tbuckley/cabot-search huggingface dataset:
Efficient Regulation of VEGF Expression by Promoter-Targeted Lentiviral shRNAs Based on Epigenetic Mechanism
Authors: Mikko P. Turunen, Tiia Lehtola, Suvi E. Heinonen, Genet S. Assefa, Petra Korpisalo, Roseanne Girnary, Christopher K. Glass, Sami Väisänen, Seppo Ylä-Herttuala
Journal: Circulation Research (2009)

We studied a possibility that shRNAs can lead to transcriptional gene activation at the promoter level via epigenetic mechanism.The purpose of this study was to test the effects on vascular endothelial growth factor (VEGF-A) expression by promoter targeted small hairpin RNAs (shRNAs) in vitro and in experimental animals in vivo using stable local lentiviral gene transfer.One shRNA was identified which strongly increased VEGF-A expression in C166 endothelial cells at mRNA and protein level whereas another shRNA decreased VEGF-A expression. Quantitative chromatin immunoprecipitation analysis revealed that the repressing shRNA caused epigenetic changes, which increased nucleosome density within the promoter and transcription start site and led to repression of VEGF-A expression. Epigenetic changes caused by the activating shRNA were opposite to those caused by the repressing shRNA. These results were confirmed in vivo in an ischemic mouse hindlimb model after local gene transfer where VEGF-A upregulation achieved by promoter-targeted shRNA increased vascularity and blood flow.We show that lentivirus-mediated delivery of shRNA molecules targeted to specific regions in the mVEGF-A promoter either induce or repress VEGF-A expression via epigenetic modulation. Thus, we describe a new approach of gene therapy, epigenetherapy, based on an epigenetic mechanism at the promoter level. Controlling transcription through manipulation of specific epigenetic marks provides a novel approach for the treatment of several diseases.
Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis
Authors: M V Machado, G A Michelotti, T de Almeida Pereira, J Boursier, L Kruger, M Swiderska-Syn, G Karaca, G Xie, C D Guy, B Bohinc, K R Lindblom, E Johnson, S Kornbluth, A M Diehl
Journal: Gut (2014)

<h3>Objective</h3> Caspase-2 is an initiator caspase involved in multiple apoptotic pathways, particularly in response to specific intracellular stressors (eg, DNA damage, ER stress). We recently reported that caspase-2 was pivotal for the induction of cell death triggered by excessive intracellular accumulation of long-chain fatty acids, a response known as lipoapoptosis. The liver is particularly susceptible to lipid-induced damage, explaining the pandemic status of non-alcoholic fatty liver disease (NAFLD). Progression from NAFLD to non-alcoholic steatohepatitis (NASH) results, in part, from hepatocyte apoptosis and consequential paracrine-mediated fibrogenesis. We evaluated the hypothesis that caspase-2 promotes NASH-related cirrhosis. <h3>Design</h3> Caspase-2 was localised in liver biopsies from patients with NASH. Its expression was evaluated in different mouse models of NASH, and outcomes of diet-induced NASH were compared in wild-type (WT) and caspase-2-deficient mice. Lipotoxicity was modelled <i>in vitro</i> using hepatocytes derived from WT and caspase-2-deficient mice. <h3>Results</h3> We showed that caspase-2 is integral to the pathogenesis of NASH-related cirrhosis. Caspase-2 is localised in injured hepatocytes and its expression was markedly upregulated in patients and animal models of NASH. During lipotoxic stress, caspase-2 deficiency reduced apoptosis, inhibited induction of profibrogenic hedgehog target genes in mice and blocked production of hedgehog ligands in cultured hepatocytes. <h3>Conclusions</h3> These data point to a critical role for caspase-2 in lipid-induced hepatocyte apoptosis <i>in vivo</i> for the production of apoptosis-associated fibrogenic factors and in the progression of lipid-induced liver fibrosis. This raises the intriguing possibility that caspase-2 may be a promising therapeutic target to prevent progression to NASH.
Exercise and Respiratory Training Improve Exercise Capacity and Quality of Life in Patients With Severe Chronic Pulmonary Hypertension
Authors: Derliz Mereles, Nicola Ehlken, Sandra Kreuscher, Stefanie Ghofrani, Marius M. Hoeper, Michael Halank, F. Joachim Meyer, Gabriele Karger, Jan Buss, Jana Juenger, Nicole Holzapfel, Christian Opitz, Jörg Winkler, Felix F.J. Herth, Heinrike Wilkens, Hugo A. Katus, Horst Olschewski, Ekkehard Grünig
Journal: Circulation (2006)

Background— Pulmonary hypertension (PH) is associated with restricted physical capacity, limited quality of life, and a poor prognosis because of right heart failure. The present study is the first prospective randomized study to evaluate the effects of exercise and respiratory training in patients with severe symptomatic PH. Methods and Results— Thirty patients with PH (21 women; mean age, 50±13 years; mean pulmonary artery pressure, 50±15 mm Hg; mean World Health Organization [WHO] class, 2.9±0.5; pulmonary arterial hypertension, n=23; chronic thromboembolic PH, n=7) on stable disease-targeted medication were randomly assigned to a control (n=15) and a primary training (n=15) group. Medication remained unchanged during the study period. Primary end points were the changes from baseline to week 15 in the distance walked in 6 minutes and in scores of the Short Form Health Survey quality-of-life questionnaire. Changes in WHO functional class, Borg scale, and parameters of echocardiography and gas exchange also were assessed. At week 15, patients in the primary and secondary training groups had an improved 6-minute walking distance; the mean difference between the control and the primary training group was 111 m (95% confidence interval, 65 to 139 m; P &lt;0.001). Exercise training was well tolerated and improved scores of quality of life, WHO functional class, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achieved workload. Systolic pulmonary artery pressure values at rest did not change significantly after 15 weeks of exercise and respiratory training (from 61±18 to 54±18 mm Hg) within the training group. Conclusions— This study indicates that respiratory and physical training could be a promising adjunct to medical treatment in severe PH. The effects add to the beneficial results of modern medical treatment.
Effect of Priming with Granulocyte Colony-Stimulating Factor on the Outcome of Chemotherapy for Acute Myeloid Leukemia
Authors: Bob Löwenberg, Wim van Putten, Matthias Theobald, Jurg Gmür, Leo Verdonck, Pieter Sonneveld, Martin Fey, Harry Schouten, Georgine de Greef, Augustin Ferrant, Tibor Kovacsovics, Alois Gratwohl, Simon Daenen, Peter Huijgens, Marc Boogaerts
Journal: New England Journal of Medicine (2003)

Sensitization of leukemic cells with hematopoietic growth factors may enhance the cytotoxicity of chemotherapy in acute myeloid leukemia (AML).In a multicenter randomized trial, we assigned patients (age range, 18 to 60 years) with newly diagnosed AML to receive cytarabine plus idarubicin (cycle 1) and cytarabine plus amsacrin (cycle 2) with granulocyte colony-stimulating factor (G-CSF) (321 patients) or without G-CSF (319). G-CSF was given concurrently with chemotherapy only. Idarubicin and amsacrin were given at the end of a cycle to allow the cell-cycle-dependent cytotoxicity of cytarabine in the context of G-CSF to have a greater effect. The effect of G-CSF on disease-free survival was assessed in all patients and in cytogenetically distinct prognostic subgroups.After induction chemotherapy, the rates of response were not significantly different in the two groups. After a median follow-up of 55 months, patients in complete remission after induction chemotherapy plus G-CSF had a higher rate of disease-free survival than patients who did not receive G-CSF (42 percent vs. 33 percent at four years, P=0.02), owing to a reduced probability of relapse (relative risk, 0.77; 95 percent confidence interval, 0.61 to 0.99; P=0.04). G-CSF did not significantly improve overall survival (P=0.16). Although G-CSF did not improve the outcome in the subgroup with an unfavorable prognosis, the 72 percent of patients with standard-risk AML benefited from G-CSF therapy (overall survival at four years, 45 percent, as compared with 35 percent in the group that did not receive G-CSF [relative risk of death, 0.75; 95 percent confidence interval, 0.59 to 0.95; P=0.02]; disease-free survival, 45 percent vs. 33 percent [relative risk, 0.70]; 95 percent confidence interval, 0.55 to 0.90; P=0.006).Sensitization of leukemic cells with growth factors is a clinically applicable means of enhancing the efficacy of chemotherapy in patients with AML.
Genetic alteration and gene expression modulation during cancer progression.
Authors: Cathie Garnis, Timon PH Buys, Wan L Lam
Journal: Molecular Cancer (2004)

Cancer progresses through a series of histopathological stages. Progression is thought to be driven by the accumulation of genetic alterations and consequently gene expression pattern changes. The identification of genes and pathways involved will not only enhance our understanding of the biology of this process, it will also provide new targets for early diagnosis and facilitate treatment design. Genomic approaches have proven to be effective in detecting chromosomal alterations and identifying genes disrupted in cancer. Gene expression profiling has led to the subclassification of tumors. In this article, we will describe the current technologies used in cancer gene discovery, the model systems used to validate the significance of the genes and pathways, and some of the genes and pathways implicated in the progression of preneoplastic and early stage cancer.
ACQUIRED IMMUNODEFICIENCY SYNDROME AFTER TRAVELLING IN AFRICA: AN EPIDEMIOLOGICAL STUDY IN SEVENTEEN CAUCASIAN PATIENTS
Authors: D. Vittecoq, R.T. Roue, C. Mayaud, F. Borsa, M. Armengaud, B. Autran, T. May, M. Stern, P. Chavanet, P. Jeantils, J. Modai, F. Rey, J.C. Chermann
Journal: The Lancet (1987)
Charting the Host Adaptation of Influenza Viruses
Authors: M. dos Reis, A. U. Tamuri, A. J. Hay, R. A. Goldstein
Journal: Molecular Biology and Evolution (2010)

Four influenza pandemics have struck the human population during the last 100 years causing substantial morbidity and mortality. The pandemics were caused by the introduction of a new virus into the human population from an avian or swine host or through the mixing of virus segments from an animal host with a human virus to create a new reassortant subtype virus. Understanding which changes have contributed to the adaptation of the virus to the human host is essential in assessing the pandemic potential of current and future animal viruses. Here, we develop a measure of the level of adaptation of a given virus strain to a particular host. We show that adaptation to the human host has been gradual with a timescale of decades and that none of the virus proteins have yet achieved full adaptation to the selective constraints. When the measure is applied to historical data, our results indicate that the 1918 influenza virus had undergone a period of preadaptation prior to the 1918 pandemic. Yet, ancestral reconstruction of the avian virus that founded the classical swine and 1918 human influenza lineages shows no evidence that this virus was exceptionally preadapted to humans. These results indicate that adaptation to humans occurred following the initial host shift from birds to mammals, including a significant amount prior to 1918. The 2009 pandemic virus seems to have undergone preadaptation to human-like selective constraints during its period of circulation in swine. Ancestral reconstruction along the human virus tree indicates that mutations that have increased the adaptation of the virus have occurred preferentially along the trunk of the tree. The method should be helpful in assessing the potential of current viruses to found future epidemics or pandemics.
Infusion of cytomegalovirus (CMV)–specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy
Authors: Hermann Einsele, Eddy Roosnek, Nathalie Rufer, Christian Sinzger, Susanne Riegler, Jürgen Löffler, Ulrich Grigoleit, Arnaud Moris, Hans-Georg Rammensee, Lothar Kanz, Annette Kleihauer, Friederike Frank, Gerhard Jahn, Holger Hebart
Journal: Blood (2002)
Action to Stop Smoking in Suspected Tuberculosis (ASSIST) in Pakistan
Authors: Kamran Siddiqi, Amir Khan, Maqsood Ahmad, Omara Dogar, Mona Kanaan, James N. Newell, Heather Thomson
Journal: Annals of Internal Medicine (2013)

Background: Tobacco use is responsible for a large proportion of the total disease burden from tuberculosis. Pakistan is one of the 10 high-burden countries for both tuberculosis and tobacco use. Objective: To assess the effectiveness of a behavioral support intervention and bupropion in achieving 6-month continuous abstinence in adult smokers with suspected pulmonary tuberculosis. Design: Cluster randomized, controlled trial. (Current Controlled Trials: ISRCTN08829879) Setting: Health centers in the Jhang and Sargodha districts in Pakistan. Patients: 1955 adult smokers with suspected tuberculosis. Intervention: Health centers were randomly assigned to provide 2 brief behavioral support sessions (BSS), BSS plus 7 weeks of bupropion therapy (BSS+), or usual care. Measurements: The primary end point was continuous abstinence at 6 months after the quit date and was determined by carbon monoxide levels in patients. Secondary end points were point abstinence at 1 and 6 months. Results: Both treatments led to statistically significant relative risks (RRs) for abstinence compared with usual care (RR for BSS+, 8.2 [95% CI, 3.7 to 18.2]; RR for BSS, 7.4 [CI, 3.4 to 16.4]). Equivalence between the treatments could not be established. In the BSS+ group, 275 of 606 patients (45.4% [CI, 41.4% to 49.4%]) achieved continuous abstinence compared with 254 of 620 (41.0% [CI, 37.1% to 45.0%]) in the BSS group and 52 of 615 (8.5% [CI, 6.4% to 10.9%]) in the usual care group. There was substantial heterogeneity of program effects across clusters. Limitations: Imbalances in the urban and rural proportions and smoking habits among treatment groups, and inability to confirm adherence to bupropion treatment and validate longer-term abstinence or the effect of smoking cessation on tuberculosis outcomes. Conclusion: Behavioral support alone or in combination with bupropion is effective in promoting cessation in smokers with suspected tuberculosis. Primary Funding Source: International Development Research Centre.
TUBERCULOSIS AND VINEGAR.
Authors: JOHN ASHBURTON CUTTER
Journal: JAMA (1898)

The enormous amount of work done in bacteriologic lines as to tuberculin has been of such little avail as to treatment and prevention, that I have no hesitation in bringing before the Section in a few words, a record of work that has been done on other lines and to the glory of medicine in that this work has cured the desperately sick and prevented the pre-tubercular becoming tubercular. Dr. John Christian read a Latin inaugural thesis at Jena, October, 1729, in which reference is made to the coagulation of living blood by vinegar which he says dissolves silica and poisons like viper's venom. He laid down the law,<i>"Causa coagulationis sanguinis est acidum."</i> In "The Relation of Alimentation and Disease," Dr. James H. Salisbury recounts his investigations made on 1,028 hogs fed with sour foods in 1858. Salisbury in the preface, page iii, says: "I had been a graduate
Vascular Endothelial Growth Factor Trap Blocks Tumor Growth, Metastasis Formation, and Vascular Leakage in an Orthotopic Murine Renal Cell Cancer Model
Authors: Henk M.W. Verheul, Hans Hammers, Karen van Erp, Yonfeng Wei, Tolib Sanni, Brenda Salumbides, David Z. Qian, George D. Yancopoulos, Roberto Pili
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Angiogenesis inhibitors have shown clinical benefit in patients with advanced renal cell cancer, but further therapeutic improvement is needed. Vascular endothelial growth factor (VEGF) Trap is a newly developed VEGF-blocking agent with stronger affinity and broader activity than the anti-VEGF antibody bevacizumab. In this study, we tested the activity of VEGF Trap in an orthotopic murine model of renal cancer with spontaneous lung metastases. Experimental Design: Murine syngeneic renal cell carcinoma cells (RENCA) transfected with a luciferase-expressing vector were injected into the renal capsule of BALB/c mice. I.p. treatment with VEGF Trap or control protein (10 or 25 mg/kg twice weekly) was started shortly after tumor injection to prevent tumor development (prevention model) or after established tumors were formed to inhibit tumor growth and metastasis formation (intervention model). Results: In the prevention model, VEGF Trap inhibited tumor growth by 87 ± 14% compared with control (P = 0.007) and significantly prolonged survival. In the intervention model, VEGF Trap inhibited tumor growth by 74 ± 9% (P &amp;lt; 0.001) and the formation of lung metastases was inhibited by 98% (P &amp;lt; 0.004). Microvascular density was reduced by 66% due to VEGF Trap treatment (P &amp;lt; 0.001). In addition, VEGF Trap prevented fibrinogen leakage into the tumor microenvironment representative for reduced vascular leaking as shown by immunohistochemical staining. Conclusions: VEGF Trap is a potent inhibitor of RENCA tumor growth and metastasis formation and blocks the biological function of VEGF in vivo. These results support further clinical development of VEGF Trap for renal cell cancer and other cancer types.
STUDIES ON THE PATHOGENESIS OF FEVER
Authors: M. Kenton King, W. Barry Wood
Journal: The Journal of Experimental Medicine (1958)

An endogenous pyrogen, which is indistinguishable from leucocytic pyrogen, has been demonstrated in the blood streams of rabbits with fevers caused by experimental pneumococcal and streptococcal infections. Like the endogenous pyrogen previously detected in the serum of animals with fever produced by the intravenous injection of typhoid vaccine, the newly discovered circulating factor acts directly upon the thermoregulatory centers of the brain. Its origin from polymorphonuclear leucocytes at the site of infection appears to have been established. The possible relationship of this circulating endogenous pyrogen to the pathogenesis of other forms of fever is discussed.
Alterations in the desquamation-related proteolytic cleavage of corneodesmosin and other corneodesmosomal proteins in psoriatic lesional epidermis
Authors: M. Simon, R. Tazi-Ahnini, N. Jonca, C. Caubet, M.J. Cork, G. Serre
Journal: British Journal of Dermatology (2008)

Desquamation occurs after proteolysis of corneodesmosomal proteins, including corneodesmosin (CDSN), by proteases of the kallikrein family, particularly KLK7. Impaired desquamation is one of the features of psoriasis, and psoriasis-associated single nucleotide polymorphisms of the CDSN gene may potentially modify the proteolysis of the encoded protein.To test whether the proteolysis of CDSN and other corneodesmosomal components is altered in psoriatic epidermis.Total protein extracts obtained by tape-stripping of nonlesional and lesional skin from 11 patients were compared by immunoblotting experiments.An almost intact form of CDSN that has never been observed previously in the normal upper stratum corneum was detected in the lesional skin extracts, showing an altered proteolytic processing of the protein. This form was also observed in the nonlesional skin extracts, but in lower amounts. For most patients, increased amounts of desmoglein 1, plakoglobin and of high molecular weight fragments of desmocollin 1 were detected in the lesional skin. For most of them, similar amounts of KLK7 were immunodetected in both nonlesional and lesional skin extracts. No particular differences were observed related to the psoriasis type, the HLA-Cw6 status of the patients or any particular CDSN polymorphisms.We detected a near full-length form of CDSN that has not been previously observed in normal stratum corneum. The results suggest a reduced degradation of all corneodesmosomal proteins in psoriatic lesions which probably reflects the persistence of corneodesmosomes.
Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin
Authors: S.C. Cavalher-Machado
Journal: European Respiratory Journal (2004)

Hormones play a modulating role in allergic inflammation. An inverse relationship between atopy and diabetes mellitus was reported. The mechanisms regulating this interaction are not completely understood. This study examined whether insulin influences mast cell activation following antigen challenge in rats. The experimental design included alloxan-induced diabetic rats and matching controls. Experiments were performed 30 days after alloxan injection. The animals were sensitised by <i>s.c.</i> injection of ovalbumin (OA) and aluminium hydroxide. OA-induced airway contraction, morphometric analysis of airway mast cells and tissue histamine quantification were evaluated in the isolated main bronchus and intrapulmonary bronchus upon exposure to antigen <i>in vitro</i>. Relative to controls, a reduced contraction to OA was observed in bronchial segments isolated from diabetic rats. This was accompanied by a 50% reduction in the number of degranulated mast cells and in histamine release. A complete recovery of the impaired responses was observed under the influence of insulin. In conclusion, the data suggested that insulin might modulate the controlling of mast cell degranulation; therefore, the early-phase response to antigen provocation, which represents a new insight into a better understanding of the mechanisms, accounted for the decreased risk of asthma among type-1 diabetic patients.
A comparative and developmental approach to cognitive universals: A possible role for heterochrony
Authors: Warren P. Roberts
Journal: Behavioral and Brain Sciences (1998)

From a developmental and comparative perspective, folk biology is a core “meme.” The universality and resistance to change in such core “memes” may be a function of the developmental timing of cognitive domains during childhood. Evidence from cognitive development in humans, monkeys, and apes is discussed. Suggestions for a developmental research program are offered.
THE STIMULATION OF NON-SPECIFIC HOST RESISTANCE TO INFECTION BY CHEMICALLY MODIFIED ENDOTOXIN
Authors: Barnet M. Sultzer, Henry H. Freedman
Journal: The Journal of Experimental Medicine (1962)

An acetylated derivative prepared from Salmonella typhosa O-901 endotoxin has been found to retain the ability to stimulate non-specific host resistance to a variety of bacterial infections. Relative to the parent endotoxin, the derivative has been reduced in the gross in its pyrogenicity to rabbits and lethality to mice. With the use of this chemically modified preparation under a variety of conditions, the direct dissociation of the toxic properties of endotoxin from its protective capacity appears evident. In young male mice, the endotoxin and its derivative produced a leucocytosis but no leucopenia. However, no direct correlation could be found with the level of the peripheral white blood cells and resistance to infection with Escherichia coli. Furthermore, under the conditions employed, passive transfer of early resistance to infection by serum or plasma was not detectable.