Chemical genetic analysis of FTY720- and Ca2+ -sensitive mutants reveals a functional connection between FTY720 and membrane trafficking.

Genes Cells. 2020 Jul 18;:

Authors: Hagihara K, Kanda Y, Ishida K, Satoh R, Takasaki T, Maeda T, Sugiura R

Abstract
FTY720, a sphingosine-1-phosphate (S1P) analog, is used as an immune modulator to treat multiple sclerosis. Accumulating evidence has suggested the mode of action of FTY720 independent of an S1P modulator. In fission yeast, FTY720 induces an increase in intracellular Ca2+ and ROS levels. We have previously identified 49 genes of which deletion causes FTY720 sensitivity. Here, we characterized the FTY720-sensitive mutants in terms of their relevance to the Ca2+ homeostasis and identified the 16 FTY720- and Ca2+ - sensitive mutants (fcs mutants). Most of the FTY720-sensitive mutants showed elevated Ca2+ levels and exhibited Ca2+ dysregulation by FTY720 treatment. One of the functional categories among the genes whose deletion renders cells susceptible to FTY720 and Ca2+ include the Golgi/endosomal membrane trafficking. Notably, FTY720, but not phosphorylated FTY720 incapable of inducing Ca2+ increase, inhibited the secretion of acid phosphatase in the wild-type cells. Importantly, secretory defects of the Golgi/endosomal trafficking mutants, Vps45, or Ryh1 deletion, were further exacerbated by FTY720. Our fcs mutant screen also identified the adenylyl cyclase-associated protein Cap1 and a Rictor homolog Ste20, whose deletion markedly exacerbated FTY720-sensitive secretory impairment. Collectively, our data may suggest a synergistic impact of FTY720 combined with secretion perturbation on proliferation and Ca2+ homeostasis.

PMID: 32682352 [PubMed - as supplied by publisher]

Evaluation of the suitability of 19 pharmacogenomics biomarkers for individualized metformin therapy for type 2 diabetes patients.

Drug Metab Pers Ther. 2020 Jun 30;35(2):

Authors: Xhakaza L, Abrahams-October Z, Pearce B, Masilela CM, Adeniyi OV, Johnson R, Ongole JJ, Benjeddou M

Abstract
Objectives Type 2 Diabetes mellitus is a progressive metabolic disease characterized by relative insulin insufficiency and insulin resistance resulting in hyperglycemia. Despite the widespread use of metformin, there is considerable variation in treatment response; with approximately one-third of patients failing to achieve adequate glycemic control. Studies have reported the involvement of single nucleotide polymorphisms and their interactions in genetic pathways i.e., pharmacodynamics and pharmacokinetics. This study aims to investigate the association between 19 pharmacogenetics biomarkers and response to metformin treatment. Methods MassARRAY panels were designed and optimized by Inqaba Biotechnical Industries, to genotype 19 biomarkers for 140 type 2 diabetic outpatients. Results The CT genotype of the rs12752688 polymorphism was significantly associated with increased response to metformin therapy after correction (OR=0.33, 95% CI [0.16-0.68], p-value=0.006). An association was also found between the GA genotype of SLC47A2 rs12943590 and a decreased response to metformin therapy after correction (OR=2.29, 95% CI [1.01-5.21], p-value=0.01). Conclusions This is the first study investigating the association between genetic variants and responsiveness to medication for diabetic patients from the indigenous Nguni population in South Africa. It is suggested that rs12752688 and rs12943590 be included in pharmacogenomics profiling systems to individualize metformin therapy for diabetic patients from African populations.

PMID: 32681778 [PubMed - as supplied by publisher]

Self-estimation of phenylketonuria patients on therapeutic diet. Psychological support.

Drug Metab Pers Ther. 2020 Jun 30;35(2):

Authors: Iakovou KK, Schulpis K

Abstract
Objectives Self-esteem is the degree to which the qualities and characteristics contained in one's self-concept are perceived to be positive. The aim of this study was to evaluate the self-esteem scores in phenylketonuria (PKU) patients on "strict", "loos" and "off diet". Sixty PKU patients were divided in three equal groups. Methods Group a: "on strict", group b: "on loos" and group c: "off diet". A special questionnaire for self-esteem scores was created for these patients. Results Before psychological support, group a patients demonstrated 6/20 (30%) very high self-esteem, 9/20 (45%) high and 5/25 (25%) moderate. After support 14/20 (70%) were turned to very high, 5/20 (25%) represented high except one whose degrees remained an altered. group b 4/20 (20%) were very high, 7/20 (35%) were high, 3/20 (15%) moderate and the rest of them showed low self-esteem degrees, after support, 10/20 (50%) showed very high, 5/20 (25%) became high, 3/20 (15%) turned to moderate and 2/20 (10%) remained unaltered. Group c, 1/20 (5%) were very high self-esteemed, 7/20 (35%) were high, 6/20 (30%) were moderate and 6/20 (30%) with low self-esteemed, at the end of support, 6/20 (30%) become very high, 8/20 (40%) with high, 4/20 (20.0%), moderate self-esteem whereas the rest were unaltered. Conclusions Very high and high self-esteem degrees were demonstrated in patients who follow their PKU diet. Moderate and low self-esteem degrees were predominantly found in patients on loos and or off diet. Psychological supports commonly result in amelioration of self-esteem degrees.

PMID: 32681775 [PubMed - as supplied by publisher]

Educational and Ethical Considerations for Genetic Test Implementation Within Health Care Systems.

Netw Syst Med. 2020;3(1):58-66

Authors: Kurnat-Thoma E

Abstract
Introduction: The precision medicine (PM) era presents unprecedented proliferation of genetic/genomic initiatives, information, and bioinformatic tools to enhance targeted molecular diagnosis and therapeutic treatments. As of February 29, 2020, the National Institutes of Health (NIH) National Center for Biotechnology Information (NCBI) Genetic Testing Registry contained 64,860 genetic tests for 12,268 conditions and 18,686 genes from 560 laboratories, and the Food and Drug Administration had 404 entries for pharmacogeneomic biomarkers used in drug labeling. Population-based research initiatives including NIH's All of Us and Veterans Affairs' Million Veteran Program, and the UK Biobank, combine use of genomic biorepositories with electronic medical records (i.e., National Human Genome Research Institute's [NHGRI's] electronic Medical Records and Genomics [eMERGE] Network). Learning health care systems are implementing clinical genomics screening programs and precision oncology programs. However, there are insufficient medical geneticists, nurse geneticists, and genetics counselors to implement expanding number of clinical genetic tests that are required for PM implementation. Methods: A scoping review of current (2014-2019) trends in U.S. genomic medicine translation, PM health care provider workforce education and training resources, and genomic clinical decision support (CDS) implementation tools was conducted. Results: Health care delivery institutions and systems are beginning to implement genetic tests that are driving PM, particularly in the areas of oncology, pharmacogenetics, obstetrics, and prenatal diagnostics. To ensure safe adoption and clinical translation of PM, health care systems have an ethical responsibility to ensure their providers and front-line staff are adequately prepared to order, use, and interpret genetic test information. Conclusion: There are a number of high-quality evidenced-based educational resources and CDS tools available. Strong partnerships between health care system leaders, front-line providers and staff coupled with reasonable goal setting can help drive PM translation interests.

PMID: 32676590 [PubMed]

Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

Genet Med. 2020 Jul 17;:

Authors: Beitelshees AL, Stevenson JM, El Rouby N, Dillon C, Empey PE, Fielstein EM, Johnson JA, Limdi NA, Ong HH, Franchi F, Angiolillo DP, Peterson JF, Rosenman MB, Skaar TC, Tuteja S, Cavallari LH, IGNITE Pharmacogenetics Working Group

Abstract
PURPOSE: Genotype-guided antiplatelet therapy is increasingly being incorporated into clinical care. The purpose of this study is to determine the extent to which patients initially genotyped for CYP2C19 to guide antiplatelet therapy were prescribed additional medications affected by CYP2C19.
METHODS: We assembled a cohort of patients from eight sites performing CYP2C19 genotyping to inform antiplatelet therapy. Medication orders were evaluated from time of genotyping through one year. The primary endpoint was the proportion of patients prescribed two or more CYP2C19 substrates. Secondary endpoints were the proportion of patients with a drug-genotype interaction and time to receiving a CYP2C19 substrate.
RESULTS: Nine thousand one hundred ninety-one genotyped patients (17% nonwhite) with a mean age of 68 ± 3 years were evaluated; 4701 (51%) of patients received two or more CYP2C19 substrates and 3835 (42%) of patients had a drug-genotype interaction. The average time between genotyping and CYP2C19 substrate other than antiplatelet therapy was 25 ± 10 days.
CONCLUSIONS: More than half of patients genotyped in the setting of CYP2C19-guided antiplatelet therapy received another medication impacted by CYP2C19 in the following year. Given that genotype is stable for a patient's lifetime, this finding has implications for cost effectiveness, patient care, and treatment outcomes beyond the indication for which it was originally performed.

PMID: 32678355 [PubMed - as supplied by publisher]

Intracoronary Administration of Allogeneic Cardiosphere-Derived Cells Immediately Prior to Reperfusion in Pigs With Acute Myocardial Infarction Reduces Infarct Size and Attenuates Adverse Cardiac Remodeling.

J Cardiovasc Pharmacol Ther. 2020 Jul 17;:1074248420941672

Authors: Sousonis V, Sfakianaki T, Ntalianis A, Nanas I, Kontogiannis C, Aravantinos D, Kapelios C, Katsaros L, Nana M, Sampaziotis D, Sanoudou D, Papalois A, Malliaras K

Abstract
BACKGROUND: Allogeneic cardiosphere-derived cells (CDCs) exert cardioprotective effects when administered intracoronarily after reperfusion in animal models of acute myocardial infarction (AMI). The "no-reflow" phenomenon develops rapidly post-reperfusion and may undermine the efficacy of cell therapy, due to poor cell delivery in areas of microvascular obstruction (MVO). We hypothesized that CDC-induced cardioprotection would be enhanced by cell administration prior to reperfusion, when microvasculature is still relatively intact, to facilitate widespread cell delivery within the ischemic area.
METHODS AND RESULTS: We studied 81 farm pigs; 55 completed the specified protocols. A dose-optimization study in infarcted pigs demonstrated that the doses of 5 million and 10 million CDCs are the maximum safe doses that can be administered intracoronarily at 5 minutes prior to and at 5 minutes post-reperfusion, respectively, without aggravating MVO. Quantification of acute cell retention by polymerase chain reaction demonstrated that cell delivery prior to reperfusion resulted in higher cardiac cell retention compared to delivery post-reperfusion. We then performed a randomized, placebo-controlled study to assess the long-term efficacy of intracoronary infusion of 5 million allogeneic CDCs, delivered at 5 minutes prior to reperfusion, in a porcine model of AMI. The CDC therapy resulted in decreased scar size, improved regional systolic function, and attenuation of adverse cardiac remodeling (manifested as preserved global systolic function, preserved end-systolic volume, and decreased interstitial fibrosis) compared to placebo at 30 days post-MI.
CONCLUSIONS: Dose-optimized intracoronary infusion of allogeneic CDCs prior to reperfusion in a porcine model of AMI is feasible, safe and confers long-term benefits.

PMID: 32677460 [PubMed - as supplied by publisher]

Reduced LINC00551 expression promotes proliferation and invasion of esophageal squamous cancer by increase in HSP27 phosphorylation.

J Cell Physiol. 2020 Jul 17;:

Authors: Peng X, Zhou Y, Chen Y, Tang L, Wang G, Jiang H, Wang X, Tao Y, Zhuang W

Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers, and long noncoding RNAs (lncRNAs) regulate gene expression or activities. This study investigated the role of lncRNA LINC00551 in ESCC development and progression. Three paired ESCC and normal tissues were subjected to next-generation sequencing and we identified 82 upregulated and 60 downregulated lncRNAs, including LINC00551, which was confirmed to markedly downregulated in 78 ESCC tissues and in the Gene Expression Profiling Interactive Analysis data set. Downregulated LINC00551 expression was associated with lymph node metastasis, advanced TNM stage, and tumor size. Moreover, downregulated LINC00551 expression was also associated with poor progression-free survival and overall survival of ESCC patients. In vitro and in vivo, LINC00551 overexpression inhibited ESCC cell proliferation and invasion, whereas knockdown of LINC00551 expression promoted ESCC cell proliferation and invasion. RNA pull-down and mass spectrometry assays identified the potential LINC00551 binding proteins, and HSP27 was a promising LINC00551 targeting proteins after RNA immunoprecipitation assay. At the protein level, LINC00551 bound to and decreased HSP27 phosphorylation, and in turn, downregulated ESCC cell proliferation and invasion. The current study demonstrated the functional significance of LINC00551 in ESCC development, progression, and prognosis. Further study will assess LINC00551 as a novel prognostic marker or therapeutic target for ESCC.

PMID: 32677057 [PubMed - as supplied by publisher]

Pharmacokinetic and Pharmacogenetic Study of Etoposide in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors.

Pharm Res. 2020 Jul 16;37(7):147

Authors: Moeung S, Chevreau C, Marsili S, Massart C, Fléchon A, Delva R, Gravis G, Lotz JP, Bay JO, Gross-Goupil M, Filleron T, Delmas C, Lafont T, Chatelut E, Thomas F

Abstract
BACKGROUND: Etoposide dosing is based on body surface area. We evaluated if further dose individualization would be required for high dose (HD) etoposide within the TI-CE (taxol, ifosfamide, carboplatin, and etoposide) protocol.
METHODS: Eighty-eight patients received 400 mg/m2/day of etoposide as a 1-hour IV infusion on 3 consecutive days over 3 cycles as part of a phase II trial evaluating efficacy of therapeutic drug monitoring (TDM) of carboplatin in the TI-CE HD protocol. Pharmacokinetic (PK) data were analyzed using population PK model on NONMEM to quantify inter- and intra-individual variabilities. Relationship between etoposide exposure and pharmacodynamic (PD) endpoints, and between selected genetic polymorphisms and tumor response or toxicity were evaluated.
RESULTS: The inter-patient, inter- and intra-cycle variabilities of clearance were 16%, 9% and 0.1%, respectively. The PK-PD relationship was not significant despite a trend toward higher etoposide exposure in patients responding to treatment. A significant correlation was found between exposure and extended neutropenia at cycle 3. A significant association between UGT1A1*28 polymorphism and late neutropenia was observed but needs further evaluation.
CONCLUSIONS: The present study suggests that neither a priori dose individualization nor dose adaptation using TDM is required validating body surface area dosing of etoposide in the TI-CE protocol.

PMID: 32676789 [PubMed - in process]

Hydroxychloroquine and Potential Drug Interactions in Older Adults.

Arch Bronconeumol. 2020 Jul 13;:

Authors: Velasco-González V, Fernández-Araque A, Sainz-Gil M, Jimeno N, Martín LH, Verde Z

PMID: 32675039 [PubMed - as supplied by publisher]

Immunological therapeutics in acute aortic syndrome.

Asian Cardiovasc Thorac Ann. 2020 Jul 16;:218492320943350

Authors: Rimmer LJ, Moughal S, Bashir M

Abstract
Acute aortic syndrome is a group of interlinked conditions with common presenting symptoms, including aortic dissection, penetrating atherosclerotic ulcer, and intramural hematoma. Pharmacological management of acute aortic syndrome is a growing area, with key themes to address the underlying inflammatory pathways believed to be the cause. Research into interleukins, matrix metalloproteinases, and granulocyte macrophage colony-stimulating factor are just some of the many immunological properties being investigated and translated into medical therapies. Stem cell experiments may indicate further advances in the pathologies of acute aortic syndrome. The study of pharmacogenomics to improve treatment across different genomes is also a novel area outlined in this paper.

PMID: 32674584 [PubMed - as supplied by publisher]

Enrollment of Diverse Populations in the INGENIOUS Pharmacogenetics Clinical Trial.

Front Genet. 2020;11:571

Authors: Shah-Williams E, Levy KD, Zang Y, Holmes AM, Stoughton C, Dexter P, Skaar TC

Abstract
Recruitment of diverse populations and subjects living in Medically Underserved Areas and Populations (MUA/P's) into clinical trials is a considerable challenge. Likewise, representation of African-Americans in pharmacogenetic trials is often inadequate, but critical for identifying genetic variation within and between populations. To identify enrollment patterns and variables that predict enrollment in a diverse underserved population, we analyzed data from the INGENIOUS (Indiana GENomics Implementation and Opportunity for the UnderServed), pharmacogenomics implementation clinical trial conducted at a community hospital for underserved subjects (Safety net hospital), and a statewide healthcare system (Academic hospital). We used a logistic regression model to identify patient variables that predicted successful enrollment after subjects were contacted and evaluated the reasons that clinical trial eligible subjects refused enrollment. In both healthcare systems, African-Americans were less likely to refuse the study than non-Hispanic Whites (Safety net, OR = 0.68, and p < 0.002; Academic hospital, OR = 0.64, and p < 0.001). At the Safety net hospital, other minorities were more likely to refuse the study than non-Hispanic Whites (OR = 1.58, p < 0.04). The odds of refusing the study once contacted increased with patient age (Safety net hospital, OR = 1.02, p < 0.001, Academic hospital, OR = 1.02, and p < 0.001). At the Academic hospital, females were less likely to refuse the study than males (OR = 0.81, p = 0.01) and those not living in MUA/P's were less likely to refuse the study than those living in MUA/P's (OR = 0.81, p = 0.007). The most frequent barriers to enrollment included not being interested, being too busy, transportation, and illness. A lack of trust was reported less frequently. In conclusion, African-Americans can be readily recruited to pharmacogenetic clinical trials once contact has been successfully initiated. However, health care initiatives and increased recruitment efforts of subjects living in MUA/Ps are needed. Enrollment could be further enhanced by improving research awareness and knowledge of clinical trials, reducing time needed for participation, and compensating for travel.

PMID: 32670350 [PubMed]

[PHARMACOGENETIC ASPECTS OF TREATMENT OF PATIENTS WITH CHRONIC HEART FAILURE (REVIEW)].

Georgian Med News. 2020 May;(302):63-68

Authors: Pavlova L, Kukes V, Shikh E, Badriddinova L, Tsvetkov D, Berechikidze I

Abstract
This article reviews data for pharmacogenetics findings for treatment for chronic heart insufficiency of heart failure. Also, it discusses connections of genetic polymorphism with a risk of developing heart failure and how it affects the choice of a treatments medicine. The article investigates genetically determined factors of the risk of developing glycoside toxicity. One of the causes is polymorphism of the MDR1 gene encoding glycoprotein P, a transporter, that is involved in the absorption of drugs in the intestines and excretion by the kidneys. Also, the genetic characteristics of ACE in patients with heart failure are discussed. The data is presented from the study of the role of genetic liver metabolism polymorphism regarding efficacy and safety of loop diuretic torasemide. Data for genetic polymorphism of the metabolism of the main beta blocker, used in chronic heart failure metoprolosuccinate is also discussed. Data for roll β1-AP polymorphism in the clinical use of β-AB in patients with heart failure. Further observations are needed from longer studies, that will evaluate long-term efficacy and safety outcomes for medicines related to genetic traits.

PMID: 32672692 [PubMed - as supplied by publisher]

The effect of the VKORC1 promoter variant on warfarin responsiveness in the Saudi WArfarin Pharmacogenetic (SWAP) cohort.

Sci Rep. 2020 Jul 15;10(1):11613

Authors: Al Ammari M, AlBalwi M, Sultana K, Alabdulkareem IB, Almuzzaini B, Almakhlafi NS, Aldrees M, Alghamdi J

Abstract
Warfarin is a frequently prescribed oral anticoagulant with a narrow therapeutic index, requiring careful dosing and monitoring. However, patients respond with significant inter-individual variability in terms of the dose and responsiveness of warfarin, attributed to genetic polymorphisms within the genes responsible for the pharmacokinetics and pharmacodynamics of warfarin. Extensive warfarin pharmacogenetic studies have been conducted, including studies resulting in genotype-guided dosing guidelines, but few large scale studies have been conducted with the Saudi population. In this study, we report the study design and baseline characteristics of the Saudi WArfarin Pharmacogenomics (SWAP) cohort, as well as the association of the VKORC1 promoter variants with the warfarin dose and the time to a stable INR. In the 936 Saudi patients recruited in the SWAP study, the minor allele C of rs9923231 was significantly associated with a 8.45 mg higher weekly warfarin dose (p value = 4.0 × 10-46), as well as with a significant delay in achieving a stable INR level. The addition of the rs9923231 status to the model, containing all the significant clinical variables, doubled the warfarin dose explained variance to 31%. The SWAP cohort represents a valuable resource for future research with the objective of identifying rare and prevalent genetic variants, which can be incorporated in personalized anticoagulation therapy for the Saudi population.

PMID: 32669629 [PubMed - in process]

COVID-19-Related Collapsing Glomerulopathy in a Kidney Transplant Recipient.

Am J Kidney Dis. 2020 Jul 12;:

Authors: Lazareth H, Péré H, Binois Y, Chabannes M, Schurder J, Bruneau T, Karras A, Thervet E, Rabant M, Veyer D, Pallet N

Abstract
We report a case of a kidney transplant recipient who presented with acute kidney injury and nephrotic-range proteinuria in a context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Kidney biopsy revealed collapsing glomerulopathy. Droplet-based digital PCR did not detect the presence of SARS-CoV-2 RNA in the biopsy fragment, and the virus was barely detectable in the plasma at the time of the biopsy. SARS-CoV-2 RNAemia peaked several days later, followed by a seroconversion despite the absence of circulating CD19-positive lymphocytes at admission due to rituximab-based treatment of antibody-mediated rejection 3 months earlier. Genotyping for the two risk alleles of the apolipoprotein L1 (APOL1) gene revealed that the donor carried the low-risk G0/G2 genotype. This case illustrates that COVID-19 may promote a collapsing glomerulopathy in kidney allografts with a low-risk APOL1 genotype, in the absence of detectable SARS-CoV2 RNA in the kidney, and that podocyte injury may precede SARS-CoV2 RNAemia.

PMID: 32668317 [PubMed - as supplied by publisher]

Implications of Efavirenz Pharmacogenetics when Switching from Efavirenz- to Dolutegravir-containing Antiretroviral Regimens.

Clin Infect Dis. 2020 Jul 15;:

Authors: Haas DW, Acosta EP

Abstract
Many patients switch from efavirenz- to dolutegravir-based regimens. In a Phase 1 dolutegravir-efavirenz interaction study, mean dolutegravir Cmin decreased by 60% and 85% among CYP2B6 normal and slow/intermediate metabolizers, respectively. Mean efavirenz half-life was 2.7-times greater in slow versus normal metabolizers. Slow metabolizers will experience more prolonged subtherapeutic dolutegravir concentrations.

PMID: 32667979 [PubMed - as supplied by publisher]

Aberrant ASPM expression mediated by transcriptional regulation of FoxM1 promotes the progression of gliomas.

J Cell Mol Med. 2020 Jul 15;:

Authors: Zeng WJ, Cheng Q, Wen ZP, Wang JY, Chen YH, Zhao J, Gong ZC, Chen XP

Abstract
Gliomas are the most common form of malignant tumour in the central nervous system. However, the molecular mechanism of the tumorigenesis and progression of gliomas remains unclear. In this study, we used the GEO database to identify genes differentially expressed in gliomas and predict the prognosis of glioma. We observed that ASPM mRNA was increased obviously in glioma tissue, and higher ASPM mRNA expression predicted worse disease prognosis. ASPM was highly expressed in glioma cell lines U87-MG and U251, and knockdown of ASPM expression in these cells significantly repressed the proliferation, migration and invasion ability and induced G0/G1 phase arrest. In addition, down-regulation of ASPM suppressed the growth of glioma in nude mice. Five potential binding sites for transcription factor FoxM1 were predicted in the ASPM promoter. FoxM1 overexpression significantly increased the expression of ASPM and promoted the proliferation and migration of glioma cells, which was abolished by ASPM ablation. ChIP and dual-luciferase reporter analysis confirmed that FoxM1 bound to the ASPM promoter at -236 to -230 bp and -1354 to -1348 bp and activated the transcription of ASPM directly. Collectively, our results demonstrated for the first time that aberrant ASPM expression mediated by transcriptional regulation of FoxM1 promotes the malignant properties of glioma cells.

PMID: 32667745 [PubMed - as supplied by publisher]

Structure-function analysis of naturally occurring apolipoprotein A-I L144R, A164S and L178P mutants provides insight on their role on HDL levels and cardiovascular risk.

Cell Mol Life Sci. 2020 Jul 14;:

Authors: Gkolfinopoulou C, Soukou F, Dafnis I, Kellici TF, Sanoudou D, Mavromoustakos T, Stratikos E, Chroni A

Abstract
Naturally occurring point mutations in apolipoprotein A-I (apoA-I), the major protein component of high-density lipoprotein (HDL), may affect plasma HDL-cholesterol levels and cardiovascular risk. Here, we evaluated the effect of human apoA-I mutations L144R (associated with low HDL-cholesterol), L178P (associated with low HDL-cholesterol and increased cardiovascular risk) and A164S (associated with increased cardiovascular risk and mortality without low HDL-cholesterol) on the structural integrity and functions of lipid-free and lipoprotein-associated apoA-I in an effort to explain the phenotypes of subjects carrying these mutations. All three mutants, in lipid-free form, presented structural and thermodynamic aberrations, with apoA-I[L178P] presenting the greatest thermodynamic destabilization. Additionally, apoA-I[L178P] displayed reduced ABCA1-mediated cholesterol efflux capacity. When in reconstituted HDL (rHDL), apoA-I[L144R] and apoA-I[L178P] were more thermodynamically destabilized compared to wild-type apoA-I, both displayed reduced SR-BI-mediated cholesterol efflux capacity and apoA-I[L144R] showed severe LCAT activation defect. ApoA-I[A164S] was thermodynamically unaffected when in rHDL, but exhibited a series of functional defects. Specifically, it had reduced ABCG1-mediated cholesterol and 7-ketocholesterol efflux capacity, failed to reduce ROS formation in endothelial cells and had reduced capacity to induce endothelial cell migration. Mechanistically, the latter was due to decreased capacity of rHDL-apoA-I[A164S] to activate Akt kinase possibly by interacting with endothelial LOX-1 receptor. The impaired capacity of rHDL-apoA-I[A164S] to preserve endothelial function may be related to the increased cardiovascular risk for this mutation. Overall, our structure-function analysis of L144R, A164S and L178P apoA-I mutants provides insights on how HDL-cholesterol levels and/or atheroprotective properties of apoA-I/HDL are impaired in carriers of these mutations.

PMID: 32666307 [PubMed - as supplied by publisher]

Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma.

Neurooncol Adv. 2020 Jan-Dec;2(1):vdaa075

Authors: Vairy S, Le Teuff G, Bautista F, De Carli E, Bertozzi AI, Pagnier A, Fouyssac F, Nysom K, Aerts I, Leblond P, Millot F, Berger C, Canale S, Paci A, Poinsignon V, Chevance A, Ezzalfani M, Vidaud D, Di Giannatale A, Hladun-Alvaro R, Petit FM, Vassal G, Geoerger B, Le Deley MC, Grill J

Abstract
Background: New rescue regimens are needed for pediatric refractory/recurrent low-grade glioma. Nilotinib is a tyrosine kinase inhibitor that has potential synergistic effects with vinblastine on angiogenesis, tumor cell growth, and immunomodulation.
Methods: This phase I trial aimed to determine the recommended doses of this combination for phase II trials (RP2D) using the dual-agent Bayesian continual reassessment method. Nilotinib was given orally twice daily (BID) in combination with once-weekly vinblastine injections for a maximum of 12 cycles of 28 days (clinicaltrials.gov, NCT01884922).
Results: Thirty-five pediatric patients were enrolled across 4 dose levels. The median age was 7 years and 10 had neurofibromatosis type 1. Patients had received a median of 3 prior treatment lines and 25% had received more than 4 previous treatment lines. Dose-limiting toxicity (DLT) during cycle 1 was hematologic, dermatologic, and cardiovascular. The RP2D was identified at 3 mg/m2 weekly for vinblastine with 230 mg/m2 BID for nilotinib (estimated probability of DLT = 18%; 95% credibility interval, 7-29%). Fifteen patients completed the 12 cycles; 2 stopped therapy prematurely due to toxicity and 18 due to disease progression. Three patients achieved a partial response leading to an objective response rate of 8.8% (95% confidence interval [CI], 1.9-23.7), and the disease control rate was 85.3% (95% CI, 68.9-95.1). The 12-month progression-free survival was 37.1% (95% CI, 23.2-53.67).
Conclusions: Vinblastine and nilotinib combination was mostly limited by myelosuppression and dermatologic toxicity. The efficacy of the combination at the RP2D is currently evaluated in a randomized phase II trial comparing this regimen to vinblastine alone.

PMID: 32666050 [PubMed]

Irinotecan-Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview.

Int J Mol Sci. 2020 Jul 12;21(14):

Authors: Kciuk M, Marciniak B, Kontek R

Abstract
Irinotecan has been used in the treatment of various malignancies for many years. Still, the knowledge regarding this drug is expanding. The pharmacogenetics of the drug is the crucial component of response to irinotecan. Furthermore, new formulations of the drug are introduced in order to better deliver the drug and avoid potentially life-threatening side effects. Here, we give a comprehensive overview on irinotecan's molecular mode of action, metabolism, pharmacogenetics, and toxicity. Moreover, this article features clinically used combinations of the drug with other anticancer agents and introduces novel formulations of drugs (e.g., liposomal formulations, dendrimers, and nanoparticles). It also outlines crucial mechanisms of tumor cells' resistance to the active metabolite, ethyl-10-hydroxy-camptothecin (SN-38). We are sure that the article will constitute an important source of information for both new researchers in the field of irinotecan chemotherapy and professionals or clinicians who are interested in the topic.

PMID: 32664667 [PubMed - in process]

FAM13A affects body fat distribution and adipocyte function.

Nat Commun. 2020 03 19;11(1):1465

Authors: Fathzadeh M, Li J, Rao A, Cook N, Chennamsetty I, Seldin M, Zhou X, Sangwung P, Gloudemans MJ, Keller M, Attie A, Yang J, Wabitsch M, Carcamo-Orive I, Tada Y, Lusis AJ, Shin MK, Molony CM, McLaughlin T, Reaven G, Montgomery SB, Reilly D, Quertermous T, Ingelsson E, Knowles JW

Abstract
Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution.

PMID: 32193374 [PubMed - indexed for MEDLINE]