An association study of ABCG2 rs2231142 on the concentrations of allopurinol and its metabolites

ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid‐lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross‐sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

ABCG2 is a gene that codes for the human BCRP. It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid‐lowering agent used to treat this condition. It is not clear if pharmacokinetic changes are involved in the underlying mechanism of those observations.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed whether the rs2231142 loss‐of‐function variant is associated with decreased oxypurinol concentrations.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Further investigations of the links between ABCG2 rs2231142 and the pharmacodynamics of allopurinol are needed.     

N- and Calpha-methylation in biologically active peptides: synthesis, structural and functional aspects

Numerous backbone constraints can be used to develop pseudopeptides or pseudomimetics of biologically active peptides. Among those, N- and Calpha-methyl amino acids that can be incorporated by solid-phase peptide synthesis in a bioactive sequence represent important tools to restrict phi and psi angles of peptide backbone. This review will focus on the chemical syntheses of N- and Calpha-methyl amino acids, their effects on peptide conformation and structure, and their role on the peptide stability towards enzymatic degradation and on the biological activities of the resulting analogues.     

Comparison between ultrasound and magnetic resonance imaging in assessment of fetal cytomegalovirus infection

OBJECTIVE: To evaluate whether fetal brain magnetic resonance imaging (MRI) adds useful information to the one obtained by ultrasound in fetuses with cytomegalovirus (CMV) infection. METHODS: MRI and ultrasonographic findings were analyzed retrospectively in 38 fetuses with proven congenital CMV infection. Both techniques were performed on the same week at a mean gestational age of 33 weeks (24-37). The referral indications were maternal seroconversion (n = 19), and ultrasound findings (n = 19). The results were compared with the fetopathologic examination in cases with fetal death or termination of pregnancy (TOP) or the infant's neurological examination. RESULTS: The 38 cases were classified into three groups, depending on ultrasound findings at referral. Group 1: no ultrasound features (n = 11); group 2: extracerebral features without cerebral abnormalities at ultrasound (n = 13); group 3: presence of cerebral features at ultrasound (n = 14). In group 1, MRI was always normal. In group 2, MRI revealed cerebral features in six cases (46%). In group 3, MRI always confirmed the lesions seen at ultrasound and highlighted other cerebral features. CONCLUSIONS: MRI can provide important additional information with regard to abnormal gyration, cerebellar hypoplasia, or abnormal signal in white matter. It is certainly useful in the assessment of fetuses with extracerebral features without brain abnormalities detected with ultrasounds. If the fetal ultrasound is strictly normal in an infected fetus, MRI may not detect brain anomalies; however, it seems difficult to not perform this noninvasive procedure.     

Transplanted human cones incorporate into the retina and function in a murine cone degeneration model

Once human photoreceptors die, they do not regenerate, thus, photoreceptor transplantation has emerged as a potential treatment approach for blinding diseases. Improvements in transplant organization, donor cell maturation, and synaptic connectivity to the host will be critical in advancing this technology for use in clinical practice. Unlike the unstructured grafts of prior cell-suspension transplantations into end-stage degeneration models, we describe the extensive incorporation of induced pluripotent stem cell (iPSC) retinal organoid–derived human photoreceptors into mice with cone dysfunction. This incorporative phenotype was validated in both cone-only as well as pan-photoreceptor transplantations. Rather than forming a glial barrier, Müller cells extended throughout the graft, even forming a series of adherens junctions between mouse and human cells, reminiscent of an outer limiting membrane. Donor-host interaction appeared to promote polarization as well as the development of morphological features critical for light detection, namely the formation of inner and well-stacked outer segments oriented toward the retinal pigment epithelium. Putative synapse formation and graft function were evident at both structural and electrophysiological levels. Overall, these results show that human photoreceptors interacted readily with a partially degenerated retina. Moreover, incorporation into the host retina appeared to be beneficial to graft maturation, polarization, and function.     

Novel Chronic Anaplasmosis in Splenectomized Patient,Amazon Rainforest

We report a case of unusual human anaplasmosis in the Amazon rainforest of French Guiana. Molecular typing demonstrated that the pathogen is a novel Anaplasma species, distinct to all known species, and more genetically related to recently described Anaplasma spp. causing infections in rainforest wild fauna of Brazil.     

Kinetics of the SARS-CoV-2 Antibody Avidity Response Following Infection and Vaccination

Serological assays capable of measuring antibody responses induced by previous infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been critical tools in the response to the COVID-19 pandemic. In this study, we use bead-based multiplex assays to measure IgG and IgA antibodies and IgG avidity to five SARS-CoV-2 antigens (Spike (S), receptor-binding domain (RBD), Nucleocapsid (N), S subunit 2, and Membrane-Envelope fusion (ME)). These assays were performed in several cohorts of healthcare workers and nursing home residents, who were followed for up to eleven months after SARS-CoV-2 infection or up to six months after vaccination. Our results show distinct kinetic patterns of antibody quantity (IgG and IgA) and avidity. While IgG and IgA antibody levels waned over time, with IgA antibody levels waning more rapidly, avidity increased with time after infection or vaccination. These contrasting kinetic patterns allow for the estimation of time since previous SARS-CoV-2 infection. Including avidity measurements in addition to antibody levels in a classification algorithm for estimating time since infection led to a substantial improvement in accuracy, from 62% to 78%. The inclusion of antibody avidity in panels of serological assays can yield valuable information for improving serosurveillance during SARS-CoV-2 epidemics.     

First imaging results of an intraindividual comparison of 11C-acetate and 18F-fluorocholine PET/CT in patients with prostate cancer at early biochemical first or second relapse after prostatectomy or radiotherapy

Purpose

¹⁸F-Fluorocholine (FCH) and ¹¹C-acetate (ACE) PET are widely used for detection of recurrent prostate cancer (PC). We present the first results of a comparative, prospective PET/CT study of both tracers evaluated in the same patients presenting with recurrence and low PSA to compare the diagnostic information provided by the two tracers.

Methods

The study group comprised 23 patients studied for a rising PSA level after radical prostatectomy (RP, 7 patients, PSA ≤3 ng/ml), curative radiotherapy (RT, 7 patients, PSA ≤5 ng/ml) or RP and salvage RT (9 patients, PSA ≤5 ng/ml). Both FCH and ACE PET/CT scans were performed in a random sequence a median of 4 days (range 0 to 11 days) apart. FCH PET/CT was started at injection (307?±?16 MBq) with a 10-min dynamic acquisition of the prostate bed, followed by a whole-body PET scan and late (45 min) imaging of the pelvis. ACE PET/CT was performed as a double whole-body PET scan starting 5 and 22 min after injection (994?±?72 MBq), and a late view (45 min) of the prostate bed. PET/CT scans were blindly reviewed by two independent pairs of two experienced nuclear medicine physicians, discordant subgroup results being discussed to reach a consensus for positive, negative end equivocal results.

Results

PET results were concordant in 88 out of 92 local, regional and distant findings (Cohen’s kappa 0.929). In particular, results were concordant in all patients concerning local status, bone metastases and distant findings. Lymph-node results were concordant in 19 patients and different in 4 patients. On a per-patient basis results were concordant in 22 of 23 patients (14 positive, 5 negative and 3 equivocal). In only one patient was ACE PET/CT positive for nodal metastases while FCH PET/CT was overall negative; interestingly, the ACE-positive and FCH-negative lymph nodes became positive in a second FCH PET/CT scan performed a few months later.

Conclusion

Overall, ACE and FCH PET/CT showed excellent concordance, on both a per-lesion and a per-patient basis, suggesting that both tracers perform equally for recurrent prostate cancer staging.