the condition is compara- tively benign, that suitable treatment is available when it is required, and that frequently no particular specific remedies are necessary.Such an attitude can do much for the patient, simplify his care and supervision, and permit the judicious use of appropriate remedies as and when these appear necessary.Most people, and hypertensive patients in particular, feel better, make more headway, and have a lower pres- sure when under the protective and understanding care of a sympathetic and encouraging adviser.Relief from emotional stresses with the resolution of conscious or subconscious conflicts is of importance, particularly in
Influence of Organ Environment on Extracellular Matrix Degradative Activity and Metastasis of Human Colon Carcinoma Cells
Authors: M. Nakajima, K. Morikawa, A. Fabra, C. D. Bucana, I. J. Fidler
Journal: JNCI Journal of the National Cancer Institute (1990)

Orthotopic implantation of human colon carcinoma cells is useful for studying the behavior of metastatic subpopulations. We observed that the parental line and variants of human colon carcinoma KM12 cells were all tumorigenic following implantation into the subcutis or cecal wall of BALB/c nude mice. Their ability to metastasize to distant organ sites varied, however, with the site of growth. Subcutaneous (SC) tumors did not produce visceral metastases, whereas cecal tumors metastasized to the regional mesenteric lymph nodes and to the liver. To examine the influence of organ environment on the extracellular matrix-degrading activity of the tumors, we inoculated human colon carcinoma cells into the subcutis or cecal wall and after 7 weeks isolated and cultured the tumors in serum-free medium. The conditioned media of SC tumors contained very low levels of type IV collagenase (gelatinase) and heparanase (heparan sulfate-specific endo-β-D-glucuronidase) whereas the media of the cecal wall tumors contained high levels of both. Zymograms of the media revealed that the intracecal human colon carcinomas secreted more than three times the amount of latent and active forms of 92-kd type IV collagenase than did the SC tumors. Moreover, only the conditioned media of intracecal tumors contained latent and active forms of 64-kd type IV collagenase. Histochemical analysis using rabbit antiserum raised against the synthetic peptides of 72-kd procollagenase type IV showed type IV collagenase in the intracecal tumors; human colon carcinoma growing SC, however, were not stained significantly. These results suggest that factors in the organ environment may affect production and secretion of tumor extracellular matrix-degrading enzymes, and these factors may modify the metastatic behavior of human colon carcinoma cells in nude mice. [J Natl Cancer Inst 82:1890–1898, 1990]
Exposure Assessment Error and its Handling in Nutritional Epidemiology
Authors: Lenore Kohlmeier, Bärbel Bellach
Journal: Annual Review of Public Health (1995)

Exposure assessment is the weakest element in nutritional epidemiologic studies. In the absence of an adequate arsenal of biomarkers of intake in the United States, food frequency questionnaires are widely used to assess habitual frequency of consumption of foods. These tools need to be designed for the population under study, based on prior information on the eating behavior of the population. The questions to be addressed to insure appropriate application of these tools are presented. The influence of various sources and types of measurement error on various scientific hypotheses is addressed. In assessment of nutrient adequacy, information on intra- to interindividual variation of the nutrient or substance of interest is essential. Risk assessment requires examination of sources and extent of bias and differential and nondifferential measurement error within the study. The theory required for error correction is well developed, but rarely carried out because of lack of software and lack of information needed to calibrate the measures.
Iron potentiates liver injury in the rat nutritional model of non-alcoholic steatohepatitis (NASH)
Authors: Richard Kirsch, Robert V. Verdonk, Makhaya Twala, Carolinah Valashiya, Annelie De Vries, Enid G. Shephard, Ralph E. Kirsch, Pauline de la M. Hall
Journal: Journal of Hepatology (2002)
Communication between Dutch rheumatologists and occupational physicians in the occupational rehabilitation of patients with rheumatic diseases
Authors: P D M de Buck
Journal: Annals of the Rheumatic Diseases (2002)

Background: Rheumatic diseases are a major cause of permanent work disability. In the process of occupational rehabilitation several health professionals may have a role. Objective: To assess the quality and quantity of communication and cooperation between Dutch rheumatologists and occupational physicians. Methods: A postal survey among 187 Dutch rheumatologists. Results: 153/187 rheumatologists (82%) returned the questionnaire. They considered reducing pain and fatigue to be their major responsibility in the process of occupational rehabilitation, followed by improving work participation (68/153 (44%)) and quality of work (55/153 (36%)). Although 112/153 (73%) of the rheumatologists judged the communication and cooperation with occupational physicians as reasonable to good, 119/153 (78%) of them were willing to improve the collaboration. Perceived bottlenecks mentioned were a lack of clarity about the occupational physician9s position and activities, and the absence of practice guidelines. The most important prerequisites for improvement were found to be guarantees about the occupational physician9s professional independence and more clarity about the competence of the occupational physicians and how they used the information provided. Conclusion: Dutch rheumatologists are willing to improve cooperation and communication with occupational physicians. The perceived lack of clarity about their mutual tasks appears to be a major obstacle. Thus the development of a joint education programme and a guideline for occupational rehabilitation in rheumatic diseases may be appropriate first steps towards improvement.
Independent impact of gout on the risk of acute myocardial infarction among elderly women: a population-based study
Authors: Mary A De Vera, M Mushfiqur Rahman, Vidula Bhole, Jacek A Kopec, Hyon K Choi
Journal: Annals of the Rheumatic Diseases (2010)

Background Men with gout have been found to have an increased risk of acute myocardial infarction (AMI), but no corresponding data are available among women. Objective To evaluate the potential independent association between gout and the risk of AMI among elderly women, aged ≥65 years. Methods A population-based cohort study was conducted using the British Columbia Linked Health Database and compared incidence rates of AMI between 9642 gout patients and 48 210 controls, with no history of ischaemic heart disease. Cox proportional hazards models stratified by gender were used to estimate the relative risk (RR) for AMI, adjusting for age, comorbidities and prescription drug use. Results Over a 7-year median follow-up, 3268 incident AMI cases, were identified, 996 among women. Compared with women without gout, the multivariate RRs among women with gout were 1.39 (95% CI 1.20 to 1.61) for all AMI and 1.41 (95% CI 1.19 to 1.67) for non-fatal AMI. These RRs were significantly larger than those among men (multivariate RRs for all AMI and non-fatal AMI, 1.11 and 1.11; p values for interaction, 0.003 and 0.005, respectively). Conclusion These population-based data suggest that women with gout have an increased risk for AMI and the magnitude of excess risk is higher than in men.
Update in Pulmonary Hypertension 2005
Authors: Marius M. Hoeper, Lewis J. Rubin
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

This article summarizes and puts into perspective the most important advances made in 2005 in the field of pulmonary vascular disease. The focuswill be entirely on pathogenetic and therapeutic aspects of pulmonary hypertension, although important articles have also been published in other areas of pulmonary vascular disease, including pulmonary embolism (1, 2) and high-altitude pulmonary edema (3, 4).
A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis
Authors: Ludwig Kappos, Ernst-Wilhelm Radue, Paul O'Connor, Chris Polman, Reinhard Hohlfeld, Peter Calabresi, Krzysztof Selmaj, Catherine Agoropoulou, Malgorzata Leyk, Lixin Zhang-Auberson, Pascale Burtin
Journal: New England Journal of Medicine (2010)

Oral fingolimod, a sphingosine-1-phosphate–receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis.
Adjuvant Therapy after Curative Resection for Hepatocellular Carcinoma Associated with Hepatitis Virus
Authors: Shoji Kubo, Shigekazu Takemura, Chikaharu Sakata, Yorihisa Urata, Takahiro Uenishi
Journal: Liver Cancer (2013)

The outcome after curative resection for hepatocellular carcinoma (HCC) is still unsatisfactory because of the high rate of recurrence of HCC, including intrahepatic metastasis originating from the primary carcinoma and multicentric carcinogenesis after surgery. The rate of recurrence, particularly of multicentric carcinogenesis after surgery, is affected by persistent active hepatitis and hepatic fibrosis caused by chronic hepatitis B or C. In patients with hepatitis B virus (HBV)-related HCC, a high viral load is a strong risk factor for HCC recurrence. Nucleos(t)ide analogues improve the outcome after curative resection for HBV-related HCC. Interferon therapy improves the outcome after curative resection for hepatitis C virus (HCV)-related HCC by decreasing recurrence and preserving or improving liver function when treatment is successful. Low-dose intermittent interferon therapy has also been reported to be effective in suppressing HCC recurrence. New antiviral agents including protease or polymerase inhibitors are expected to be effective because these agents can eradicate HCV in most patients who receive such treatment.