tbuckley/cabot-search huggingface dataset:
Expression Profiling in Progressive Stages of Fumarate-Hydratase Deficiency: The Contribution of Metabolic Changes to Tumorigenesis
Authors: Houman Ashrafian, Linda O'Flaherty, Julie Adam, Violetta Steeples, Yuen-Li Chung, Phil East, Sakari Vanharanta, Heli Lehtonen, Emma Nye, Emine Hatipoglu, Melroy Miranda, Kimberley Howarth, Deepa Shukla, Helen Troy, John Griffiths, Bradley Spencer-Dene, Mohammed Yusuf, Emanuela Volpi, Patrick H. Maxwell, Gordon Stamp, Richard Poulsom, Christopher W. Pugh, Barbara Costa, Chiara Bardella, Maria Flavia Di Renzo, Michael I. Kotlikoff, Virpi Launonen, Lauri Aaltonen, Mona El-Bahrawy, Ian Tomlinson, Patrick J. Pollard
Journal: Cancer Research (2010)

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by mutations in the Krebs cycle enzyme fumarate hydratase (FH). It has been proposed that "pseudohypoxic" stabilization of hypoxia-inducible factor-α (HIF-α) by fumarate accumulation contributes to tumorigenesis in HLRCC. We hypothesized that an additional direct consequence of FH deficiency is the establishment of a biosynthetic milieu. To investigate this hypothesis, we isolated primary mouse embryonic fibroblast (MEF) lines from Fh1-deficient mice. As predicted, these MEFs upregulated Hif-1α and HIF target genes directly as a result of FH deficiency. In addition, detailed metabolic assessment of these MEFs confirmed their dependence on glycolysis, and an elevated rate of lactate efflux, associated with the upregulation of glycolytic enzymes known to be associated with tumorigenesis. Correspondingly, Fh1-deficient benign murine renal cysts and an advanced human HLRCC-related renal cell carcinoma manifested a prominent and progressive increase in the expression of HIF-α target genes and in genes known to be relevant to tumorigenesis and metastasis. In accord with our hypothesis, in a variety of different FH-deficient tissues, including a novel murine model of Fh1-deficient smooth muscle, we show a striking and progressive upregulation of a tumorigenic metabolic profile, as manifested by increased PKM2 and LDHA protein. Based on the models assessed herein, we infer that that FH deficiency compels cells to adopt an early, reversible, and progressive protumorigenic metabolic milieu that is reminiscent of that driving the Warburg effect. Targets identified in these novel and diverse FH-deficient models represent excellent potential candidates for further mechanistic investigation and therapeutic metabolic manipulation in tumors.
Possible consequences of elimination diets in asymptomatic immediate hypersensitivity to fish
Authors: C. H. Larramendi, M. Martín Esteban, C. Pascual Marcos, A. Fiandor, J. M. Díaz Pena
Journal: Allergy (1992)

The natural history of IgE antibodies to food without related symptoms is unknown. We have followed the progress of 7 children with various atopic diseases and asymptomatic immediate hypersensitivity to fish, treated with elimination diet in spite of full alimentary tolerance. During the diet period, between 24 and 113 months, all 7 patients presented immediate symptoms upon accidental exposure to or challenge tests with fish (skin symptoms in all 7 cases, digestive in 5, respiratory in 4, and anaphylaxis in 2), which differed from those related to atopic diseases previously present. The levels of fish-specific IgE (prick test, RAST) remained unchanged or were increased. These findings suggest that during elimination diet, and perhaps due to minimal and hidden contact with the allergen, the patients' degree of sensitization may increase, turning an asymptomatic into a symptomatic immediate hypersensitivity.
Zidovudine in Persons with Asymptomatic HIV Infection and CD4+ Cell Counts Greater than 400 per Cubic Millimeter
Authors: David A. Cooper, Jose M. Gatell, Susanne Kroon, Nathan Clumeck, Judith Millard, Frank-D Goebel, Johan N. Bruun, Georg Stingl, Rex L. Melville, Juan Gonzalez-Lahoz, John W. Stevens, A. Paul Fiddian
Journal: New England Journal of Medicine (1993)

Zidovudine therapy is of benefit in the treatment of symptomatic and asymptomatic human immunodeficiency virus (HIV) infection in persons with CD4+ cell counts of less than 500 per cubic millimeter. The efficacy, safety, and duration of benefit of zidovudine in those with 500 or more CD4+ cells per cubic millimeter are uncertain.
Cyclodextrin and Polyethylenimine Functionalized Mesoporous Silica Nanoparticles for Delivery of siRNA Cancer Therapeutics
Authors: Jianliang Shen, Han-Cheon Kim, Hua Su, Feng Wang, Joy Wolfram, Dickson Kirui, Junhua Mai, Chaofeng Mu, Liang-Nian Ji, Zong-Wan Mao, Haifa Shen
Journal: Theranostics (2014)

Effective delivery holds the key to successful in vivo application of therapeutic small interfering RNA (siRNA).In this work, we have developed a universal siRNA carrier consisting of a mesoporous silica nanoparticle (MSNP) functionalized with cyclodextrin-grafted polyethylenimine (CP).CP provides positive charge for loading of siRNA through electrostatic interaction and enables effective endosomal escape of siRNA.Using intravital microscopy we were able to monitor tumor enrichment of CP-MSNP/siRNA particles in live mice bearing orthotopic MDA-MB-231 xenograft tumors.CP-MSNP delivery of siRNA targeting the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2) resulted in effective knockdown of gene expression in vitro and in vivo.Suppression of PKM2 led to inhibition of tumor cell growth, invasion, and migration.
Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma
Authors: Ni Chen, Meiping Ren, Rong Li, Xin Deng, Yongjie Li, Kai Yan, Lamei Xiao, Yan Yang, Liqun Wang, Mao Luo, William P Fay, Jianbo Wu
Journal: Molecular Cancer (2015)

An increased incidence of venous thromboembolism (VTE) is associated with anti-vascular endothelial growth factor (VEGF) treatment in cancer. However, the mechanism underlying this effect remains elusive. In this study, we examined the effect of bevacizumab, a humanized monoclonal antibody against VEGF-A, on VTE in a murine xenograft A549 cell tumor model.Inferior vena cava stenosis model and FeCl3-induced saphenous vein thrombosis model were performed in a mouse xenograft models of human lung adenocarcinoma.We found that treatment with bevacizumab significantly increased the thrombotic response to inferior vena cava obstruction and femoral vein injury. Plasminogen activator inhibitor (PAI-1) expression in tumors, plasma, and thrombi was significantly increased by bevacizumab. However, bevacizumab did not enhance VTE in PAI-1-deficient mice, suggesting that PAI-1 is a major mediator of bevacizumab's prothrombotic effect. VEGF inhibited expression of PAI-1 by A549 cells, and this effect was neutralized by bevacizumab, suggesting that bevacizumab increases PAI-1 expression in vivo by blocking the inhibitory effect of VEGF on PAI-1 expression by tumor cells. Pharmacological inhibition of PAI-1 with PAI-039 blocked bevacizumab-induced venous thrombosis.Collectively, these findings indicate that PAI-1 plays a role in VTE associated with antiangiogenic therapy and the inhibition of PAI-1 shows efficacy as a therapeutic strategy for the prevention of bevacizumab-associated VTE.
Update in Transplantation 2005
Authors: Marc Estenne, Robert M. Kotloff
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

The current status of the field over the past several years was summarized in the 2005 Official Report of the Registry of the International Society for Heart and Lung Transplantation (ISHLT) (1). The overall level of activity reported in 2003 was close to that of 2002, including 931 bilateraland 772 singlelung transplantations, and 74 heart–lung transplantations. The number of bilateral procedures surpassed the number of single procedures by a larger amount in 2003 than in 2002, and the number of heart–lung procedures continued to decrease. The primary indications were chronic obstructive pulmonary disease (COPD)/ 1-antitrypsin deficiency for 61.2% of all single procedures and 32% of all bilateral procedures, idiopathic pulmonary fibrosis (IPF) for 24% of all single procedures, and cystic fibrosis (CF) for 32% of all bilateral procedures. Survival rates at 3 yr have improved from 55.7% for patients undergoing transplantation surgery between 1988 and 1994 to 63.3% for patients undergoing transplantation between 2000 and June 2003.
Infant respiratory symptoms in relation to mite allergen exposure
Authors: RT van Strien, AP Verhoeff, JH van Wijnen, G Doekes, G de Meer, B Brunekreef
Journal: European Respiratory Journal (1996)

The relationship between the Dermatophagoides pteronyssinus (Der p) I content of house dust and the respiratory symptoms reported for young infants was studied. One hundred and four infants, aged 3-15 months, were selected during July-September 1993 through the Dutch postnatal health care service, using a short screening questionnaire to identify mothers with respiratory allergy to house dust and/or pets. Forty-eight were selected from this group of mothers ("high risk" infants) and 56 infants were selected when neither of the parents reported allergy or chronic respiratory symptoms ("low risk" infants). All homes were visited in October 1993. Dust samples were collected from the infant's mattress and from other places in the home, and the Der p I content was measured in dust extracts. The results indicate that on more than half of the mattresses, the Der p I level was over 2,000 ng.g-1, the level suggested to be associated with an increased risk of sensitization. Information on respiratory symptoms ("wheeze" and "prolonged cough") experienced since birth was obtained by questionnaire from one of the parents on the dust sampling day. The occurrence of respiratory symptoms in the infants appeared to be positively related to the Der p I concentration of the dust. Although no objective measurements of respiratory symptoms were available, the results of this study suggest that exposure to mite allergen in early life may lead to respiratory symptoms that are suggestive of airway obstruction in the first year of life.
Public health's Holy Grail
Authors: Kamran Abbasi
Journal: BMJ (2004)

Think again about childhood depressionIn 2003, more than 50 000 children were prescribed antidepressants in the United Kingdom, even though antidepressants have been shown to be largely ineffective, and possibly dangerous, in this age group.On p 1394 Timimi re-examines childhood and adolescent depression, discussing contemporary cultural beliefs and the organisation of family life as well as presenting currently available evidence.Arguing that sociocultural changes and a change in the meaning given to childhood problems have probably caused increasing happiness in young people, she proposes a multiperspective approach with more emphasis on non-medical treatments to deal with children's unhappiness and their families.
High-Dose Isotretinoin Treatment and the Rate of Retrial, Relapse, and Adverse Effects in Patients With Acne Vulgaris
Authors: Rachel C. Blasiak, Christopher R. Stamey, Craig N. Burkhart, Aida Lugo-Somolinos, Dean S. Morrell
Journal: JAMA Dermatology (2013)

<h3>Importance</h3> Isotretinoin is the most effective treatment for acne. The ideal dosing regimen is unknown. <h3>Objective</h3> To determine the rates of relapse of acne vulgaris and retrial of isotretinoin after high cumulative-dose treatment and the changes to the adverse effect profile. <h3>Design, Setting, and Participants</h3> A prospective, observational, intervention study was conducted from August 1, 2008, to August 31, 2010, in a single academic tertiary care center with multiple providers. A total of 180 patients with acne resistant to other treatments were enrolled. Of these, 116 participated in the 12-month follow-up survey, for a response rate of 64.4%. <h3>Exposure</h3> Patients received isotretinoin, with dosing based on the providers’ judgment. Patients were divided into 2 groups on the basis of cumulative dosing (&lt;220 mg/kg and ≥220 mg/kg). <h3>Main Outcomes and Measures</h3> Relapse (treatment with a prescription topical or oral acne medication after a course of isotretinoin) or retrial (retreatment with isotretinoin) at 12-month follow-up and adverse effects experienced during and after 12 months of treatment. <h3>Results</h3> The mean age of the participants was 19.3 years, 51.9% were female, and 74.1% were white. At 12 months’ follow-up, 97.4% of the patients reported that their acne was improved. Overall, acne in 32.7% of patients in the study relapsed at 12 months, and 1.72% of the patients required a retrial. In the lower-dose treatment group (&lt;220 mg/kg), the relapse rate was 47.4% (95% CI, 32.3%-63.0%) compared with 26.9% (95% CI, 18.3%-37.8%) in the high-dose group (<i>P</i> = .03). Almost 100% of the patients in both treatment groups developed cheilitis and xerosis during treatment. Retinoid dermatitis was significantly more common in the high-dose treatment group (53.8% vs 31.6%;<i>P</i> = .02). None of the other adverse effects was significantly different between the 2 groups. <h3>Conclusions and Relevance</h3> The dosing regimen used in the present study is considerably higher than that used in previous studies of isotretinoin. At 1 year after completion of isotretinoin treatment, we found that patients receiving 220 mg/kg or more had a significantly decreased risk of relapse. Rash was the only adverse effect that was significantly more common in the high-dose group during treatment. This study suggests that significantly higher doses of isotretinoin are effective for treating acne and decreasing relapse rates without increasing adverse effects.
Neutrophil Emigration in the Skin, Lungs, and Peritoneum: Different Requirements for CD11/CD18 Revealed by CD18-deficient Mice
Authors: Joseph P. Mizgerd, Hiroshi Kubo, Gregory J. Kutkoski, Sabrina D. Bhagwan, Karin Scharffetter-Kochanek, Arthur L. Beaudet, Claire M. Doerschuk
Journal: The Journal of Experimental Medicine (1997)

To determine the role of CD11/CD18 complexes in neutrophil emigration, inflammation was induced in the skin, lungs, or peritoneum of mutant mice deficient in CD18 (CD18−/− mutants). Peripheral blood of CD18−/− mutants contained 11-fold more neutrophils than did blood of wild-type (WT) mice. During irritant dermatitis induced by topical application of croton oil, the number of emigrated neutrophils in histological sections of dermis was 98% less in CD18−/− mutants than in WT mice. During Streptococcus pneumoniae pneumonia, neutrophil emigration in CD18−/− mutants was not reduced. These data are consistent with expectations based on studies using blocking antibodies to inhibit CD11/CD18 complexes, and on observations of humans lacking CD11/CD18 complexes. The number of emigrated neutrophils in lung sections during Escherichia coli pneumonia, or in peritoneal lavage fluid after 4 h of S. pneumoniae peritonitis, was not reduced in CD18−/− mutants, but rather was greater than the WT values (240 ± 30 and 220 ± 30% WT, respectively). Also, there was no inhibition of neutrophil emigration during sterile peritonitis induced by intraperitoneal injection of thioglycollate (90 ± 20% WT). These data contrast with expectations. Whereas CD11/CD18 complexes are essential to the dermal emigration of neutrophils during acute dermatitis, CD18−/− mutant mice demonstrate surprising alternative pathways for neutrophil emigration during pneumonia or peritonitis.
Phosphodiesterase 4D Regulates Baseline Sarcoplasmic Reticulum Ca <sup>2+</sup> Release and Cardiac Contractility, Independently of L-Type Ca <sup>2+</sup> Current
Authors: Sanja Beca, Peter B. Helli, Jeremy A. Simpson, Dongling Zhao, Gerrie P. Farman, Peter P. Jones, Xixi Tian, Lindsay S. Wilson, Faiyaz Ahmad, S.R. Wayne Chen, Matthew A. Movsesian, Vincent Manganiello, Donald H. Maurice, Marco Conti, Peter H. Backx
Journal: Circulation Research (2011)

Rationale: Baseline contractility of mouse hearts is modulated in a phosphatidylinositol 3-kinase-γ–dependent manner by type 4 phosphodiesterases (PDE4), which regulate cAMP levels within microdomains containing the sarcoplasmic reticulum (SR) calcium ATPase type 2a (SERCA2a). Objective: The goal of this study was to determine whether PDE4D regulates basal cardiac contractility. Methods and Results: At 10 to 12 weeks of age, baseline cardiac contractility in PDE4D-deficient (PDE4D −/− ) mice was elevated mice in vivo and in Langendorff perfused hearts, whereas isolated PDE4D −/− cardiomyocytes showed increased whole-cell Ca 2+ transient amplitudes and SR Ca 2+ content but unchanged L-type calcium current, compared with littermate controls (WT). The protein kinase A inhibitor R p -adenosine-3′,5′ cyclic monophosphorothioate (R p -cAMP) lowered whole-cell Ca 2+ transient amplitudes and SR Ca 2+ content in PDE4D −/− cardiomyocytes to WT levels. The PDE4 inhibitor rolipram had no effect on cardiac contractility, whole-cell Ca 2+ transients, or SR Ca 2+ content in PDE4D −/− preparations but increased these parameters in WT myocardium to levels indistinguishable from those in PDE4D −/− . The functional changes in PDE4D −/− myocardium were associated with increased PLN phosphorylation but not cardiac ryanodine receptor phosphorylation. Rolipram increased PLN phosphorylation in WT cardiomyocytes to levels indistinguishable from those in PDE4D −/− cardiomyocytes. In murine and failing human hearts, PDE4D coimmunoprecipitated with SERCA2a but not with cardiac ryanodine receptor. Conclusions: PDE4D regulates basal cAMP levels in SR microdomains containing SERCA2a-PLN, but not L-type Ca 2+ channels or ryanodine receptor. Because whole-cell Ca 2+ transient amplitudes are reduced in failing human myocardium, these observations may have therapeutic implications for patients with heart failure.
Tools for anti‐inflammatory drug design: <i>In vitro</i> models of leukocyte migration
Authors: Emma K. Frow, Jill Reckless, David J. Grainger
Journal: Medicinal Research Reviews (2004)

Abstract Inhibiting leukocyte recruitment is now a major focus in the design of novel anti‐inflammatory drugs. Following the identification of lead compounds from conventional high‐throughput screens using appropriate receptors or enzymes, it is important to validate the action of the compounds in a suitable in vitro model of leukocyte migration. Here, we review a range of different experimental approaches to modelling leukocyte migration, and identify the multi‐well filter migration assay as the best compromise between the amount of resources required to screen multiple compounds and the amount of information gained about the effects of the compounds on cell movement behavior. However, there are pitfalls in the interpretation of data obtained using the multi‐well filter migration assay, which arise from the imperfect correlation between the number of cells undergoing migration and the inhibitory activity of the test substances. We examine a number of such pitfalls and provide practical approaches to mitigate these problems as far as possible. We recommend a general strategy for screening inhibitors of cell migration using in vitro functional assays. While being more resource intensive than surrogate measures such as calcium flux, functional approaches nevertheless provide superior correlations with anti‐inflammatory activity in vivo . © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 3, 276–298, 2004
Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model
Authors: Yasushi Takagi, Jun Takahashi, Hidemoto Saiki, Asuka Morizane, Takuya Hayashi, Yo Kishi, Hitoshi Fukuda, Yo Okamoto, Masaomi Koyanagi, Makoto Ideguchi, Hideki Hayashi, Takayuki Imazato, Hiroshi Kawasaki, Hirofumi Suemori, Shigeki Omachi, Hidehiko Iida, Nobuyuki Itoh, Norio Nakatsuji, Yoshiki Sasai, Nobuo Hashimoto
Journal: Journal of Clinical Investigation (2005)

Parkinson disease (PD) is a neurodegenerative disorder characterized by loss of midbrain dopaminergic (DA) neurons. ES cells are currently the most promising donor cell source for cell-replacement therapy in PD. We previously described a strong neuralizing activity present on the surface of stromal cells, named stromal cell–derived inducing activity (SDIA). In this study, we generated neurospheres composed of neural progenitors from monkey ES cells, which are capable of producing large numbers of DA neurons. We demonstrated that FGF20, preferentially expressed in the substantia nigra, acts synergistically with FGF2 to increase the number of DA neurons in ES cell–derived neurospheres. We also analyzed the effect of transplantation of DA neurons generated from monkey ES cells into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–treated (MPTP-treated) monkeys, a primate model for PD. Behavioral studies and functional imaging revealed that the transplanted cells functioned as DA neurons and attenuated MPTP-induced neurological symptoms.
Volume Changes in Gray Matter in Patients With Schizophrenia
Authors: Hilleke E. Hulshoff Pol, Hugo G. Schnack, Madelief G.B.C. Bertens, Neeltje E.M. van Haren, Ingeborg van der Tweel, Wouter G. Staal, Wim F.C. Baaré, René S. Kahn
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Schizophrenia is generally characterized by a progressive decline in functioning. Although structural brain abnormalities, particularly decrements in gray matter volume, are considered important to the pathology of schizophrenia, it is not resolved whether the brain abnormalities become more prominent over time. METHOD: Magnetic resonance brain images from 159 patients with schizophrenia and 158 healthy comparison subjects between 16 and 70 years of age were compared. Using linear regression analysis, the authors analyzed the relationship between the volumes of the total brain, gray and white matter, cerebellum, and lateral and third ventricles with patient age. RESULTS: Total brain (–2.2%), cerebral gray matter (–3.3%), prefrontal gray matter (–4.4%), and prefrontal white matter (–3.5%) volumes were smaller, and lateral (27%) and third (30%) ventricle and peripheral CSF (11%) volumes were larger in schizophrenia patients. A significant group-by-age interaction for gray matter volume was found, as shown by a steeper regression slope between age and gray matter volume in patients (–3.43 ml/year) than in healthy comparison subjects (–2.74 ml/year). CONCLUSIONS: The smaller brains of the patients with schizophrenia can be explained by decreases in gray matter volume. Moreover, the finding that the smaller gray matter volume was more pronounced in older patients with schizophrenia may suggest progressive loss of cerebral gray matter in schizophrenia patients.
Rate of Change in Myocardial Glycogen and Lactic Acid Following Arrest of Coronary Circulation
Authors: H. L. CONN, JOHN C. WOOD, GUILLERMO S. MORALES
Journal: Circulation Research (1959)

Comparative studies of glycogen content, rate of glycolysis, and lactic acid accumulation were carried out over a 2 hour period in potassium-arrested hearts excised from dogs with and without preliminary infusion of glucose and insulin. Glycogen consumption occurred at 60 to 100 per cent of the expected rate for 60 min., but was subsequently much less in both groups of animals. Lactic acid accumulation apparently was a critical factor with respect to continued metabolism after 60 min. Reperfusion of the coronary circulation after 90 min. of circulatory arrest revealed damage to the coronary microcirculation.