Br J Clin Pharmacol. 2023 Jan 14. doi: 10.1111/bcp.15662. Online ahead of print.

ABSTRACT

AIM: Diabetes mellitus affects the pharmacokinetics of cytochrome P450 3A4/5 (CYP3A4/5) substrates. We evaluated the relationship between hemoglobin A1c (HbA1c) levels and the pharmacokinetics of controlled-release tacrolimus.

METHODS: This retrospective observational cohort study included kidney transplant recipients (>18 years) with controlled-release tacrolimus orally. CYP3A5 genotypes were categorized as expressers (*1/*1 or *1/*3) and non-expressers (*3/*3). Multiple linear regression analysis determined the predictors for trough concentration/dose-normalized body weight (C/D) ratio of tacrolimus at 7 days, 6 months, and 12 months after administration. Correlations between the C/D ratio and HbA1c levels at baseline and 6 and 12 months after tacrolimus initiation were evaluated with Bonferroni correction.

RESULTS: Out of 42 patients (CYP3A5 expressers, n=17, and non-expressers, n=25), the multiple linear regression analysis showed that the C/D ratio on day 7 was marginally higher in CYP3A5 non-expressers than in CYP3A5 expressers (r=0.43, p=0.028). Factors impacting the elevation of tacrolimus C/D ratio after 6 and 12 months of treatment were male sex and CYP3A5 non-expressers (r=0.59, p<0.001) and increased HbA1c levels and CYP3A5 non-expressers (r=0.62, p<0.001), respectively. The C/D ratio and HbA1c levels after 12 months was positively correlated in CYP3A5 non-expressers (y=54.6x-194.6, r=0.63, p=0.004, Bonferroni-correction). Furthermore, intra-individual changes in the C/D ratio and HbA1c levels from 6 to 12 months were nearly correlated (y=54.5x+20.2, r=0.41, p=0.036, Bonferroni-correction).

CONCLUSION: HbA1c and CYP3A5 genotypes might be considered to understand the inter- and intra-individual variability in blood tacrolimus concentrations after 6 months post kidney transplantation.

PMID:36640105 | DOI:10.1111/bcp.15662

Invest New Drugs. 2023 Jan 13. doi: 10.1007/s10637-023-01328-9. Online ahead of print.

ABSTRACT

BACKGROUND: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs.

METHODS: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration-time curve from 0 to 24 h (AUC0-24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays.

RESULTS: There was a significant association between the AUC0-24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0-24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively).

CONCLUSION: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

PMID:36637703 | DOI:10.1007/s10637-023-01328-9

Int J Bipolar Disord. 2023 Jan 13;11(1):3. doi: 10.1186/s40345-022-00281-5.

ABSTRACT

BACKGROUND: CACNA1C rs1006737 A allele, identified as a genetic risk variant for bipolar disorder (BD), is associated with anomalous functional connectivity in adults with and without BD. Studies have yet to investigate the association of CACNA1C rs1006737 with resting-state functional connectivity (rsFC) in youth BD.

METHODS: Participants included 139 youth with BD-I, -II, or -not otherwise specified, ages 13-20 years, including 27 BD A-carriers, 41 BD non-carriers, 32 healthy controls (HC) A-carriers, and 39 HC non-carriers. Anterior cingulate cortex (ACC), amygdala, and orbitofrontal cortex (OFC) were examined as regions-of-interest in seed-to-voxel analyses. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and race.

RESULTS: We observed a main effect of BD diagnosis on rsFC between the right amygdala and the right occipital pole (p = 0.02), and a main effect of rs1006737 genotypes on rsFC between the right OFC and bilateral occipital cortex (p < 0.001). Two significant BD diagnosis-by-CACNA1C rs1006737 interactions were also identified. The A allele was associated with positive rsFC between the right ACC and right amygdala in BD but negative rsFC in HC (p = 0.01), and negative rsFC between the left OFC and left putamen in BD but positive rsFC in HC (p = 0.01).

CONCLUSION: This study found that the rs1006737 A allele, identified as a genetic risk variant for BD in adults, was differentially associated with rsFC in youth with BD in regions relevant to emotion, executive function, and reward. Future task-based approaches are warranted to better understand brain connectivity in relation to CACNA1C in BD.

PMID:36637564 | DOI:10.1186/s40345-022-00281-5

Immunohorizons. 2023 Jan 1;7(1):1-16. doi: 10.4049/immunohorizons.2200091.

ABSTRACT

NK cells are major effector cells involved in the elimination of early tumors and prevent metastasis. They often have an impaired function in patients with cancer. Preclinical studies have demonstrated NK cell activation as the adjunctive effect of invariant NKT (iNKT) cells. Activation of iNKT cells after administration of the glycolipid ligand α-galactosylceramide, loaded with CD1d-expressing human PBMC-derived APCs (APC/Gal), is an attractive cancer therapy to optimize the use of NK cells. However, the subsets of NK cells that are activated following iNKT cell activation as well as the period of NK cell activation remain unclear. In this study, we report that the granzyme B-expressing NK cell response in postoperative lung cancer patients was enhanced 49 d after administration of APC/Gal in a phase II study. We found maximum IFN-γ production on day 49 in 13 out of 27 APC/Gal-treated patients. On day 49, 14 out of 27 patients (51.9%) had higher IFN-γ production by iNKT cells (>6-fold higher than the baseline level). This increment significantly correlated with granzyme B-expressing NK cells. Although IFN-γ production was lower in patients in the nontreated group, we detected maximum IFN-γ production 12 mo after the resection of lung cancer (9 out of 29 patients [31%]). These findings suggest that elimination of cancer cells leads to increased NK cell function, which can be further enhanced by APC/Gal therapy.

PMID:36637516 | DOI:10.4049/immunohorizons.2200091

Pharmacogenomics. 2023 Jan 13. doi: 10.2217/pgs-2022-0135. Online ahead of print.

ABSTRACT

Fluoropyrimidines (FPs) are antineoplastic drugs widely used in the treatment of various solid tumors. Nearly 30% of patients treated with FP chemotherapy experience severe FP-related toxicity, and in some cases, toxicity can be fatal. Patients with reduced activity of DPD, the main enzyme responsible for the breakdown of FP, are at an increased risk of experiencing severe FP-related toxicity. While European regulatory agencies and clinical societies recommend pre-treatment DPD deficiency screening for patients starting treatment with FPs, this is not the case with American ones. Pharmacogenomic guidelines issued by several pharmacogenetic organizations worldwide recommend testing four DPD gene (DPYD) risk variants, but these can predict only a proportion of toxicity cases. New evidence on additional common DPYD polymorphisms, as well as identification and functional characterization of rare DPYD variants, could partially address the missing heritability of DPD deficiency and FP-related toxicity.

PMID:36636997 | DOI:10.2217/pgs-2022-0135

BMC Pulm Med. 2023 Jan 12;23(1):14. doi: 10.1186/s12890-022-02290-7.

ABSTRACT

BACKGROUND: Lung adenocarcinoma (LUAD) is characterized by high morbidity and mortality rates and poor prognosis. N7-methylguanosine play an increasingly vital role in lung adenocarcinoma. However, the prognostic value of N7-methylguanosine related-miRNAs in lung adenocarcinoma remains unclear.

METHODS: In the study, the mRNA and miRNA expression profiles and corresponding clinical informations were downloaded from the public database. The prognostic signature was built using least absolute shrinkage and selection operator Cox analysis. The Kaplan-Meier method was used to compare survival outcomes between the high- and low-risk groups. Signatures for the development of lung adenocarcinoma were tested using univariate and multivariate Cox regression models. Single-sample gene set enrichment analysis was used to determine the immune cell infiltration score. First, we predicted METTL1 and WDR4 chemosensitivities based on a public pharmacogenomics database. The area under the receiver operating characteristic curve showed that the performance of signature in 1-,3-, and 5-year survival predictions were 0.68, 0.65, and 0.683, respectively.

RESULTS: We established a novel prognostic signature consisting of 9 N7-Methylguanosine related miRNAs using least absolute shrinkage and selection operator Cox analysis. Patients in the high-risk group had shorter survival times than those in the low-risk group did. The calibration curves at 1, 3, and 5-year also illustrate the high predictive power of the structure. Signature was corrected using the Toumor stage. The expression levels of METTL1 and WDR4 significantly correlated with the sensitivity of cancer cells to antitumor drugs.

CONCLUSIONS: A novel signature constructed using 9 N7-methylguanosine related-miRNAs can be used for prognostic prediction.

PMID:36635678 | DOI:10.1186/s12890-022-02290-7

Theranostics. 2023 Jan 1;13(2):578-595. doi: 10.7150/thno.76614. eCollection 2023.

ABSTRACT

Inhibition of Myc promotes the regression of many types of tumors, including prostate cancer. However, the success of anti-Myc therapy is hampered by the lack of a strategy to effectively deliver the inhibitors to the tumor site and by the feedback mechanisms that cancer cells use to adapt to metabolic reprogramming. Methods: The effects of Myc inhibitors (10074-G5 or 10058-F4), alone or in combination with 6-diazo-5-oxo-L-norleucine (DON), were evaluated in cultured human or murine prostate cancer cells by cell viability assay, qRT-PCR and Western blot. To facilitate the in vivo therapeutic evaluation, a prodrug conjugate of 10074-G4 and DON (10074-DON) was developed, which could be effectively loaded into a polysaccharide-based nanocarrier (PS). Results: The treatment with Myc inhibitors led to significant induction of glutamine: fructose-6-phosphate amidotransferase-1 (GFAT1) and enhanced protein glycosylation. Mechanistically, Myc inhibition triggered GFAT1 induction through the IREα-Xbp1s pathway. The combination use of Myc inhibitors and GFAT1 inhibitor DON led to a synergistic effect in inhibiting the proliferation and migration of prostate cancer cells. Enhanced in vivo delivery of 10074-DON via the PS nanocarrier led to a significant inhibition of tumor growth along with an improvement in tumor immune microenvironment in several PCa animal models. Conclusion: Simultaneous targeting of Myc and GFAT-1 may represent a novel strategy for the treatment of prostate cancer.

PMID:36632215 | PMC:PMC9830436 | DOI:10.7150/thno.76614

Transl Clin Pharmacol. 2022 Dec;30(4):172-181. doi: 10.12793/tcp.2022.30.e22. Epub 2022 Dec 23.

ABSTRACT

For personalized drug dosing, prediction models may be utilized to overcome the inter-individual variability. Multiple linear regression has been used as a conventional method to model the relationship between patient features and optimal drug dose. However, linear regression cannot capture non-linear relationships and may be adversely affected by non-normal distribution and collinearity of data. To overcome this hurdle, machine learning models have been extensively adapted in drug dose prediction. In this tutorial, random forest and neural network models will be trained in tandem with a multiple linear regression model on the International Warfarin Pharmacogenetics Consortium dataset using the scikit-learn python library. Subsequent model analyses including performance comparison, permutation feature importance computation and partial dependence plotting will be demonstrated. The basic methods of model training and analysis discussed in this article may be implemented in drug dose-related studies.

PMID:36632078 | PMC:PMC9810489 | DOI:10.12793/tcp.2022.30.e22

Med (N Y). 2023 Jan 9:S2666-6340(22)00524-4. doi: 10.1016/j.medj.2022.12.008. Online ahead of print.

ABSTRACT

BACKGROUND: South Asians (SAs) represent ∼25% of the world's population and account for >50% of global cardiovascular (CV) deaths, yet they continue to be underrepresented in contemporary clinical trials. The REDUCE-IT study demonstrated in a high-risk and predominantly White population that icosapent ethyl (IPE) lowered major adverse cardiovascular events by 25%. We sought to determine the generalizability of these results to a high-risk population of SAs with established CV disease living in Canada.

METHODS: This was a cross-sectional observational study of 200 statin-treated SAs (≥45 years) with atherosclerotic CV disease (ASCVD) (NCT05271591). SA ethnicity was self-identified as being of Anglo-Indian, Bangladeshi, Bengali, Bhutanese, Goan, Gujarati, Indian, Jatt, Kashmiri, Maharashtrian, Malayali, Nepali, Pakistani, Punjabi, Sindhi, Sinhalese, Sri Lankan, Tamil, Telugu, or other SA. ASCVD was defined as the presence of coronary, carotid, or peripheral atherosclerosis.

FINDINGS: Mean age of the cohort was 67 years, where 82% were men and 57% had diabetes. The predominant ASCVD phenotype was coronary artery disease (94%). Mean (SD) baseline LDL-C and triglycerides were 1.70 (0.8) mmol/L and 1.42 (1.0) mmol/L, respectively. Three-quarters were on high-intensity statin therapy. According to the Health Canada/Canadian Cardiovascular Society Guidelines and FDA-approved indication, 33% and 25% of the participants were, respectively, eligible for IPE.

CONCLUSIONS: A large proportion of high-intensity, statin-treated, high-risk patients with ASCVD and of self-reported SA ethnicity are eligible for IPE. These data have important translational implications for SAs who are at a disproportionately higher risk of CV morbidity and mortality.

FUNDING: This study was funded by an unrestricted grant provided by HLS Therapeutics Inc, Canada.

PMID:36630964 | DOI:10.1016/j.medj.2022.12.008

Br J Clin Pharmacol. 2023 Jan 11. doi: 10.1111/bcp.15659. Online ahead of print.

ABSTRACT

AIMS: Doxorubicin-induced cardiotoxicity (DIC) is a significant cause of mortality in cancer care. This study was conducted to establish the frequency of DIC in Zimbabwean breast cancer patients on doxorubicin and to test the DIC predictive power of genetic biomarkers.

METHODS: A cohort of 50 Zimbabwean breast cancer patients treated with doxorubicin were followed up for 12 months with serial echocardiography and genotyped for UGTA1A6*4, SLC28A3 and RARG. 11% of the patients experienced DIC.

RESULTS: The frequency of SLC28A3 (rs7853758), UGT1A6*4 (rs17863783) and RARG (rs2229774) was 60.7%, 17.9% and 14.3% respectively. No association between DIC and the three variants was observed.

CONCLUSIONS: This is the first study on the prevalence of DIC and associated genetic biomarker predictive evaluation in Zimbabwean breast cancer patients. The genetic frequencies observed in our study were different to that reported in other populations. A larger sample size with a longer follow up time will be necessary in future studies.

PMID:36630266 | DOI:10.1111/bcp.15659

Brain Imaging Behav. 2023 Jan 11. doi: 10.1007/s11682-023-00757-7. Online ahead of print.

ABSTRACT

Brain-derived neurotrophic factor (BDNF) is the most abundant brain neurotrophin and plays a critical role in neuronal growth, survival and plasticity, implicated in the pathophysiology of Bipolar Disorders (BD). The single-nucleotide polymorphism in the BDNF gene (BDNF rs6265) has been associated with decreased hippocampal BDNF secretion and volume in met carriers in different populations, although the val allele has been reported to be more frequent in BD patients. The anterior cingulate cortex (ACC) is a key center integrating cognitive and affective neuronal connections, where consistent alterations in brain metabolites such as Glx (Glutamate + Glutamine) and N-acetylaspartate (NAA) have been consistently reported in BD. However, little is known about the influence of BDNF rs6265 on neurochemical profile in the ACC of Healthy Controls (HC) and BD subjects. The aim of this study was to assess the influence of BDNF rs6265 on ACC neurometabolites (Glx, NAA and total creatine- Cr) in 124 euthymic BD type I patients and 76 HC, who were genotyped for BDNF rs6265 and underwent a 3-Tesla proton magnetic resonance imaging and spectroscopy scan (1 H-MRS) using a PRESS ACC single-voxel (8cm3) sequence. BDNF rs6265 polymorphism showed a significant two-way interaction (diagnosis × genotype) in relation to NAA/Cr and total Cr. While met carriers presented increased NAA/Cr in HC, BD-I subjects with the val allele revealed higher total Cr, denoting an enhanced ACC metabolism likely associated with increased glutamatergic metabolites observed in BD-I val carriers. However, these results were replicated only in men. Therefore, our results support evidences that the BDNF rs6265 polymorphism exerts a complex pleiotropic effect on ACC metabolites influenced by the diagnosis and sex.

PMID:36630045 | DOI:10.1007/s11682-023-00757-7

Pharmacogenomics. 2023 Jan 11. doi: 10.2217/pgs-2022-0137. Online ahead of print.

ABSTRACT

Anxiety and depression coexist with cognitive impairment in Alzheimer's disease along with other concomitant disorders (>60%), which require multipurpose treatments. Polypharmaceutical regimens cause drug-drug interactions and adverse drug reactions, potentially avoidable in number and severity with the implementation of pharmacogenetic procedures. The accumulation of defective variants (>30 genes per patient in more than 50% of cases) in pharmagenes (pathogenic, mechanistic, metabolic, transporter, pleiotropic) influences the therapeutic response to antidementia, antidepressant and anxiolytic drugs in polyvalent regimens. APOE, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP4F2, COMT, MAOB, CHAT, GSTP1, NAT2, SLC30A8, SLCO1B1, ADRA2A, ADRB2, BCHE, GABRA1, HMGCR, HTR2C, IFNL3, NBEA, UGT1A1, ABCB1, ABCC2, ABCG2, SLC6A2, SLC6A3, SLC6A4, MTHFR and OPRM1 variants affect anxiety and depression in Alzheimer's disease.

PMID:36628952 | DOI:10.2217/pgs-2022-0137

Innov Pharm. 2022 Dec 12;13(3). doi: 10.24926/iip.v13i3.4956. eCollection 2022.

ABSTRACT

Since disease is a natural aspect of life, human deep space missions will largely depend on preventing disease, diagnosis, and treatment. Pharmaceuticals are used to identify, treat, prevent, or cure illnesses, but they are unstable on Earth and even more so in space. What if the pharmacist could prepare small quantities of medicines in space, on site, as needed? The alteration in pharmacokinetic and pharmacodynamic (PK-PD) and pharmacogenomics with flying and medications will need to be customised for each person individually and specifically at the point of need because of drug stability issues. We can't meet the expense of bringging everything we might need, so pharmacists must devise ways to manufacture medications in-situ and on-demand. With this skill, pharmacists would be able to fulfill the demand of any exploration mission that involved spaceflight with robust pharmaceuticals that would be stable enough to last the duration of the mission, comprehensive enough to treat all potential medical events, safe, and effective, notwithstanding the known PK-PD and pharmacogenetic alterations that take place during spaceflight. The purpose of this article was to review topics related with Astropharmacy. The topics include: the need of Astropharmacy in space, health-related problems caused by hostile space conditions, storage problems in space, methods to establish the stability and effectiveness of pharmaceutical products in space, and alteration in human physiology including PK-PD and pharmacogenomics and highlight the pharmacist's potential roles in the pharmacies orbiting the space.

PMID:36627911 | PMC:PMC9815863 | DOI:10.24926/iip.v13i3.4956

Innov Pharm. 2022 Dec 12;13(3). doi: 10.24926/iip.v13i3.4890. eCollection 2022.

ABSTRACT

Background: Pharmacogenomics (PGx) can provide more precision in determining causation of adverse drug reactions (ADRs) from drug-drug-gene interaction clinical application. Case Summary: Patient was an intermediate CYP2C19 metabolizer on stable therapy taking a low but therapeutic dose of sertraline for depression and anxiety over a period of 20 years. The patient then became hyponatremic and cognitively impaired after addition of cannabidiol (CBD) to this sertraline regimen. The proposed mechanism was drug-drug-gene interaction of CBD further inhibiting the CYP2C19 metabolism of sertraline and increasing drug exposure to produce moderate to severe hyponatremia and subsequent cognitive dysfunction. Practice Implications: Pharmacogenomics (PGx) testing may assist in etiology of patient symptoms from adverse drug reactions (ADRs) or drug-drug interactions by combining these with detection and application of drug-gene interactions. This case shows inhibition of CYP2C19 by CBD to further increase sertraline exposure, producing hyponatremia and subsequent cognitive dysfunction through CYP2C19 phenoconversion by CBD.

PMID:36627907 | PMC:PMC9815864 | DOI:10.24926/iip.v13i3.4890

Mol Cancer. 2023 Jan 10;22(1):5. doi: 10.1186/s12943-022-01706-6.

ABSTRACT

BACKGROUND: Accumulated evidence highlights the significance of the crosstalk between epigenetic and epitranscriptomic mechanisms, notably 5-methylcytosine (5mC) and N6-methyladenosine (m6A). Herein, we conducted a widespread analysis regarding the crosstalk between 5mC and m6A regulators in hepatocellular carcinoma (HCC).

METHODS: Pan-cancer genomic analysis of the crosstalk between 5mC and m6A regulators was presented at transcriptomic, genomic, epigenetic, and other multi-omics levels. Hub 5mC and m6A regulators were summarized to define an epigenetic and epitranscriptomic module eigengene (EME), which reflected both the pre- and post-transcriptional modifications.

RESULTS: 5mC and m6A regulators interacted with one another at the multi-omic levels across pan-cancer, including HCC. The EME scoring system enabled to greatly optimize risk stratification and accurately predict HCC patients' clinical outcomes and progression. Additionally, the EME accurately predicted the responses to mainstream therapies (TACE and sorafenib) and immunotherapy as well as hyper-progression. In vitro, 5mC and m6A regulators cooperatively weakened apoptosis and facilitated proliferation, DNA damage repair, G2/M arrest, migration, invasion and epithelial-to-mesenchymal transition (EMT) in HCC cells. The EME scoring system was remarkably linked to potential extrinsic and intrinsic immune escape mechanisms, and the high EME might contribute to a reduced copy number gain/loss frequency. Finally, we determined potential therapeutic compounds and druggable targets (TUBB1 and P2RY4) for HCC patients with high EME.

CONCLUSIONS: Our findings suggest that HCC may result from a unique synergistic combination of 5mC-epigenetic mechanism mixed with m6A-epitranscriptomic mechanism, and their crosstalk defines therapeutic response and pharmacogenomic landscape.

PMID:36627693 | DOI:10.1186/s12943-022-01706-6

Eur J Neurol. 2023 Jan 10. doi: 10.1111/ene.15678. Online ahead of print.

ABSTRACT

BACKGROUND: Response predictors to erenumab (ERE) in migraine patients would benefit their clinical management. We investigate associations between patients' clinic characteristics and polymorphisms at CALCRL and RAMP1 genes and response to ERE treatment measured as clinically meaningful improvement of the headache impact test 6 (HIT-6) score.

METHODS: Post-hoc analysis of a prospective, multicenter, investigator-initiated study involving 110 migraine patients starting ERE 70 mg/month. Demographics, medical history, and migraine-related burden measured by HIT-6 score were collected during 3 months before and after ERE start. Selected polymorphic variants of calcitonin receptor-like receptor and receptor activity-modifying protein-1 genes were determined using Real-time PCR. Logistic regression models identified independent predictors for response to ERE, defined as HIT-6 score improvement ≥8 points (HIT-6 responders [HIT-6RESP], vs. HIT-6 non-responders [HIT-6NRESP]).

RESULTS: At month 3, 58 (52.7%) patients were HIT-6RESP. Comorbid hypertension predicted a lower probability of being HIT-6RESP [OR (95%CI] 0.160 (0.047-0.548), p=0.003). Compared to major alleles, minor alleles CALCRL rs6710852G and RAMP rs6431564G conferred an increased probability of being HIT-6RESP [for each G allele: OR (95%CI): 2.82(1.03-7.73), p=0.043; OR 95%CI): 2.10(1.05-4.22), p=0.037]. RAMP1 rs13386048A and RAMP1 rs12465864G decreased this probability [for each rs13386048A, OR (95%CI): 0.53(0.28-0.98), p=0.042; for each rs12465864G, OR(95%CI): 0.32(0.13-0.75), p=0.009). A genetic risk score based on the presence and number of identified risk alleles resulted independently associated with HIT-6RESP (OR, 0.49; 95%CI, 0.33-0.72; p= 0.0003) surviving Bonferroni's correction.

CONCLUSIONS: Response to ERE was associated with comorbid hypertension and specific allelic variants at CALCRL and RAMP1 genes. Results require confirmation in future studies.

PMID:36627267 | DOI:10.1111/ene.15678

Nutr Neurosci. 2023 Jan;26(1):72-84. doi: 10.1080/1028415X.2021.2017662. Epub 2022 Jan 4.

ABSTRACT

Although the pathogenesis of Parkinson's Disease (PD) is not completely understood, there is a consensus that it can be caused by multifactorial mechanisms involving genetic susceptibility, epigenetic modifications induced by toxins and mitochondrial dysfunction. In the past 20 years, great efforts have been made in order to clarify molecular mechanisms that are risk factors for this disease, as well as to identify bioactive agents for prevention and slowing down of its progression. Nutraceutical products have received substantial interest due to their nutritional, safe and therapeutic effects on several chronic diseases. The aim of this review was to gather the main evidence of the epigenetic mechanisms involved in the neuroprotective effects of phenolic compounds currently under investigation for the treatment of toxin-induced PD. These studies confirm that the neuroprotective actions of polyphenols involve complex epigenetic modulations, demonstrating that the intake of these natural compounds can be a promising, low-cost, pharmacogenomic strategy against the development of PD.

PMID:36625764 | DOI:10.1080/1028415X.2021.2017662

Microbiol Spectr. 2023 Jan 10:e0316122. doi: 10.1128/spectrum.03161-22. Online ahead of print.

ABSTRACT

Although the pour plate method is widely employed in microbiological quality control, it has certain drawbacks, including having to melt the culture medium before seeding. In this study, the preparation of the culture medium was modified by using a lower concentration of agar (10 g/L), which was separated from the nutrients during sterilization. The new protocol was assessed in media frequently used in microbiological quality control of food, cosmetics, and pharmaceutical products, with tryptic soy agar (TSA), Sabouraud 4% dextrose agar (SDA), and violet red bile glucose agar (VRBG). In comparison with the conventionally produced media, the modifications significantly improved the growth of Saccharomyces cerevisiae in SDA, Staphylococcus aureus, Salmonella enterica subsp. enterica serovar Typhimurium, and Candida albicans in TSA and Escherichia coli ATCC 8739 and ATCC 25922 and S. Typhimurium in VRBG. The modified VRBG was also more selective for Pseudomonas aeruginosa. Regarding physicochemical properties, a significantly lower pH was observed in TSA and VRBG and lower strength values in TSA. Sterilizing agar separately from the other components of the medium and reducing the agar concentration to 10 g/L can improve microorganism growth and enhance the selectivity of differential media in the pour plate method. These modifications could facilitate the automation of this culture technique. IMPORTANCE In the era of rapid microbiological methods, there is a need to improve long-established culture techniques. Drawbacks of the pour plate method include having to melt each medium separately before seeding. For this technique, we demonstrate that separating the agar from the other components of commonly used media during sterilization and reducing the agar concentration to 10 g/L can enhance microbial growth. The new protocol could have advantages in routine laboratory practice because less agar is required and the same molten agar suspension can be used to prepare different media. Moreover, these modifications could facilitate the automation of the pour plate method.

PMID:36625633 | DOI:10.1128/spectrum.03161-22

Data Brief. 2022 Dec 25;46:108851. doi: 10.1016/j.dib.2022.108851. eCollection 2023 Feb.

ABSTRACT

This article contains raw and processed data related to research published by Vega et al. (2022). This complementary dataset provides further insight into the experimental validation of a single common carotid artery occlusion (CCAO) model upon pretreatment with pertussis toxin (PTX). We present data showing the extent of different PTX concentrations on neurological severity measured by Bederson score following CCAO. In addition, data indicate a protective effect of isoflurane on cerebral infarction and neurological deficits, as well as the consequences of PTX pretreatment on reperfusion after occlusion using time-of-flight magnetic resonance angiography. With these data, we aim to provide detailed experimental settings of this newly described model.

PMID:36624761 | PMC:PMC9823129 | DOI:10.1016/j.dib.2022.108851

J Clin Pharmacol. 2023 Jan 9. doi: 10.1002/jcph.2203. Online ahead of print.

ABSTRACT

Atezolizumab, a humanized anti-PD-L1 monoclonal antibody, was initially approved in 2016, around the same time the sponsor published the minimum serum concentration to target to maintain saturation of receptor occupancy (6 μg/mL). The initially approved dose regimen of 1200 mg every 3 weeks (q3w) was subsequently modified to 840 mg q2w or 1680 mg q4w through pharmacokinetic simulations. Yet, each standard regimen yields steady-state trough concentrations (CMIN,SS ) far exceeding (∼40-fold) the stated target concentration. Additionally, steady-state AUC (AUCSS ) at 1200 mg q3w was significantly (p = 0.027) correlated with probability of adverse events of special interest (AESI) in NSCLC patients, and coupled with excess exposure, provide multiple incentives to explore alternative dose regimens to lower the exposure burden while maintaining an effective CMIN,SS . In this study, we first identified 840 mg q6w as an extended-interval regimen that could robustly maintain 6 μg/mL (≥ 99% of virtual patients [VPs; n = 1000] simulated), then applied that regimen to an approach that administers two "loading doses" of standard interval regimens for a future clinical trial aiming to personalize dose regimens. Each standard dose was simulated for two loading doses, then 840 mg q6w thereafter; all yielded cycle 7 CMIN,SS above 6 μg/mL in >99% of VPs. Further, AUCSS from 840 mg q6w resulted in a flattening (p = 0.63) of the exposure-response relationship with AESI. We next aim to verify this in a clinical trial seeking to validate extended-interval dosing in a personalized approach using therapeutic drug monitoring. This article is protected by copyright. All rights reserved.

PMID:36624662 | DOI:10.1002/jcph.2203