Evaluation of Dopamine D3 Receptor Antagonists PG01037, PG01042, and VK4-116 Against D1R-induced Dyskinesia

Parkinson’s Disease (PD) results in motor deficits that can be relieved with L-DOPA, a dopamine (DA) replacement therapy. Unfortunately, chronic treatment often leads to L-DOPA-induced dyskinesia (LID), a debilitating side effect characterized by abnormal involuntary movements (AIMs). Overactivity of the direct striatonigral pathway is seen in LID and is characterized by potent changes in D1 and D3 receptors (D1R, D3R). Further, D1R and D3R may physically and functionally interact to form D1R-D3R heteromer thereby potentiating LID. This D1R-D3R heteromer uniquely switches from G-protein dependent to G-protein independent signaling, allowing for an avenue to manage LID. To uncover the role of these pathways in LID, Sprague-Dawley rats were rendered hemi-parkinsonian and treated daily for 2 weeks with L-DOPA (6 mg/kg; s.c.) to induce stable LID. In a within subjects, counterbalanced design, they were then split into treatment groups that received D3R antagonists: PG01037 (10, 30 mg/kg; i.p.), PG01042 (5, 10 mg/kg; i.p.), or VK4-116 (10, 20 mg/kg; i.p.). PG01037 (PG1) is a mixed D3R antagonist, acting at both the G-protein dependent and independent pathways. PG01042 (PG2) acts as an antagonist on G-protein independent signaling and VK4-116 acts as a G-protein dependent antagonist. All drugs were tested against D1R agonist-induced dyskinesia with SKF38393 (2mg/kg; s.c.). The only effects found were with PG2 which implicates promotion of the D1R G-protein dependent pathway as contributing to D1R-induced dyskinesia. Future studies with these drugs and L-DOPA treatment should unveil the importance of D1R, D3R, and D1R-D3R influences in the presence of the natural ligand DA.https://orb.binghamton.edu/research_days_posters_2021/1038/thumbnail.jp

Ground-Based Rayleigh-Mie Doppler Lidar for Wind Measurements in the Middle Atmosphere

A unique Rayleigh-Mie Doppler wind lidar, measuring Doppler shift between the emitted and backscattered light using directdetection technique is deployed at Observatory of Haute Provence Southern France) and at Reunion island (tropical Indian Ocean). The instrument was shown capable of wind measurements between 5 and 50 km with accuracy better than 1 m/s up to 30 km. The system consists of a monomode Nd:Yag laser operating at 532 nm, three telescopes and a double-edge Fabry-Perot interferometer. The laser light is sent alternatively in the vertical as well as zonal and meridional directions at 40° from the zenith using a rotating mirror. The two components of the horizontal wind are obtained from the measurement of the Doppler shift of the return signal spectrally filtered by the Fabry-Perot etalon. After demonstration of the method in 1989 the measurements were used for studying stratospheric dynamics as well as for constructing wind climatology up to 50 km altitude. A new system, featuring a more compact design was installed at Maïdo observatory at Reunion Island (21° S). The design of the instrument, results of observations and comparison against GPS radiosondes are presented. Application of Doppler lidar for validation of the future ADM-Aeolus satellite mission is discussed as well

Integrative analysis of drug response and clinical outcome in acute myeloid leukemia

Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML. [Display omitted] •Acute myeloid leukemia patient cohort with clinical, molecular, drug response data•Validation and discovery of diverse biological features of drug response•Broad mapping of tumor cell differentiation state affecting response to drugs•Modeling reveals a strong and targetable determinant of clinical outcome Bottomly et al. present a functional genomic resource composed of molecular, clinical, and drug response data on acute myeloid leukemia patient specimens. Through integration of all of these data, they identify genetic and cell differentiation state features that predict drug response, and they utilize modeling to identify targetable determinants of clinical outcome