ESMO Open. 2021 May 10;6(3):100153. doi: 10.1016/j.esmoop.2021.100153. Online ahead of print.

ABSTRACT

Most anticancer molecules are administered in body-size-based dosing schedules, bringing up unsolved issues regarding pharmacokinetic data in heavy patients. The worldwide spread of obesity has not been matched by improved methods and strategies for tailored drug dosage in this population. The weight or body surface area (BSA)-based approaches may fail to fully reflect the complexity of the anthropometric features besides obesity in cancer patients suffering from sarcopenia. Likewise, there is a lack of pharmacokinetic data on obese patients for the majority of chemotherapeutic agents as well as for new target drugs and immunotherapy. Therefore, although the available findings point to the role of dose intensity in cancer treatment, and support full weight-based dosing, empirical dose capping often occurs in clinical practice in order to avoid toxicity. Thus a panel of experts of the Associazione Italiana Oncologia Medica (AIOM), Associazione Medici Diabetologi (AMD), Società Italiana Endocrinologia (SIE), and Società Italiana Farmacologia (SIF), provides here a consensus statement for appropriate cytotoxic chemotherapy and new biological cancer drug dosing in obese patients.

PMID:33984679 | DOI:10.1016/j.esmoop.2021.100153

Eur J Pharmacol. 2021 May 10:174169. doi: 10.1016/j.ejphar.2021.174169. Online ahead of print.

ABSTRACT

Diabetes, characterized by high glucose levels, has been listed to be one of the world's major causes of death. Around 1.6 million deaths are attributed to this disease each year. Persistent hyperglycemic conditions in diabetic patients affect various organs of the body leading to diabetic complications and worsen the disease condition. Current treatment strategies for diabetes include biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, insulin and its analogs, DPP-4(dipeptidyl peptidase-4) and GLP-1 (glucagon-like peptide) analogs. However, many side effects contributing to the devastation of the disease are associated with them. Sodium glucose co-tranporter-2 (SGLT2) inhibition has been reported to be new insulin-independent approach to diabetes therapy. It blocks glucose uptake in the kidneys by inhibiting SGLT2 transporters, thereby promoting glycosuria. Dapagliflozin, empagliflozin and canagliflozin are the most widely used SGLT2 inhibitors. They are effective in controlling blood glucose and HbA1c levels with no side effects including hypoglycemia or weight gain which makes them preferable to other anti-diabetic drugs. However, treatment is found to be associated with inter-individual drug response to SGLT2 inhibitors and adverse drug reactions which are also affected by genetic variations. There have been very few pharmacogenetics trials of these drugs. This review discusses the various SGLT2 inhibitors, their pharmacokinetics, pharmacodynamics and genetic variation influencing the inter-individual drug response.

PMID:33984301 | DOI:10.1016/j.ejphar.2021.174169

Adv Clin Exp Med. 2021 May 12. doi: 10.17219/acem/128764. Online ahead of print.

ABSTRACT

BACKGROUND: NF-κB is an essential player in cancer biology, especially in tumor development, due to its constitutive activation, and because a four-base deletion (ATTG) in the NF-κB1 promoter region at site -94, alters mRNA stability and regulates translation efficiency. This polymorphism is a good candidate risk marker and modulator of clinical course in chronic lymphocytic leukemia (CLL). As the effect of this NF-κB1 gene polymorphism has not been studied in patients with CLL so far, the present study was undertaken to find out whether the NF-κB1 promoter -94 ins/del ATTG polymorphism might be an essential genetic risk factor and/or modulatory disease player associated with CLL.

OBJECTIVES: The NF-κB1 -94 ins/del ATTG (rs28362491) polymorphism was investigated as a potential CLL susceptibility and progression factor, along with demonstration of potential modulation of the stage of clinical disease based on Rai classification.

MATERIAL AND METHODS: The associations of NF-κB1 -94 ins/del ATTG polymorphism with CLL and its clinical manifestation in 282 Polish individuals, including 156 CLL patients, were analyzed using polymerase chain reaction (PCR) with primers including a labeled forward primer, followed by capillary electrophoresis.

RESULTS: A higher occurrence of the del/del homozygosity was observed among patients when compared to controls, resulting in an increase in CLL risk of more than twofold in patients carrying this homozygous genotype (OR = 2.23, p = 0.02, 95% CI = 1.14-4.37). Moreover, the del/del-positive patients more frequently presented the less aggressive disease phenotype (Rai 0), suggesting a low probability of progression to more advanced disease.

CONCLUSIONS: The NF-κB1 -94 del/del genetic variant, although associated with increased risk of CLL disease, may be associated with maintenance of disease severity in the early, mildest stage. The likelihood of disease progression may increase as the frequency of wild-type (insertion) alleles for this polymorphism increases.

PMID:33982453 | DOI:10.17219/acem/128764

Heliyon. 2021 Apr 20;7(4):e06852. doi: 10.1016/j.heliyon.2021.e06852. eCollection 2021 Apr.

ABSTRACT

Antituberculosis drug-induced liver injury (ATDILI) is the common adverse reaction of antituberculosis drugs. Glutathione S-transferases (GSTs), which are phase II metabolizing enzymes for detoxification, are recognized as potential mediators of hepatotoxicity. However, role of GSTs polymorphisms in ATDILI pathogenesis has never been observed in Thais. This study aimed to investigate associations between GSTs and ATDILI susceptibility. This retrospective case-control multicentered study was conducted by the collaboration from ten secondary and tertiary care hospitals across Thailand, including Northern, Central, and Southern parts of Thailand. We enrolled 80 tuberculosis (TB) patients with ATDILI and 174 those without ATDILI into the study. Polymerase chain reaction (PCR) was used to determine genetic polymorphisms of GSTM1 and GSTT1 genes. CYP2E1 genotyping data were derived from microarray data. We illustrated that GSTT1 null and GSTM1/GSTT1 dual null genotypes were correlated with an increased risk of ATDILI with odds ratio (OR) at 1.83 (95% confidence interval (CI), 1.00 to 3.35; P = 0.049) and 2.12 (95%CI, 1.02 to 4.38; P = 0.044), respectively. Interestingly, GSTT1 null and GSTM1/GSTT1 dual null genotypes were found to be correlated with an increased risk of ATDILI in Thai TB patients who carried CYP2E1 wild type phenotype with OR 2.99 (95%CI, 1.07 to 8.39; P = 0.037) and 3.44 (95%CI, 1.01 to 11.71; P = 0.048), respectively. Collectively, GSTT1 null and GSTM1/GSTT1 dual null genotypes were associated with a higher risk of ATDILI in Thai TB patients, which may serve as alternative genetic biomarkers for ATDILI.

PMID:33981901 | PMC:PMC8082558 | DOI:10.1016/j.heliyon.2021.e06852

Front Oncol. 2021 Apr 26;11:628613. doi: 10.3389/fonc.2021.628613. eCollection 2021.

ABSTRACT

Gastric cancer has one of the highest mortality rate in the world, but the treatment is still limited. Building on previous studies, mechanistic studies on propranolol in gastric cancer mice models and gastric cancer patients were performed. Propranolol inhibited the in vitro proliferation of gastric cancer cells in a time- and concentration-dependent manner. Consistent findings were observed in MFC tumors engrafted 615 mice, which were treated with propranolol at 10 mg/kg daily for 14 days. Propranolol inhibited the phosphorylation of AKT, MEK, and ERK proteins than control in mice tumor tissues respectively (p-AKT 26.16 vs. 56.82, P = 0.0196, p-MEK 28.27 vs. 59.28, P = 0.1102, p-ERK 48.2 vs. 107.4, P = 0.0062). Propranolol had antiproliferative activity in gastric cancer patients receiving 60 mg daily for 7 days prior to surgery(ki67 44.8 vs 125.3 for placebo; P = 0.02). Phosphorylated AKT, MEK, and ERK did not differ between propranolol and placebo treatment in gastric cancer patients. The expression of molecules on CD8+ T cells was not changed both in mice model and patients nor was there a statistically significant difference in CD8+ T cell subsets in patients, although suggestion of an effect was evident. These results prove that propranolol may inhibit the growth of gastric cancer in mice model and patients and the possible mechanism was via inhibiting the AKT and MAPK pathways, but the frequency of tumor infiltration CD8+ T cells did not increase significantly.

PMID:33981600 | PMC:PMC8108985 | DOI:10.3389/fonc.2021.628613

Front Pharmacol. 2021 Apr 26;12:588063. doi: 10.3389/fphar.2021.588063. eCollection 2021.

ABSTRACT

Adverse drug reactions are a public health issue that draws widespread attention, especially for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which have high mortality and lack of efficacious treatment. Though T-cell-mediated HLA-interacted immune response has been extensively studied, our understanding of the mechanism is far from satisfactory. This review summarizes infection (virus, bacterial, and mycoplasma infection), an environmental risk factor, as a trigger for SJS/TEN. The mutations or polymorphisms of drug metabolic enzymes, transporters, receptors, the immune system genes, and T-cell-mediated apoptosis signaling pathways that contribute to SJS/TEN are discussed and summarized. Epigenetics, metabolites, and mobilization of regulatory T cells and tolerogenic myeloid precursors are emerged directions to study SJS/TEN. Ex vivo lymphocyte transformation test has been exploited to aid in identifying the causative drugs. Critical questions on the pathogenesis of SJS/TEN underlying gene polymorphisms and T cell cytotoxicity remain: why some of the patients carrying the risky genes tolerate the drug and do not develop SJS/TEN? What makes the skin and mucous membrane so special to be targeted? Do they relate to skin/mucous expression of transporters? What is the common machinery underlying different HLA-B alleles associated with SJS/TEN and common metabolites?

PMID:33981213 | PMC:PMC8107822 | DOI:10.3389/fphar.2021.588063

J Affect Disord. 2021 Apr 28;289:135-143. doi: 10.1016/j.jad.2021.04.040. Online ahead of print.

ABSTRACT

BACKGROUND: Bipolar disorder (BD) is among the most heritable psychiatric disorders, particularly in early-onset cases, owing to multiple genes of small effect. Here we examine a multi-gene risk score (MGRS), to address the gap in multi-gene research in early-onset BD.

METHODS: MGRS was derived from 34 genetic variants relevant to neuropsychiatric diseases and related systemic processes. Multiple MGRS were calculated across a spectrum of inclusion p-value thresholds, based on allelic associations with BD. Youth participants (123 BD, 103 healthy control [HC]) of European descent were included, of which 101 participants (58 BD, 43 HC) underwent MRI T1-weighted structural neuroimaging. Hierarchical regressions examined for main effects and MGRS-by-diagnosis interaction effects on 6 regions-of-interest (ROIs). Vertex-wise analysis also examined MGRS-by-diagnosis interactions.

RESULTS: MGRS based on allelic association p≤0.60 was most robust, explaining 6.8% of variance (t(226)=3.46, p=.001). There was an MGRS-by-diagnosis interaction effect on ventrolateral prefrontal cortex surface area (vlPFC; β=.21, p=.0007). Higher MGRS was associated with larger vlPFC surface area in BD vs. HC. There were 8 significant clusters in vertex-wise analyses, primarily in fronto-temporal regions, including vlPFC.

LIMITATIONS: Cross-sectional design, modest sample size.

CONCLUSIONS: There was a diagnosis-by-MGRS interaction effect on vlPFC surface area, a region involved in emotional processing, emotional regulation, and reward response. Vertex-wise analysis also identified several clusters overlapping this region. This preliminary study provides an example of an approach to imaging-genetics that is intermediate between candidate gene and genome-wide association studies, enriched for genetic variants with established relevance to neuropsychiatric diseases.

PMID:33979723 | DOI:10.1016/j.jad.2021.04.040

World J Biol Psychiatry. 2021 May 12:1-68. doi: 10.1080/15622975.2021.1878427. Online ahead of print.

ABSTRACT

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

PMID:33977870 | DOI:10.1080/15622975.2021.1878427

Lakartidningen. 2021 May 11;118:21023.

ABSTRACT

The Genomic Medicine Sweden (GMS) initiative aims to strengthen precision medicine across the country. This will be accomplished through the implementation of large-scale sequencing techniques in Swedish healthcare. With a patient-centered view, initial efforts will focus on rare diseases, cancer, pharmacogenomics, and infectious diseases, and subsequently extend to complex diseases. GMS is being implemented as a broad collaborative project involving healthcare, universities with medical faculty, SciLifeLab, industry and patient organizations. To deliver top tier diagnostics, regional genomic medicine centers (GMC) are currently under establishment together with a national informatics infrastructure for data sharing. GMS will also offer a unique resource for research that could pave the way for the development of novel drugs, and enhance collaboration with industry. In summary, GMS provides Sweden with an opportunity to take an international forefront position in the field of precision medicine.

PMID:33977514

Indian J Pharmacol. 2021 Jan-Feb;53(1):19-24. doi: 10.4103/ijp.IJP_495_19.

ABSTRACT

INTRODUCTION: Pharmacogenomics is a growing field of science that explores the genetic contributions in an individual's response to the drug, so as to choose the right drug in the right doses tailored to a patient's genetic makeup. Although pharmacogenomics information is incorporated in chapters discussing relevant drugs, it has not been materialized into clinical practice yet and still, it remains a challenge due to limited knowledge and accessibility of the pharmacogenomic tests to diagnose these polymorphisms. With this background, the objective of the study was to assess the knowledge and perception of pharmacogenomics among second-year MBBS students and to sensitize them regarding pharmacogenomics.

MATERIALS AND METHODS: A cross-sectional study was done in which 138 medical students responded to a preformed semi-structured assessment tool. It comprised two main components (1) knowledge and (2) relevance of pharmacogenomics in medical education and clinical practice.

RESULTS: Ninety-five percent students defined pharmacogenomics correctly, but only 54% were aware of genetic variations in drug targets, metabolizing enzymes, and transporters affecting drug therapy. Only 15% knew about the availability of pharmacogenomics tests in India. Eighty-four percent of students felt that incorporating pharmacogenomics education in the MBBS curriculum is a must for precision medicine.

CONCLUSION: Second-year MBBS students had good knowledge of pharmacogenomics, but knowledge about the application in clinical practice and interpretation of pharmacogenomics was limited. Therefore, we recommend (1) basic pharmacogenomic education at all levels of medical curricula, (2) development of case-based knowledge application modules, (3) regular continuing medical education to update about available screening tools/biomarkers, and (4) patient and public awareness programs so that they receive personalized/precision medicine with optimum efficacy and reduced side effects and health-care costs.

PMID:33975995 | DOI:10.4103/ijp.IJP_495_19

J Clin Pharmacol. 2021 May 11. doi: 10.1002/jcph.1909. Online ahead of print.

ABSTRACT

Most patients experience severe hematological toxicities during treatment with gemcitabine; thus, preventing such toxicities would improve the treatment effects and patients' quality of life. We analyzed 13 polymorphisms in the transporters, metabolizing enzymes, targets and genes involved in DNA damage and the folate pathway among 132 patients treated with gemcitabine and studied their association with the severity of the hematological toxicities. Single-locus analysis showed that the SNPs RRM1 rs12806698 and rs11031918 and DCTD rs7663494 were significantly associated with severe neutropenia; hENT1 rs760370, hCNT3 rs7867504 and rs4877831 were associated with severe leucopenia; CDA rs2072671, DCTD rs7663494 and WEE1 rs3910384 were associated with severe anemia; and MTHFR rs1801133 was associated with severe thrombocytopenia after stringent Bonferroni correction (P<0.0038). The gene-gene interaction analysis identified the overall best models, including a two-way interaction model (hCNT3 rs7867504 and dCK rs12648166) for severe leucopenia (P = 0.0022) and a three-locus model (CDA rs207671, DCTD rs7663494 and WEE1 rs3910384) for severe anemia with a strong synergistic effect (P = 0.0001). The association with hematological toxicity was further strengthened by the results of a haplotype analysis, wherein the homozygous genotype combination of rs3910384 CC, rs2072671 AA, rs12648166 GG, rs7867504 CC and rs7663494 TT conferred high genetic susceptibility to severe thrombocytopenia. Our results suggested that the gene-gene interaction of gemcitabine metabolic pathway genes and WEE1 contributes to susceptibility to gemcitabine-induced hematological toxicity. Moreover, we proposed a promising data mining analysis approach (generalized multifactor dimensionality reduction, GMDR) to detect and characterize gene-gene interactions. This article is protected by copyright. All rights reserved.

PMID:33974709 | DOI:10.1002/jcph.1909

Bosn J Basic Med Sci. 2021 Apr 20. doi: 10.17305/bjbms.2021.5646. Online ahead of print.

ABSTRACT

Type 2 diabetes (T2D) has a continuously rising prevalence worldwide. Pharmacogenetics has been recognized as a promising concept for pharmacological treatment of T2D, as antidiabetic drugs are not equally effective and safe for all patients, and the costs of diabetes treatment are increasing. The latest published guidelines on T2D treatment firmly endorse the use of newer antidiabetic drugs, sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP-IVi), and glucagon-like peptide-1 receptor agonists (GLP-1RA), considering their satisfactory pharmacological effect and good safety profile. Furthermore, SGLT2i and GLP-1RA show protective effects in patients with established atherosclerotic cardiovascular disease and chronic kidney disease. However, there has been growing evidence that the effectiveness and safety of these drug classes could depend on genetic variability. Here, we summarized the results of the published studies on the pharmacogenetic biomarkers for the three drug classes. A number of genetic variations have been investigated so far. The explored candidate genes mostly encode drug targets, drug-metabolizing enzymes, and genes linked to T2D risk. Although many of the results are promising, it is still necessary to obtain more information from larger controlled studies to confirm their clinical significance. This approach may lead towards more personalized treatment for patients with T2D.

PMID:33974529 | DOI:10.17305/bjbms.2021.5646

Bioinformatics. 2021 May 11:btab320. doi: 10.1093/bioinformatics/btab320. Online ahead of print.

ABSTRACT

MOTIVATION: Ordinal classification problems arise in a variety of real-world applications, in which samples need to be classified into categories with a natural ordering. An example of classifying high-dimensional ordinal data is to use gene expressions to predict the ordinal drug response, which has been increasingly studied in pharmacogenetics. Classical ordinal classification methods are typically not able to tackle high-dimensional data and standard high-dimensional classification methods discard the ordering information among the classes. Existing work of high-dimensional ordinal classification approaches usually assume a linear ordinality among the classes. We argue that manually-labeled ordinal classes may not be linearly arranged in the data space, especially in high-dimensional complex problems.

RESULTS: We propose a new approach that can project high-dimensional data into a lower discriminating subspace, where the innate ordinal structure of the classes is uncovered. The proposed method weights the features based on their rank correlations with the class labels and incorporates the weights into the framework of linear discriminant analysis. We apply the method to predict the response to two types of drugs for patients with Multiple Myeloma, respectively. A comparative analysis with both ordinal and nominal existing methods demonstrates that the proposed method can achieve a competitive predictive performance while honoring the intrinsic ordinal structure of the classes. We provide interpretations on the genes that are selected by the proposed approach to understand their drug-specific response mechanisms.

AVAILABILITY AND IMPLEMENTATION: The data underlying this article are available in the Gene Expression Omnibus Database at https://www.ncbi.nlm.nih.gov/geo/ and can be accessed with accession number GSE9782 and GSE68871. The source code for FWOC can be accessed at https://github.com/pisuduo/Feature-Weighted-Ordinal-Classification-FWOC.

PMID:33974007 | DOI:10.1093/bioinformatics/btab320

Per Med. 2021 May 11. doi: 10.2217/pme-2020-0120. Online ahead of print.

ABSTRACT

This article summarizes the background, content and outcomes of a special meeting that was convened among oncologists and scientists to discuss the role of pharmacogenetic (PGx) testing in pediatric clinical oncology practice. This meeting provided an opportunity for what the lead author (AM Issa) refers to as the 'voice of the clinician' dynamic to be amplified in order to better understand how personalized or precision medicine applications such as PGx testing are adopted and incorporated into clinical settings and what we can learn from the experiences of current and ongoing implementation PGx approaches to further the implementation of precision medicine applications in real-world environments. Group dynamics and clinical experience with PGx testing and return of results shaped the discussion.

PMID:33973801 | DOI:10.2217/pme-2020-0120

Pharmacogenomics. 2021 May 11. doi: 10.2217/pgs-2020-0187. Online ahead of print.

ABSTRACT

Pharmacogenetic testing is available to healthcare professionals to guide drug selection and prevent adverse events. However, its implementation in the clinical practice of psychiatry/neurology still has barriers, mainly due to a lack of evidence. We conducted a literature search on Cochrane Library, Embase and Pubmed, from their inception to 18 June 2020. We included 16 published systematic reviews. The most studied drug categories were anticonvulsants and selective serotonin reuptake inhibitors associated with human leukocyte antigen and cytochrome P450 genes (HLA-A, HLA-B, CYP2C9, CYP2D6, CYP2C19), classified as critically low quality/low quality. There is a need for more robust studies with adequate design to assess the potential benefits of adopting pharmacogenetics in health systems and services.

PMID:33973477 | DOI:10.2217/pgs-2020-0187

Lakartidningen. 2021 May 11;118:20176.

ABSTRACT

Serious adverse drug reactions, drug intolerance, and lack of effect are major problems in healthcare. Pharmacogenomics is the part of precision medicine that aims to develop predictive risk markers in this respect and establish such testing in clinical practice. The nation-wide project Genomic Medicine Sweden (GMS) is undertaking large-scale sequencing to predict risk of drug toxicity and lack of efficacy in malignant diseases. The aim is to facilitate an improved, individualized treatment with increased patient safety. In addition to accurate genotyping, other technical or infrastructure-related aspects need to be considered for a successful implementation in healthcare, for example electronic accessibility and visibility of pharmacogenomic data of long-standing relevance for an individual's ongoing and future drug treatment.

PMID:33973222

J Immunother Cancer. 2021 May;9(5):e002372. doi: 10.1136/jitc-2021-002372.

ABSTRACT

BACKGROUND: Emerging evidence has highlighted the importance of extracellular vesicle (EV)-based biomarkers of resistance to immunotherapy with checkpoint inhibitors in metastatic melanoma. Considering the tumor-promoting implications of urokinase-type plasminogen activator receptor (uPAR) signaling, this study aimed to assess uPAR expression in the plasma-derived EVs of patients with metastatic melanoma to determine its potential correlation with clinical outcomes.

METHODS: Blood samples from 71 patients with metastatic melanoma were collected before initiating immunotherapy. Tumor-derived and immune cell-derived EVs were isolated and analyzed to assess the relative percentage of uPAR+ EVs. The associations between uPAR and clinical outcomes, sex, BRAF status, baseline lactate dehydrogenase levels and number of metastatic sites were assessed.

RESULTS: Responders had a significantly lower percentage of tumor-derived, dendritic cell (DC)-derived and CD8+ T cell-derived uPAR +EVs at baseline than non-responders. The Kaplan-Meier survival curves for the uPAR+EV quartiles indicated that higher levels of melanoma-derived uPAR+ EVs were strongly correlated with poorer progression-free survival (p<0.0001) and overall survival (p<0.0001). We also found a statistically significant correlation between lower levels of uPAR+ EVs from both CD8+ T cells and DCs and better survival.

CONCLUSIONS: Our results indicate that higher levels of tumor-derived, DC-derived and CD8+ T cell-derived uPAR+ EVs in non-responders may represent a new biomarker of innate resistance to immunotherapy with checkpoint inhibitors. Moreover, uPAR+ EVs represent a new potential target for future therapeutic approaches.

PMID:33972390 | DOI:10.1136/jitc-2021-002372

Int J Biol Macromol. 2021 May 7:S0141-8130(21)01015-1. doi: 10.1016/j.ijbiomac.2021.05.046. Online ahead of print.

ABSTRACT

Human serum albumin (HSA) is widely used for the treatment of diverse clinical conditions to restore plasma volume, manage burns and treat hypoproteinemia.Although the HSA preparations should ideally preserve its functionality, the structural integrity and antioxidant properties of HSA may be compromised as a result of the manufacturing process. The present study examined seven commercially available HSA preparations for clinical use to investigate their post-translational modifications (PTMs) and antioxidant activity, including DPPH radical-scavenging, peroxyl radical antioxidant and metal binding activities, by means of mass spectrometry and Ellman's assay. The results confirmed that most of the PTMs of HSA and especially the oxidation of the free thiol residue varied between the different commercial albumins and the percentage of these PTMs were higher than those of physiological HSA. Moreover, HSA-DA isoform was increased at the end of the stability time and new oxidative modifications occurred in these samples. In conclusion, the bioprocesses for production of commercial albumins are responsible of their wide heterogeneity, being the ethanol fractionation and their storage conditions the more critical phases. Nonetheless, the Kedrion albumin shows a high content of free thiol and a lower concentration of PTMs than other commercial albumins.

PMID:33971232 | DOI:10.1016/j.ijbiomac.2021.05.046

CNS Neurosci Ther. 2021 May 10. doi: 10.1111/cns.13654. Online ahead of print.

ABSTRACT

AIMS: Glioma is a highly invasive brain tumor, which makes prognosis challenging and renders patients resistant to various treatments. Induction of cell death is promising in cancer therapy. Ferroptosis, a recently discovered regulated cell death, can be induced for killing glioma cells. However, the prognostic prediction of ferroptosis-related genes (FRGs) in glioma remains elusive.

METHODS: The mRNA expression profiles and gene variation and corresponding clinical data of glioma patients and NON-TUMOR control were downloaded from public databases. Risk score based on a FRGs signature was constructed in REMBRANDT cohort and validated in other datasets including CGGA-693, CGGA-325, and TCGA.

RESULTS: Our results demonstrated that the majority of FRGs was differentially expressed among GBM, LGG, and NON-TUMOR groups (96.6%). Furthermore, the glioma patients with low-risk score exhibited a more satisfactory clinical outcome. The better prognosis was also validated in the glioma patients with low-risk score no matter to which grade they were affiliated. Functional analysis revealed that the high-risk score group was positively correlated with the enrichment scores for immune checkpoint blockade-related positive signatures, indicating the critical role of glioma immunotherapy via risk score.

CONCLUSION: A novel FRGs-related risk score can predict prognosis and immunotherapy in glioma patients.

PMID:33969928 | DOI:10.1111/cns.13654

Front Genet. 2021 Apr 21;12:667231. doi: 10.3389/fgene.2021.667231. eCollection 2021.

ABSTRACT

The transmembrane serine protease 2 (TMPRSS2) is the major host protease that enables entry of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) into host cells by spike (S) protein priming. Single nucleotide polymorphisms (SNPs) in the gene TMPRSS2 have been associated with susceptibility to and severity of H1N1 or H1N9 influenza A virus infections. Functional variants may influence SARS-CoV-2 infection risk and severity of Coronavirus disease 2019 (COVID-19) as well. Therefore, we analyzed the role of SNPs in the gene TMPRSS2 in a German case-control study. We performed genotyping of the SNPs rs2070788, rs383510, and rs12329760 in the gene TMPRSS2 in 239 SARS-CoV-2-positive and 253 SARS-CoV-2-negative patients. We analyzed the association of the SNPs with susceptibility to SARS-CoV-2 infection and severity of COVID-19. SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding their demographics. The CC genotype of TMPRSS2 rs383510 was associated with a 1.73-fold increased SARS-CoV-2 infection risk, but was not correlated to severity of COVID-19. Neither TMPRSS2 rs2070788 nor rs12329760 polymorphisms were related to SARS-CoV-2 infection risk or severity of COVID-19. In a multivariable analysis (MVA), the rs383510 CC genotype remained an independent predictor for a 2-fold increased SARS-CoV-2 infection risk. In summary, our report appears to be the first showing that the intron variant rs383510 in the gene TMPRSS2 is associated with an increased risk to SARS-CoV-2 infection in a German cohort.

PMID:33968142 | PMC:PMC8097083 | DOI:10.3389/fgene.2021.667231