A comparison of cannabidiolic acid with other treatments for anticipatory nausea using a rat model of contextually elicited conditioned gaping

Rationale

The effectiveness of cannabidiolic acid (CBDA) was compared with other potential treatments for anticipatory nausea (AN), using a rat model of contextually elicited conditioned gaping reactions.

Objective

The potential of ondansetron (OND), Δ⁹-tetrahydrocannabinol (THC), chlordiazepoxide (CDP), CBDA, and co-administration of CBDA and tetrahydrocannabinolic acid (THCA) to reduce AN and modify locomotor activity was evaluated.

Materials and methods

Following four pairings of a novel context with lithium chloride (LiCl), the rats were given a test for AN. On the test trial, they received pretreatment injections of the following: vehicle, OND (0.1 or 1.0 mg/kg), THC (0.5 mg/kg), CBDA (0.0001, 0.001, 0.01, 0.1 mg/kg or 1.0 mg/kg), CDP (1, 5, or 10 mg/kg) or co-administration of subthreshold doses of CBDA (0.1 μg/kg), and THCA (5 μg/kg). Immediately following the AN test trial in all experiments, rats were given a 15 min locomotor activity test. Finally, the potential of CBDA (0.001, 0.01, 0.1, and 1 mg/kg) to attenuate conditioned freezing to a shock-paired tone was assessed.

Results

THC, CBDA, and CDP, but not OND, reduced contextually elicited gaping reactions. Co-administration of subthreshold doses of CBDA and THCA also suppressed AN, and this effect was blocked by pretreatment with either a cannabinoid receptor 1 (CB₁) receptor antagonist or a 5-hydroxytryptamine 1A (5-HT_1A) receptor antagonist. CDP (but not CBDA, THC or CBDA and THCA) also suppressed locomotor activity at effective doses. CBDA did not modify the expression of conditioned fear.

Conclusions

CBDA has therapeutic potential as a highly potent and selective treatment for AN without psychoactive or locomotor effects.     

Mutations of the SBDS gene are present in most patients with Shwachman-Diamond syndrome

Shwachman-Diamond Syndrome (SDS) is a rare multisystem disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and metaphyseal chondrodysplasia. Recent studies show that mutations of SBDS, a gene of unknown function, are present in the majority of patients with SDS. In the present study, we show that most, but not all, patients classified based on rigorous clinical criteria as having SDS had compound heterozygous mutations of SBDS. Full-length SBDS protein was not detected in leukocytes of SDS patients with the most common SBDS mutations, consistent with a loss-of-function mechanism. In contrast, SBDS protein was expressed at normal levels in SDS patients without SBDS mutations. These data confirm the absence of SBDS mutations in this subgroup of patients and suggest that SDS is a genetically heterogeneous disorder. The presence (or absence) of SBDS mutations may define subgroups of patients with SDS who share distinct clinical features or natural history.     

Rickettsia parkeri and Rickettsia montanensis,Kentucky and Tennessee,USA

We found that 14.3% (15/105) of Amblyomma maculatum and 3.3% (10/299) of Dermacentor variabilis ticks collected at 3 high-use military training sites in west-central Kentucky and northern Tennessee, USA, were infected with Rickettsia parkeri and Rickettsia montanensis, respectively. These findings warrant regional increased public health awareness for rickettsial pathogens and disease.     

A phase I dose escalation study of oral bexarotene in combination with intravenous decitabine in patients with AML

The response rate of non‐M3 acute myeloid leukemia (AML) to all trans retinoic acid has been limited. Using Affymetrix expression arrays, we found that in diverse AML blasts RXRA was expressed at higher levels than RARA and that mouse Ctsg‐PML‐RARA leukemia responded to bexarotene, a ligand for RXRA. We therefore performed a phase I study of combination bexarotene and decitabine in elderly and relapsed AML patients. We found that this combination was well tolerated, although outcomes were modest (1 CRi, and 3 PR among 19 patients). Correlative studies found that patients with clinical response had increased differentiation to bexarotene both in vivo and ex vivo, suggesting that pre‐treatment analysis might identify a more susceptible subgroup of patients. Am. J. Hematol. 89:E103–E108, 2014. © 2014 Wiley Periodicals, Inc.     

Childhood Sexual Abuse and HIV-Related Risks Among Men Who Have Sex with Men in Washington,DC

Childhood sexual abuse (CSA) has been reported to be disproportionately higher among men who have sex with men (MSM) than among heterosexual men; it has also been found to be significantly positively associated with HIV status and HIV risk factors, including unprotected anal intercourse. The purpose of this study was to assess the correlates of CSA in a sample of community-recruited MSM, investigate race as a potential effect modifier, and describe the independent association between CSA and HIV infection in Washington, DC. A total of 500 MSM were recruited by venue-based sampling in 2008 as part of the National HIV Behavioral Surveillance. More than one-half of MSM identified as White, while one-third identified as Black. CSA was reported by 17.5 % of the 451 MSM, with the first instance of abuse occurring at a median age of 8.3 (interquartile range = 5.0, 11.0). In multivariable analysis, HIV-positive men were significantly more likely to report a history of CSA compared to HIV-negative men after adjusting for intimate partner violence in the last 12 months, having been arrested in the last 12 months, and depressive symptoms. HIV-positive MSM had more than four times the odds of reporting CSA after controlling for other correlates (aOR = 4.19; 95 % CI 2.26, 7.75). Despite hypothesizing that race modified the effect of CSA on HIV infection we found this was not the case in this sample. More research is needed to investigate the potential pathway between a history of CSA and HIV infection, and how this contributes to driving the HIV epidemic among MSM in Washington, DC.     

Ethanol and cocaine: Environmental place conditioning,stereotypy, and synergism in planarians

More than 90% of individuals who use cocaine also report concurrent ethanol use, but only a few studies, all conducted with vertebrates, have investigated pharmacodynamic interactions between ethanol and cocaine. Planaria, a type of flatworm often considered to have the simplest ‘brain,’ is an invertebrate species especially amenable to the quantification of drug-induced behavioral responses and identification of conserved responses. Here, we investigated stereotypical and environmental place conditioning (EPC) effects of ethanol administered alone and in combination with cocaine. Planarians displayed concentration-related increases in C-shaped movements following exposure to ethanol (0.01–1%) (maximal effect: 9.9 ± 1.1 C-shapes/5 min at 0.5%) or cocaine (0.1–5 mM) (maximal effect: 42.8 ± 4.1 C-shapes/5 min at 5 mM). For combined administration, cocaine (0.1–5 mM) was tested with submaximal ethanol concentrations (0.01, 0.1%); the observed effect for the combination was enhanced compared to its predicted effect, indicating synergism for the interaction. The synergy with ethanol was specific for cocaine, as related experiments revealed that combinations of ethanol and nicotine did not result in synergy. For EPC experiments, ethanol (0.0001–1%) concentration-dependently increased EPC, with significant environmental shifts detected at 0.01 and 1%. Cocaine (0.001–1 μM) produced an inverted U-shaped concentration–effect curve, with a significant environmental shift observed at 0.01 μM. For combined exposure, variable cocaine concentrations (0.001–1 μM) were administered with a statistically ineffective concentration of ethanol (0.0001%). For each concentration of cocaine, the environmental shift was enhanced by ethanol, with significance detected at 1 μM. Cocaethylene, a metabolite of cocaine and ethanol, also produced C-shapes and EPC. Lidocaine (0.001–10 μM), an anesthetic and analog of cocaine, did not produce EPC or C-shaped movements. Evidence from planarians that ethanol produces place-conditioning effects and motor dysfunction, and interacts synergistically with cocaine, suggests that aspects of ethanol neuropharmacology are conserved across species.     

Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk

Cancer driver mutations (CDMs) are necessary and causal for carcinogenesis and have advantages as reporters of carcinogenic risk. However, little progress has been made toward developing measurements of CDMs as biomarkers for use in cancer risk assessment. Impediments for using a CDM-based metric to inform cancer risk include the complexity and stochastic nature of carcinogenesis, technical difficulty in quantifying low-frequency CDMs, and lack of established relationships between cancer driver mutant fractions and tumor incidence. Through literature review and database analyses, this review identifies the most promising targets to investigate as biomarkers of cancer risk. Mutational hotspots were discerned within the 20 most mutated genes across the 10 deadliest cancers. Forty genes were identified that encompass 108 mutational hotspot codons overrepresented in the COSMIC database; 424 different mutations within these hotspot codons account for approximately 63,000 tumors and their prevalence across tumor types is described. The review summarizes literature on the prevalence of CDMs in normal tissues and suggests such mutations are direct and indirect substrates for chemical carcinogenesis, which occurs in a spatially stochastic manner. Evidence that hotspot CDMs (hCDMs) frequently occur as tumor subpopulations is presented, indicating COSMIC data may underestimate mutation prevalence. Analyses of online databases show that genes containing hCDMs are enriched in functions related to intercellular communication. In its totality, the review provides a roadmap for the development of tissue-specific, CDM-based biomarkers of carcinogenic potential, comprised of batteries of hCDMs and can be measured by error-correct next-generation sequencing. Environ. Mol. Mutagen. 61:152–175, 2020. Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.     

Two novel adenoviruses found in Cave Myotis bats (Myotis velifer) in Oklahoma

Bats are carriers of potentially zoonotic viruses, therefore it is crucial to identify viruses currently found in bats to better understand how they are maintained in bat populations and evaluate risks for transmission to other species. Adenoviruses have been previously detected in bats throughout the world, but sampling is still limited. In this study, 30 pooled-guano samples were collected from a cave roost of Myotis velifer in Oklahoma. A portion of the DNA polymerase gene from Adenoviridae was amplified successfully in 18 M. velifer samples; however, DNA sequence was obtained from only 6 of these M. velifer samples. One was collected in October 2016, one in March 2017, and 4 in July 2017. The October and March samples contained viral DNA that was 3.1% different from each other but 33% different than the novel viral sequence found in the July 2017 samples. Phylogenetic analysis of these fragments confirmed our isolates were from the genus Mastadenovirus and had genetic diversity ranging from 20 to 50% when compared to other bat adenoviruses.

     

Time course study of the antigen-specific immune response to a PLGA microparticle vaccine formulation

Microparticle-based vaccine delivery systems are known to promote enhanced immune responses to protein antigens and can elicit T_H1-biased responses when used in combination with Toll-like receptor (TLR) agonists. It is important to understand the kinetics of the immune responses to microparticle-based protein vaccines in order to predict the duration of protective immunity and to optimize prime-boost vaccination regimens. We carried out a 10-week time course study to investigate the magnitude and kinetics of the antibody and cellular immune responses to poly(lactic-co-glycolic acid) (PLGA) microparticles containing 40 μg ovalbumin (OVA) protein and 16 μg CpG-ODN adjuvant (MP/OVA/CpG) in comparison to OVA-containing microparticles, soluble OVA plus CpG, or OVA formulated with Alhydrogel^® aluminum adjuvant. Mice vaccinated with MP/OVA/CpG developed the highest T_H1-associated IgG2b and IgG2c antibody titers, while also eliciting T_H2-associated IgG1 antibody titers on par with Alhydrogel^®-formulated OVA, with all IgG subtype titers peaking at day 56. The MP/OVA/CpG vaccine also induced the highest antigen-specific splenocyte IFN-γ responses, with high levels of IFN-γ responses persisting until day 42. Thus the MP/OVA/CpG formulation produced a sustained and heightened humoral and cellular immune response, with an overall T_H1 bias, while maintaining high levels of IgG1 antibody equivalent to that seen with Alhydrogel^® adjuvant. The time course kinetics study provides a useful baseline for designing vaccination regimens for microparticle-based protein vaccines.