tbuckley/cabot-search huggingface dataset:
374. Development of a Genetic Vaccine Conferring Protective Immunity Against α-Cobratoxin Following a Single Administration of an Adenovirus Vector Encoding a Modified, Non-Toxic Cobratoxin Variant
Authors: Robert G. Pergolizzi, Rachel Dragos, Alexander Ropper, Andre Menez, Ronald G. Crystal
Journal: Molecular Therapy (2004)

Approximately 300,000 venomous snakebites occur throughout the world each year, almost 40,000 of which result in death. Little has changed over the past century regarding the medical approach to the risk of snakebite, and there are no vaccines available to protect against the common poisonous snakes. The present study presents a new paradigm for the development of vaccines to protect against snakebite, using knowledge of the structure and action of specific toxins combined with a gene-based strategy to deliver a toxin gene modified to render it non-toxic while maintaining its 3-dimensional structure and hence its ability to function as an immunogen. As a model for this approach, we developed a genetic vaccine to protect against α-cobratoxin (CTX), a potent, post-synaptic neurotoxin that is the major toxic component of the venom of Naja naja kathouia, the spectacled cobra. To develop the vaccine, substitutions in the CTX cDNA were introduced at 2 residues critical for binding to the nicotinic acetylcholine receptor (Asp27 to Arg, Arg33 to Gly) and a third substitution (Val37) which was silent at the amino acid level. The mutated CTX (mCTX) retained the overall antigenic structure of native CTX, while reducing receptor binding 10,000-fold (Fruchart-Gaillard et al. Proc Natl Acad Sci USA 2002; 99: 3216–3221). The mutated CTX expression cassette was delivered either as a plasmid (pmCTX) or in the context of a replication deficient adenovirus vector (AdmCTX). To assess whether expression of the mutated CTX in vivo leads to the development of protective immunity, BALB/c mice were challenged by IV administration of 2 μg of α-cobratoxin protein 21 days after IV injection of the mCTX plasmid vaccine. For animals receiving either no treatment (naive) or IV injection of Null plasmid, 80% died from the α-cobratoxin challenge. However, 100% of animals receiving a single IV dose of the mCTX plasmid vaccine survived, i.e., not only was it safe to express the mutated cobratoxin, but it evoked protective immunity. Similarly, BALB/c mice were challenged by IV administration of 2 μg of α-cobratoxin protein 21 days after IV injection of 109 particle units of AdmCTX (the vaccine in the context of an Ad vector) or AdNull (as a control). Animals receiving AdmCTX or AdNull and no challenge suffered no ill effects, but ≥80% of naive animals or those receiving AdNull died within10 min from the CTX protein challenge. In contrast, 100% of animals receiving a single IV dose of AdmCTX 21 days prior to challenge survived. The data demonstrates that both plasmid and adenovirus-based vaccines can be developed to protect against lethal challenge with α-cobratoxin. The effectiveness of this approach might serve as a basis to consider the development of a global public health program to protect the lives of those at risk for death by snakebite.
Abstract 3857: Induction of ALDH1A2 expression is critical for cancer stem cell properties in neuroblastoma
Authors: Noriyuki Nishimura, Tri Budi Hartomo, Thi Van Huyen Pham, Nobuyuki Yamamoto, Satoshi Hrase, Akira Hayakawa, Daiichiro Hasegawa, Keiichiro Kawasaki, Yoshiyuki Kosaka, Masafumi Matsuo, Yasuhiro Takeshima, Kazumoto Iijima, Hisahide Nishio
Journal: Cancer Research (2014)

Abstract Neuroblastoma is an aggressive tumor characterized by its heterogeneity ranging from spontaneous regression to malignant progression, and accounts for ∼15% of all cancer-related deaths in children. Despite current aggressive therapies, over 50% of high-risk neuroblastoma patients have experienced a tumor relapse. As in most cancers, recurrent neuroblastoma is primarily driven by chemoresistant cancer stem cells (CSCs), which are identified as a subpopulation of cancer cells with the multipotent ability to self-renew, generate differentiated progeny, and recapitulate a heterogeneous population of cancer cells in xenograft cancers. An increasing number of studies isolated CSCs as spheres, side population cells, and cell-surface marker-positive cells based on the markers associated with stem cell populations in a variety of cancers. Although high activity of aldehyde dehydrogenase (ALDH), which catalyzed the oxidation of aldehydes to carboxylates and comprised 19 isoforms in human cells, was used to identify and isolate CSCs from many types of cancers, it remained to be characterized in neuroblastoma. In the present study, we investigated the ALDH activity and the expression profile of 19 ALDH isoforms in spheres and parental cells of neuroblastoma. The ALDH activity was enriched in spheres compared to parental cells, while the expression profile was considerably varied among different neuroblastoma cells. Among ALDH isoforms consistently induced in spheres, ALDH1A2 knockdown most severely impaired the sphere and colony formation. Reciprocally, increased expression of ALDH1A2 enhanced these functions in neuroblastoma cells. ALDH1A2 expression was further correlated with the differentiation of neuroblastoma xenografts, the resistance to 13-cis-retinoic acid (13-cRA), and the overall survival of neuroblastoma patients. These results suggest that the induction of ALDH1A2 expression is critical for CSC properties in neuroblastoma. Citation Format: Noriyuki Nishimura, Tri Budi Hartomo, Thi Van Huyen Pham, Nobuyuki Yamamoto, Satoshi Hrase, Akira Hayakawa, Daiichiro Hasegawa, Keiichiro Kawasaki, Yoshiyuki Kosaka, Masafumi Matsuo, Yasuhiro Takeshima, Kazumoto Iijima, Hisahide Nishio. Induction of ALDH1A2 expression is critical for cancer stem cell properties in neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3857. doi:10.1158/1538-7445.AM2014-3857
Passive Smoke Exposure and Risk of Death From Coronary Heart Disease
Authors: Stephen J Jay
Journal: JAMA (2003)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 4217: Nuclear expression of BCL10 has a role in the regulation of cell growth and progression of pancreatic cancer through the activation of NF-κB-related signaling
Authors: Sung-Hsin Kuo, Shih-Hung Yang, Kun-Huei Yeh, Pei-Yen Yeh, Yu-Wen Tien, Hsiao-Wei Lee, Li-Tzong Chen, Ann-Lii Cheng
Journal: Cancer Research (2014)

Abstract Background: We previously reported that activation of TNF-α results in upregulation of NF-κB and nuclear translocation of BCL3 and BCL10 in breast cancer cell line and lymphoma cell line (J Biol Chem 2006;281:167-75, Blood 2008;112:2927-34). Furthermore, we recently demonstrated that BCL10 plays an important role in controlling the growth of cervical cancer cells through NF-κB dependent cyclin D1 regulation (Gynecol Oncol 2012;126:245-51). Since NF-κB activation has been shown to occur in the pathogenesis of pancreatic cancer, we sought to investigate whether BCL10-signaling possesses clinical significance in relation to pancreatic cancer. Methods: Three pancreatic cancer cell lines (PANC-1, AsPC-1, and BxPC-3) were used in this study. Cell cycle was analyzed by flow cytometry. The expression of protein and mRNA of BCL10- and NF-κB- related signaling was assessed by immunoblotting and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. The DNA-binding activity of NF-κB was determined by the luciferase assay. The expression of BCL10, and NF-κB in tumor cells from recurrent, locally advanced, and metastatic pancreatic patients who received chemotherapy was examined using immunohistochemical staining. Results: We transfected three pancreatic cancer cell lines with BCL10 small interfering RNA (siRNA), and discovered that the down-regulation of BCL10 inhibited the viability of these pancreatic cancer cells through the G1 arrest. BCL10 siRNA treatment inhibited the expression of p-IKKβ and p-IκB, and nuclear BCL3 translocation, and also down-regulated NF-κB activation and its downstream cell cycle proteins, c-Myc, and cyclin B1. The results of qRT-PCR showed that BCL10 siRNA treatment inhibited the mRNA expression levels of BCL10, BCL3, c-Myc, and cyclin B1. Our results reveal that patients with nuclear BCL10 expression had a worse median overall survival than those without (7.9 months versus 16.9 months, p = 0.007). Furthermore, nuclear expression of BCL10 was closely associated with nuclear BCL3 expression (p &amp;lt; 0.001), and NF-κB activation (p &amp;lt; 0.001). Conclusions: Our findings indicate that nuclear BCL10 plays an important role in controlling the growth and progression of pancreatic cancer cells through NF-κB-related signaling pathway. Citation Format: Sung-Hsin Kuo, Shih-Hung Yang, Kun-Huei Yeh, Pei-Yen Yeh, Yu-Wen Tien, Hsiao-Wei Lee, Li-Tzong Chen, Ann-Lii Cheng. Nuclear expression of BCL10 has a role in the regulation of cell growth and progression of pancreatic cancer through the activation of NF-κB-related signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4217. doi:10.1158/1538-7445.AM2014-4217
Abstract 16573: End-Stage Human Failing Hearts Increase Cardiac Progenitor Cells by Switching to a Developmental Program
Authors: David L Simpson, Rachana Mishra, Evan J Colletti, Sudhish Sharma, Sunjay Kaushal
Journal: Circulation (2011)

Background: Human cases of end-stage heart failure provide the rare opportunity to test whether the cells within these hearts exhibit different phenotypic characteristics than those in healthy hear...
Effects of sugar and aspartame on aggression and activity in children
Authors: M J Kruesi, J L Rapoport, E M Cummings, C J Berg, D R Ismond, M Flament, M Yarrow, C Zahn-Waxler
Journal: American Journal of Psychiatry (1987)

Habitual sugar consumption and behavior following challenge by sugar and aspartame were studied in 30 preschool boys. The 18 subjects whose parents considered them sugar reactive had more disruptive behavior problems at baseline than the other 12 subjects. Habitual sugar consumption correlated only with duration of aggression against property in alleged responders. Double-blind crossover challenges with aspartame, saccharin, sucrose, and glucose produced no significant effect on aggression or observers' ratings of behavior. Lower actometer counts followed the trials of aspartame, but the difference was not apparent to observers. It is unlikely that sugar and aspartame are clinically significant causes of disruptive behavior.
Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study
Authors: Anita Kohli, Rama Kapoor, Zayani Sims, Amy Nelson, Sreetha Sidharthan, Brian Lam, Rachel Silk, Colleen Kotb, Chloe Gross, Gebeyehu Teferi, Kate Sugarman, Phillip S Pang, Anu Osinusi, Michael A Polis, Vinod Rustgi, Henry Masur, Shyam Kottilil
Journal: The Lancet Infectious Diseases (2015)
Death in England: An Illustrated History
Authors: Paul Keeley
Journal: BMJ (2000)

Eds Peter C Jupp, Clare Gittings

Manchester University Press, £19.99, pp 304

ISBN 0 7190 5811 2

Rating: ![Graphic][1]  ![Graphic][2]  ![Graphic][3] 

When I was a child in primary school one of the hymns we used to sing had, as part of the chorus, the words: “When the death shades round us gather, Teach, oh, teach us how to die.” It is a measure of the rapid change in our societal attitudes to death in the intervening 25 years that such a hymn is unlikely to be found in a …

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Subacute cutaneous lupus erythematosus and its association with drugs: a population-based matched case-control study of 234 patients in Sweden
Authors: C.M. Grönhagen, C.M. Fored, M. Linder, F. Granath, F. Nyberg
Journal: British Journal of Dermatology (2012)

Background Numerous case reports about drug-induced (DI) subacute cutaneous lupus erythematosus (SCLE) have been published. Various drug types with different latencies has been proposed as triggers for this autoimmune skin disease. Objectives To evaluate the association between exposure to certain suspected drugs (previously implicated to induce SCLE) and a subsequent diagnosis of SCLE. Methods We performed a population-based matched case–control study in which all incident cases of SCLE (n = 234) from 2006 to 2009 were derived from the National Patient Register. The control group was selected from the general population, matched (1 : 10) for gender, age and county of residence. The data were linked to the Prescribed Drug Register. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the association between exposures to certain suspected drugs and the development of SCLE. Results During the 6 months preceding SCLE diagnosis, 166 (71%) of the patients with SCLE had at least one filled prescription of the suspected drugs. The most increased ORs were found for terbinafine (OR 52·9, 95% CI 6·6–∞), tumour necrosis factor-α inhibitors (OR 8·0, 95% CI 1·6–37·2), antiepileptics (OR 3·4, 95% CI 1·9–5·8) and proton pump inhibitors (OR 2·9, 95% CI 2·0–4·0). Conclusions We found an association between drug exposure and SCLE. More than one third of the SCLE cases could be attributed to drug exposure. No significant OR was found for thiazides, which might be due to longer latency and therefore missed with this study design. DI-SCLE is reversible once the drug is discontinued, indicating the importance of screening patients with SCLE for potentially triggering drugs. A causal relationship cannot be established from this study and the underlying pathogenesis remains unclear.
Abstract 3887: Wnt11 Overexpression in MSCs Protects Myocardium Against Ischemic Reperfusion Injury via Upregulation of GATA-4
Authors: Ying Dai, Shi Zuo, Xu Ning, Yigang Wang, Muhammad Ashraf, Meifeng Xu
Journal: Circulation (2008)

We have studied the augmented effect of Wnt11 transfected mesenchymal stem cells (MSCs Wnt11 ) which show upregulation of GATA-4 on cardioprotection. We hyothesize that GATA-4 overexpression mediates cardioprotection. Cardioprotection by MSCs was investigated by 1) co-culture CM with MSCs and 2) transplantation of MSCs (1.5×10 6 /50μl) into the border area of ischemic rat hearts after ligation of the left anterior descending coronary artery. GATA-4 was overexpressed by transfection of GATA-4 gene via adenoviral vectors to MSCs (MSCs GATA-4 ). Loss of GATA-4 in MSCs Wnt11 was carried out by transfecting GATA-4-siRNA into MSCs Wnt11 using oligofectamine. Expression of GATA-4 in MSCs Wnt11 was assayed by quantitative PCR. GATA-4 was significantly upregulated in MSCs Wnt11 compared to MSCs GFP , especially, when cells were exposed to low oxygen microenvironment (Fig. 1 ). Hearts transplanted with MSCs Wnt11 showed a significant improvement in cardiac function compared to those transplanted with MSCs GFP . TUNEL positive cells in hearts treated with MSCs Wnt11 were significantly reduced (0.57±0.17%) compared to MSCs GFP (1.84±0.38% VS 6.51±1.00%, p&lt;0.05). Moreover, annexin-V + CM were significantly less when co-cultured with MSCs Wnt11 and MSCs GATA-4 than those co-cultured with MSCs GFP ( Fig. 2 ). The effect of MSCs Wnt11 was abolished by GATA-4-siRNA-MSCs Wnt11 ( Tab. 1 ). These results suggest that MSCs Wnt11 exert a powerful cardioprotective effect via overexpression of GATA-4. Figure 1. Figure 2. Table 1. Cardiacfunction aftertransplantation of various MSCS
Abstract 16573: Dilated Cardiomyopathy Related to Pseudoacromegaly
Authors: Sachin Shah, Sarju Ganatra, David M Venesy
Journal: Circulation (2014)

Background: Pseudoacromegaly is a rare disorder characterized by tissue overgrowth and acromegaloid features in the absence of growth hormone (GH) or insulin like growth factor-1 (IGF-1) oversecretion. Cardiomyopathy is a known complication of acromegaly but an association with pseudoacromegaly has not been previously reported. Case: A 22 year old male with hypertension and type II diabetes presented with dyspnea. His mother had gigantism and died in her 30s from heart failure. Physical examination revealed features of gigantism and acanthosis nigricans. His troponin I, BNP and ECG were unremarkable. An echocardiogram revealed a dilated left ventricle (LV end diastolic dimension (LVEDD) of 7.9 cm) and ejection fraction (EF) of 15%, noninvasive myocardial perfusion imaging was normal. His serum GH, prolactin, ACTH, TSH, cortisol levels and pituitary MRI were normal. Serum IGF-1 was low with elevated plasma fasting insulin and C-peptide. He was diagnosed with a dilated cardiomyopathy secondary to pseudoacro...
Aldosterone Blockade in Patients With Acute Myocardial Infarction
Authors: Henry A. Solomon
Journal: Circulation (2003)

the Editor: In Dr Bertram Pitt's excellent editorial, "Aldosterone blockade in patients with acute myocardial infarction," 1 the first word in the next-to-last line of the left column on page 2525 should, I believe, read "hyperkalemia" rather than "hypokalemia."In addition, in discussing the possible mechanisms by which aldosterone blockade might result in a decrease in sudden cardiac death, one might have included the rather old demonstration that administration of intravenous potassium canrenoate, an antialdosterone agent, to patients with acute myocardial infarction reduces ventricular extrasystoles and ventricular fibrillation, 2 as well as the more recent observation that aldosterone alters myocardial repolarization by increasing monophasic action potential duration. 3
Abstract 11072: Profiling of a Platelet Proteome Discriminates Between Subjects and the Effects of Antiplatelet Agents Alone and in Combination
Authors: Simone Marcone, Desmond J Fitzgerald
Journal: Circulation (2014)

Protein profiling of biological samples provides an integrated measurement of genetic, environmental and drug effects. We examined the response to a number of antiplatelet drugs alone and in combination on the human platelet secreteome following stimulation with thrombin. The drugs included a P2Y12 antagonist (PSB0739) and a PAR-1 antagonist (RWJ56110) at concentration (10nM) that blocked the platelet responses to their respective agonists, and aspirin (10microM). Thrombin (1U/ml) was used to stimulate aggregation and secretion of washed platelets despite the presence of the drugs. Platelets were obtained from healthy donors and drugs added in vitro. The proteome profile was determined by label-free quantitative mass spectrometry (Q Exactive and MaxQuant software). The profile was markedly different between individuals (n=3) but it was similar for the same individual over 3 separate samples obtained weeks apart. The addition of the antiplatelet agents showed a similar strong individual clustering of all proteins (&gt;1,000). Cluster analysis of the 270 proteins that changed with drug showed marked differences between drugs although there was no impact on platelet aggregation. Similarly, combinations of 2 or 3 drugs demonstrated distinctive clustering of changes in the protein profile. Functional ontology of the proteome showed marked differences between drugs with very distinctive patterns. Similarly, drugs differed clearly in their effects on discrete functional protein clusters, such as ‘coagulation proteins’. Our findings suggest that individuals have distinct platelet proteomes (‘proteome barcode’) that remain evident in the presence of drug. Despite this, antiplatelet drugs exhibit distinct effects on the platelet proteome, when applied alone and in combination. The profiling of the platelet proteome better discriminates the effects of antiplatelet drugs than is possible with platelet aggregation and may help tailor therapy more effectively.
<i>RFC1</i> 80G&gt;A Is a Genetic Determinant of Methotrexate Efficacy in Rheumatoid Arthritis: A Human Genome Epidemiologic Review and Meta‐Analysis of Observational Studies
Authors: Tabitha N. Kung, Jessica Dennis, YiQing Ma, Gang Xie, Vivian Bykerk, Janet Pope, Carter Thorne, Edward Keystone, Katherine A. Siminovitch, France Gagnon
Journal: Arthritis & Rheumatology (2013)

Associations have been reported between candidate genes and the response to methotrexate (MTX) in rheumatoid arthritis (RA) patients, but most of the studies have been small and have yielded conflicting results. This study was undertaken to provide a systematic review of all genetic variant associations with MTX efficacy and toxicity, and to conduct a meta-analysis evaluating the most commonly studied single-nucleotide polymorphism for which prior cumulative analysis has been lacking.A systematic review and meta-analysis were performed to identify genetic variant associations with MTX efficacy and toxicity. Studies were identified from the Medline, EMBase, HuGENet Navigator, and Cochrane Library databases through December 2012, and from the 2009-2011 abstracts of the American College of Rheumatology and the European League Against Rheumatism annual meeting proceedings. Additional unpublished genotype data from a Canadian cohort of patients with early RA were also included.Among the 87 identified studies examining genetic associations with MTX efficacy and toxicity, the reduced folate carrier 1 gene (RFC1) variant 80G>A (Arg(27) His, rs1051266) was selected for random-effects meta-analysis. RFC1 80G>A was associated with MTX efficacy in both the recessive model (odds ratio [OR] 1.42, 95% confidence interval [95% CI] 1.04-1.93) and the additive model (OR 1.28, 95% CI 1.10-1.49). Restriction of the sensitivity analyses to studies that involved Caucasian subjects only and that used similar outcome measures (MTX failure versus nonfailure) maintained and improved the associations in both models. No significant association between RFC1 80G>A and MTX toxicity was detected.In these analyses of available data from observational studies, RFC1 80G>A was found to be associated with MTX efficacy, but not toxicity, in RA patients. This variant merits further prospective analysis as a potential predictor of MTX efficacy. Variability in the definitions of response in pharmacogenetic studies is a source of data heterogeneity that should be addressed.