49 research outputs found
Expression of V1A and GRP receptors leads to cellular transformation and increased sensitivity to substance-P analogue-induced growth inhibition.
Small-cell lung cancer (SCLC) is a particularly aggressive cancer, which metastasises early. Despite initial sensitivity to radio- and chemo-therapy, it invariably relapses, so that the 2-year survival remains less than 5%. Neuropeptides particularly arginine vasopressin (AVP) and gastrin-releasing peptide (GRP) act as autocrine and paracrine growth factors and the expression of these and their receptors are a hallmark of the disease. Substance-P analogues including [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance-P (SP-D) and [Arg6,D-Trp7,9,NmePhe8]-substance-P (6-11) (SP-G) inhibit the growth of SCLC cells by modulating neuropeptide signalling. We show that GRP and V1A receptors expression leads to the development of a transformed phenotype. Addition of neuropeptide provides some protection from etoposide-induced cytotoxicity. Receptor expression also leads to an increased sensitivity to substance-P analogue-induced growth inhibition. We show that SP-D and SP-G act as biased agonists at GRP and V1A receptors causing blockade of Gq-mediated Ca2+ release while directing signalling to activate ERK via a pertussis toxin-sensitive pathway. This is the first description of biased agonism at V1A receptors. This unique pharmacology governs the antiproliferative properties of these agents and highlights their potential therapeutic potential for the treatment of SCLC and particularly in tumours, which have developed resistance to chemotherapy
Hepatitis C Virus infection in Irish drug users and prisoners : a scoping review
Background: Hepatitis C infection is a major public health concern globally. In Ireland, like other European countries, people who use drugs (PWUD) and prisoners carry a larger HCV disease burden than the general population. Recent advances in HCV management have made HCV elimination across Europe a realistic goal. Engaging these two marginalised and underserved populations remains a challenge. The aim of this review was to map key findings and identify gaps in the literature (published and unpublished) on HCV infection in Irish PWUD and prisoners.Methods: A scoping review guided by the methodological framework set out by Levac and colleagues (based on previous work by Arksey & O’Malley).Results: A total of 58 studies were identified and divided into the following categories; Epidemiology, Guidelines and Policy, Treatment Outcomes, HCV -related Health Issues and qualitative research reporting on Patients’ and Health Providers’ Experiences. This review identified significantly higher rates of HCV infection among Irish prisoners and PWUD than the general population. There are high levels of undiagnosed and untreated HCV infection in both groups. There is poor engagement by Irish PWUD with HCV services and barriers have been identified. Prison hepatology nurse services have a positive impact on treatment uptake and outcomes. Identified gaps in the literature include; lack of accurate epidemiological data on incident infection, untreated chronic HCV infection particularly in PWUD living outside Dublin and those not engaged with OST. Conclusion: Ireland like other European countries has high levels of undiagnosed and untreated HCV infection. Collecting, synthesising and identifying gaps in the available literature is timely and will inform national HCV screening, treatment and prevention strategies
Antioxidant vitamins C and E ameliorate hyperglycaemia-induced oxidative stress in coronary endothelial cells
A-to-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypoedited in glioblastoma multiforme
Editing in microRNAs, particularly in seed can significantly alter the choice of their target genes. We show that out of 13 different human tissues, different regions of brain showed higher adenosine to inosine (A-to-I) editing in mature miRNAs. These events were enriched in seed sequence (73.33%), which was not observed for cytosine to uracil (17.86%) editing. More than half of the edited miRNAs showed increased stability, 72.7% of which had ΔΔG values less than -6.0 Kcal/mole and for all of them the edited adenosines mis-paired with cytosines on the pre-miRNA structure. A seed-editing event in hsa-miR-411 (with A – C mismatch) lead to increased expression of the mature form compared to the unedited version in cell culture experiments. Further, small RNA sequencing of GBM patient identified significant miRNA hypoediting which correlated with downregulation of ADAR2 both in metadata and qRT-PCR based validation. Twenty-two significant (11 novel) A-to-I hypoediting events were identified in GBM samples. This study highlights the importance of specific sequence and structural requirements of pre-miRNA for editing along with a suggestive crucial role for ADAR2. Enrichment of A-to-I editing in seed sequence highlights this as an important layer for genomic regulation in health and disease, especially in human brain
Twenty years on, the Methadone Treatment Protocol in Ireland: Reflections on General Practice
Background: Opioid dependence, characterised by socio economic disadvantage and significant morbidity and mortality, remains a major public health problem in Ireland. Through the methadone treatment protocol (MTP), Irish general practice has been a leader in the introduction and expansion of Irish harm reduction services, including opioid substitution treatment (OST), needle and syringe programs (NSP) and naloxone provision. These services have been effective in engaging opiate users in treatment, reducing human deficiency virus (HIV) and hepatitis C virus (HCV) transmission and reducing drug related morbidities. Challenges remain in relation to choice of substitution treatments, timely access to OST services, adequate coverage of NSP, naloxone provision and increasing drug related deaths.Methods: A narrative review was conducted and designed to present a broad perspective on the Irish MTP, and to describe its history and development in terms of clinical care, stakeholder views and changing trends.Results: Three themes emerged from the analysis; The History of the Methadone Treatment Protocol, Service User and Provider Views, and Challenges and Developments. Despite initial concern about methadone maintenance treatment (MMT) in Ireland, increased participation by Irish GPs in the treatment of opioid dependence is observed over the last two decades. There are now over 10,000 people on methadone treatment in Ireland, with 40% treated in general practice. The MTP provides structure, remuneration and guidance to GPs and is underpinned by; training, ongoing education and a system of quality assurance provided by the Irish College of General Practice (ICGP). Challenges include the negative views of patients around how methadone services are delivered, the stigma associated with methadone treatment, the lack of choice around substitution medication, waiting lists for treatment in certain areas and rates of fatal overdose.Conclusion: Twenty years of the MTP has been the mainstay of harm reduction services in Ireland. It has provided a network of specially trained GPs who provide methadone to over 10,000 patients across Ireland within a structured framework of training, quality assurance and remuneration. With the ongoing commitment of Irish specialists in the field of addiction medicine, further improvements to support and treat patients can be made
Ectopic pregnancy secondary to in vitro fertilisation-embryo transfer: pathogenic mechanisms and management strategies
Provasopressin expression by breast cancer cells: implications for growth and novel treatment strategies
The arginine vasopressin (AVP) gene is expressed in certain cancers such as breast cancer, where it is believed to act as an autocrine growth factor. However, little is known about the regulation of the AVP protein precursor (proAVP) or AVP-mediated signaling in breast cancer and this study was undertaken to address some of the basic issues. The cultured cell lines examined (Mcf7, Skbr3, BT474, ZR75, Mcf10a) and human breast cancer tissue extract were found to express proAVP mRNA. Western analysis revealed multiple forms of proAVP protein were present in cell lysates, corresponding to those detected in human hypothalamus extracts. Monoclonal antibodies directed against different regions of proAVP bound to intact live Mcf7 and Skbr3 cells. Dexamethasone increased the amount of proAVP-associated glycopeptide (VAG) secreted by Skbr3 cells and a combination of dexamethasone, IBMX and 8br-cAMP increased cellular levels of VAG. Exogenous AVP (1, 10, and 100 nM) elevated phospho-ERK1/2 levels, and increased cell proliferation was observed in the presence of 10 nM AVP. Concurrent treatment with the V1a receptor antagonist SR49059 reduced the effects of AVP on proliferation in Mcf7 cells, and abolished it in Skbr3 cells. Results here show that proAVP components are found at the surface of Skbr3 and Mcf7 cells and are also secreted from these cells. In addition, they show that AVP promotes cancer cell growth, apparently through a V1-type receptor-mediated pathway and subsequent ERK1/2 activation. Thus, strategies for targeting proAVP should be examined for their effectiveness in diagnosing and treating breast cancer