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Aims: This study examined the social, material and temporal effects of extended-release buprenorphine depot treatment (BUP-XR), among a group of participants commencing BUP-XR in Australia, and considered the situated potentials of these new opioid agonist treatment technologies. Methods: Using a longitudinal qualitative design, 36 participants (25 men, 11 women; mean age 44 years) were interviewed, with 32 followed-up, to generate accounts of BUP-XR experiences. Analysis was informed by sociological approaches which attend to the multiple effects of novel health interventions as they are put to use and made to work, with a focus on tracing change over time. Analysis: The shift from daily to monthly dosing altered how opioid agonist treatment was experienced, reconfigured participants’ relationship to treatment, and affected the temporal patterns of participants’ lives. Extending temporal relations released participants from short-term cycles of living and produced different forms of subjectivity, bringing about both transformation and loss. Monthly dosing, and a sense of normalcy characterized by absenting the routines and felt effects of drugs or treatment medications, potentiated a feeling of stability for many participants. For some, disrupting daily routines precipitated disconnection from treatment and social care relations. The transition from daily to monthly dosing required adaptation and new ways of engaging with treatment and care, with medication acting as a bridge to care without necessarily being the focal point. Conclusions: As BUP-XR treatment gains traction internationally, it will be important to attend to the multiple, and sometimes unexpected, effects this intervention makes in the social and material lives of clients. How choice, social connection, and care can be maintained to help secure BUP-XR’s longer-term impact, and how clients can be supported to adjust to what is felt to be a new normal, will be considerations in future treatment delivery.

Combination therapy with JQ1 and panobinostat synergistically reduces neuroblastoma cell viability.

JQ1 and panobinostat do not cooperatively regulate GSK3β and Aurora A expression, and LIN28B does not regulate Aurora A expression.

The BET bromodomain proteins BRD3 and BRD4 induce N-Myc expression, but do not function synergistically.

The BET bromodomain protein BRD2 does not regulate N-Myc expression.

The top 35 genes most dramatically down-regulated by JQ1 and panobinostat combination therapy.

JQ1 and panobinostat do not cooperatively induce apoptosis in normal non-malignant cells.

Purpose: Patients with neuroblastoma associated with MYCN oncogene amplification experience a very poor prognosis. BET bromodomain inhibitors are among the most promising novel anticancer agents as they block BRD3 and BRD4 from activating oncogene transcription. However, treatment with BET bromodomain inhibitors alone does not result in cancer remission in many murine models.Experimental Design: MYCN-amplified neuroblastoma cells were treated with vehicle control, the BET bromodomain inhibitor JQ1, the histone deacetylase inhibitor panobinostat, or the combination of JQ1 and panobinostat. Genes modulated by JQ1, panobinostat, or the combination therapy were identified by Affymetrix microarray, and cell proliferation and apoptosis were examined by Alamar blue assays and flow cytometry analysis. Modulation of LIN28B promoter activity by BRD3 and BRD4 was examined by chromatin immunoprecipitation and luciferase assays. In addition, neuroblastoma-bearing mice were treated with vehicle control, JQ1, and/or panobinostat.Results: LIN28B was one of the top genes synergistically reduced by JQ1 and panobinostat. BRD3 and BRD4 directly bound to the LIN28B gene promoter and activated LIN28B gene transcription, and knocking down LIN28B reduced the expression of N-Myc protein, but not N-Myc mRNA. JQ1 and panobinostat synergistically reduced LIN28B gene and N-Myc protein expression, and synergistically induced growth inhibition and apoptosis in neuroblastoma cells, but not normal nonmalignant cells in vitro. In neuroblastoma-bearing mice, JQ1 and panobinostat synergistically and considerably reduced N-Myc protein expression in tumor tissues and blocked tumor progression.Conclusions: Our findings have identified a novel strategy to reduce the N-Myc oncoprotein expression and a novel therapeutic approach for the treatment of aggressive neuroblastoma. Clin Cancer Res; 22(10); 2534–44. ©2016 AACR.

Combination therapy with JQ1 and panobinostat exerts synergistic anticancer effects in neuroblastoma cells.

JQ1 and panobinostat synergistically modulate gene expression.

Background Opioid agonist treatment (OAT) is an effective intervention for opioid dependence. Extended-release buprenorphine injections (BUP-XR) may have additional potential benefits over sublingual buprenorphine. This single-arm trial evaluated outcomes among people receiving 48 weeks of BUP-XR in diverse community healthcare settings in Australia, permitting examination of outcomes when BUP-XR is delivered in standard practice. Methods Participants were recruited from a network of specialist public drug treatment services, primary care and some private practices in three states. Following a minimum 7 days on 8–32 mg of sublingual buprenorphine (±naloxone), participants received monthly subcutaneous BUP-XR injections administered by a healthcare practitioner and completed monthly research interviews. The primary endpoint was retention in treatment at 48 weeks. Findings Participants (n = 100) were 28% women, mean age 44 years with a long history of OAT (median 5.8 years); heroin was the most common opioid of concern (58%). Treatment retention at 24 and 48 weeks was 86% and 75%, respectively. Participants with past-month injecting drug use (OR 0.23; 95%CI: 0.09–0.61) or heroin use (OR 0.23; 95%CI: 0.08–0.65) at baseline had lower odds of being retained in treatment to 48 weeks. Reductions in multiple forms of extra-medical drug use were observed. Improvements in quality of life, participation in employment, and treatment satisfaction measures were also observed. Interpretation This real-world implementation study of BUP-XR demonstrated high retention and treatment satisfaction. This study provides important additional data on the uptake and experience of clients, with relevance for policy makers, health service planners, administrators, and practitioners. Funding Indivior. Trial registration ClinicalTrials.gov Identifier: NCT03809143

Stigma has corrosive effects on all aspects of care and can undermine individual and population health outcomes. Addiction-related stigma has implications for opiate agonist treatment (OAT) and the people who receive, provide and fund it. It is important to understand how stigma is made in OAT and the political purposes that it serves, in order to change the relations of stigma and avoid the reproduction of stigma in the delivery of new treatment formulations, such as extended release buprenorphine (BUP-XR).Semi-structured qualitative interviews were conducted at two time points with participants in a prospective single-arm, multicentre, open-label trial of monthly BUP-XR. Thirty-six participants (25 men, 11 women) were interviewed, and of these 32 participated in a second interview to explore their experience of transition from other treatment to BUP-XR.Participants were highly aware of the of the social and material effects of stigma through the negative stereotypes attached to OAT and those who receive it. Participants narrated examples of how stigma governed as a biopower in the relations and practices of OAT provision at numerous levels: structural (such as in public discourse about OAT and the people who receive it, in media, in perceptions about the decisions of investment in medical technologies); organisational (policies about legitimate access to OAT); interpersonal (with health workers) and individual (self-identities). BUP-XR allowed greater freedom and normalcy for clients. The experience of BUP-XR drew attention to the stigmatising potential of time, place and things associated with other OAT requiring daily (or frequent) dosing, accentuating how stigma comes to be materialised as a relational effect of everyday practices.Receiving BUP-XR allowed participants to avoid some of the everyday biopolitical powers of other forms of OAT and to reshape self-identities. The altering of relations between time, place and things associated with other forms of OAT allowed participants to feel as though they "pass as normal" . However, the negative public discourse and stigma of OAT is a potential threat to BUP-XR to realise its potential for individual and population benefits.

IntroductionOpioid agonist treatment is effective for opioid dependence and newer extended-release buprenorphine (BUP-XR) injections represent a significant development. The Community Long-Acting Buprenorphine (CoLAB) study aims to evaluate client outcomes among people with opioid dependence receiving 48 weeks of BUP-XR treatment, and examines the implementation of BUP-XR in diverse community healthcare settings in Australia.Methods and analysisThe CoLAB study is a prospective single-arm, multicentre, open-label trial of monthly BUP-XR injections in people with opioid dependence. Participants are being recruited from a network of general practitioner and specialist drug treatment services located in the states of New South Wales, Victoria and South Australia in Australia. Following a minimum 7 days on 8–32 mg of sublingual buprenorphine (±naloxone), participants will receive monthly subcutaneous BUP-XR injections administered by a healthcare practitioner at intervals of 28 days (−2/+14 days). The primary endpoint is participant retention in treatment at 48 weeks after treatment initiation. Secondary endpoints will evaluate dosing schedule variations, craving, withdrawal, substance use, health and well-being, and client-reported treatment experience. Qualitative and costing substudies will examine implementation barriers and facilitators at the client and provider level.Ethics and disseminationThe study has received ethics approval from the St Vincent’s Hospital Sydney Human Research Ethics Committee (Ref. HREC/18/SVH/221). The findings will be disseminated via publication in peer-reviewed journals, presentations at national and international scientific conferences, and in relevant community organisation publications and forums.Trial registration numberNCT03809143Protocol identifierCoLAB1801, V.4.0 dated 01 August 2019

Background and Objectives: To demonstrate the feasi- bility of a novel, thin film, laser-activated adhesive in sealing penetrative corneal wounds with a view to replac- ing sutures in ophthalmic operations. Methods: A previously described thin film adhesive com- posed of chitosan and indocyanine green activated by in- frared laser (808 nm) was used to seal penetrating corneal wounds ranging from 1 to 6 mm in size in enucle- ated bovine eyes. The excised corneas were subjected to pressure tests to evaluate the strength of the corneal repairs and compared to sutures and commercial fibrin glue, Tisseel 1 . Temperatures at the adhesive-tissue in- terface were measured and histological examinations of the repairs performed to investigate potential tissue dam- age. Biodegradability of the films was monitored in lyso- zyme solutions at concentrations reported in tears. Results: The adhesive effectively sealed corneal wounds, withstanding pressures of 140-320 mmHg, far in excess of the normal intraocular pressure. In contrast, pressures of 40-80 mm Hg were determined using a combination of sutures with Tisseel 1 as a sealant. The laser-activation process was 1.5-5 times faster than other procedures studied and required no curing time. A transient, mean temperature of 56 � 28C was measured at the adhesive- tissue interface while histology showed no tissue damage as a consequence of the irradiation process. Irradiation had no significant influence on adhesive biodegradation in vitro, which lost approximately 30% of their initial weight in a lysozyme solution (6 mg ml � 1 ). Conclusions: The thin film adhesive was found to be an effective in sealing corneal wounds with considerable advantages over sutures, including speed of application and sealing strength and biodegradability. Lasers Surg. Med. 43:490-498, 2011. 2011 Wiley-Liss, Inc.

Purpose: Patients with neuroblastoma associated with MYCN oncogene amplification experience a very poor prognosis. BET bromodomain inhibitors are among the most promising novel anticancer agents as they block BRD3 and BRD4 from activating oncogene transcription. However, treatment with BET bromodomain inhibitors alone does not result in cancer remission in many murine models. Experimental Design: MYCN-amplified neuroblastoma cells were treated with vehicle control, the BET bromodomain inhibitor JQ1, the histone deacetylase inhibitor panobinostat, or the combination of JQ1 and panobinostat. Genes modulated by JQ1, panobinostat, or the combination therapy were identified by Affymetrix microarray, and cell proliferation and apoptosis were examined by Alamar blue assays and flow cytometry analysis. Modulation of LIN28B promoter activity by BRD3 and BRD4 was examined by chromatin immunoprecipitation and luciferase assays. In addition, neuroblastoma-bearing mice were treated with vehicle control, JQ1, and/or panobinostat. Results: LIN28B was one of the top genes synergistically reduced by JQ1 and panobinostat. BRD3 and BRD4 directly bound to the LIN28B gene promoter and activated LIN28B gene transcription, and knocking down LIN28B reduced the expression of N-Myc protein, but not N-Myc mRNA. JQ1 and panobinostat synergistically reduced LIN28B gene and N-Myc protein expression, and synergistically induced growth inhibition and apoptosis in neuroblastoma cells, but not normal nonmalignant cells in vitro. In neuroblastoma-bearing mice, JQ1 and panobinostat synergistically and considerably reduced N-Myc protein expression in tumor tissues and blocked tumor progression. Conclusions: Our findings have identified a novel strategy to reduce the N-Myc oncoprotein expression and a novel therapeutic approach for the treatment of aggressive neuroblastoma. Clin Cancer Res; 22(10); 2534–44. ©2016 AACR.

Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a stress-induced p53-target gene whose expression is modulated by transcription factors such as p53, p73, and E2F1. TP53INP1 gene encodes two isoforms of TP53INP1 proteins, TP53INP1α and TP53INP1β, both of which appear to be key elements in p53 function. In association with homeodomain-interacting protein kinase-2 (HIPK2), TP53INP1 phosphorylates p53 protein at Serine-46. This enhances p53 protein stability and its transcriptional activity, leading to transcriptional activation of p53-target genes such as p21 and PIG3, cell growth arrest and apoptosis upon DNA damage stress. The anti-proliferative and pro-apoptotic activities of TP53INP1 indicate that TP53INP1 has an important role in cellular homeostasis and DNA damage response. Deficiency in TP53INP1 expression results in increased tumorigenesis, whereas TP53INP1 expression is repressed during early stages of cancer by factors such as miR-155. This review aims to summarize the roles of TP53INP1 in blocking tumor progression through p53-dependant and p53-independent pathways, as well as the elements which repress TP53INP1 expression, hence highlighting its potential as a therapeutic target in cancer treatment.

To demonstrate the feasibility of a novel, thin film, laser-activated adhesive in sealing penetrative corneal wounds with a view to replacing sutures in ophthalmic operations.A previously described thin film adhesive composed of chitosan and indocyanine green activated by infrared laser (808 nm) was used to seal penetrating corneal wounds ranging from 1 to 6 mm in size in enucleated bovine eyes. The excised corneas were subjected to pressure tests to evaluate the strength of the corneal repairs and compared to sutures and commercial fibrin glue, Tisseel®. Temperatures at the adhesive-tissue interface were measured and histological examinations of the repairs performed to investigate potential tissue damage. Biodegradability of the films was monitored in lysozyme solutions at concentrations reported in tears.The adhesive effectively sealed corneal wounds, withstanding pressures of 140-320 mmHg, far in excess of the normal intraocular pressure. In contrast, pressures of 40-80 mm Hg were determined using a combination of sutures with Tisseel® as a sealant. The laser-activation process was 1.5-5 times faster than other procedures studied and required no curing time. A transient, mean temperature of 56 ± 2°C was measured at the adhesive-tissue interface while histology showed no tissue damage as a consequence of the irradiation process. Irradiation had no significant influence on adhesive biodegradation in vitro, which lost approximately 30% of their initial weight in a lysozyme solution (6 mg ml(-1)).The thin film adhesive was found to be an effective in sealing corneal wounds with considerable advantages over sutures, including speed of application and sealing strength and biodegradability.

Myc oncoproteins and histone deacetylases (HDACs) exert oncogenic effects by modulating gene transcription. Paradoxically, N-Myc induces p53 gene expression. Tumor protein 53-induced nuclear protein 1 (TP53INP1) phosphorylates p53 protein at serine 46, leading to enhanced p53 activity, transcriptional activation of p53 target genes and programmed cell death. We aimed to identify the mechanism through which N-Myc overexpressing p53 wild-type neuroblastoma cells acquired resistance to apoptosis.Gene and protein expression was analysed by real-time RT-PCR and immunoblot. Cell survival/death was examined by flow cytometry study of Annexin V-staining. The prognostic value of TP53INP1 expression in tumor tissues was investigated in three independent cohorts of neuroblastoma patients. TP53INP1 was one of the genes most significantly repressed by HDAC2 and N-Myc according to Affymetrix microarray gene expression datasets. HDAC2 and N-Myc reduced TP53INP1 gene expression by direct binding to the TP53INP1 gene promoter, leading to transcriptional repression of TP53INP1, p53 protein de-phosphorylation at serine 46, neuroblastoma cell proliferation and survival. Moreover, low levels of TP53INP1 expression in human neuroblastoma tissues correlated with high levels of N-Myc expression and poor patient outcome, and the BET bromodomain inhibitors JQ1 and I-BET151 reduced N-Myc expression and reactivated TP53INP1 expression in neuroblastoma cells. These findings identify TP53INP1 repression as an important co-factor for N-Myc oncogenesis, and provide further evidence for the potential application of BET bromodomain inhibitors in the therapy of N-Myc-induced neuroblastoma. Citation Format: Jeyran Shahbazi, Christopher J. Scarlett, Murray Norris, Bing Liu, Michelle Haber, Andrew E. Tee, Alice Carrier, Andrew V. Biankin, Wendy B. London, Glenn M. Marshall, Richard Lock, Tao Liu. Histone deacetylase 2 and N-Myc reduce p53 protein phosphorylation at serine 46 by repressing gene transcription of tumor protein 53-induced nuclear protein 1. [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 5138. doi:10.1158/1538-7445.AM2014-5138