Induction of epstein-barr virus (EBV) lytic cycle in vitro causes lipid peroxidation, protein oxidation and DNA damage in lymphoblastoid B cell lines

<p>Abstract</p> <p>Background</p> <p>We investigated the oxidative modifications of lipids, proteins and DNA, potential molecular targets of oxidative stress, in two lymphoblastoid cell lines: B95-8 and Raji, after EBV lytic cycle induction. Conjugated dienes level was measured as biomarker of lipid peroxidation. Malondialdehyde adduct and protein carbonyl levels, as well as protein thiol levels were measured as biomarkers of protein oxidation. DNA fragmentation was evaluated as biomarker of DNA oxidation.</p> <p>Results</p> <p>After 48 h (peak of lytic cycle), a significant increase in conjugated dienes level was observed in B95-8 and Raji cell lines (p = 0.0001 and p = 0.019 respectively). Malondialdehyde adduct, protein carbonyl levels were increased in B95-8 and Raji cell lines after EBV lytic cycle induction as compared to controls (MDA-adduct: p = 0.008 and p = 0.006 respectively; Carbonyl: p = 0.003 and p = 0.0039 respectively). Proteins thiol levels were decreased by induction in B95-8 and Raji cell lines (p = 0.046; p = 0.002 respectively). DNA fragmentation was also detected in B95-8 and Raji cell lines after EBV lytic cycle induction as compared to controls.</p> <p>Conclusion</p> <p>The results of this study demonstrate the presence of increased combined oxidative modifications in lipids, proteins in B95-8 and Raji cells lines after EBV lytic cycle induction. These results suggest that lipid peroxidation, protein oxidation and DNA fragmentation are generally induced during EBV lytic cycle induction and probably contribute to the cytopathic effect of EBV.</p

Controversies in Targeted Therapy of Adult T Cell Leukemia/Lymphoma: ON Target or OFF Target Effects?

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

The Leukemic Fly: Promises and Challenges

Leukemia involves different types of blood cancers, which lead to significant mortality and morbidity. Murine models of leukemia have been instrumental in understanding the biology of the disease and identifying therapeutics. However, such models are time consuming and expensive in high throughput genetic and drug screening. Drosophila melanogaster has emerged as an invaluable in vivo model for studying different diseases, including cancer. Fruit flies possess several hematopoietic processes and compartments that are in close resemblance to their mammalian counterparts. A number of studies succeeded in characterizing the fly&rsquo;s response upon the expression of human leukemogenic proteins in hematopoietic and non-hematopoietic tissues. Moreover, some of these studies showed that these models are amenable to genetic screening. However, none were reported to be tested for drug screening. In this review, we describe the Drosophila hematopoietic system, briefly focusing on leukemic diseases in which fruit flies have been used. We discuss myeloid and lymphoid leukemia fruit fly models and we further highlight their roles for future therapeutic screening. In conclusion, fruit fly leukemia models constitute an interesting area which could speed up the process of integrating new therapeutics when complemented with mammalian models

Inflammatory Markers and MicroRNAs: The Backstage Actors Influencing Prognosis in Colorectal Cancer Patients

Background: Colorectal cancer (CRC) remains a deadly disease, afflicting the lives of millions worldwide. The prognosis of CRC patients is best predicted by surgical resection and pathological analysis of specimens. Emerging evidence has attributed a significant role to inflammatory markers and microRNAs (miRNAs) in the prognosis and survival of CRC patients. Aim: Here, we review the literature on inflammatory markers and miRNAs with an established role on survival rates, response to systemic chemotherapy, and other clinic-pathological parameters in CRC patients. Results: Our literature review revealed a critical role of inflammatory markers&mdash;specifically, the acute-phase proteins, inflammatory cytokines, and blood cell ratios&mdash;on prognostic outcomes in CRC patients. MiRNAs, on the other hand, were useful in predicting prognosis and clinical response and accordingly stratifying CRC patients for optimal drug selection. Conclusion: These biomarkers are easily measured in routine blood exams and can be used in adjunct to the tumor-node-metastasis (TNM) staging system to identify high-risk patients and those who are more likely to benefit from chemotherapy and other targeted therapies. However, more prospective studies are needed for the validation of these discussed prognostic and predictive biomarkers

Arsenic/interferon-a triggered apoptosis in HTLV-I transformed cells is associated with proteasome mediated tax degradation and reversal of NF-κB activation

HTLV-I associated Adult T cell leukemia /lymphoma (ATL) is a malignancy of mature activated T cells resistant to conventional chemotherapy. The viral transactivator oncoprotein Tax plays a critical role in HTLV-I-induced transformation and resistance to apoptosis, through the activation of the NF-KB pathway by inducing IicB-a and IicE'-β degradation. We have previously shown that the combination of arsenic trioxide (As) and interferon-ot (IFN) is highly effective to induce cell cycle arrest and apoptosis in HTLVI positive cells compared to HTLV-1 negative T cells. We have also demonstrated that cell death induction by As and IFN in HTLV-I transformed cells is only partially dépendant upon caspase activation and is not associated with modulation of bcl-2, bax or p 53 expression. In this study, we show that the combination of As and IFN induces the downregulation of Tax by the proteasome in both HTLV-I transformed cells and in T-cdls transiently transfected with Tax. This is associated with an upregulation of iKB-a, tofiβ and iKB-e through inhibition of their proteasomal degradation. Furthermore, As/EN treatment inhibits NF-KB reporter gene induction after Tax transfection and results in a sharp decrease in RelA DNA binding NF-KB complexes in HTLV-I transformed cells due to the cytoplasmic retention of RelA. Although Tax was previously shown to bind proteasome subunits to enhance lKB-a degradation, using kinetic studies we showed that As alone increases lKB-a level before the occurrence of Tax down-regulation. This sugge sts that As and As/IFN alters the proteasome function qualitatively to differentially enhance Tax degradation and inhibit lKB-a degradation. Such specific targeting of the viral oncoprotein by IFN/As treatment, reminiscent of As targeting of PML/RARa in acute promyelocytic leukemia, provides strong rational for combined IFN/As therapy in ATL patients. Indeed, preliminary results of a phase II clinical trial in relapsed/refractory ATL patients are encouraging suggesting the possibility of introducing As in the first line therapy of ATL.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Insights on the Biomarker Potential of Exosomal Non-Coding RNAs in Colorectal Cancer: An In Silico Characterization of Related Exosomal lncRNA/circRNA–miRNA–Target Axis

Colorectal cancer (CRC) is one of the most common cancer types, ranking third after lung and breast cancers. As such, it demands special attention for better characterization, which may eventually result in the development of early detection strategies and preventive measures. Currently, components of bodily fluids, which may reflect various disease states, are being increasingly researched for their biomarker potential. One of these components is the circulating extracellular vesicles, namely, exosomes, which are demonstrated to carry various cargo. Of importance, the non-coding RNA cargo of circulating exosomes, especially long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and micro RNAs (miRNAs), may potentially serve as significant diagnostic and prognostic/predictive biomarkers. In this review, we present existing evidence on the diagnostic and prognostic/predictive biomarker value of exosomal non-coding RNAs in CRC. In addition, taking advantage of the miRNA sponging functionality of lncRNAs and circRNAs, we demonstrate an experimentally validated CRC exosomal non-coding RNA-regulated target gene axis benefiting from published miRNA sponging studies in CRC. Hence, we present a set of target genes and pathways downstream of the lncRNA/circRNA–miRNA–target axis along with associated significant Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, which may collectively serve to better characterize CRC and shed light on the significance of exosomal non-coding RNAs in CRC diagnosis and prognosis/prediction

miRNA expression in advanced Algerian breast cancer tissues.

Breast cancer is one of the commonest cancers among Algerian females. Compared to Western populations, the median age of diagnosis of breast cancer is much lower in Algeria. The objective of this study is to explore the expression of several miRNAs reported to be deregulated in breast cancer. The miRNAs miR-21, miR-125b, miR-100, miR-425-5p, miR-200c, miR-183 and miR-182 were studied on tumor and normal adjacent Algerian breast tissues using quantitative reverse transcription real time PCR, and the results were analyzed according to clinical characteristics. Compared to the normal adjacent tissues, miR-21, miR-183, miR-182, miR-425-5p and miR-200c were found to be upregulated while miR-100 and miR-125b were insignificantly deregulated. A positive correlation was noted among miR-183, miR-182 and miR-200c and among miR-425-5p, miR-183, miR-200c and miR-21. Further global miRNA microarray profiling studies can aid in finding ethnic specific miRNA biomarkers in the Algerian breast cancer population