tbuckley/cabot-search huggingface dataset:
Biphasic Activation of the JAK/STAT Pathway by Angiotensin II in Rat Cardiomyocytes
Authors: Hiroaki Kodama, Keiichi Fukuda, Jing Pan, Shinji Makino, Motoaki Sano, Toshiyuki Takahashi, Shingo Hori, Satoshi Ogawa
Journal: Circulation Research (1998)

Abstract —This study was designed to demonstrate the characteristic pattern of angiotensin II–induced JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) activation in cultured rat cardiomyocytes by comparing it with leukemia inhibitory factor (LIF)-induced activation. Angiotensin II (10 −7 mol/ l ) induced rapid phosphorylation of JAK2 and Tyk2, but not JAK1, and phosphorylated STAT1 and STAT2, but not STAT3, in the early stage up to 30 minutes. The time course of JAK/STAT activation by angiotensin II was apparently slower than that by LIF. Interestingly, angiotensin II phosphorylated STAT3 and rephosphorylated STAT1 in the late stage at 120 minutes. We also found that angiotensin II induced the formation of interferon-stimulating gene factor (ISGF) complexes biphasically, in the early stage at 15 to 30 minutes and in the late stage at 120 minutes, and that angiotensin II induced delayed activation of the sis -inducing factor (SIF) complex at 120 minutes. Formation of ISGF and SIF complexes in response to angiotensin II paralleled the phosphorylation pattern of STAT1 and STAT3 and was quite different from those obtained in response to LIF. The phosphorylation of STAT1 was suppressed by pretreatment with the angiotensin II type-1 (AT 1 ) receptor antagonist CV11974, but the delayed addition of CV11974 failed to suppress phosphorylation of STAT3 at 120 minutes. In conclusion, angiotensin II–induced JAK/STAT activation in rat cardiomyocytes is biphasic and entirely different from LIF-induced activation.
American Society of Clinical Oncology Clinical Practice Guidelines: Opportunities and Challenges
Authors: Mark R. Somerfield, Kaitlin Einhaus, Karen L. Hagerty, Melissa C. Brouwers, Jerome Seidenfeld, Gary H. Lyman
Journal: Journal of Clinical Oncology (2008)

The American Society of Clinical Oncology (ASCO) published its first clinical practice guideline, which focused on the use of hematopoietic colony-stimulating factors, in 1994. Since then, ASCO has published 24 additional guidelines or technology assessments on a range of topics and is developing 11 additional guidelines. Guidelines are among ASCO's most valued products, according to membership surveys and data from the JCO.org Web site. However, the same data from ASCO members have highlighted a number of limitations to the guideline program. These relate to the timelines of guideline updates, difficulties locating guidelines and related products, and challenges to implementing ASCO guidelines in everyday clinical practice. This article outlines the concrete steps that the ASCO Health Services Committee (HSC) is taking to address these limitations, including the institution of a more aggressive guideline updating schedule, a transition from narrative to systematic literature reviews to support the practice recommendations, a new Board of Directors–approved policy to permit endorsement of other groups’ guidelines, and a robust Clinical Tools and Resources program that offers a range of guideline dissemination and implementation aids. Additional work is underway to establish stronger and deeper collaborations with practicing oncologists to expand their role in the review, field testing, and implementation of guideline clinical tools and resources. Finally, the HSC is discussing evaluation of the guidelines program to maximize the impact of ASCO clinical practice guidelines on clinical decision making and, ultimately, the quality of cancer care.
HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis.
Authors: K Ito, H J Bian, M Molina, J Han, J Magram, E Saar, C Belunis, D R Bolin, R Arceo, R Campbell, F Falcioni, D Vidović, J Hammer, Z A Nagy
Journal: The Journal of Experimental Medicine (1996)

To investigate the development of HLA-DR-associated autoimmune diseases, we generated transgenic (Tg) mice with HLA-DRA-IE alpha and HLA-DRB1*0401-IE beta chimeric genes. The transgene-encoded proteins consisted of antigen-binding domains from HLA-DRA and HLA-DRB1*0401 molecules and the remaining domains from the IE(d)-alpha and IE(d)-beta chains. The chimeric molecules showed the same antigen-binding specificity as HLA-DRB1*0401 molecules, and were functional in presenting antigens to T cells. The Tg mice were backcrossed to MHC class II-deficient (IA beta-, IE alpha-) mice to eliminate any effect of endogenous MHC class II genes on the development of autoimmune diseases. As expected, IA alpha beta or IE alpha beta molecules were not expressed in Tg mice. Moreover, cell-surface expression of endogenous IE beta associated with HLA-DRA-IE alpha was not detectable in several Tg mouse lines by flow cytometric analysis. The HLA-DRA-IE alpha/HLA-DRB1*0401-IE beta molecules rescued the development of CD4+ T cells in MHC class II-deficient mice, but T cells expressing V beta 5, V beta 11, and V beta 12 were specifically deleted. Tg mice were immunized with peptides, myelin basic protein (MBP) 87-106 and proteolipid protein (PLP) 175-192, that are considered to be immunodominant epitopes in HLA-DR4 individuals. PLP175-192 provoked a strong proliferative response of lymph node T cells from Tg mice, and caused inflammatory lesions in white matter of the CNS and symptoms of experimental allergic encephalomyelitis (EAE). Immunization with MBP87-106 elicited a very weak proliferative T cell response and caused mild EAE. Non-Tg mice immunized with either PLP175-192 or MBP87-106 did not develop EAE. These results demonstrated that a human MHC class II binding site alone can confer susceptibility to an experimentally induced murine autoimmune disease.
Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants
Authors: Melissa C. Hanson, Monica P. Crespo, Wuhbet Abraham, Kelly D. Moynihan, Gregory L. Szeto, Stephanie H. Chen, Mariane B. Melo, Stefanie Mueller, Darrell J. Irvine
Journal: Journal of Clinical Investigation (2015)

Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. Further, NP-cdGMP promoted durable antibody titers that were substantially higher than those promoted by the well-studied TLR agonist monophosphoryl lipid A and comparable to a much larger dose of unformulated cdGMP, without the systemic toxicity of the latter. These results demonstrate that nanoparticulate delivery safely targets CDNs to the dLNs and enhances the efficacy of this adjuvant. Moreover, this approach can be broadly applied to other small-molecule immunomodulators of interest for vaccines and immunotherapy.
Myocyte Turnover in the Aging Human Heart
Authors: Jan Kajstura, Narasimman Gurusamy, Barbara Ogórek, Polina Goichberg, Carlos Clavo-Rondon, Toru Hosoda, Domenico D'Amario, Silvana Bardelli, Antonio P. Beltrami, Daniela Cesselli, Rossana Bussani, Federica del Monte, Federico Quaini, Marcello Rota, Carlo A. Beltrami, Bruce A. Buchholz, Annarosa Leri, Piero Anversa
Journal: Circulation Research (2010)

RETRACTION This article has been retracted: Circ Res . 2018;123:e00. DOI: 10.1161/RES.0000000000000247
Efficacy of iron-fortified whole maize flour on iron status of schoolchildren in Kenya: a randomised controlled trial
Authors: Pauline EA Andang'o, Saskia JM Osendarp, Rosemary Ayah, Clive E West, David L Mwaniki, Corine A De Wolf, Rob Kraaijenhagen, Frans J Kok, Hans Verhoef
Journal: The Lancet (2007)
Gene expression profiling-derived immunohistochemistry signature with high prognostic value in colorectal carcinoma
Authors: Wenjun Chang, Xianhua Gao, Yifang Han, Yan Du, Qizhi Liu, Lei Wang, Xiaojie Tan, Qi Zhang, Yan Liu, Yan Zhu, Yongwei Yu, Xinjuan Fan, Hongwei Zhang, Weiping Zhou, Jianping Wang, Chuangang Fu, Guangwen Cao
Journal: Gut (2013)

Gene expression profiling provides an opportunity to develop robust prognostic markers of colorectal carcinoma (CRC). However, the markers have not been applied for clinical decision making. We aimed to develop an immunohistochemistry signature using microarray data for predicting CRC prognosis.We evaluated 25 CRC gene signatures in independent microarray datasets with prognosis information and constructed a subnetwork using signatures with high concordance and repeatable prognostic values. Tumours were examined immunohistochemically for the expression of network-centric and the top overlapping molecules. Prognostic values were assessed in 682 patients from Shanghai, China (training cohort) and validated in 343 patients from Guangzhou, China (validation cohort). Median follow-up duration was 58 months. All p values are two-sided.Five signatures were selected to construct a subnetwork. The expression of GRB2, PTPN11, ITGB1 and POSTN in cancer cells, each significantly associated with disease-free survival, were selected to construct an immunohistochemistry signature. Patients were dichotomised into high-risk and low-risk subgroups with an optimal risk score (1.55). Compared with low-risk patients, high-risk patients had shorter disease-specific survival (DSS) in the training (HR=6.62; 95% CI 3.70 to 11.85) and validation cohorts (HR=3.53; 95% CI 2.13 to 5.84) in multivariate Cox analyses. The signature better predicted DSS than did tumour-node-metastasis staging in both cohorts. In those who received postoperative chemotherapy, high-risk score predicted shorter DSS in the training (HR=6.35; 95% CI 3.55 to 11.36) and validation cohorts (HR=5.56; 95% CI 2.25 to 13.71).Our immunohistochemistry signature may be clinically practical for personalised prediction of CRC prognosis.
A Clinical Lecture ON A FIFTH SERIES OF CASES OF TOTAL EXTIRPATION OF THE PROSTATE FOR RADICAL CURE OF ENLARGEMENT OF THAT ORGAN: Delivered at the Medical Graduates' College and Polyclinic
Authors: P. J. Freyer
Journal: BMJ (1903)

and enclosing in its mass the prostatic urethra.Strange as it may seem, the patient has not suffered from the mutilation, and the same result has been observed by Freyer and other operators who have had a like experience.The after-management of these cases needs the utmost care, but the surprisingly good results which follow are worth all the time and trouble which the surgeon devotes to them.
Gallstone Size and the Risk of Gallbladder Cancer
Authors: Fernando Trevino
Journal: JAMA (1984)

<h3>To the Editor.—</h3> The article by Diehl<sup>1</sup>that investigated gallstone size and the risk of gallbladder cancer presented some valuable cross-cultural data. Unfortunately, the article did not specify the method used to determine ethnicity. It is imperative to know whether Mexican origin was self-reported, determined on the basis of language spoken, interviewer observed, or determined on the basis of the person's surname, as each method yields varying results.<sup>2</sup>More importantly, if self-reporting was not used, it is entirely possible (even though there is a large Mexican-American population residing in San Antonio, Tex) that Hispanics other than those of Mexican origin were included in the Mexican-American sample. Furthermore, Diehl differentiated cancer cases on the basis of whether patients were born in a Latin American country. It seems to us that, if the Mexican-American sample excluded non-Mexican-origin Hispanics, birth in Mexico would have been the preferred basis for comparison, especially
Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial
Authors: P Yeni, D A Cooper, J P Aboulker, A G Babiker, D Carey, J H Darbyshire, M Floridia, P M Girard, R L Goodall, M H Hooker, A Mijch, V Meiffredy, B Salzberger
Journal: The Lancet (2006)
MSH6 and MUTYH Deficiency Is a Frequent Event in Early-Onset Colorectal Cancer
Authors: María Dolores Giráldez, Francesc Balaguer, Luis Bujanda, Miriam Cuatrecasas, Jenifer Muñoz, Virginia Alonso-Espinaco, Mikel Larzabal, Anna Petit, Victoria Gonzalo, Teresa Ocaña, Leticia Moreira, José María Enríquez-Navascués, C. Richard Boland, Ajay Goel, Antoni Castells, Sergi Castellví-Bel
Journal: Clinical Cancer Research (2010)

Early-onset colorectal cancer (CRC) is suggestive of a hereditary predisposition. Lynch syndrome is the most frequent CRC hereditary cause. The MUTYH gene has also been related to hereditary CRC. A systematic characterization of these two diseases has not been reported previously in this population.We studied a retrospectively collected series of 140 patients ≤50 years old diagnosed with nonpolyposis CRC. Demographic, clinical, and familial features were obtained. Mismatch repair (MMR) deficiency was determined by microsatellite instability (MSI) analysis, and immunostaining for MLH1, MSH2, MSH6, and PMS2 proteins. Germline MMR mutations were evaluated in all MMR-deficient cases. Tumor samples with loss of MLH1 or MSH2 protein expression were analyzed for somatic methylation. Germline MUTYH mutations were evaluated in all cases. BRAF V600E and KRAS somatic mutational status was also determined.Fifteen tumors (11.4%) were MSI, and 20 (14.3%) showed loss of protein expression (7 for MLH1/PMS2, 2 for isolated MLH1, 3 for MSH2/MSH6, 7 for isolated MSH6, and 1 for MSH6/PMS2). We identified 11 (7.8%) germline MMR mutations, 4 in MLH1, 1 in MSH2, and 6 in MSH6. Methylation analysis revealed one case with somatic MLH1 methylation. Biallelic MUTYH mutations were detected in four (2.8%) cases. KRAS and BRAF V600E mutations were present in 39 (27.9%) and 5 (3.6%) cases, respectively.Loss of MSH6 expression is the predominant cause of MMR deficiency in early-onset CRC. Our findings prompt the inclusion of MSH6 and MUTYH screening as part of the genetic counseling of these patients and their relatives.
Current and potential future drug treatments for osteoporosis.
Authors: S Patel
Journal: Annals of the Rheumatic Diseases (1996)

There has been a major interest in the drug treatment of osteoporosis and an increase in the number of drugs available in most countries. The ideal drug (one which increases or restores bone density and trabecular connectivity) is still not available. However, in patients with relatively preserved trabecular connectivity and moderately reduced bone density, several agents have shown substantial clinical benefit. Oestrogens are still the mainstay of drug treatment, but the risks of breast cancer versus the cardiovascular and skeletal benefits with long term use have to be assessed in the individual. Newer tissue specific oestrogens show some promise in this respect. The bisphosphonates and possibly fluoride are likely to be the major alternatives to oestrogens in the medium term. The newer bisphosphonates, alendronate and in the future risedronate, are likely to supersede etidronate. Calcitriol probably has a limited role, confined to those patients in whom HRT or bisphosphonates are not appropriate. Calcium supplementation, or an increase in dietary intake if deficient, irrespective of which agent is used, is also of benefit. In older patients there is considerable support for using a combination of calcium and vitamin D. Whether combination treatment, for example oestrogens, bisphosphonates, and calcium together, will result in greater efficacy remains to be conclusively shown, but may be an attractive option in younger patients with higher bone turnover. Apart from fluoride, bone formation stimulators are unlikely to have a major role until the next century, although it may be possible to use growth factors as part of an ADFR regimen (A = activate remodelling, D = depress resorption, F = free formation, and R = repeat). This is still an important theoretical approach and needs further work with newer agents to see if increased efficacy can be found. In addition sequential treatment may be necessary in view of the limited time periods over which particular agents, such as intermittent fluoride (four years), have been examined, and this will have to be individually tailored. Other approaches include trying to increase peak bone mineral density, although influencing the young to prevent a disease that may not manifest itself for half a century is daunting.
Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis
Authors: M K de Vries, I E van der Horst-Bruinsma, M T Nurmohamed, L A Aarden, S O Stapel, M J L Peters, J C van Denderen, B A C Dijkmans, G J Wolbink
Journal: Annals of the Rheumatic Diseases (2008)

Background: Immunogenicity, specifically the onset of antibodies against tumour necrosis factor (TNF) blocking agents, seems to play an important role in non-response to treatment with these drugs. Objectives: To assess the relation of clinical response of ankylosing spondylitis (AS) to etanercept with etanercept levels, and the presence of antibodies to etanercept. Methods: Patients with AS were treated with etanercept 25 mg twice weekly, according to the international Assessment in Ankylosing Spondylitis (ASAS) working group consensus statement. Sera were collected at baseline and after 3 and 6 months of treatment. Clinical response was defined as a 50% improvement or as an absolute improvement of 2 points on a (0–10 scale) Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. Functional etanercept levels were measured by a newly developed ELISA, measuring the binding of etanercept to TNF. Antibodies against etanercept were measured with a two-site assay and antigen binding test. Clinical data were used to correlate disease activity with serum etanercept levels. Results: In all, 53 consecutive patients were included. After 3 months of treatment 40 patients (76%) fulfilled the response criteria. Mean etanercept levels were 2.7 mg/litre and 3.0 mg/litre after 3 and 6 months respectively. Characteristics and etanercept levels of responders and non-responders were similar. No antibodies to etanercept were detected with any of the assays. Conclusion: Etanercept levels of responders and non-responders were similar and no antibodies to etanercept were detected with any of the assays. This study indicates that etanercept is much less immunogenic compared with the other TNF-blocking agents.
Human immune recognition-based multicomponent subunit vaccines against tuberculosis
Authors: S B Sable, I Verma, D Behera, G K Khuller
Journal: European Respiratory Journal (2005)

The cell-mediated immune response, with its shift in favour of type-1 over type-2 T-helper cell immune response, is generally regarded as essential to protection against mycobacterial infections. The aim of this study was to evaluate the protective potential of two multicomponent subunit vaccines (MSV-1 and MSV-2) against tuberculosis (TB) based on human immune recognition. MSV-1 consisted of five immunodominant antigens (TB10.4, early secretory antigenic target (ESAT)-6, culture filtrate protein (CFP)-8, CFP-10 and CFP-15) selected from a group of polypeptides, which induced a predominant T-cell response in immune human subjects, whereas MSV-2 consisted of antigens (CFP-11, CFP-21, CFP-22.5, Mycobacterium tuberculosis protein (MPT)-64 and CFP-31) selected from a group of polypeptides which induced a subdominant T-cell response along with the antibody response. Both of these sets of polypeptides were extensively recognised in healthy individuals with significant interferon gamma release compared to the diseased population. In C57BL/6J mice, at the level of the lungs, the order of protective efficacy for the test vaccines was: bacille Calmette–Guérin (BCG)&gt;MSV-2&gt;MSV-1. The protective efficacy of MSV-1 was found to be significantly less than that of MSV-2 and BCG at the level of spleen, whereas that of MSV-2 was comparable to that of BCG. The results of this study indicate that high T-helper cell type 1 response-inducing polypeptides selected on the basis of human immune recognition do not necessarily impart protection during vaccination experiments.
Exhaled nitric oxide in 4-year-old children: relationship with asthma and atopy
Authors: J. E. Brussee
Journal: European Respiratory Journal (2005)

Airway inflammation is an early feature of asthma. Early detection and anti-inflammatory treatment may have important therapeutic impact. Exhaled nitric oxide is a noninvasive marker of airway inflammation. The current study investigated the association between exhaled nitric oxide and asthma, wheezing phenotypes, atopy and blood eosinophilia in a large group of 4-yr-old children from the general population. All children participated in the Prevention and Incidence of Asthma and Mite Allergy study, a birth cohort study of high-risk (atopic mother) and low-risk children in the Netherlands. Nitric oxide levels were successfully determined in 429 children. Although there was overlap in the distribution of values of children with and without asthma or atopy, mean values were higher in children with atopy or doctor9s diagnosed asthma (geometric mean (ppb) 9.4 and 10.0, respectively) as compared to those without (7.7 and 7.9). Values were highest in atopic symptomatic children. Values were not associated with wheezing phenotype or blood eosinophilia. This study is one of the few large-scale epidemiological studies among 4-yr-old children from the general population showing that children with symptoms of asthma and atopy have higher levels of exhaled nitric oxide than those without.