Detection of somatostatin receptors in human osteosarcoma

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IgE-Mediated Multimorbidities in Allergic Asthma and the Potential for Omalizumab Therapy

Allergic asthma often coexists with different pathological conditions, called multimorbidities, that are mostly of allergic nature and share a common underlying inflammatory pathophysiological mechanism. Multimorbidities of allergic asthma may influence asthma control, its severity, and patients' response to treatment, and contribute to the overall socioeconomic burden of the disease. Immunoglobulin E (IgE) is known to play a central role in the pathogenesis of various allergic diseases, including asthma. Thus, IgE-mediated immunologic pathways present an attractive target for intervention in asthma and multimorbidities. In this review, we discuss the most frequently reported IgE-mediated multimorbidities in allergic asthma, including allergic rhinitis, rhinoconjunctivitis, atopic dermatitis, vernal keratoconjunctivitis, chronic rhinosinusitis with nasal polyps, food allergies, and allergic bronchopulmonary aspergillosis. Omalizumab is a recombinant humanized monoclonal antibody against IgE and has been in use to treat allergic asthma for more than a decade. We comprehensively review the clinical evidence for omalizumab in the treatment of the aforementioned multimorbidities in allergic asthma

Phosphoproteomics Screen Reveals Akt Isoform-Specific Signals Linking RNA Processing to Lung Cancer

The three Akt isoforms are functionally distinct. Here we show that their phosphoproteomes also differ, suggesting that their functional differences are due to differences in target specificity. One of the top cellular functions differentially regulated by Akt isoforms is RNA processing. IWS1, an RNA processing regulator, is phosphorylated by Akt3 and Akt1 at Ser720/Thr721. The latter is required for the recruitment of SETD2 to the RNA Pol II complex. SETD2 trimethylates histone H3 at K36 during transcription, creating a docking site for MRG15 and PTB. H3K36me3-bound MRG15 and PTB regulate FGFR-2 splicing, which controls tumor growth and invasiveness downstream of IWS1 phosphorylation. Twenty-one of the twenty-four non-small-cell-lung carcinomas we analyzed express IWS1. More importantly, the stoichiometry of IWS1 phosphorylation in these tumors correlates with the FGFR-2 splicing pattern and with Akt phosphorylation and Akt3 expression. These data identify an Akt isoform-dependent regulatory mechanism for RNA processing and demonstrate its role in lung cancer

Use of interrupter technique in assessment of bronchial responsiveness in normal subjects

BACKGROUND: A number of subjects, especially the very young and the elderly, are unable to cooperate and to perform forced expiratory manoeuvres in the evaluation of bronchial hyperresponsiveness (BHR). The objective of our study was to investigate the use of the interrupter technique as a method to measure the response to provocation and to compare it with the conventional PD(20 )FEV(1). METHODS: We studied 170 normal subjects, 100 male and 70 female (mean ± SD age, 38 ± 8.5 and 35 ± 7.5 years, respectively), non-smoking from healthy families. These subjects had no respiratory symptoms, rhinitis or atopic history. A dosimetric cumulative inhalation of methacholine was used and the response was measured by the dose which increases baseline end interruption resistance by 100% (PD(100)Rint, EI) as well as by percent dose response ratio (DRR). RESULTS: BHR at a cut-off level of 0.8 mg methacholine exhibited 31 (18%) of the subjects (specificity 81.2%), 21 male and 10 female, while 3% showed a response in the asthmatic range. The method was reproducible and showed good correlation with PD(20)FEV(1 )(r = 0.76, p < 0.005), with relatively narrow limits of agreement at -1.39 μmol and 1.27 μmol methacholine, respectively, but the interrupter methodology proved more sensitive than FEV(1 )in terms of reactivity (DRR). CONCLUSIONS: Interrupter methodology is clinically useful and may be used to evaluate bronchial responsiveness in normal subjects and in situations when forced expirations cannot be performed

Acetylator phenotypes in Greece

Three groups of patients from various areas of Greece were studied as to their acetylisoniazid index (ratio of acetylisoniazid to isoniazid in plasma 4 hrs after ingestion of 300 mg INH). The first group consisted of 79 patients being treated for pulmonary and extrapulmonary tuberculosis. The second group consisted of 47 patients suffering from bronchogenic carcinoma. And the third group consisted of 14 patients with "classical" Rheumatoid Arthritis. The overall distribution of N-acetyliosis phenotypes was found to be in agreement with distributions reported in other European populations (59,52% slow VS, 40,48% fast). People from different areas of Greece were found to be consistent as to their acetyloisoniazid index mean values variation, and phenotype distribution. Comparison of the group of patients suffering from bronchogenic carcinoma with the group of tuberculosis patients failed to reveal a relationship between N-acetyliosis phenotypes and bronchogenic carcinoma. The group of patients with Rheumatoid Arthritis presented with higher acetyloisoniazid index values when compared to controls. An inversion of the expected radio between fast and slow phenotypes was observed, but this did not reach a statistically significant value.Ο φαινότυπος ισονιαζιδικού μεταβολισμού καθορίστηκε με μετρήσεις του Δείκτη ακετυλοϊσονιαζίδης (κλάσμα ακετυλοϊσονιαζίδης προς ισονιαζίδη στο πλάσμα 4 ώρες μετά τη λήψη από το στόμα 300 mg ΙΝΗ) σε τρεις ομάδες ασθενών με καταγωγή από διαφορετικές περιοχές της Ελλάδας. Η πρώτη ομάδα αποτελείτο από 79 ασθενείς που υποβάλλοντο σε θεραπευτική αγωγή για πνευμονική, ή εξωπνευμονική, φυματίωση. Η δεύτερη ομάδα αποτελείτο από 47 ασθενείς που έπασχαν από βρογχογενή καρκίνο πνεύμονος. Η τρίτη ομάδα αποτελείτο από 14 ασθενείς με "κλασική" Ρευματοειδή Αρθρίτιδα. Η κατανομή των φαινοτύπων ήταν 59,52% για τους βραδείς και 40,48% για τους ταχείς ακετυλιωτές, και δεν διέφερε από αναφερόμενε ς αναλογίες σε άλλες ευρωπαϊκές χώρες. Οι μέσες τιμές του δείκτη ακετυλοϊσονιαζίδης και η φαινοτυπική κατανομή δεν διέφεραν σημαντικά μεταξύ των γεωγραφικών περιοχών που μελετήσαμε. Η σύγκριση της ομάδας των ασθενών με βρογχογενή καρκίνο πνεύμονος με την ομάδα των ασθενών με φυματίωση, δεν απέδειξε σχέση μεταξύ φαινοτύπου Ν-ακετυλίωσης και βρογχογενούς καρκίνου πνεύμονος. Η ομάδα των ασθενών με Ρευματοειδή Αρθίτιδα παρουσίασε υψηλότερες τιμές δείκτη ακετυλοϊσονιαζίδης, όταν συγκρίθηκε με τις ομάδες ελέγχου. Επίσης, παρατηρήθηκε τάση αναστροφής της αναμενόμενης σχέσης ταχέων - βραδέων φαινοτύπων, αλλά η διαφορά δεν ήταν στατιστικά σημαντική όταν έγινε σύγκριση με ομάδα ελέγχου

Asthma patients are Still Fighting for Breath

Fighting for Breath, survey conducted by EFA in 2005, showed that high proportions of patients (pts) were living with uncontrolled severe asthma symptoms, with possible reasons for poor quality of life (QoL) as exposure to passive smoking, lack of treatment by specialist and absence of new treatments. A decade apart in 2016, we conducted Still Fighting for Breath (GfK on behalf of Novartis upon EFA’s invitation), an online survey in 1333 pts with severe persistent asthma (SPA) from 9 countries (Fig1a), aimed to assess impact of SPA on patients’ QoL. Here we compare the impact of severe persistent asthma on patient’s lives between the two surveys. Large discrepancy was seen between the proportion of pts who perceived their asthma to be well-controlled (42%) and the pts who were well-controlled as per GINA assessment (6%). Impact of asthma on psychological well-being and other activities is given in Fig1b. Though steps have been taken to improve the QoL of asthma pts (law banning smoking in public spaces, new treatments), in the last decade the QoL of severe asthmatic pts has not ameliorated significantly (Fig1c). There is a need for improved management (support and strategies) of pts with SPA and better coordination of efforts (enhancing asthma education, assessing perception of control, patient-physician interaction, guideline implementation, treatment compliance, involvement of pts organisations), which would enable these pts to achieve better disease control

Smoking and severe persistent asthma

Smoking has detrimental effects on different clinical aspects of asthma, like accelerated decline in lung function, diminished symptom control, worse quality of life(QoL) and impaired therapeutic response. Fighting for Breath, a survey conducted by EFA(2005) showed that a worrying number of uncontrolled asthmatic patients(pts) indicated exposure to passive smoking as possible reason for poor QoL. After a decade, we conducted Still Fighting for Breath(GfK on behalf of Novartis upon EFA's invitation), an online survey in 1333 pts with severe persistent asthma(SPA) to assess the impact of SPA on pts’ daily life(fig1). Though law banning smoking in public spaces is implemented, still a high proportion of pts(88%) reported disruption in activities of daily living with 38% presenting poor perception of their disease control(disconnect b/w Pts perception and GINA assessment). Asthmatics identified exposure to smoking as trigger for exacerbations, with 63% of them(68% of caregivers) avoiding smoky premises. Percentage of smokers with SPA was higher than the general population in some of the countries. Current smokers with asthma were significantly more frequently diagnosed with anxiety(47%) and depression (41%) than never-smokers(40% and 27%, resp.) and ex-smokers(42% and 28%, resp.)(z-test, Α = 0.05). Thus, there is a need for improved management and support(smoking cessation, treatment, assessment of perception and psychological conditions) of asthmatic smokers with SPA

The Downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 Axis and by Human Cytomegalovirus (HCMV) Associated Factors Allows the Activation of the HCMV Major IE Promoter and the Transition to Productive Infection

<div><p>Earlier studies had suggested that epigenetic mechanisms play an important role in the control of human cytomegalovirus (HCMV) infection. Here we show that productive HCMV infection is indeed under the control of histone H3K27 trimethylation. The histone H3K27 methyltransferase EZH2, and its regulators JARID2 and NDY1/KDM2B repress GFI1, a transcriptional repressor of the major immediate-early promoter (MIEP) of HCMV. Knocking down EZH2, NDY1/KDM2B or JARID2 relieves the repression and results in the upregulation of GFI1. During infection, the incoming HCMV rapidly downregulates the GFI1 mRNA and protein in both wild-type cells and in cells in which EZH2, NDY1/KDM2B or JARID2 were knocked down. However, since the pre-infection levels of GFI1 in the latter cells are significantly higher, the virus fails to downregulate it to levels permissive for MIEP activation and viral infection. Following the EZH2-NDY1/KDM2B-JARID2-independent downregulation of GFI1 in the early stages of infection, the virus also initiates an EZH2-NDY1/ΚDM2Β-JARID2-dependent program that represses GFI1 throughout the infection cycle. The EZH2 knockdown also delays histone H3K27 trimethylation in the immediate early region of HCMV, which is accompanied by a drop in H3K4 trimethylation that may contribute to the shEZH2-mediated repression of the major immediate early HCMV promoter. These data show that HCMV uses multiple mechanisms to allow the activation of the HCMV MIEP and to prevent cellular mechanisms from blocking the HCMV replication program.</p></div