Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the posttranslational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.
We detected enteroviral RNA and cultured infectious virus from a series of banked breast milk samples from the mother of an infant with neonatal sepsis; sequencing of the enterovirus isolate identified it as echovirus type 18. In this case, it is possible that enterovirus transmission occurred through the breast milk. CASE REPORTA female infant was the 3,470-g product of a 36-week-gestation pregnancy, born to a 29-year-old G 3 P 2012 mother via elective repeat Caesarian section. The infant's Apgar score was 9 at 1 min and at 5 min, and she required only routine resuscitation. The pregnancy course and maternal prenatal laboratory tests were unremarkable. The infant had a normal physical examination at birth and was admitted to the well-baby nursery but was transferred to the neonatal intensive care unit (NICU) at 24 h, when it was noted that she was in respiratory distress. As part of her sepsis evaluation in the NICU, a complete blood count (CBC) and serum electrolytes were normal, and a Creactive protein (CRP) concentration was low, at 1.3 mg/dl (normal is Ͻ1.0 mg/dl). The cerebrospinal fluid (CSF) profile was normal, and an enteroviral PCR from the CSF was negative. Her respiratory symptoms resolved rapidly, and she was quickly weaned from nasal cannula oxygen. She had elevated unconjugated bilirubin to a maximum value of 15.9 mg/dl (the normal range is 0.2 to 1.0 mg/dl) and required phototherapy until day 4 of life.On day 4 of life, the patient's temperature rose to 100.9°F (38.2°C), and she became difficult to arouse. Her suck diminished in strength, but she continued to tolerate oral bottle feedings of freshly expressed breast milk. She again required oxygen by nasal cannula. Her physical examination was significant for a diffusely erythematous macular blanching rash. A sepsis evaluation was repeated, and she was treated with ampicillin, gentamicin, and acyclovir. Her CBC was within normal limits, and her CRP concentration was found to be elevated to 5.3 mg/dl and continued to rise over the next 24 h to a peak of 18.3 mg/dl (Fig. 1). A repeated analysis of the CSF was significant for monocytosis, with a glucose concentration of 44 mg/dl (normal is 45 to 75 mg/dl), a protein concentration of 94 mg/dl (normal is 15 to 45 mg/dl), and a white blood cell count of 40/l, with 80% monocytes, 3% lymphocytes, and 17% segmented neutrophils, and no red blood cells. Blood and CSF samples were submitted for bacterial culture, and CSF and serum samples were sent for herpes simplex virus (HSV) and enterovirus analysis by PCR. No bacteria were seen by Gram's stain of the CSF, and all cultures were negative. HSV PCR of the CSF was negative, but the quantity of CSF was insufficient to test for enteroviruses by PCR. However, an enterovirus PCR of her serum was positive, and all antimicrobials were discontinued. Except for a minimal transaminitis, the remainder of her laboratory evaluation was normal. There were no other signs of liver dysfunction.Over the next 3 days, the patient continued to have a lowgrade fever, a rash, and...
This paper describes an automated workflow for the determination of selected reaction monitoring (SRM) transitions and optimum mass spectrometric (MS) instrument parameters. The approach uses a Nanomate from Advion Biosciences for automated infusion of small amounts of sample in combination with Automaton optimization software from Sciex. The results are stored in the Analyst software Compound Database for automated acquisition method building. Comparisons are presented between the more traditional optimization methods of manual flow injection optimization, Autotune infusion optimization, Automaton flow injection optimization and the Nanomate-Automaton optimization approach. Data is also presented to show that acquisition methods developed on the Sciex model API3000 instrument can be effectively transferred to the Sceix API4000 and API5000 model instruments.
In this manuscript, the European Bioanalysis Forum reports back on their discussions on practical and scientific considerations related to bioanalytical applications of quantitative polymerase chain reaction. This publication follows an earlier publication in which the European Bioanalysis Forum recommends to consider principles of context of use when defining assay acceptance criteria for method validation criteria and sample analysis.
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