•Withdrawal from acute nicotine exposure was characterized using ICSS in rats.•There was a modest spontaneous withdrawal effect after a single nicotine injection.•The antidepressant bupropion blocked ...mecamylamine-precipitated withdrawal.•The nAChR antagonists DHßE and mecamylamine precipitated ICSS threshold elevations.•These models may be useful for studying the early development of nicotine withdrawal.
Establishing preclinical models of the development of nicotine withdrawal following acute nicotine exposure could inform tobacco addiction-related research, treatment, and policy. To this end, this lab has previously reported that rats exhibit withdrawal-like elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) following acute nicotine exposure. The goal of this study was to provide further pharmacological characterization of ICSS as a measure of spontaneous and antagonist-precipitated withdrawal from acute nicotine.
Rats exhibited a small increase in ICSS thresholds over time following a single nicotine injection (1.0 mg/kg, s.c.), suggesting a modest spontaneous withdrawal effect (Experiment 1). In Experiment 2, the antidepressant bupropion (5.0 mg/kg, i.p.), which is used to treat tobacco addiction and attenuates nicotine withdrawal in both humans and rodents, blocked elevations in ICSS thresholds induced by a single injection of nicotine (0.5 mg/kg, s.c.) followed ≈ 2 h later by the non-selective, non-competitive nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (3.0 mg/kg, s.c.). In Experiment 3a, s.c. administration of the competitive, relatively selective α4ß2 nAChR antagonist dihydro-beta-erythroidine (DHßE) (5.6 mg/kg, but not 3.0 mg/kg) following each of 5 daily injections of nicotine (0.5 mg/kg, s.c.) elevated ICSS thresholds. Mecamylamine (3.0 mg/kg, s.c.) also elevated ICSS thresholds when administered following all 5 daily nicotine injections (0.5 mg/kg, s.c., Experiment 3b).
These findings provide further characterization of elevations in ICSS thresholds as a measure of withdrawal from acute nicotine exposure. Further use of these models may be useful for understanding the early development of nicotine withdrawal.
Relief from increases in anxiety during nicotine withdrawal contributes to tobacco addiction. While a variety of anxiogenic stimuli elicit avoidance of the center of an open field (thigmotaxis) in ...rodents, effects of nicotine withdrawal on thigmotaxis have not been studied extensively. The goal of this study was to evaluate determinants of increases in thigmotaxis during mecamylamine-precipitated nicotine withdrawal in rats. We evaluated several variables implicated in severity of other measures of precipitated nicotine withdrawal: mecamylamine dose, duration of nicotine infusion, number of withdrawal episodes, and age. In Experiment 1, mecamylamine elicited increases in thigmotaxis in adult rats receiving a chronic nicotine infusion (3.2 mg/kg/day for >7 days) at only the highest mecamylamine dose tested (4.0 mg/kg). In Experiment 2, repeated administration of 4.0 mg/kg mecamylamine throughout the course of a 2-week chronic nicotine infusion (3.2 mg/kg/day) did not affect thigmotaxis when administered following 2 days of the infusion, but elicited significant increases in thigmotaxis at longer infusion durations. In Experiment 3, adolescents tested under the same protocol used in adults in Experiment 2 did not exhibit increased thigmotaxis at any point during the 2-week nicotine infusion, even though we used higher nicotine doses (4.7 or 6.4 mg/kg/day) to account for the faster metabolism of nicotine in adolescents compared to adults. Our findings provide the first systematic characterization of determinants of increases in thigmotaxis during precipitated nicotine withdrawal in rats. Further use of this model may be useful for characterizing the mechanisms underlying the anxiogenic component of nicotine withdrawal.
•We evaluated determinants of thigmotaxis during nicotine withdrawal in rats.•Several procedural variables (e.g., mecamylamine dose) affected thigmotaxis in adults.•Nicotine withdrawal did not increase thigmotaxis in adolescents.•This model may be useful for studying the anxiogenic component of nicotine withdrawal.
The ELIANA trial showed that 61 (81%) of 75 paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia achieved overall remission after treatment with ...tisagenlecleucel, a chimeric antigen receptor targeted against the CD19 antigen. We aimed to evaluate patient-reported quality of life in these patients before and after tisagenlecleucel infusion.
ELIANA, a global, single-arm, open-label, phase 2 trial, was done in 25 hospitals across Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Norway, Spain, and the USA. Patients with B-cell acute lymphoblastic leukaemia aged at least 3 years at the time of screening and 21 years or younger at the time of initial diagnosis who were in second or greater bone marrow relapse, chemorefractory, relapsed after allogeneic stem-cell transplantation, or were otherwise ineligible for allogeneic stem-cell transplantation were enrolled. Patients received a single intravenous administration of a target dose of 0·2–5 × 106 transduced viable T cells per kg for patients weighing 50 kg or less or 0·1–2·5 × 108 transduced viable T cells for patients weighing more than 50 kg. The primary outcome, reported previously, was the proportion of patients who achieved remission. A prespecified secondary endpoint, reported here, was patient-reported quality of life measured with the Pediatric Quality of Life Inventory (PedsQL) and European Quality of Life-5 Dimensions questionnaire (EQ-5D). Patients completed the questionnaires at baseline, day 28, and months 3, 6, 9, and 12 after treatment. The data collected were summarised using descriptive statistics and post-hoc mixed models for repeated measures. Change from baseline response profiles were illustrated with cumulative distribution function plots. The proportion of patients achieving the minimal clinically important difference and normative mean value were reported. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT02435849.
Between April 8, 2015, and April 25, 2017, 107 patients were screened, 92 were enrolled, and 75 received tisagenlecleucel. 58 patients aged 8–23 years were included in the analysis of quality of life. At baseline, 50 (86%) patients had completed the PedsQL questionnaire and 48 (83%) had completed the EQ-5D VAS. Improvements in patient-reported quality-of-life scores were observed for all measures at month 3 after tisagenlecleucel infusion (mean change from baseline to month 3 was 13·3 95% CI 8·9–17·6 for the PedsQL total score and 16·8 9·4–24·3 for the EQ-5D visual analogue scale). 30 (81%) of 37 patients achieved the minimal clinically important difference at month 3 for the PedsQL total score and 24 (67%) of 36 patients achieved this for the EQ-5D visual analogue scale.
These findings, along with the activity and safety results of ELIANA, suggest a favourable benefit–risk profile of tisagenlecleucel in the treatment of paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia.
Novartis.
Bacterial genomes vary extensively in terms of both gene content and gene sequence. This plasticity hampers the use of traditional SNP-based methods for identifying all genetic associations with ...phenotypic variation. Here we introduce a computationally scalable and widely applicable statistical method (SEER) for the identification of sequence elements that are significantly enriched in a phenotype of interest. SEER is applicable to tens of thousands of genomes by counting variable-length k-mers using a distributed string-mining algorithm. Robust options are provided for association analysis that also correct for the clonal population structure of bacteria. Using large collections of genomes of the major human pathogens Streptococcus pneumoniae and Streptococcus pyogenes, SEER identifies relevant previously characterized resistance determinants for several antibiotics and discovers potential novel factors related to the invasiveness of S. pyogenes. We thus demonstrate that our method can answer important biologically and medically relevant questions.
The purpose of this research is to develop magnetic resonance imaging (MRI) visible immunomodulatory microspheres (IMM-MS) for efficient image guided cancer immunotherapy. IMM-MS composed of ...recombinant interferon gamma (IFN-γ), iron oxide nanocubes (IONC), and biodegradable poly(lactide-co-glycolide) (PLGA) were successfully prepared via a double-emulsion method. The prepared IMM-MS exhibited a sustained IFN-γ release and highly sensitive MR T 2 contrast effects. Finally, in an orthotopic liver tumor VX2 rabbit model, successful hepatic intra-arterial (IA) transcatheter delivery of IMM-MS to liver tumors was confirmed with MR images. The deposition of IMM-MS significantly increased NK-cell infiltration into the liver tumor site.
Creation of a VX2 tumor model has traditionally required a laparotomy and surgical implantation of tumor fragments. Open surgical procedures are invasive and require long procedure times and recovery ...that can result in post-operative morbidity and mortality. The purpose of this study is to report the results of a percutaneous ultrasound guided method for creation of a VX2 model in rabbit livers. A total of 27 New Zealand white rabbits underwent a percutaneous ultrasound guided approach, where a VX2 tumor fragment was implanted in the liver. Magnetic resonance imaging was used to assess for tumor growth and necropsy was performed to determine rates of tract seeding and metastatic disease. Ultrasound guided tumor implantation was successful in all 27 rabbits. One rabbit died 2 days following the implantation procedure. Two rabbits had no tumors seen on follow-up imaging. Therefore, tumor development was seen in 24/26 (92%) rabbits. During the follow-up period, tract seeding was seen in 8% of rabbits and 38% had extra-hepatic metastatic disease. Therefore, percutaneous ultrasound guided tumor implantation safely provides reliable tumor growth for establishing hepatic VX2 tumors in a rabbit model with decreased rates of tract seeding, compared to previously reported methods.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We present genome engineering technologies that are capable of fundamentally reengineering genomes from the nucleotide to the megabase scale. We used multiplex automated genome engineering (MAGE) to ...site-specifically replace all 314 TAG stop codons with synonymous TAA codons in parallel across 32 Escherichia coli strains. This approach allowed us to measure individual recombination frequencies, confirm viability for each modification, and identify associated phenotypes. We developed hierarchical conjugative assembly genome engineering (CAGE) to merge these sets of codon modifications into genomes with 80 precise changes, which demonstrate that these synonymous codon substitutions can be combined into higher-order strains without synthetic lethal effects. Our methods treat the chromosome as both an editable and an evolvable template, permitting the exploration of vast genetic landscapes.
The Hippo pathway is an important regulator of cell growth, proliferation, and migration. TEAD transcription factors, which lie at the core of the Hippo pathway, are essential for regulation of organ ...growth and wound repair. Dysregulation of TEAD and its regulatory cofactor Yes-associated protein (YAP) have been implicated in numerous human cancers and hyperproliferative pathological processes. Hence, the YAP–TEAD complex is a promising therapeutic target. Here, we use in silico molecular docking using Bristol University Docking Engine to screen a library of more than 8 million druglike molecules for novel disrupters of the YAP–TEAD interaction. We report the identification of a novel compound (CPD3.1) with the ability to disrupt YAP–TEAD protein–protein interaction and inhibit TEAD activity, cell proliferation, and cell migration. The YAP–TEAD complex is a viable drug target, and CPD3.1 is a lead compound for the development of more potent TEAD inhibitors for treating cancer and other hyperproliferative pathologies.
Serum levels of an interleukin-1 receptor family member called suppressor of tumorigenicity 2 (ST2) predict response to therapy for graft-versus-host disease (GVHD) and improve on clinical grading in ...assessing the risk of death without relapse after allogeneic transplantation.
Although mortality related to graft-versus-host disease (GVHD) after allogeneic hematopoietic stem-cell transplantation has been reduced,
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acute GVHD remains a major complication of allogeneic transplantation, occurring in approximately half the transplant recipients.
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High-dose systemic glucocorticoids remain the first-line therapy for GVHD,
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although just half of patients have complete resolution of GVHD by day 28 after therapy initiation.
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Patients who do not have a response to GVHD therapy are at high risk for death without relapse of the primary disease for which the transplantation was performed within 6 months after therapy initiation.
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We previously reported that a model . . .
Germanium–tin alloy nanowires hold promise as silicon-compatible optoelectronic elements with the potential to achieve a direct band gap transition required for efficient light emission. In contrast ...to Ge1–x Sn x epitaxial thin films, free-standing nanowires deposited on misfitting germanium or silicon substrates can avoid compressive, elastic strains that inhibit formation of a direct gap. We demonstrate strong room temperature photoluminescence, consistent with band edge emission from both Ge core nanowires, elastically strained in tension, and the almost unstrained Ge1–x Sn x shells grown around them. Low-temperature chemical vapor deposition of these core-shell structures was achieved using standard precursors, resulting in Sn incorporation that significantly exceeds the bulk solubility limit in germanium.
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