Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma.

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation and apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.

Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitor.

Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that jumonji domain containing 6, arginine demethylase, and lysine hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven human neuroblastoma. JMJD6 cooperates with MYC in cellular transformation of murine neural crest cells by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a 'molecular glue' that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.

Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys.

RATIONALE: Combinations of mu and kappa-opioid receptor (KOR) agonists have been proposed as analgesic formulations with reduced abuse potential. The feasibility of this approach has been increased by the development of KOR agonists with biased signaling profiles that produce KOR-typical antinociception with fewer KOR-typical side effects. OBJECTIVE: The present study determined if the biased KOR agonists, nalfurafine and triazole 1.1, could reduce choice for oxycodone in rhesus monkeys as effectively as the typical KOR agonist, salvinorin A. METHODS: Adult male rhesus monkeys (N = 5) responded under a concurrent schedule of food delivery and intravenous cocaine injections (0.018 mg/kg/injection). Once trained, cocaine (0.018 mg/kg/injection) or oxycodone (0.0056 mg/kg/injection) was tested alone or in combination with contingent injections of salvinorin A (0.1-3.2 µg/kg/injection), nalfurafine (0.0032-0.1 µg/kg/injection), triazole 1.1 (3.2-100.0 µg/kg/injection), or vehicle. In each condition, the cocaine or oxycodone dose, as well as the food amount, was held constant across choice components, while the dose of the KOR agonist was increased across choice components. RESULTS: Cocaine and oxycodone were chosen over food on more than 80% of trials when administered alone or contingently with vehicle. When KOR agonists were administered contingently with either cocaine or oxycodone, drug choice decreased in a dose-dependent manner. Salvinorin A and triazole 1.1 decreased drug-reinforcer choice without altering total trials completed (i.e., choice allocation shifted to food), while nalfurafine dose dependently decreased total trials completed. CONCLUSIONS: These results demonstrate that salvinorin A and triazole 1.1, but not nalfurafine, selectively reduce cocaine and oxycodone self-administration independent of nonspecific effects on behavior, suggesting that G-protein bias does not appear to be a moderating factor in this outcome. Triazole 1.1 represents an important prototypical compound for developing novel KOR agonists as deterrents for prescription opioid abuse.

Psychosis secondary to thyrotoxicosis that persisted post-thyroidectomy: a case report.

BACKGROUND: This case report is of a patient with psychosis secondary to thyrotoxicosis that persisted and reemerged after definitive treatment of thyroidectomy, which is a unique occurrence in the literature. CASE PRESENTATION: This patient is a male between 30 and 35 years of age with a history of Graves Disease and no past psychiatric history who was admitted to the hospital due to psychosis secondary to thyrotoxicosis. The thyrotoxicosis was treated with surgical removal, but the psychotic symptoms persisted after surgery and normalization of standard thyroid functional measures. The symptoms were of sufficient significance for inpatient psychiatric hospitalization, a rare occurrence. Ultimately after an extended stay in the psychiatric unit, the patient's symptoms stabilized with a second-generation antipsychotic, and the patient was discharged from the psychiatric unit. CONCLUSION: This case is evidence that the link between psychosis and hyperthyroidism is still poorly understood due to the patient's psychotic symptoms persisting after the definitive treatment of thyroidectomy and the fact that it required anti-psychotic medications for normalization.

Increased hippocampal cannabinoid 1 receptor expression is associated with protection from severe seizures in pregnant mice with reduced uterine perfusion pressure.

Eclampsia, new-onset seizures in pregnancy, can complicate preeclampsia, a hypertensive pregnancy disorder. The mechanisms contributing to increased risk of seizures in preeclampsia are not fully known. One mechanism could be abnormal endocannabinoid system (ECS) activity and impaired neuromodulation. Indeed, increased placental cannabinoid receptor 1 (CB1R) expression and reduced serum anandamide, a CB1R ligand, have been reported in preeclampsia patients. We hypothesized that reduced uterine perfusion pressure (RUPP), used to mimic preeclampsia, leads to changes in hippocampal CB1R expression, and that manipulating CB1R activity will change seizure severity in RUPP mice. Pregnant mice underwent sham or RUPP surgery on gestational day (GD)13.5. On GD18.5, mice received: no drug treatment, pentylenetetrazol (PTZ, 40 mg/kg), Rimonabant (10 mg/kg) + PTZ, or 2-AG (1 mg/kg) + PTZ. Behaviors were video recorded (15 min for Rimonabant and 2-AG, followed by 30 min for PTZ), and the hippocampus was harvested. The expression of CB1R and ECS proteins was measured in hippocampal homogenates, synaptosomes, and cytosol. Hippocampal CB1R increased in homogenates and cytosolic fraction, and was unchanged in synaptosomes of RUPP mice. Increased CB1R colocalization on glutamate-releasing neurons within hippocampal CA1 was observed in RUPP mice. Rimonabant modestly increased seizure scores over time in RUPP mice. PTZ after rimonabant pretreatment increased seizure scores and duration, while reducing latency in sham mice, with little to no change in RUPP mice. Furthermore, RUPP mice had lower seizure scores over time than sham following CB1R blockade and activation. These data suggest that RUPP modifies CB1R activity prior to seizure induction, which protects mice from worse seizure outcomes.

Quantification of observable behaviors following oral administration of oxycodone and nalfurafine in male rhesus monkeys.

BACKGROUND: Recent preclinical studies have investigated the atypical kappa-opioid receptor (KOR) agonist, nalfurafine, as a co-formulary with mu-opioid receptor (MOR) agonists as a potential deterrent for misuse. However, no study has investigated effects of nalfurafine combined with a MOR agonist using an oral route of administration. The objective of the current study was to measure behavioral effects of orally administered oxycodone and nalfurafine, alone and combined, in rhesus monkeys using a quantitative behavioral observation procedure. METHODS: Adult male rhesus monkeys (N=5) were orally administered vehicle, oxycodone (0.56-1.8mg/kg), nalfurafine (0.001-0.0056mg/kg), or mixtures (1.0mg/kg oxycodone/0.001-0.0056mg/kg nalfurafine) in a Jell-O vehicle at multiple timepoints (10-320min). Species-typical and drug-induced behaviors were recorded by observers blinded to conditions. RESULTS: Oxycodone alone significantly increased scratch and face-rub behaviors without affecting other behaviors. Nalfurafine decreased baseline levels of scratch without affecting other behaviors, and oxycodone-nalfurafine combinations resulted in reduced oxycodone-induced scratching at a dose (0.001mg/kg) that did not produce sedation-like effects. Oxycodone combined with larger nalfurafine doses (0.0032-0.0056mg/kg) also reduced oxycodone induced scratch that were accompanied with sedation-like effects (i.e., increased lip droop). CONCLUSIONS: Nalfurafine was orally active in rhesus monkeys, and it reduced oxycodone-induced pruritus at a dose that did not produce sedation-like effects that are commonly observed with prototypical KOR agonists. Combinations of low doses of nalfurafine with MOR agonists such as oxycodone may be well-tolerated by humans who are prescribed MOR agonists for the treatment of pain.

Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor.

Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that Jumonji Domain Containing 6, Arginine Demethylase and Lysine Hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven neuroblastoma. JMJD6 cooperates with MYC in cellular transformation by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a "molecular glue" that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.

Comparison of Melioidosis Indirect Hemagglutination Assay between Three Testing Laboratories in Australia.

Melioidosis caused by Burkholderia pseudomallei causes significant morbidity and mortality in Southeast Asia and northern Australia. Clinical manifestations remain diverse, including localized skin infection, pneumonia, and chronic abscess formation. Culture remains the gold standard of diagnosis, with serology and antigen detection tests playing a role if culture is unfeasible. Serologic diagnosis remains challenging, with limited standardization across different assays. In areas of endemicity, high rates of seropositivity have been documented. The indirect hemagglutination assay (IHA) is one of the more widely used serologic tests in these areas. In Australia, only three centers perform the test. Annually, laboratory A, laboratory B, and laboratory C perform approximately 1,000, 4,500, and 500 tests, respectively. A comparison of a total of 132 sera was analyzed from the routine quality exchange program between these centers from 2010 until 2019. Overall, 18.9% of sera tested had an interpretative discrepancy between laboratories. IMPORTANCE This study found significant discrepant results between three Australian centers offering the melioidosis indirect hemagglutination assay (IHA), despite testing the same samples. We have highlighted that the IHA is a nonstandardized test, which had different source antigens at each of the different laboratories. Melioidosis is a global disease, is associated with significant mortality, and is perhaps under recognized. It is likely to have increasing impact with changing weather patterns. The IHA has been used frequently as an adjunct to the diagnosis of clinical disease and is the mainstay of determining seroprevalence within populations. Despite its relative ease of use, especially in low resource settings, our study highlights the significant limitations of the melioidosis IHA. It has wide ranging implications, serving as an impetus for developing better diagnostic tests. This study is of interest to practitioners and researchers working in the various geographic regions affected by melioidosis.

Choice between food and cocaine reinforcers under fixed and variable schedules in female and male rhesus monkeys.

Illicit drugs like cocaine may be uncertain in terms of the time and effort required to obtain them. Behavior maintained by variable schedules resembles excessive drug-taking compared with fixed schedules. However, no prior research has examined fixed versus variable schedules in drug versus nondrug choice. The present study evaluated cocaine versus food choice under fixed- (FR) and variable-ratio (VR) schedules. The simpler food versus food and cocaine versus cocaine arrangements also were included. Adult female (n = 6) and male (n = 7) rhesus monkeys chose between cocaine (0.01-0.18 mg/kg/injection) and food (4 pellets/delivery), food and food (4 pellets/delivery), or cocaine and cocaine (0.018-0.03 mg/kg/injection) under FR and VR 100 and 200 schedules. In cocaine versus food choice, cocaine's potency to maintain choice was greatest when available under a VR 100 or 200 schedule and food under an FR schedule and was lowest when cocaine was available under an FR 200 schedule and food was available under a VR 200 schedule. In food versus food choice, males chose food associated with a VR schedule more than food associated with an FR schedule. In cocaine versus cocaine choice, females and males chose cocaine associated with a VR schedule more than cocaine associated with an FR schedule, particularly under VR 200. These findings suggest that uncertainty in terms of time and effort required to obtain cocaine, or perhaps the occasional low-cost access that results from VR schedules, results in greater allocation of behavior toward drug reinforcers at the expense of more certain, nondrug alternatives. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Detection of Influenza in Managed Quarantine in Australia and the Estimated Risk of Importation.

BACKGROUND: Influenza circulated at historically low levels during 2020/2021 due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic travel restrictions. In Australia, international arrivals were required to undergo a 14-day hotel quarantine to limit new introduction of SARS-CoV-2. METHODS: We usedtesting data for travelers arriving on repatriation flights to Darwin, Australia, from 3 January 2021 to 11 October 2021 to identify importations of influenza virus into Australia. We used this information to estimate the risk of a case exiting quarantine while still infectious. Influenza-positive samples were sequenced, and cases were followed up to identify transmission clusters. Data on the number of cases and total passengers were used to infer the risk of influenza cases exiting quarantine while infectious. RESULTS: Despite very low circulation of influenza globally, 42 cases were identified among 15 026 returned travelers, of which 30 were A(H3N2), 2 were A(H1N1)pdm09, and 10 were B/Victoria. Virus sequencing data identified potential in-flight transmission, as well as independent infections prior to travel. Under the quarantine strategy in place at the time, the probability that these cases could initiate influenza outbreaks in Australia neared 0. However, this probability rose as quarantine requirements relaxed. CONCLUSIONS: Detection of influenza virus infections in repatriated travelers provided a source of influenza viruses otherwise unavailable and enabled development of the A(H3N2) vaccine seed viruses included in the 2022 Southern Hemisphere influenza vaccine. Failure to test quarantined returned travelers for influenza represents a missed opportunity for enhanced surveillance to better inform public health preparedness.

Effects of methadone, buprenorphine, and naltrexone on actigraphy-based sleep-like parameters in male rhesus monkeys.

Opioid use disorder (OUD) has been associated with the emergence of sleep disturbances. Although effective treatments for OUD exist, evidence suggests that these treatments also may be associated with sleep impairment. The extent to which these effects are an effect of OUD treatment or a result of chronic opioid use remains unknown. We investigated the acute effects of methadone, buprenorphine, and naltrexone on actigraphy-based sleep-like parameters in non-opioid-dependent male rhesus monkeys (Macaca mulatta, n = 5). Subjects were fitted with actigraphy monitors attached to primate collars to measure sleep-like parameters. Actigraphy recordings were conducted under baseline conditions, or following acute injections of vehicle, methadone (0.03-1.0 mg/kg, i.m.), buprenorphine (0.01-1.0 mg/kg, i.m.), or naltrexone (0.03-1.0 mg/kg, i.m.) in the morning (4 h after "lights on") or in the evening (1.5 h before "lights off"). Morning and evening treatments with methadone or buprenorphine significantly increased sleep latency and decreased sleep efficiency. The effects of buprenorphine on sleep-like measures resulted in a biphasic dose-response function, with the highest doses not disrupting actigraphy-based sleep. Buprenorphine induced a much more robust increase in sleep latency and decrease in sleep efficiency compared to methadone, particularly with evening administration, and detrimental effects of buprenorphine on sleep-like measures were observed up to 25.5 h after drug injection. Treatment with naltrexone, on the other hand, significantly improved sleep-like measures, with evening treatments improving both sleep latency and sleep efficiency. The currently available pharmacotherapies for OUD significantly alter sleep-like parameters in non-opioid-dependent monkeys, and opioid-dependent mechanisms may play a significant role in sleep-wake regulation.

Epidemiological and clinical characteristics of legionellosis in Northern Australia, 2010-2021.

Objective: This study describes characteristics of the legionellosis cases occurring between 2010 and 2021 in the Northern Territory (NT), Australia. Methods: We retrospectively reviewed 53 cases of legionellosis during the defined period and documented patient and clinical characteristics, diagnostics, and seasonality of infection. Results: All cases were sporadic. The incidence rate in the NT was higher than the Australian median rate (2.1 and 1.5 per 100,000 population per year respectively). Aboriginal and Torres Strait Islander patients presented at a younger age than did non-Indigenous patients (median 41 and 60 years of age respectively), and overall there was a male preponderance. There was a higher proportion of legionellosis in the months with increased humidity, with a greater number of L. longbeachae infections detected overall (59%) than of L. pneumophila (41%). The majority of cases were diagnosed serologically (57% of L. pneumophilia and 93% of L. longbeachae ). Conclusions: Legionellosis in the NT is more common, seasonal, and may be underreported due to current reliance on serological testing for diagnosis. The higher incidence of legionellosis, and the younger age of Aboriginal and Torres Strait Islander patients of the NT, have public health implications, given that the clinical presentation of legionellosis is indistinguishable from other forms of pneumonia.

The G-protein biased kappa opioid agonists, triazole 1.1 and nalfurafine, produce non-uniform behavioral effects in male rhesus monkeys.

Kappa-opioid receptor (KOR) agonists have been studied as potential treatments for pain, pruritus, and substance-use disorders, but prototypical KOR agonists produce side-effects like dysphoria and sedation. Atypical KOR agonists that exhibit G-protein biased signaling at the KOR have been reported to produce therapeutic-like effects with fewer or reduced side effects relative to prototypical KOR agonists. In the current report, behavioral profiles were determined using a behavioral scoring system that was modified to quantify drug-induced behaviors in nonhuman primates (NHPs). Profiles were determined for a prototypical and two biased KOR agonists, alone and combined with the mu-opioid receptor (MOR) agonist, oxycodone. Five adult male rhesus monkeys implanted with intravenous catheters were administered a range of doses of the KOR agonist, U50-488H (0.01-0.1 mg/kg) and the biased KOR agonists, nalfurafine (0.0001-0.001 mg/kg) and triazole 1.1 (0.32-1.0 mg/kg), alone and combined with the MOR agonist, oxycodone (0.01-0.32 mg/kg). In addition, the largest triazole 1.1 dose tested (1.0 mg/kg) was administered in time-course determinations (0-56 min), alone and combined with oxycodone (0.1 mg/kg). U50-488H and nalfurafine produced sedative-like and motor-impairing effects. Triazole 1.1 had a milder side-effect profile, in some instances producing sedative-like effects but to a lesser degree compared with the other KOR agonists, particularly for lip droop and rest/sleep posture. All KOR agonists reduced oxycodone-induced scratch, but nalfurafine produced behavior-disrupting and sedative-like effects when combined with oxycodone that were not observed with triazole 1.1. The duration of triazole 1.1's behavioral effects was relatively short, dissipating entirely by 56 min. Our results suggest that KOR agonists with comparable pharmacology to triazole 1.1 may be useful therapeutics with reduced side-effect profiles, and the mechanisms conferring these benefits may be attributed to factors other than G-protein bias.

Genomic Evidence of In-Flight SARS-CoV-2 Transmission, India to Australia, April 2021.

Epidemiologic and genomic investigation of SARS-CoV-2 infections associated with 2 repatriation flights from India to Australia in April 2021 indicated that 4 passengers transmitted SARS-CoV-2 to >11 other passengers. Results suggest transmission despite mandatory mask use and predeparture testing. For subsequent flights, predeparture quarantine and expanded predeparture testing were implemented.

Treatment-resistant depression with anhedonia: Integrating clinical and preclinical approaches to investigate distinct phenotypes.

In our clinical work with treatment-resistant depressed (TRD) patients, certain patterns have emerged in terms of patients' presentations of anhedonia. Multiple studies have investigated anhedonia either as a state or a trait variable in depression, but anhedonia is a multifaceted construct and, as we better understand anhedonia, we increase our ability to measure and treat it. With the aim of personalizing medicine for more efficacious treatments, this paper focuses on clinical patterns we have seen in anhedonic TRD and argues for studies to be done in support of translational, face, and construct validity. Three representative clinical presentations of TRD with anhedonia are described: a congenital type, a stress-induced type, and a type exacerbated by medication. Each case is followed with discussion relating the clinical features to clinical and preclinical research relevant to putative mechanisms for the case. Animal models that are best suited to investigate and validate the existence of etiologies and mechanisms underlying anhedonia constructs unique to each case are proposed, as are potential directions for research in humans.

Preclinical Studies on Nalfurafine (TRK-820), a Clinically Used KOR Agonist.

Nalfurafine has been used clinically in Japan for treatment of itch in kidney dialysis patients and in patients with chronic liver diseases. A one-year post-marketing study showed nalfurafine to be safe and efficacious without producing side effects of typical KOR agonists such as anhedonia and psychotomimesis. In this chapter, we summarize in vitro characterization and in vivo preclinical studies on nalfurafine. In vitro, nalfurafine is a highly potent and moderately selective KOR full agonist; however, whether it is a biased KOR agonist is a matter of debate. In animals, nalfurafine produced anti-pruritic effects in a dose range lower than that caused side effects, including conditioned place aversion (CPA), hypolocomotion, motor incoordination, consistent with the human data. In addition, nalfurafine showed antinociceptive effects in several pain models at doses that did not cause the side effects mentioned above. It appears to be effective against inflammatory pain and mechanical pain, but less so against thermal pain, particularly high-intensity thermal pain. U50,488H and nalfurafine differentially modulated several signaling pathways in a brain region-specific manners. Notably, U50,488H, but not nalfurafine, activated the mTOR pathway, which contributed to U50,488H-induced CPA. Because of its lack of side effects associated with typical KOR agonists, nalfurafine has been investigated as a combination therapy with an MOR ligand for pain treatment and for its effects on opioid use disorder and alcohol use disorder, and results indicate potential usefulness for these indications. Thus, although in vitro data regarding uniqueness of nalfurafine in terms of signaling at the KOR are somewhat equivocal, in vivo results support the assertion that nalfurafine is an atypical KOR agonist with a significantly improved side-effect profile relative to typical KOR agonists.

Therapeutically targeting oncogenic CRCs facilitates induced differentiation of NB by RA and the BET bromodomain inhibitor.

Retinoic acids (RAs) are the most successful therapeutics for cancer differentiation therapy used in high-risk neuroblastoma (NB) maintenance therapy but are limited in effectiveness. This study identifies a strategy for improving efficacy through disruption of cancer cell identity via BET inhibitors. Mutations that block development are theorized to cause NB through retention of immature cell identities contributing to oncogenesis. NB has two interchangeable cell identities, maintained by two different core transcriptional regulatory circuitries (CRCs): a therapy-resistant mesenchymal/stem cell state and a proliferative adrenergic cell state. MYCN amplification is a common mutation of high-risk NB and recently found to block differentiation by driving high expression of the adrenergic CRC transcription factor ASCL1. We investigated whether disruption of immature CRCs can promote RA-induced differentiation since only a subset of NB patients responds to RA. We found that silencing ASCL1, a critical member of the adrenergic CRC, or global disruption of CRCs with the BET inhibitor JQ1, suppresses gene expression of multiple CRC factors, improving RA-mediated differentiation. Further, JQ1 and RA synergistically decrease proliferation and induce differentiation in NB cell lines. Our findings support preclinical studies of RA and BET inhibitors as a combination therapy in treating NB.

The kappa-opioid receptor agonist, triazole 1.1, reduces oxycodone self-administration and enhances oxycodone-induced thermal antinociception in male rats.

RATIONALE: Triazole 1.1 is a novel kappa-opioid receptor (KOR) agonist reported to produce antinociception without KOR-typical adverse effects. When combined with the mu-opioid receptor (MOR) agonist, oxycodone, triazole 1.1 blocks oxycodone-induced pruritis without producing sedation-like effects in nonhuman primates. However, it is unknown if triazole 1.1 can reduce the abuse-related effects or enhance the antinociceptive effects of oxycodone similarly to other KOR agonists. OBJECTIVES: The aim of the present study was to quantitatively compare the behavioral effects of triazole 1.1 to the KOR agonists, U50,488h and nalfurafine, on oxycodone self-administration and oxycodone-induced thermal antinociception when administered as mixtures with oxycodone. METHODS: In the self-administration study, male Sprague-Dawley (SD) rats (n = 6) self-administered intravenous (i.v.) oxycodone alone (0.056 mg/kg/inj) or combined with U50,488 h (0.032-0.32 mg/kg/inj), nalfurafine (0.00032-0.0032 mg/kg/inj), or triazole 1.1 (0.32-1.8 mg/kg/inj) under a progressive-ratio schedule of reinforcement. In a hot plate assay, male SD rats (n = 6) received i.v. injections of oxycodone (1.0-5.6 mg/kg), U50,488h (1.0-18.0 mg/kg), nalfurafine (0.01-1.0 mg/kg), or triazole 1.1 (3.2-32.0 mg/kg) alone or in combinations of fixed proportion with oxycodone based on the relative potencies of the single drugs. Each study concluded with administration of the KOR antagonist nor-BNI and some degree of retesting of the previous conditions to verify that the behavioral effects were mediated by KOR activation. RESULTS: All KOR agonists reduced oxycodone self-administration in a dose-dependent manner. Moreover, all single drugs and drug combinations produced dose-dependent, fully efficacious thermal antinociception. All KOR agonist:oxycodone combinations produced either additive or super-additive thermal antinociception. Finally, each KOR agonist was blocked in effect by nor-BNI in both behavioral measures. CONCLUSION: This study demonstrates that triazole 1.1 reduces oxycodone's reinforcing effects and enhances oxycodone-induced antinociception to degrees that are comparable to typical KOR agonists. Given triazole 1.1's mild adverse-effect profile, developing MOR-KOR agonist combinations from the triazole 1.1 series may render new pain therapeutics with reduced abuse liability.

Viral hepatitis in correctional facilities in the Northern Territory of Australia 2003-2017.

BACKGROUND: The demographic of Northern Territory prison population differs than elsewhere in Australia and the prevalence of hepatitis B and hepatitis C may therefore be somewhat different from other jurisdictions. There has been no study which has specifically described the serological results of a large proportion of prisoners in Northern Territory correctional facilities over an extended period of time. METHODS: This retrospective longitudinal study reviewed serological results and testing rates for hepatitis B, and hepatitis C performed in correctional facilities in the Northern Territory of Australia between July 1st, 2003 and June 30th, 2017. RESULTS: The proportion of positive records over 14 years for hepatitis B surface antigen (HBsAg) was 641/12,066 (5.3, 95% CI 4.9-5.7), for hepatitis B core antibody (anti-HBc) 4937/12,138 (40.1, 95%CI 39.8-41.6), for hepatitis B surface antibody (anti-HBs) 6966/13,303 (52.4, 95% CI 51.5-53.2), and for hepatitis C antibody 569/12,153 (4.7, 95% CI 4.3-5.1). The proportion of prisoners tested for hepatitis B and hepatitis C has decreased since 2015, while a high proportion of prisoners remain non-immune to hepatitis B. CONCLUSION: There is a relatively high proportion of positive serological markers of hepatitis B, and a lower proportion of positive hepatitis C serology in the Northern Territory's correctional facilities compared to overall Australian rates. As the proportion of prisoners tested for hepatitis B and C has decreased recently, and a high proportion of prisoners remain non-immune to hepatitis B, there are opportunities to increase testing and vaccination rates in this population.