tbuckley/cabot-search huggingface dataset:
Hyperactive Sleeping Beauty Transposase Enables Persistent Phenotypic Correction in Mice and a Canine Model for Hemophilia B
Authors: Martin A Hausl, Wenli Zhang, Nadine Müther, Christina Rauschhuber, Helen G Franck, Elizabeth P Merricks, Timothy C Nichols, Mark A Kay, Anja Ehrhardt
Journal: Molecular Therapy (2010)

Sleeping Beauty (SB) transposase enables somatic integration of exogenous DNA in mammalian cells, but potency as a gene transfer vector especially in large mammals has been lacking. Herein, we show that hyperactive transposase system delivered by high-capacity adenoviral vectors (HC-AdVs) can result in somatic integration of a canine factor IX (cFIX) expression-cassette in canine liver, facilitating stabilized transgene expression and persistent haemostatic correction of canine hemophilia B with negligible toxicity. We observed stabilized cFIX expression levels during rapid cell cycling in mice and phenotypic correction of the bleeding diathesis in hemophilia B dogs for up to 960 days. In contrast, systemic administration of an inactive transposase system resulted in rapid loss of transgene expression and transient phenotypic correction. Notably, in dogs a higher viral dose of the active SB transposase system resulted into transient phenotypic correction accompanied by transient increase of liver enzymes. Molecular analysis of liver samples revealed SB-mediated integration and provide evidence that transgene expression was derived mainly from integrated vector forms. Demonstrating that a viral vector system can deliver clinically relevant levels of a therapeutic protein in a large animal model of human disease paves a new path toward the possible cure of genetic diseases. Sleeping Beauty (SB) transposase enables somatic integration of exogenous DNA in mammalian cells, but potency as a gene transfer vector especially in large mammals has been lacking. Herein, we show that hyperactive transposase system delivered by high-capacity adenoviral vectors (HC-AdVs) can result in somatic integration of a canine factor IX (cFIX) expression-cassette in canine liver, facilitating stabilized transgene expression and persistent haemostatic correction of canine hemophilia B with negligible toxicity. We observed stabilized cFIX expression levels during rapid cell cycling in mice and phenotypic correction of the bleeding diathesis in hemophilia B dogs for up to 960 days. In contrast, systemic administration of an inactive transposase system resulted in rapid loss of transgene expression and transient phenotypic correction. Notably, in dogs a higher viral dose of the active SB transposase system resulted into transient phenotypic correction accompanied by transient increase of liver enzymes. Molecular analysis of liver samples revealed SB-mediated integration and provide evidence that transgene expression was derived mainly from integrated vector forms. Demonstrating that a viral vector system can deliver clinically relevant levels of a therapeutic protein in a large animal model of human disease paves a new path toward the possible cure of genetic diseases.
Prognostic staging of acute pulmonary embolism: are we closer to the holy grail?
Authors: Adam Torbicki
Journal: European Respiratory Journal (2014)

Management strategy and its influence on the outcomes for patients with acute pulmonary embolism (PE) has been an area of chronic debate and unresolved controversies. During the last decade at least 50 publications have provided important evidence on prognostic markers, with the hope of improving risk stratification and, consequently, treatment decisions for PE. Such markers ranged from simple clinical signs to variables, which require sophisticated laboratory tests and modern cardiovascular imaging. Paradoxically, messages most relevant to a practicing clinician confronting a patient with acute PE, so far, seem to emerge from clinical evaluation. Signs of shock or significant hypotension became universally accepted markers of high risk PE, justifying emergency thrombolysis [1]. More recently, several clinical scores have been reliably validated to identify patients at a very low risk of adverse outcomes, despite confirmed PE [2–4]. If adequately anticoagulated, such patients may be offered an option of early discharge and ambulatory therapy [5].

The trial by Bova et al . [6] attempts to solve a remaining important clinical problem , i.e. that of identifying patients with acute PE who are at a particularly high risk of adverse outcome, despite normal systemic arterial pressure. Previous similar attempts have not been successful, mostly because of a low positive prognostic value of individual laboratory-risk markers for early PE-related mortality, in this particular patient subgroup.

Nevertheless, in initially hemodynamically stable patients, deaths do occur either because of early recurrence of PE or the decompensation of the right ventricle that has been submitted to excessive and prolonged overload. Progressive dilatation of right heart chambers, functional tricuspid regurgitation, increasing wall strain and oxygen myocardial, in a setting of diminished functional right ventricular coronary perfusion and hypoxaemia, may initiate and feed a rapid vicious circle, which leads …
Complement Activation by Cremophor EL as a Possible Contributor to Hypersensitivity to Paclitaxel: an In Vitro Study
Authors: Janos Szebeni, Carl R. Alving, Franco M. Muggia
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: Cancer patients treated with the anticancer drug, paclitaxel (Taxol) often experience mild to severe hypersensitivity reactions. It is not known how these reactions are induced and whether the inducer is paclitaxel or its vehicle (i.e., Cremophor EL in 50% ethanol). Molecules present in Cremophor EL are similar in structure to certain nonionic block copolymers that activate complement proteins (i.e., proteins involved in various immune processes). To explore the role of complement in the observed hypersensitivity reactions, we studied the effects of paclitaxel and Cremophor EL plus ethanol on human complement in vitro. Methods: Serum specimens from healthy individuals and cancer patients were incubated with paclitaxel or with relevant control compounds (Cremophor EL with ethanol, ethanol only, docetaxel, and cyclosporine), and markers of complement activation (SC5b-9 and Bb) were measured by enzyme-linked immunosorbent assay. Similar incubations were performed in the presence of inhibitors of complement activation (i.e., EGTA/Mg2+ and soluble complement receptor type 1 [sCR1]). Results: Paclitaxel in Cremophor EL plus ethanol caused increased formation of SC5b-9 in serum specimens from 10 of 10 healthy control subjects and from five of 10 cancer patients. Experiments with one or more individual sera indicated the above effect was due to Cremophor EL plus ethanol, that increased formation of Bb also occurred, that the drug-induced rise in SC5b-9 was inhibited by sCR1, and that EGTA/Mg2+ partially inhibited SC5b-9 formation and stimulated Bb formation. Implication: The role of complement activation in hypersensitivity reactions associated with administration of paclitaxel in Cremophor EL plus ethanol should be studied in vivo.
Endoplasmic reticulum stress and hypertension — a new paradigm?
Authors: Alyssa H. Hasty, David G. Harrison
Journal: Journal of Clinical Investigation (2012)

Hypertension occurs in approximately 30% of individuals in Western populations and is known to be a major cause of stroke, heart failure, and myocardial infarction. Despite this, the molecular etiology of hypertension remains poorly understood. In this issue of the JCI, Young et al. show that endoplasmic reticulum (ER) stress is an essential signaling event for angiotensin II–induced hypertension in cells of the central nervous system. This provides new insight into the molecular mechanisms that drive hypertension and suggests a potential target for future therapy.
Effect of point-of-care CD4 cell count tests on retention of patients and rates of antiretroviral therapy initiation in primary health clinics: an observational cohort study
Authors: Ilesh V Jani, Nádia E Sitoe, Eunice R Alfai, Patrina L Chongo, Jorge I Quevedo, Beatriz M Rocha, Jonathan D Lehe, Trevor F Peter
Journal: The Lancet (2011)
Tumor Suppressive MicroRNAs miR-34a/c Control Cancer Cell Expression of ULBP2, a Stress-Induced Ligand of the Natural Killer Cell Receptor NKG2D
Authors: Anja Heinemann, Fang Zhao, Sonali Pechlivanis, Jürgen Eberle, Alexander Steinle, Sven Diederichs, Dirk Schadendorf, Annette Paschen
Journal: Cancer Research (2011)

Malignant cells express ligands for the natural killer cell immunoreceptor NKG2D, which sensitizes to early recognition and elimination by cytotoxic lymphocytes and provides an innate barrier against tumor development. However, the mechanisms that control NKG2D ligand (NKG2DL) expression in tumor cells remain unknown. We recently identified the NKG2DL ULBP2 as strong prognostic marker in human malignant melanoma. Here, we provide evidence that the tumor-suppressive microRNAs (miRNA) miR-34a and miR-34c control ULBP2 expression. Reporter gene analyses revealed that both miRNAs directly targeted the 3'-untranslated region of ULBP2 mRNA and that levels of miR-34a inversely correlated with expression of ULBP2 surface molecules. Accordingly, treatment of cancer cells with miRNA inhibitors led to upregulation of ULBP2, whereas miR-34 mimics led to downregulation of ULBP2, diminishing tumor cell recognition by NK cells. Treatment with the small molecule inhibitor Nutlin-3a also decreased ULBP2 levels in a p53-dependent manner, which was due to a p53-mediated increase in cellular miR-34 levels. Taken together, our study shows that tumor-suppressive miR-34a and miR-34c act as ULBP2 repressors. These findings also implicate p53 in ULBP2 regulation, emphasizing the role of the specific NKG2DL in tumor immune surveillance.
Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study
Authors: M. Moehler, A. Mueller, T. Trarbach, F. Lordick, T. Seufferlein, S. Kubicka, M. Geißler, S. Schwarz, P.R. Galle, S. Kanzler
Journal: Annals of Oncology (2010)
Novel mechanism for the generation of human xeno-autoantibodies against the nonhuman sialic acid <i>N</i>-glycolylneuraminic acid
Authors: Rachel E. Taylor, Christopher J. Gregg, Vered Padler-Karavani, Darius Ghaderi, Hai Yu, Shengshu Huang, Ricardo U. Sorensen, Xi Chen, Jaime Inostroza, Victor Nizet, Ajit Varki
Journal: The Journal of Experimental Medicine (2010)

The nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc) is metabolically incorporated into human tissues from certain mammalian-derived foods, and this occurs in the face of an anti-Neu5Gc “xeno-autoantibody” response. Given evidence that this process contributes to chronic inflammation in some diseases, it is important to understand when and how these antibodies are generated in humans. We show here that human anti-Neu5Gc antibodies appear during infancy and correlate with weaning and exposure to dietary Neu5Gc. However, dietary Neu5Gc alone cannot elicit anti-Neu5Gc antibodies in mice with a humanlike Neu5Gc deficiency. Other postnatally appearing anti-carbohydrate antibodies are likely induced by bacteria expressing these epitopes; however, no microbe is known to synthesize Neu5Gc. Here, we show that trace exogenous Neu5Gc can be incorporated into cell surface lipooligosaccharides (LOS) of nontypeable Haemophilus influenzae (NTHi), a human-specific commensal/pathogen. Indeed, infant anti-Neu5Gc antibodies appear coincident with antibodies against NTHi. Furthermore, NTHi that express Neu5Gc-containing LOS induce anti-Neu5Gc antibodies in Neu5Gc-deficient mice, without added adjuvant. Finally, Neu5Gc from baby food is taken up and expressed by NTHi. As the flora residing in the nasopharynx of infants can be in contact with ingested food, we propose a novel model for how NTHi and dietary Neu5Gc cooperate to generate anti-Neu5Gc antibodies in humans.
Possible cancer hazard associated with 5-methoxypsoralen in suntan preparation.
Authors: P Forlot
Journal: BMJ (1980)

discussing the problems of working with the elderly, and the usefulness of bringing in aspects of normal life and using appropriate activities as a means of counteracting the apathy of institutional life.We hope and believe that this form of specific intervention by social workers has made a difference in some small way to the quality of life of the elderly people we worked with, and that there is much more urgent work to be done in this field.
<i>HRPT2,</i>a Marker of Parathyroid Cancer
Authors: Lee S. Weinstein, William F. Simonds
Journal: New England Journal of Medicine (2003)

Primary hyperparathyroidism is a state of excess secretion of parathyroid hormone and hypercalcemia, often with skeletal and renal complications. The disease usually results from a single parathyroid adenoma. Less commonly, tumors occur in multiple parathyroid glands, and in these cases the disease may be familial. Familial primary hyperparathyroidism may occur in several genetically distinct disorders, including multiple endocrine neoplasia types 1 and 2A, the hyperparathyroidism–jaw tumor (HPT-JT) syndrome, and familial hypocalciuric hypercalcemia, or it can present as a solitary abnormality (as in familial isolated hyperparathyroidism).(See Glossary.)Primary hyperparathyroidism occurs in virtually all patients with multiple endocrine neoplasia type 1, . . .
Myoglobin tames tumor growth and spread
Authors: Ulrich Flögel, Chi V. Dang
Journal: Journal of Clinical Investigation (2009)

Tumor growth is accompanied by tissue hypoxia, but does this reduced oxygen availability promote further tumor expansion, resulting in a vicious cycle? In this issue of the JCI, Galluzzo et al. report that increasing oxygen tension in tumor cells by ectopically expressing the oxygen-binding hemoprotein myoglobin indeed affects tumorigenesis (see the related article beginning on page 865). Tumors derived from cells transfected with myoglobin grew more slowly, were less hypoxic, and were less metastatic. These results will spur further mechanistic inquiry into the role of hypoxia in tumor expansion.
Respiratory Function Among Preterm Infants Whose Mothers Smoked During Pregnancy
Authors: AH-FONG HOO, MATTHIAS HENSCHEN, CAROL DEZATEUX, KATE COSTELOE, JANET STOCKS
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

We examined whether the adverse effects of prenatal exposure to tobacco on lung development are limited to the last weeks of gestation by comparing respiratory function in preterm infants whose mothers had and had not smoked during pregnancy. Maximal forced expiratory flow (Vmax FRC) and time to peak tidal expiratory flow as a proportion of total expiratory time (TPTEF:TE) were measured prior to discharge from hospital in 108 preterm infants (mean [SD] gestational age, 33.5 [1.8] wk), 40 of whose mothers had smoked during pregnancy. Infant urinary cotinine was less than 4 ng/ml in those born to nonsmokers, but it was as high as 458 ng/ml in exposed infants (p < 0.0001). TPTEF:TE was significantly lower in infants exposed to tobacco in utero (mean [SD], 0.369 [0.109]) when compared with those who were not (0.426 [0.135]) (p <= 0.02). Vmax FRC was also reduced in exposed infants (mean [SD], 85.2 [41.7] ml/s versus 103.8 [49.7] ml/s) (p = 0.07). After allowing for sex, ethnic group, body size, postnatal age, and socioeconomic status, TPTEF:TE remained significantly diminished in infants exposed prenatally to tobacco (p < 0.05). Thus, impaired respiratory function is evident in infants born on average 7 wk prior to the expected delivery date, suggesting that the adverse effects of prenatal exposure to tobacco are not limited to the last weeks of pregnancy.
A study of the anti-inflammatory and analgesic action of ibuprofen in sports injuries
Authors: G. Albiol
Journal: British Journal of Sports Medicine (1980)

ORA VA opened the discussion and stated that Staff appeared to be the first to publish a description of the ilio-tibial band syndrome clearly.Other work on this condition found in runners has been published recently; Orava (1978) used conservative methods only, but Noble (1979) found operative treatment necessary in 3% of his cases.P. STAFF used indirect stretching by deep friction in a transverse direction, as the ilio-tibial band cannot be stretched longitudinally.Stretching is an important part of treating overuse injuries to prevent scar contraction.P. RENSTROM mentioned ruptures of the soleus muscle, seen mainly in sprinters, with haematomata tracking to the anterior aspect of the leg, unlike the gastrocnemius tears, noted by Corrigan.B. CORRIGAN suggested that bleeding on the anterior aspect of the leg was likely to be from a rupture of the capsule of the knee joint, but agreed that it is difficult to differentiate between these conditions.J. G. P. WILLIAMS regarded the inertia of body weight as a significant force of resistance in the unfit subject, and could also account for steeplechase injuries attributed to awkward landings.
Protective immunity elicited by recombinant bacille Calmette-Guerin (BCG) expressing outer surface protein A (OspA) lipoprotein: a candidate Lyme disease vaccine.
Authors: C K Stover, G P Bansal, M S Hanson, J E Burlein, S R Palaszynski, J F Young, S Koenig, D B Young, A Sadziene, A G Barbour
Journal: The Journal of Experimental Medicine (1993)

The current vaccine against tuberculosis, Mycobacterium bovis strain bacille Calmette-Guerin (BCG), offers potential advantages as a live, innately immunogenic vaccine vehicle for the expression and delivery of protective recombinant antigens (Stover, C.K., V.F. de la Cruz, T.R. Fuerst, J.E. Burlein, L.A. Benson, L.T. Bennett, G.P. Bansal, J.F. Young, M.H. Lee, G.F. Hatfull et al. 1991. Nature [Lond]. 351:456; Jacobs, W.R., Jr., S.B. Snapper, L. Lugosi and B.R. Bloom. 1990. Curr. Top. Microbiol. Immunol. 155:153; Jacobs, W.R., M. Tuckman, and B.R. Bloom. 1987. Nature [Lond.]. 327:532); but as an attenuated intracellular bacterium residing in macrophages, BCG would seem to be best suited for eliciting cellular responses and not humoral responses. Since bacterial lipoproteins are often among the most immunogenic of bacterial antigens, we tested whether BCG expression of a target antigen as a membrane-associated lipoprotein could enhance the potential for a recombinant BCG vaccine to elicit high-titered protective antibody responses to target antigens. Immunization of mice with recombinant BCG vaccines expressing the outer surface protein A (OspA) antigen of Borrelia burgdorferi as a membrane-associated lipoprotein resulted in protective antibody responses that were 100-1,000-fold higher than responses elicited by immunization with recombinant BCG expressing OspA cytoplasmically or as a secreted fusion protein. Furthermore, these improved antibody responses were observed in heterogeneous mouse strains that vary in their immune responsiveness to OspA and sensitivity to BCG growth. Thus, expression of protective antigens as chimeric membrane-associated lipoproteins on recombinant BCG may result in the generation of new candidate vaccines against Lyme borreliosis and other human or veterinary diseases where humoral immunity is the protective response.
FLT3 Ligand Enhances the Cancer Therapeutic Potency of Naked RNA Vaccines
Authors: Sebastian Kreiter, Mustafa Diken, Abderraouf Selmi, Jan Diekmann, Sebastian Attig, Yves Hüsemann, Michael Koslowski, Christoph Huber, Özlem Türeci, Ugur Sahin
Journal: Cancer Research (2011)

Abstract Intranodal immunization with antigen-encoding naked RNA may offer a simple and safe approach to induce antitumor immunity. RNA taken up by nodal dendritic cells (DC) coactivates toll-like receptor (TLR) signaling that will prime and expand antigen-specific T cells. In this study, we show that RNA vaccination can be optimized by coadministration of the DC-activating Fms-like tyrosine kinase 3 (FLT3) ligand as an effective adjuvant. Systemic administration of FLT3 ligand prior to immunization enhanced priming and expansion of antigen-specific CD8+ T cells in lymphoid organs, T-cell homing into melanoma tumors, and therapeutic activity of the intranodal RNA. Unexpectedly, plasmacytoid DCs (pDC) were found to be essential for the adjuvant effect of FLT3 ligand and they were systemically expanded together with conventional DCs after treatment. In response to FLT3 ligand, pDCs maintained an immature phenotype, internalized RNA, and presented the RNA-encoded antigen for efficient induction of antigen-specific CD8+ T-cell responses. Coadministration of FLT3 ligand with RNA vaccination achieved remarkable cure rates and survival of mice with advanced melanoma. Our findings show how to improve the simple and safe strategy offered by RNA vaccines for cancer immunotherapy. Cancer Res; 71(19); 6132–42. ©2011 AACR.
Obesity, Arterial Stiffness, and Cardiovascular Risk
Authors: Michel E. Safar, Se[Combining Acute Accent]bastien Czernichow, Jacques Blacher
Journal: Journal of the American Society of Nephrology (2006)

Long-term follow-up studies have indicated that obesity is an independent predictor of cardiovascular risk in both genders. Increased arterial stiffness, as reflected by an increased pulse wave velocity, is significantly and independently associated with higher risk for cardiovascular morbidity and mortality. In recent years, it has been demonstrated that individuals with obesity are likely to have an increase in aortic stiffness, independent of BP level, ethnicity, and age. The pathophysiologic mechanisms that link abdominal adiposity to stiffening are not fully understood. This report focuses on the role of arterial stiffness in individuals with obesity and on the association between this hemodynamic feature and cardiovascular risk.
Impacts of peroxisome proliferator-activated receptor-γ activation on cigarette smoke-induced exacerbated response to bacteria
Authors: Mathieu C. Morissette, Pamela Shen, Danya Thayaparan, Martin R. Stämpfli
Journal: European Respiratory Journal (2014)

Chronic obstructive pulmonary disease (COPD) is characterised by a state of chronic pulmonary inflammation punctuated by microbial exacerbations. Despite advances in treatment options, COPD remains difficult to manage. In this study, we investigated the potential of peroxisome proliferator-activated receptor (PPAR)γ activation as a new therapy against cigarette smoke-induced inflammation and its associated bacterial exacerbation. C57BL/6 mice were exposed to room air or cigarette smoke for either 4 days or 4 weeks and treated either prophylactically or therapeutically with rosiglitazone. The impact of rosiglitazone on cigarette smoke-induced exacerbated response to the bacterial pathogen nontypeable Haemophilus influenzae (NTHi) was studied using the therapeutic treatment protocol. We found that rosiglitazone was able to reduce cigarette smoke-induced neutrophilia both when administered prophylactically or therapeutically. Therapeutic intervention with rosiglitazone was also effective in preventing cigarette smoke-induced neutrophilia exacerbation following NTHi infection. Moreover, the anti-inflammatory effects of rosiglitazone did not lead to an increase in the pulmonary bacterial burden, unlike dexamethasone. Altogether, our data suggest that pharmacological activation of PPARγ may be an effective therapeutic approach to improve COPD management, as it is able to reduce cigarette smoke-induced inflammation and decrease the magnitude of bacterial exacerbations, without compromising the ability of the immune system to control the infection.