tbuckley/cabot-search huggingface dataset:
Patients suffering from non-IgE-mediated cow’s milk protein intolerance cannot be diagnosed based on IgG subclass or IgA responses to milk allergens
Authors: H. Hochwallner, U. Schulmeister, I. Swoboda, T. E. Twaroch, H. Vogelsang, L. Kazemi-Shirazi, M. Kundi, N. Balic, S. Quirce, H. Rumpold, R. Fröschl, F. Horak, B. Tichatschek, C. L. Stefanescu, Z. Szépfalusi, N. G. Papadopoulos, A. Mari, C. Ebner, G. Pauli, R. Valenta, S. Spitzauer
Journal: Allergy (2011)

To cite this article: Hochwallner H, Schulmeister U, Swoboda I, Twaroch TE, Vogelsang H, Kazemi-Shirazi L, Kundi M, Balic N, Quirce S, Rumpold H, Fröschl R, Horak F, Tichatschek B, Stéfanescu CL, Szépfalusi Z, Papadopoulos NG, Mari A, Ebner C, Pauli G, Valenta R, Spitzauer S. Patients suffering from non-IgE-mediated cow's milk protein intolerance cannot be diagnosed based on IgG subclass or IgA responses to milk allergens. Allergy 2011; 66: 1201–1207. Background: Cow's milk is one of the most common causes of food allergy. In two-thirds of patients, adverse symptoms following milk ingestion are caused by IgE-mediated allergic reactions, whereas for one-third, the mechanisms are unknown. Aim of this study was to investigate whether patients suffering from non-IgE-mediated cow's milk protein intolerance can be distinguished from persons without cow's milk protein intolerance based on serological measurement of IgG and IgA specific for purified cow's milk antigens. Methods: We determined IgG1–4 subclass and IgA antibody levels to purified recombinant αS1-casein, αS2-casein, β-casein, κ-casein, α-lactalbumin, and β-lactoglobulin in four patient groups by ELISA: Patients with IgE-mediated cow's milk allergy (CMA, n = 25), patients with non-IgE-mediated cow's milk protein intolerance (CMPI, n = 19), patients with gastrointestinal symptoms not associated with cow's milk ingestion (GI, n = 15) and control persons without gastrointestinal problems (C, n = 26). Cow's milk-specific IgE levels were determined by ImmunoCAP. Results: Only CMA patients had IgE antibodies to cow's milk. Cow's milk allergic patients mounted the highest IgG1 and IgG4 antibody levels to αS1-casein, αS2-casein, β-casein, κ-casein, and α-lactalbumin. No elevated levels of IgG4, IgA, and complement-binding IgG subclasses (IgG1, IgG2, IgG3) to purified cow's milk allergens were found within the CMPI patients compared to persons without cow's milk protein intolerance (GI and C groups). Conclusion: Cow's milk protein intolerant patients cannot be distinguished from persons without cow's milk protein intolerance on the basis of IgG subclass or IgA reactivity to cow's milk allergens.
Screening for tuberculosis by sputum culture among risk groups in a TB low- incidence country
Authors: Sidse Graff Jensen, Nete Wrona Olsen, Niels Seersholm, Torgny Wilcke, Troels Lillebæk, Axel Kok-Jensen
Journal: European Respiratory Journal (2014)

Background: Tuberculosis (TB) incidence in Denmark is 7/100.000. However ongoing transmission of Mycobacterium Tuberculosis (MT) is still seen among risk groups i.e. homeless. Active case finding using mobile chest x-ray screening and contact tracing have not been sufficient to stop this transmission and mobile x-ray screening would not be available after 2011.

Aim: To evaluate whether “mobile” screening by sputum among TB-risk groups is:

1) feasible on a large scale.

2) cost effective.

And can:

3) Identify TB cases at an early stage defined as positive by culture and negative by microscopy.

Methods: A nurse with a long experience in handling TB patients visited 9 places (homeless shelters etc.) in Copenhagen. She collected one “good” sputum sample from each person. During a 12 month period we performed this screening 3 times and encouraged the participants to be re-examined on these occasions.

Results: We collected 907 sputum samples from 665 persons. Cultures were positive for MT in 21 persons (3,2% of the participants). Two were positive by microscopy (smear) and one of these two samples was negative by culture. Genotyping showed that all TB cases found by sputum screening were clustered and belonged to 3 of the most common 24 loci MIRU VNTR genotypes identified in Denmark.

Conclusion: “Mobile” screening by sputum among TB-risk groups is possible. We found a surprisingly high TB incidence among the participants. Of the culture positive TB cases found all but one were smear-negative, indicating that microscopy is not sufficient to identify TB-cases in this population and that the cases found were early and probably non-contagious cases.
Abstract 17202: Synthetic Modified RNA Driven Delivery of Insulin-Like Growth Factor-1 Promotes Early Cardiomyocyte Survival Post-Acute Myocardial Infarction
Authors: Chien-Ling Huang, Anne-Laure Leblond, Elizebeth C Turner, Arun H Kumar, Donnchadh M O’Sullivan, Kenneth Martin, Derek Whelan, Noel M Caplice
Journal: Circulation (2014)

To extend the temporal window for cytoprotection in cardiomyocytes undergoing apoptosis after hypoxia and myocardial infarction (MI), a synthetic modified RNA (modRNA) was used to drive delivery of insulin-like growth factor-1 (IGF1) within the area at risk in a murine model of MI. Transient transfection of synthetic GFP modRNA as an tracking indicator, with polyethylenimine (PEI)-based nanoparticle, showed efficient delivery of modRNA derived protein and minimum cytotoxicity in HL-1 cardiomyocytes (CM; 44±5%). ModRNA-IGF1 protein expression and secreted levels increased 3.5 fold ( p &lt;0.05) at 24 hours and peaked at 48 hours post-transfection. The expression efficiency of modRNA was further enhanced (~2 fold at 24 hours post-transfection; p &lt;0.05) under hypoxia-induced apoptosis conditions. ModRNA augmented secreted and cell associated IGF1 promoting CM survival and abrogating cell apoptosis (71±5% in controls to 37±7%, p &lt;0.05). Translation of modRNA-IGF1 was sufficient to induce downstream increases in Akt and Erk phosphorylation (3 fold and 2 fold, respectively; p &lt;0.01). Downregulation of IGF1 specific miRNA-1 and -133 (52% and 56%, respectively; p &lt;0.01) but not miR-145 expression, was also confirmed. As proof of concept, intramyocardial delivery of modRNA-IGF1 but not control modRNA-GFP significantly decreased in TUNEL-positive cells within the infarct border zone (BZ) at 24 hours (22±3% versus 53±8% in controls, p &lt;0.01). Akt phosphorylation was augmented while caspase-9 activity and cleavage was downregulated in the infarct BZ compared to controls ( p &lt;0.05). These findings demonstrate extended in vivo cytoprotective effect of IGF1 24 hours post-MI driven by synthetic modRNA delivery. This provides a novel strategy to reduce ischemic injury by controlled release of IGF1 using a controllable bioactive nanoparticle for ‘short burst’ IGF1 cytoprotective therapy.
Worsening renal function during renin–angiotensin–aldosterone system inhibitor initiation and long‐term outcomes in patients with left ventricular systolic dysfunction
Authors: Hannah Clark, Henry Krum, Ingrid Hopper
Journal: European Journal of Heart Failure (2013)

Impaired renal function is associated with worse clinical outcomes in patients with LV systolic dysfunction (LVSD) and heart failure. Renin-angiotensin-aldosterone system (RAAS) inhibitors provide clinical benefit in these settings and often worsen renal function. It is not clear whether worsening renal function (WRF) in patients exposed to these agents predicts a worse prognosis or merely reflects the pharmacological action of the drug on the kidney.We performed a meta-analysis of all RAAS inhibitor LVSD trials reporting on outcomes according to WRF (as per individual study definition) in both active intervention and placebo groups. Five major studies (SOLVD, SAVE, RALES, Val-HeFT and EPHESUS) contributed, with 20 573 patients. Compared with placebo, RAAS inhibitors reduced all-cause mortality overall [n = 20 573, relative risk ratio (RR) 0.91, 95% confidence interval (CI) 0.86-0.95, P = 0.0003], in the group with no WRF (n = 18 209, RR 0.91, 95% CI 0.83-0.99, P = 0.04), and in the WRF group (n = 2364, RR 0.72, 95% CI 0.62-0.84, P < 0.0001). Compared with no WRF, WRF was associated with increased all-cause mortality; however, this was less in the RAAS inhibitor group (n = 8905, RR 1.22, 95% CI 1.10-1.36, P = 0.0003) than in the placebo group (n = 9304, RR 1.52, 95% CI 1.37-1.69, P < 0.00001).WRF shortly after randomization is associated with worsened outcomes compared with no WRF; however, the reduction in all-cause mortality associated with the use of RAAS inhibitors was significantly greater in the presence of WRF than in the no WRF group. Clinicians should not be deterred from using RAAS inhibitors in the setting of WRF.
RFLC021, a Benzimidazole derivative, display in vitro and in vivo anti-tumor activity through tubulin depolymerization and intrinsic apoptosis pathway
Authors: Wei-Ling Chang, Chih-Shiang Chang, Jih-Hwa Guh
Journal: Clinical Cancer Research (2007)

B46   RFLC021, a benzimidazole derivative modified from combretastatin A-4, inhibited cell growth in various cancer cell lines, including prostate cancer PC-3, DU-145 and LNCaP, hepatocellular carcinoma Hep3B and HepG2, non-small cell lung cancer A549, and P-glycoprotein-rich breast cancer NCI/ADR-RES cells with IC 50  values ranging from 1.67 to 3.69μM. NCI/ADR-RES cells were sensitive to RFLC021 suggesting that this compound is not a substrate for P-glycoprotein transporter. In flow cytometry analysis, PC-3 and DU-145 cells were arrested at G2/M phases in a time- and concentration-dependent manner and induced a subsequent increase of hypodiploid phase (apoptosis).  In vitro  tubulin turbidity and immunofluorescence assays showed that RFLC021 inhibited tubulin polymerization and caused abnormal mitotic spindles in PC-3 cells. RFLC021 also activated an up-regulation of cyclin B1 expression, Cdk1 phosphorylation at Thr161 and Cdc25C phosphorylation associated with the elevation of MPM-2 levels, indicating the occurrence of mitotic arrest. RFLC021 induced the mitochondria-involved apoptosis pathways including cleavage of Mcl-1 and Bad, phosphorylation of Bcl-2 and Bcl-xL, activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase. Furthermore, RFLC021 could stimulate the activation of Ras/Raf-1 signaling pathways. The xenograft models inoculated with PC-3 cells demonstrated that RFLC021 displayed  in vivo  anti-tumor efficacy. In summary, the data suggest that RFLC021 is an effective  in vitro  and  in vivo  anticancer agent that induces anti-proliferative and apoptotic effect through the inhibition of tubulin polymerization, the induction of mitotic arrest and the triggering of mitochondria-mediated apoptotic cell death.
EGFR mutations in African American NSCLC patients occurs at a similar frequency to Caucasians but demonstrates an extreme bias to exon 19 mutations
Authors: Govindaraja Atikukke, Michele L. Cote, Ann G. Schwartz, Gadgeel Shirish, Ayman O. Soubani, Stephen P. Ethier, Fulvio Lonardo, Ramsi Haddad, David J. Edwards
Journal: Clinical Cancer Research (2010)

Abstract Oncogenomic mutations found in NSCLC are potential therapeutic targets, as seen in the dramatic responses individuals with EGFR mutations have to tyrosine kinase inhibitors. We selected 149 patients with NSCLC from previous population-based studies of lung cancer which included 80 (54%) Caucasian samples and 69 African American (46%) samples. Tumor DNA was extracted from formalin fixed paraffin embedded tissue. We examined 238 mutations in 19 oncogenes using the OncoCarta Assay v1.0 (Sequenom). We identified a total of 52 mutations in tumors from 47 individuals; the remaining 102 tumors did not have mutations in the oncogenes we assayed. Mutations were identified in EGFR (n=20), KRAS (n=19), PIK3CA (n=6), PDGFRA (n=2), AKT2 (n=1), FLT3 (n=1) and CDK1 (n=1). Consistent with previous studies, EGFR mutation was more likely to occur in non-smokers (p=3.3E-08 Fisher's test) and the significance of this effect was more pronounced when analyzed against the number of pack years smoked (p=7.3E-08, Kruskal-Wallis test). Previously published reports have suggested that African American patients are less likely to exhibit EGFR mutations compared to Caucasian NSCLC patients and are therefore less likely to respond to tyrosine kinase inhibitors. We found no difference in the proportion of EGFR mutations in African American patients (n=8, 11.6%) compared to Caucasian (n=12, 15.0%, p-value=0.54). Furthermore, EGFR mutations in African American patients were exclusively in exon 19 (n=8, 100%), whereas Caucasian patients had mutations in exon 21 (n=3, 25%) and exon 18 (n=1, 8.3%) in addition to those in exon 19 (n=8, 66.7%). Interestingly, several reports have suggested a higher rate of response of NSCLC to erlotinib, an EGFR tyrosine kinase inhibitor, associated with exon 19 deletions relative to the exon 21 L858R mutation. Thus, our oncogenomic data demonstrates that African American NSCLC patients not only harbor a similar frequency of EGFR mutation as Caucasians, but that the specific nature of the mutation may result in a higher frequency of response to EGFR targeted therapeutics.
Conference calls for sanctions and penalties to stamp out “institutional racism” in NHS
Authors: Caroline White
Journal: BMJ (2009)

Regulators need to get tough on an “institutionally racist NHS” by imposing sanctions and penalties on trusts that fail to promote race equality for staff and patients and do not meet their statutory duties, the first national NHS black and minority ethnic conference has concluded.

A succession of damning reports in recent years, the most recent of which was published in April by the former health service regulator the Healthcare Commission, have all indicated that the NHS is dragging its feet on race equality ( BMJ 2009;338:b1357, doi:10.1136/bmj.b1357).

In a series of on the spot electronic …
Return of the Prodigal Son
Authors: M. Therese Southgate
Journal: JAMA (2002)

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Abstract #5669: Immune-regulation of non-small cell lung cancer development
Authors: Magnus Johansson, Adam Beltran, Biao He, David Jablons, Lisa Coussens
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Lung cancer is the leading cause of cancer mortality in the U.S., accounting for more deaths than breast, prostate, colon, liver and kidney cancer combined. Five-year survival is poor at 15% with most patients experiencing only modest benefit from conventional therapies, thus highlighting the need for novel therapeutic approaches. Most human solid tumors bear antigens that are specifically recognized by cytotoxic T lymphocytes (CTLs), and tumor-specific CTLs have been reported in patients with malignant disease, including patients with non-small cell lung carcinoma (NSCLC). However, despite presence of tumor-specific CTLs, tumors still progress indicating that tumors utilize various mechanisms to evade CTL-mediated rejection and/or subversion of host anti-tumor immune responses. One plausible explanation for how this occurs is that accumulation of regulatory T cells (Tregs) and/or subsets of innate immune cells, e.g. immature myeloid cells (iMCs), indirectly contribute to cancer development via suppression of anti-tumor adaptive immunity and activation of pro-tumor bioactivities of iMCs. We have found that human NSCLC is associated with significant accumulations of CD45+ leukocytes as compared to adjacent normal lung tissue, where infiltrates are composed of CD4+FoxP3+ Tregs, but not of iMCs (CD45+CD34+; CD11b+CD14-CD15+ or CD14+HLA-DR-/low), indicating that local immunosuppression in NSCLC is likely imparted by Treg cells as opposed to iMCs. Moreover, in a mouse model of de novo NSCLC development, i.e. CC10-TAg mice, we also revealed accumulations of Tregs, but not of CD11b+Gr1+ iMCs. To reveal the functional significance of CD4+FoxP3+ accumulation, we evaluated dynamics and characteristics of NSCLC development by genetically manipulating CC10-TAg mice and rendered them deficient for all B and T lymphocytes (RAG1-/-), T-helper and Tregs (CD4-/-), CTLs (CD8-/-) and B cells (JH-/-). Our data indicate that complete absence of both B and T lymphocytes in CC10-TAg mice results in a significant acceleration of tumor development that is dependent on CD8+ CTLs, indicating that NSCLC progression is regulated by a balance of CTL-mediated rejection and Treg mediated immunosuppression. To be presented will be recent data evaluating the functional importance of CTLs and Tregs in NSCLC and approaches to utilize these novel observations for design of improved anti-cancer therapeutic approach for NSCLC.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5669.
The α-defensins stimulate proteoglycan-dependent catabolism of low-density lipoprotein by vascular cells : a new class of inflammatory apolipoprotein and a possible contributor to atherogenesis
Authors: Abd Al-Roof Higazi, Taher Nassar, Tomas Ganz, Daniel J. Rader, Raphael Udassin, Khalil Bdeir, Edna Hiss, Bruce S. Sachais, Kevin Jon Williams, Eran Leitersdorf, Douglas B. Cines
Journal: Blood (2000)
Erratum: Corrigendum: Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure
Authors: Mary Tang, Guang Wang, Ping Lu, Richard H Karas, Mark Aronovitz, Scott P Heximer, Kevin M Kaltenbronn, Kendall J Blumer, David P Siderovski, Yan Zhu, Michael E Mendelsohn
Journal: Nature Medicine (2003)
Microbial shift and periodontitis
Authors: Alex B. Berezow, Richard P. Darveau
Journal: Periodontology 2000 (2010)

Periodontitis, a biofilm-associated inflammatory disease of the periodontium, is a major cause of tooth loss in the world.This disease appears to have multiple etiologies, the most studied of which are microbial and immunological.The primary microbial factor contributing to disease is a shift in the content of the oral microflora, while the primary immunological factor is the destructive host inflammatory response.Several techniques have been used clinically to treat periodontitis, but the most successful ones appear to address both the bacterial and inflammatory components of the condition.Therefore, this review will detail the microbial and molecular nature of periodontitis, and it will also compare the efficacy of traditional and emerging technologies for treating this costly disease.
GCH1 Haplotype Determines Vascular and Plasma Biopterin Availability in Coronary Artery Disease
Authors: Charalambos Antoniades, Cheerag Shirodaria, Tim Van Assche, Colin Cunnington, Irmgard Tegeder, Jörn Lötsch, Tomasz J. Guzik, Paul Leeson, Jonathan Diesch, Dimitris Tousoulis, Christodoulos Stefanadis, Clifford J. Woolf, Nicholas J. Alp, Keith M. Channon, Michael Costigan
Journal: Journal of the American College of Cardiology (2008)
Abstract 665: Therapeutic targeting of breast cancer stem cells using PG-101 improves breast cancer survival
Authors: Madhuri Wadehra, Meagan Kiyohara
Journal: Cancer Research (2014)

Abstract Since the original description of CSCs in solid tumors in 2003, emerging evidence suggests the presence of multiple breast CSC states (CD44+CD24-EpCAM+, ALDH+) that might be responsible for distinct processes in breast cancer progression such as metastasis, invasion, and proliferation. It has been hypothesized that CSCs contribute to the cellular heterogeneity within cancer, the metastatic spread, and eventual recurrence. As chemotherapy and radiation are relatively ineffective at targeting CSCs, therapeutic agents that target the relatively rare CSC population are highly needed. To this end, we define another marker epithelial membrane protein-2 (EMP2) as a novel target for this population of cells. EMP2 is an oncogenic protein whose expression has been shown to correlate with tumor progression and survival in a number of human cancers including breast, ovarian, and endometrial tumors. Clinical data also revealed higher levels of EMP2 in metastatic lesions compared to primary tumors and high expression in triple negative breast cancer. In this study, we show new evidence that EMP2 is highly expressed in CSCs and regulates their proposed functions, namely mammosphere formation and invasion. Moreover, in vivo modulation of EMP2 expression in both triple negative and HER2 positive tumors show that EMP2 promotes ALDH1 expression as well as increases tumor load. We have recently developed a novel IgG1 monoclonal antibody to EMP2 termed PG-101, and we have shown that this therapy reduces primary. We now have evidence that PG-101 treatment in the primary tumor is sufficient to reduce secondary tumor formation in triple negative breast cancer cells on the order of 1:20,000 compared to the control treated mice. To extend on the benefits of PG-101, we have combined it with docetaxel in an effort to mimic the clinical setting given that the vast majority of patients treated in the neoadjuvant setting have a taxane as part of the regimen. Data using triple negative xenografts show that PG-101 in combination with docetaxel can cure up to 80% of animals treated. This effect is lasting as these mice have shown no rebound in tumor load more than 2 months following the last treatment. Collectively, these results show that PG-101 therapy has the potential to revolutionize the outcomes for women with breast cancer. Citation Format: Madhuri Wadehra, Meagan Kiyohara. Therapeutic targeting of breast cancer stem cells using PG-101 improves breast cancer survival. [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 665. doi:10.1158/1538-7445.AM2014-665