Int J Mol Med. 2021 Nov;48(5):200. doi: 10.3892/ijmm.2021.5033. Epub 2021 Sep 13.

ABSTRACT

Soon after the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) pandemic in December, 2019, numerous research teams, assisted by vast capital investments, achieved vaccine development in a fraction of time. However, almost 8 months following the initiation of the European vaccination programme, the need for prospective monitoring of the vaccine‑induced immune response, its determinants and related side‑effects remains a priority. The present study aimed to quantify the immune response following full vaccination with the BNT162b2 coronavirus disease 2019 (COVID‑19) mRNA vaccine by measuring the levels of immunoglobulin G (IgG) titers in healthcare professionals. Moreover, common side‑effects and factors associated with IgG titers were identified. For this purpose, blood samples from 517 individuals were obtained and analysed. Blood sampling was performed at a mean period of 69.0±23.5 days following the second dose of the vaccine. SARS‑CoV‑2 IgG titers had an overall mean value of 4.23±2.76. Females had higher titers than males (4.44±2.70 and 3.89 ±2.84, respectively; P=0.007), while non‑smokers had higher titers than smokers (4.48±2.79 and 3.80±2.64, respectively; P=0.003). An older age was also associated with lower antibody titers (P<0.001). Moreover, the six most prevalent adverse effects were pain at the injection site (72.1%), generalized fatigue (40.5%), malaise (36.3%), myalgia (31,0%), headache (25.8%) and dizziness/weakness (21.6%). The present study demonstrated that the immune response after receiving the BNT162b2 COVID‑19 mRNA vaccine is dependent on various modifiable and non‑modifiable factors. Overall, the findings of the present study highlight two key aspects of the vaccination programs: First, the need for prospective immunosurveillance studies in order to estimate the duration of immunity, and second, the need to identify those individuals who are at a greater risk of developing low IgG titers in order to evaluate the need for a third dose of the vaccine.

PMID:34515322 | DOI:10.3892/ijmm.2021.5033

Acta Diabetol. 2021 Sep 12. doi: 10.1007/s00592-021-01795-7. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Education might be causal to type 2 diabetes mellitus (T2DM). We triangulated cohort and genetic evidence to consolidate the causality between education and T2DM.

METHODS: We obtained observational evidence from the English Longitudinal Study of Ageing (ELSA). Self-reporting educational attainment was categorised as high (post-secondary and higher), middle (secondary), and low (below secondary or no academic qualifications) in 6,786 community-dwelling individuals aged ≥ 50 years without diabetes at ELSA wave 2, who were followed until wave 8 for the first diabetes diagnosis. Additionally, we performed two-sample Mendelian randomisation (MR) using an inverse-variance weighted (IVW), MR-Egger, weighted median (WM), and weighted mode-based estimate (WMBE) method. Steiger filtering was further applied to exclude single-nucleotide polymorphisms (SNPs) that were correlated with an outcome (T2DM) stronger than exposure (education attainment).

RESULTS: We observed 598 new diabetes cases after 10.4 years of follow-up. The adjusted hazard ratios (95% CI) of T2DM were 1.20 (0.97-1.49) and 1.58 (1.28-1.96) in the middle- and low-education groups, respectively, compared to the high-education group. Low education was also associated with increased glycated haemoglobin levels. Psychosocial resources, occupation, and health behaviours fully explained these inverse associations. In the MR analysis of 210 SNPs (R2 = 0.0161), the odds ratio of having T2DM per standard deviation-decreasing years (4.2 years) of schooling was 1.33 (1.01-1.75; IVW), 1.23 (0.37-4.17; MR-Egger), 1.56 (1.09-2.27; WM), and 2.94 (0.98-9.09; WMBE). However, applying Steiger filtering attenuated most MR results towards the null.

CONCLUSIONS: Our inconsistent findings between cohort and genetic evidence did not support the causality between education and T2DM.

PMID:34514530 | DOI:10.1007/s00592-021-01795-7

Front Pharmacol. 2021 Aug 27;12:730461. doi: 10.3389/fphar.2021.730461. eCollection 2021.

ABSTRACT

Depression disorder is one of the most serious mental illnesses in the world. Escitalopram is the essential first-line medication for depression disorder. It is the substrate of hepatic cytochrome P450 (CYP) enzyme CYP2C19 with high polymorphism. The effect of CYP2C19 on pharmacokinetics and pharmacodynamics on Caucasian population has been studied. The Clinical Pharmacogenetics Implementation Consortium Guideline provides dosing recommendations for escitalopram on CYP2C19 genotypes on the basis of the studies on Caucasian population. However, the gene frequency of the alleles of CYP2C19 showed racial differences between Chinese and Caucasian populations. Representatively, the frequency of the *2 and *3 allele, which were considered as poor metabolizer, has been shown to be three times higher in Chinese than in Caucasians. In addition, the environments might also lead to different degrees of impacts on genotypes. Therefore, the guidelines based on the Caucasians may not be applicable to the Chinese, which induced the establishment of a guideline in China. It is necessary to provide the evidence of individual treatment of escitalopram in Chinese by studying the effect of CYP2C19 genotypes on the pharmacokinetics parameters and steady-state concentration on Chinese. In this study, single-center, randomized, open-label, two-period, two-treatment crossover studies were performed. Ninety healthy Chinese subjects finished the trials, and they were included in the statistical analysis. The pharmacokinetics characteristics of different genotypes in Chinese were obtained. The results indicate that the poor metabolizer had higher exposure, and increased half-life than the extensive metabolizer and intermediate metabolite. The prediction of steady-state concentration based on the single dose trial on escitalopram shows that the poor metabolizer might have a higher steady-state concentration than the extensive metabolizer and intermediate metabolite in Chinese. The results indicate that the genetic testing before medication and the adjustment of escitalopram in the poor metabolizer should be considered in the clinical treatments in Chinese. The results provide the evidence of individual treatment of escitalopram in Chinese, which will be beneficial for the safer and more effective application of escitalopram in the Chinese population. Clinical Trial Registration: identifier ChiCTR1900027226.

PMID:34512354 | PMC:PMC8429954 | DOI:10.3389/fphar.2021.730461

Front Pharmacol. 2021 Aug 27;12:720619. doi: 10.3389/fphar.2021.720619. eCollection 2021.

ABSTRACT

Vemurafenib, a BRAF V600E inhibitor, provides therapeutic benefits for patients with melanoma, but the frequent emergence of drug resistance remains a challenge. An understanding of the mechanisms underlying vemurafenib resistance may generate novel therapeutic strategies for patients with melanoma. Here, we showed that eIF3a, a translational regulatory protein, was an important mediator involved in vemurafenib resistance. eIF3a was expressed at significantly lower levels in vemurafenib-resistant A375 melanoma cells (A375R) than in parental A375 cells. Overexpression of eIF3a enhanced the sensitivity to BRAF inhibitors by reducing p-ERK levels. Furthermore, eIF3a controlled ERK activity by regulating the expression of the phosphatase PPP2R1B via a translation mechanism, thus determining the sensitivity of melanoma cells to vemurafenib. In addition, a positive correlation between eIF3a and PPP2R1B expression was also observed in tumor samples from the Human Protein Atlas and TCGA databases. In conclusion, our studies reveal a previously unknown molecular mechanism of BRAF inhibitor resistance, which may provide a new strategy for predicting vemurafenib responses in clinical treatment.

PMID:34512348 | PMC:PMC8430041 | DOI:10.3389/fphar.2021.720619

Front Pharmacol. 2021 Aug 25;12:693453. doi: 10.3389/fphar.2021.693453. eCollection 2021.

ABSTRACT

Pharmacogenomics (PGx) studies the use of genetic data to optimize drug therapy. Numerous clinical centers have commenced implementing pharmacogenetic tests in clinical routines. Next-generation sequencing (NGS) technologies are emerging as a more comprehensive and time- and cost-effective approach in PGx. This review presents the main considerations for applying NGS in guiding drug treatment in clinical practice. It discusses both the advantages and the challenges of implementing NGS-based tests in PGx. Moreover, the limitations of each NGS platform are revealed, and the solutions for setting up and management of these technologies in clinical practice are addressed.

PMID:34512329 | PMC:PMC8424415 | DOI:10.3389/fphar.2021.693453

Ther Clin Risk Manag. 2021 Sep 4;17:927-949. doi: 10.2147/TCRM.S323387. eCollection 2021.

ABSTRACT

The rising of global geriatric population has contributed to increased prevalence of dementia. Dementia is a neurodegenerative disease, which is characterized by progressive deterioration of cognitive functions, such as judgment, language, memory, attention and visuospatial ability. Dementia not only has profoundly devastating physical and psychological health outcomes, but it also poses a considerable healthcare expenditure and burdens. Acetylcholinesterase inhibitors (AChEIs), or so-called anti-dementia medications, have been developed to delay the progression of neurocognitive disorders and to decrease healthcare needs. AChEIs have been widely prescribed in clinical practice for the treatment of Alzheimer's disease, which account for 70% of dementia. The rising use of AChEIs results in increased adverse drug reactions (ADRs) such as cardiovascular and gastrointestinal adverse effects, resulting from overstimulation of peripheral cholinergic activity and muscarinic receptor activation. Changes in pharmacokinetics (PK), pharmacodynamics (PD) and pharmacogenetics (PGx), and occurrence of drug interactions are said to be major risk factors of ADRs of AChEIs in this population. To date, comprehensive reviews in ADRs of AChEIs have so far been scarcely studied. Therefore, we aimed to recapitulate and update the diverse aspects of AChEIs, including the mechanisms of action, characteristics and risk factors of ADRs, and preventive strategies of their ADRs. The collation of this knowledge is essential to facilitate efforts to reduce ADRs of AChEIs.

PMID:34511919 | PMC:PMC8427072 | DOI:10.2147/TCRM.S323387

ESMO Open. 2021 Sep 9;6(5):100231. doi: 10.1016/j.esmoop.2021.100231. Online ahead of print.

ABSTRACT

BACKGROUND: Proton-pump-inhibitors (PPIs) are frequently prescribed for the management of anticancer drug-related gastrointestinal symptoms. Palbociclib is a weak base with pH-dependent solubility and potential drug-drug interaction at the absorption level may affect clinical pharmacokinetics. The current study was aimed at investigating the effect of co-administration of PPIs and palbociclib on progression-free survival (PFS) in metastatic breast cancer (mBC) patients.

PATIENTS AND METHODS: Patients affected by estrogen receptor-positive, human epidermal growth factor receptor 2-negative mBC, who were candidates for first-line treatment with palbociclib, were enrolled in this retrospective observational study. Patients were defined as 'no concomitant PPIs' if no PPIs were administered during palbociclib treatment, and as 'concomitant PPIs' if the administration of PPIs covered the entire or not less than two-thirds of treatment with palbociclib. All clinical interventions were made according to clinical practice.

RESULTS: A total of 112 patients were enrolled in the study; 56 belonged to the 'no concomitant PPIs' group and 56 to the 'concomitant PPIs' group. Seventy-one patients were endocrine-sensitive and received palbociclib and letrozole, and 43 were endocrine-resistant and were treated with palbociclib and fulvestrant. The most prescribed PPI was lansoprazole. Patients taking PPIs had a shorter PFS than those taking palbociclib and endocrine therapy alone (14.0 versus 37.9 months, P < 0.0001). Multivariate analysis confirmed concomitant PPIs as the only independent predictive factor for shorter PFS (P = 0.0002). PFS was significantly longer in estrogen-sensitive mBC with no concomitant PPIs compared with patients taking PPIs or estrogen-resistant patients, with and without PPIs (P < 0.0001). No correlation with adverse events was found when considering grade >2 hematological toxicities [Common Terminology Criteria for Adverse Events (CTCAE) scale].

CONCLUSIONS: The present study demonstrates that concomitant use of PPIs in mBC patients treated with palbociclib has a detrimental effect on PFS. Therefore, it is recommended to prescribe PPIs with caution in these patients, strictly adhering to the indications in the summary of product characteristics (RCP).

PMID:34509802 | DOI:10.1016/j.esmoop.2021.100231

Am J Pharm Educ. 2021 Sep 10:8683. doi: 10.5688/ajpe8683. Online ahead of print.

ABSTRACT

Connecting scientific concepts with clinical applications is an important objective of pharmacy education. In particular, as the field of precision oncology expands, it is critical that pharmacy students understand how genetic information connects with cancer treatment decisions. However, to effectively teach students about pharmacogenomics and pharmacogenetics, faculty require relevant educational resources, including those that support higher-order learning. In this commentary, we demonstrate the potential utility of publicly accessible cancer genomics databases as teaching resources for pharmacogenomics and pharmacogenetics in oncology pharmacy education. Using clinical data retrieved from a genomics database, we illustrate how case studies can be developed to target core competencies, including understanding tumor genomics profiling, somatic mutations and pharmacotherapy selection, and clinical pharmacogenetics testing. Cancer genomics databases provide readily available, cost-effective, clinical data resources that support active learning related to pharmacogenomics and pharmacogenetics education in oncology pharmacy curricula.

PMID:34507956 | DOI:10.5688/ajpe8683

Am J Physiol Heart Circ Physiol. 2021 Sep 10. doi: 10.1152/ajpheart.00058.2021. Online ahead of print.

ABSTRACT

Vascular aging is highly associated with cardiovascular morbidity and mortality. Although the senescence of vascular smooth muscle cells (VSMCs) has been well-established as a major contributor to vascular aging, intracellular and exosomal micro-RNA (miRNA) signaling pathways in senescent VSMCs have not been fully elucidated. This study aimed to identify the differential expression of intracellular and exosomal miRNA in human VSMCs (hVSMCs) during replicative senescence (RS). To achieve this aim, intracellular and exosomal miRNAs were isolated from hVSMCs and subsequently subjected to whole-genome small RNA next-generation sequencing, bioinformatics analyses and qPCR validation. Three significant findings were obtained. First, senescent hVSMC-derived exosomes tended to cluster together during RS and the molecular weight of the exosomal protein tumor susceptibility gene 101 (TSG-101) increased relative to the intracellular TSG101, suggesting potential posttranslational modifications of exosomal TSG-101. Secondly, there was a significant decrease in both intracellular and exosomal hsa-miR-155-5p expression (n = 3, FDR < 0.05), potentially being a cell type-specific biomarker of hVSMCs during RS. Importantly, hsa-miR-155-5p was found to associate with cell cycle arrest and elevated oxidative stress. Lastly, miRNAs from the intracellular pool, i.e. hsa-miR-664a-3p, hsa-miR-664a-5p, hsa-miR-664b-3p, hsa-miR-4485-3p, hsa-miR-10527-5p and hsa-miR-12136,and that from the exosomal pool, i.e. hsa-miR-7704, were upregulated in hVSMCs during RS (n = 3, FDR < 0.05). Interestingly, these novel upregulated miRNAs were not functionally well-annotated in hVSMCs to date. In conclusion, hVSMC- specific miRNA expression profiles during RS potentially provide valuable insights into the signaling pathways leading to vascular aging.

PMID:34506226 | DOI:10.1152/ajpheart.00058.2021

Pharmacogenomics. 2021 Sep 10. doi: 10.2217/pgs-2021-0067. Online ahead of print.

ABSTRACT

Aim: Cardiovascular disease represents one of the main causes of secondary morbidity and mortality in patients with childhood cancer. Patients & methods: To further address this issue, we analyzed cardiovascular complications in relation to common and rare genetic variants derived through whole-exome sequencing from childhood acute lymphoblastic leukemia survivors (PETALE cohort). Results: Significant associations were detected among common variants in the TTN gene, left ventricle ejection fraction (p ≤ 0.0005), and fractional shortening (p ≤ 0.001). Rare variants enrichment in the NOS1, ABCG2 and NOD2 was observed in relation to left ventricle ejection fraction, and in NOD2 and ZNF267 genes in relation to fractional shortening. Conclusion: Following stratification according to risk groups, the modulatory effect of rare variants was additionally found in the CBR1, ABCC5 and AKR1C3 genes. None of the associations was replicated in St-Jude Lifetime Cohort Study.

PMID:34505544 | DOI:10.2217/pgs-2021-0067

Pharmacogenomics. 2021 Sep 10. doi: 10.2217/pgs-2021-0106. Online ahead of print.

ABSTRACT

Tweetable abstract The large interindividual variability in nevirapine pharmacokinetics and clinical effects that remains unexplained by pharmacogenetic prediction is a major limitation for individualized nevirapine treatment.

PMID:34505542 | DOI:10.2217/pgs-2021-0106

Pharmacogenomics. 2021 Sep 10. doi: 10.2217/pgs-2021-0053. Online ahead of print.

ABSTRACT

Aim: The relationship between hyperuricemia and polymorphisms of transporter genes in coronary artery disease (CAD) patients in China remains unclear. Materials & methods: A total of 258 hyperuricemia patients with CAD and 242 control patients with CAD were recruited in this case-control study. Twenty-four SNPs in genes of ABCG2, PDZK1, URAT1, OAT4, GLUT9, ABCC4, NPT1 and NPT4 were genotyped using direct sequencing in all subjects. Results: The mutation of ABCG2 rs2231142 locus increases the risk of hyperuricemia, and there is a gene dose effect in the influence of mutant heterozygotes and homozygotes. rs3825017 in URAT1 and rs62293298 in GLUT9 were also confirmed to be associated with hyperuricemia. Conclusion: Age, weight, creatinine clearance rate, diuretics and SNPs on ABCG2, URAT1 and GLUT9 were all risk factors of hyperuricemia.

PMID:34505535 | DOI:10.2217/pgs-2021-0053

Hum Mol Genet. 2021 Sep 9:ddab266. doi: 10.1093/hmg/ddab266. Online ahead of print.

ABSTRACT

Several pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The genome-edited cells were evaluated for SLC47A1 expression and splicing. None of the common variants including rs2289669 showed significant association with metformin response. Genomic editing of either rs2289669 or rs8065082 did not alter SLC47A1 expression or splicing. Experimental and in silico analyses show that the rs2289669-containing haploblock does not appear to carry genetic variants that could explain its previously reported association with metformin efficacy.

PMID:34505146 | DOI:10.1093/hmg/ddab266

Pharmacogenomics J. 2021 Sep 9. doi: 10.1038/s41397-021-00254-4. Online ahead of print.

ABSTRACT

Virologic failure of antiretroviral therapy (ART) may be explained by single nucleotide polymorphisms (SNPs) in drug absorption and metabolism genes. Here, we characterized the associations between polymorphisms in cytochrome P450 enzymes' genes CYP2B6 and CYP3A4/A5, nuclear receptor genes NR1I2/3, and initial ART efficacy among 203 HIV-positive individuals from Rio de Janeiro. Association between SNPs and virologic control was evaluated after 6 and 12 months of follow-up using Cox regression models. The SNP rs2307424 (NR1I3) was associated with increased virologic response after 12 months of treatment, while rs1523127 (NR1I2), rs3003596, and rs2502815 (NR1I3) were associated with decreased response. Increased virologic response after 12 months (adjHR = 1.54; p = 0.02) was also observed among carriers of the NR1I3 haplotype rs2502815G-rs3003596A-rs2307424A versus the reference haplotype G-A-G. Our results suggest that NR1I2 and NR1I3 variants are associated with virologic responses to ART among Brazilians.

PMID:34504302 | DOI:10.1038/s41397-021-00254-4

Int J Mol Sci. 2021 Aug 30;22(17):9439. doi: 10.3390/ijms22179439.

ABSTRACT

Three strains of mice with various susceptibilities to restraint stress (RS), i.e., mice with a knocked out norepinephrine transporter gene (NET-KO), SWR/J and C57BL/6J (WT) mice were shown to serve as a good model to study the molecular mechanisms underlying different stress-coping strategies. We identified 14 miRNAs that were altered by RS in the PFC of these mice in a genotype-dependent manner, where the most interesting was let-7e. Further in silico analysis of its potential targets allowed us to identify five mRNAs (Bcl2l11, Foxo1, Pik3r1, Gab1 and Map2k4), and their level alterations were experimentally confirmed. A next-generation sequencing (NGS) approach, which was employed to find transcripts differentially expressed in the PFC of NET-KO and WT mice, showed that, among others, two additional mRNAs were regulated by mmu-let-7e, i.e., mRNAs that encode Kmt2d and Inf2. Since an increase in Bcl2l11 and Pik3r1 mRNAs upon RS in the PFC of WT mice resulted from the decrease in mmu-let-7e and mmu-miR-484 regulations, we postulated that MAPK, FoxO and PI3K-Akt signaling pathways were associated with stress resilience, although via different, genotype-dependent regulation of various mRNAs by let-7e and miR-484. However, a higher level of Kmt2d mRNA (regulated by let-7e) that was found with NGS analysis in the PFC of NET-KO mice indicated that histone methylation was also important for stress resilience.

PMID:34502349 | DOI:10.3390/ijms22179439

J Clin Med. 2021 Sep 3;10(17):3992. doi: 10.3390/jcm10173992.

ABSTRACT

On-treatment platelet reactivity in clopidogrel-treated patients can be measured with several platelet function tests (PFTs). However, the agreement between different PFTs is only slight to moderate. Polymorphisms of the CYP2C19 gene have an impact on the metabolization of clopidogrel and, thereby, have an impact on on-treatment platelet reactivity. The aim of the current study is to evaluate the differential effects of the CYP2C19 genotype on three different PFTs.

METHODS: From a prospective cohort study, we included patients treated with clopidogrel following percutaneous coronary intervention (PCI). One month after PCI, we simultaneously performed three different PFTs; light transmission aggregometry (LTA), VerifyNow P2Y12, and Multiplate. In whole EDTA blood, genotyping of the CYP2C19 polymorphisms was performed.

RESULTS: We included 308 patients treated with clopidogrel in combination with aspirin (69.5%) and/or anticoagulants (33.8%) and, based on CYP2C19 genotyping, classified them as either extensive (36.4%), rapid (34.7%), intermediate (26.0%), or poor metabolizers (2.9%). On-treatment platelet reactivity as measured by LTA and VerifyNow is significantly affected by CYP2C19 metabolizer status (p < 0.01); as metabolizer status changes from rapid, via extensive and intermediate, to poor, the mean platelet reactivity increases accordingly (p < 0.01). On the contrary, for Multiplate, no such ordering of metabolizer groups was found (p = 0.10).

CONCLUSIONS: For VerifyNow and LTA, the on-treatment platelet reactivity in clopidogrel-treated patients correlates well with the underlying CYP2C19 polymorphism. For Multiplate, no major effect of genetic background could be shown, and effects of other (patient-related) variables prevail. Thus, besides differences in test principles and the influence of patient-related factors, the disagreement between PFTs is partly explained by differential effects of the CYP2C19 genotype.

PMID:34501440 | DOI:10.3390/jcm10173992

J Clin Med. 2021 Aug 27;10(17):3859. doi: 10.3390/jcm10173859.

ABSTRACT

INTRODUCTION: Lung cancer belongs to the most common carcinoma worldwide and is the leading cause of cancer-related death. Bone morphogenetic protein-4 (BMP-4) is extracellular signaling molecule involved in many important processes, including cell proliferation and mobility, apoptosis and angiogenesis. Thrombospondin-1 (TSP-1) belongs to the extracellular matrix proteins. It participates in the cell-to-cell and cell-to-matrix interactions and thus plays important role in tumor microenvironment for cancer development and metastasis formation.

AIM: To investigate serum levels of TSP-1 and BMP-4 together with BMP-4 polymorphism in lung cancer patients.

MATERIAL AND METHODS: A total of 111 patients (76 men) with newly diagnosed lung cancer, including 102 patients with non-small cell lung cancer and 9 patients with small-cell lung cancer. Advanced stage of lung cancer was diagnosed in 99 (89%) of patients: stage IV-in 48, stage IIIB-in 33, stage IIIA-in 18 patients; there were six patients with stage II and six patients with stage I. The control group consisted of 61 healthy persons. In all the subjects, serum levels of BMP-4 and TSP-1 were measured by ELISA. With a Real-Time PCR system genotyping of BMP-4 was performed.

RESULTS: BMP-4 and TSP-1 serum levels were significantly lower in the patients with lung cancer than in the controls (TSP-1:10,109.2 ± 9581 ng/mL vs. 11,415.09 ± 9781 ng/mL, p < 0.05; BMP-4: 138.35 ± 62.59 pg/mL vs. 226.68 ± 135.86 pg/mL p < 0.001). In lung cancer patients TSP-1 levels were lower in advanced stages (9282.07 ± 4900.78 ng/mL in the stages III-IV vs. 16,933.60 ± 6299.02 ng/mL in the stages I-II, p < 0.05) and in the patients with than without lymph nodes involvement (10,000.13 ± 9021.41 ng/mL vs. 18,497.75 ± 12,548.25 ng/mL, p = 0.01). There was no correlation between TSP-1 and BMP-4 serum levels. BMP-4 gene polymorphism did not influence the results of the study.

CONCLUSION: Decreased levels of TSP-1 and BMP-4 may serve as potential indices of lung cancer, with additional importance of low TSP-1 level as a marker of advanced stage of the disease.

PMID:34501309 | DOI:10.3390/jcm10173859

J Clin Med. 2021 Aug 24;10(17):3772. doi: 10.3390/jcm10173772.

ABSTRACT

The implementation of clinical pharmacogenetics in daily practice is limited for various reasons. Today, however, it is a discipline in full expansion. Accordingly, in the recent times, several initiatives promoted its implementation, mainly in the United States but also in Europe. In this document, the genotyping results since the establishment of our Pharmacogenetics Unit in 2006 are described, as well as the historical implementation process that was carried out since then. Finally, this progress justified the constitution of La Princesa University Hospital Multidisciplinary Initiative for the Implementation of Pharmacogenetics (PriME-PGx), promoted by the Clinical Pharmacology Department of Hospital Universitario de La Princesa (Madrid, Spain). Here, we present the initiative along with the two first ongoing projects: the PROFILE project, which promotes modernization of pharmacogenetic reporting (i.e., from classic gene-drug pair reporting to complete pharmacogenetic reporting or the creation of pharmacogenetic profiles specific to the Hospital's departments) and the GENOTRIAL project, which promotes the communication of relevant pharmacogenetic findings to any healthy volunteer participating in any bioequivalence clinical trial at the Clinical Trials Unit of Hospital Universitario de La Princesa (UECHUP).

PMID:34501219 | DOI:10.3390/jcm10173772

Lakartidningen. 2021 Aug 10;118:21032.

ABSTRACT

5-fluorouracil (5-FU) is still a cornerstone in drug treatment for cancer. Some patients starting standard dosed 5-FU will experience severe adverse events (SAEs). One mechanism behind SAEs is impaired dihydropyrimidine dehydrogenase (DPD) activity, resulting in an accumulation of cytotoxic metabolites. Pre-emptive testing of DPD enzyme activity or genetic variation in its gene, DPYD, is recommended since 2020 in Sweden. We report experience from DPYD testing in 368 patients planned for 5-FU treatment. DPYD variants associated with reduced DPD activity were observed in 28 patients (8%), which is close to the expected frequency. These patients tolerated 5-FU treatment when doses were reduced according to guidelines. However, 4 out of 5 variant allele carriers starting 5-FU at standard dose due to late arrival of test results experienced SAEs. Pre-emptive testing was calculated to be cost saving and thus beneficial from a healthcare economy perspective.

PMID:34498246

BMJ Open. 2021 Sep 8;11(9):e048141. doi: 10.1136/bmjopen-2020-048141.

ABSTRACT

INTRODUCTION: The combination of biomarkers and drugs is the subject of growing interest both from regulators, physicians and companies. This study protocol of a systematic review is aimed to describe available literature evidences about the cost-effectiveness, cost-utility or net-monetary benefit of the use of biomarkers in solid tumour as tools for customising immunotherapy to identify what further research needs.

METHODS AND ANALYSIS: A systematic review of the literature will be carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines. PubMed and Embase will be queried from June 2010 to June 2021. The PICOS model will be applied: target population (P) will be patients with solid tumours treated with immune checkpoint inhibitors (ICIs); the interventions (I) will be test of the immune checkpoint predictive biomarkers; the comparator (C) will be any other targeted or non-targeted therapy; outcomes (O) evaluated will be health economic and clinical implications assessed in terms of incremental cost-effectiveness ratio, net health benefit, net monetary benefit, life years gained, quality of life, etc; study (S) considered will be economic evaluations reporting cost-effectiveness analysis, cost-utility analysis, net-monetary benefit. The quality of the evidence will be graded according to Grading of Recommendations Assessment, Development and Evaluation.

ETHICS AND DISSEMINATION: This systematic review will assess the cost-effectiveness implications of using biomarkers in the immunotherapy with ICIs, which may help to understand whether this approach is widespread in real clinical practice. This research is exempt from ethics approval because the work is carried out on published documents. We will disseminate this protocol in a related peer-reviewed journal.

PROSPERO REGISTRATION NUMBER: CRD42020201549.

PMID:34497081 | DOI:10.1136/bmjopen-2020-048141