Osteonecrosis of the Jaw Risk Factors in Bisphosphonate Treated Patients with Metastatic Cancer.

Oral Dis. 2020 Dec 04;:

Authors: Van Poznak C, Reynolds EL, Estilo CL, Hu M, Schneider BP, Hertz DL, Gersch C, Thibert J, Thomas D, Banerjee M, Rae JM, Hayes DF

Abstract
BACKGROUND: A case control study was performed to define clinical and genetic risk factors associated with osteonecrosis of the jaw in patients with metastatic cancer treated with bisphosphonates.
METHODS: Clinical data and tissues were collected from patients treated with bisphosphonates for metastatic bone disease who were diagnosed with osteonecrosis of the jaw (cases) and matched controls. Clinical data included patient, behavioral, disease, and treatment information. Genetic polymorphisms in CYP2C8 (rs1934951) and other candidate genes were genotyped. Odds ratios from conditional logistic regression models were examined to identify clinical and genetic characteristics associated with case or control status.
RESULTS: The study population consisted of 76 cases and 126 controls. In the final multivariable clinical model, patients with osteonecrosis of the jaw were less likely to have received pamidronate than zoledronic acid (odds ratio=0.18, 95% Confidence interval: 0.03-0.97, p=0.047) and more likely to have been exposed to bevacizumab (OR=5.15, 95% CI: 1.67-15.95, p=0.005). The exploratory genetic analyses suggested a protective effect for VEGFC rs2333496 and risk effects for VEGFC rs7664413 and PPARG rs1152003.
CONCLUSIONS: We observed patients with ONJ were more likely to have been exposed to bevacizumab and zoledronic and identified potential genetic predictors that require validation prior to clinical translation.

PMID: 33274559 [PubMed - as supplied by publisher]

A review of the pharmacogenomics of buprenorphine for the treatment of opioid use disorder.

J Transl Genet Genom. 2020;4:263-277

Authors: Seguí HA, Melin K, Quiñones DS, Duconge J

Abstract
As the opioid epidemic continues to grow across the United States, the number of patients requiring treatment for opioid use disorder continues to climb. Although medication-assisted treatment presents a highly effective tool that can help address this epidemic, its use has been limited. Nonetheless, with easier dosing protocols (compared to the more complex dosing required of methadone due to its long and variable half-life) and fewer prescribing limitations (may be prescribed outside the setting of federally approved clinics), the increase in buprenorphine use in the United States has been dramatic in recent years. Despite buprenorphine's demonstrated efficacy, patient-specific factors can alter the response to the medications, which may lead to treatment failure in some patients. Clinical characteristics (sex, concurrent medications, and mental health comorbidities) as well as social determinants of health (housing status, involvement with the criminal justice system, and socioeconomic status) may impact treatment outcomes. Furthermore, a growing body of data suggests that genetic variations can alter pharmacological effects and influence therapeutic response. This review will cover the available pharmacogenomic data for the use of buprenorphine in the management of opioid use disorders. Pharmacogenomic determinants that affect opioid receptors, the dopaminergic system, metabolism of buprenorphine, and adverse events are discussed. Although much of the existing data comes from observational studies, clinical research is ongoing. Nevertheless, the development of pharmacogenomic-guided strategies has the potential to reduce opioid misuse, improve clinical outcomes, and save healthcare resources.

PMID: 33274315 [PubMed]

Pharmacogenetics of the Glucagon-like Peptide-1 Receptor Agonist Liraglutide: A Step Towards Personalized Type 2 Diabetes Management.

Curr Pharm Des. 2020 Dec 03;:

Authors: Kyriakidou A, Koufakis T, Goulis DG, Vasilopoulos Y, Zebekakis P, Kotsa K

Abstract
BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder with increasing prevalence and significant burden of long-term complications. Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) are a novel treatment option for T2DM, exerting optimal effects on glucose control and weight loss, and pleiotropic actions. Pharmacogenetics, a promising research field of precision medicine, investigates how gene variations can affect individual response to drug therapy, assuming that the diverse genetic architecture of patients with T2DM could be partly associated with the considerable inter-individual variability in the therapeutic response to GLP-1 RAs. This review aims to summarize current evidence related to T2DM risk variants, affecting the incretin pathway, focusing on the pharmacogenetics of the GLP-1 RA liraglutide, and discuss their potential clinical implications in the management of this complex disorder.
METHODS: A literature search was performed using electronic biomedical databases and the findings of key studies are summarized and discussed in this narrative review.
RESULTS: Available evidence suggests the involvement of genetic polymorphisms in GLP-1 R gene in variation in glycemic response, metabolic parameters and gastric emptying in people treated with liraglutide. Polymorphisms in CNR1, CTRB1/2, TMEM114 and CHST3 loci were also shown to be implicated in the disturbance of the incretin homeostasis in T2DM. These findings warrant further investigation by future studies.
CONCLUSION: Robust findings from pharmacogenetic studies might be used to identify good responders to liraglutide treatment, in terms of both glycemic and weight control, thus reinforcing the patient-centered approach of T2DM management.

PMID: 33272167 [PubMed - as supplied by publisher]

Effectiveness of Platelet Function Analysis-Guided Aspirin and/or Clopidogrel Therapy in Preventing Secondary Stroke: A Systematic Review and Meta-Analysis.

J Clin Med. 2020 Dec 01;9(12):

Authors: Yan AR, Naunton M, Peterson GM, Fernandez-Cadenas I, Mortazavi R

Abstract
BACKGROUND: Antiplatelet medications such as aspirin and clopidogrel are used following thrombotic stroke or transient ischemic attack (TIA) to prevent a recurrent stroke. However, the antiplatelet treatments fail frequently, and patients experience recurrent stroke. One approach to lower the rates of recurrence may be the individualized antiplatelet therapies (antiplatelet therapy modification (ATM)) based on the results of platelet function analysis (PFA). This review was undertaken to gather and analyze the evidence about the effectiveness of such approaches.
METHODS: We searched Medline, CINAHL, Embase, Web of Science, and Cochrane databases up to 7 January 2020.
RESULTS: Two observational studies involving 1136 patients were included. The overall effects of PFA-based ATM on recurrent strokes (odds ratio (OR) 1.05; 95% confidence interval (CI) 0.69 to 1.58), any bleeding risk (OR 1.39; 95% CI 0.92 to 2.10) or death hazard from any cause (OR 1.19; 95% CI 0.62 to 2.29) were not significantly different from the standard antiplatelet therapy without ATM.
CONCLUSIONS: The two studies showed opposite effects of PFA-guided ATM on the recurrent strokes in aspirin non-responders, leading to an insignificant difference in the subgroup meta-analysis (OR 1.59; 95% CI 0.07 to 33.77), while the rates of any bleeding events (OR 1.04; 95% CI 0.49 to 2.17) or death from any cause (OR 1.17; 95% CI 0.41 to 3.35) were not significantly different between aspirin non-responders with ATM and those without ATM. There is a need for large, randomized controlled trials which account for potential confounders such as ischemic stroke subtypes, technical variations in the testing protocols, patient adherence to therapy and pharmacogenetic differences.

PMID: 33271959 [PubMed]

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Evaluating warfarin dosing models on multiple datasets with a novel software framework and evolutionary optimisation.

J Biomed Inform. 2020 Nov 30;:103634

Authors: Truda G, Marais P

Abstract
Warfarin is an effective preventative treatment for arterial and venous thromboembolism, but requires individualised dosing due to its narrow therapeutic range and high individual variation. Many machine learning techniques have been demonstrated in this domain. This study evaluated the accuracy of the most promising algorithms on the International Warfarin Pharmacogenetics Consortium dataset and a novel clinical dataset of South African patients. Support vectors and linear regression were amongst the top performers in both datasets and performed comparably to recent stacked ensemble approaches, whilst neural networks were one of the worst performers in both datasets. We also introduced genetic programming to automatically optimise model architectures and hyperparameters without human guidance. Remarkably, the generated models were found to match the performance of the best models hand-crafted by human experts. Finally, we present a novel software framework (Warfit-learn) for warfarin dosing research. It leverages the most successful techniques in preprocessing, imputation, and parallel evaluation, with the goal of accelerating research and making results in this domain more reproducible.

PMID: 33271340 [PubMed - as supplied by publisher]

Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function.

PLoS One. 2020;15(12):e0243145

Authors: Wang Y, Zhang K, Georgiev P, Wells S, Xu H, Lacey BM, Xu Z, Laskey J, Mcleod R, Methot JL, Bittinger M, Pasternak A, Ranganath S

Abstract
Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-specific Ste20-related serine/threonine kinase, is a negative regulator of signal transduction in immune cells, including T cells, B cells, and dendritic cells (DCs). In mice, HPK1 deficiency subverts inhibition of the anti-tumor immune response and is associated with functional augmentation of anti-tumor T cells. We have used a potent, small molecule HPK1 inhibitor, Compound 1, to investigate the effects of pharmacological intervention of HPK1 kinase activity in immune cells. Compound 1 enhanced Th1 cytokine production in T cells and fully reverted immune suppression imposed by the prostaglandin E2 (PGE2) and adenosine pathways in human T cells. Moreover, the combination of Compound 1 with pembrolizumab, a humanized monoclonal antibody against the programmed cell death protein 1 (PD-1), demonstrated a synergistic effect, resulting in enhanced interferon (IFN)-γ production. Collectively, our results suggest that blocking HPK1 kinase activity with small molecule inhibitors alone or in combination with checkpoint blockade may be an attractive approach for the immunotherapy of cancer.

PMID: 33270695 [PubMed - as supplied by publisher]

Psychological trauma occurring during adolescence is associated with an increased risk of greater waist circumference in Early Psychosis patients treated with psychotropic medication.

PLoS One. 2020;15(12):e0242569

Authors: Alameda L, Levier A, Gholam-Rezaee M, Golay P, Vandenberghe F, Delacretaz A, Baumann P, Glatard A, Dubath C, Herane-Vives A, Rodriguez V, Solida A, Do KQ, Eap CB, Conus P

Abstract
BACKGROUND: It has been suggested that exposure to Childhood Trauma [CT] may play a role in the risk of obesity in Early Psychosis [EP] patients; however, whether this is independently of age at exposure to CT and the medication profile has yet to be investigated.
METHODS: 113 EP-patients aged 18-35 were recruited from the Treatment and Early Intervention in Psychosis Program [TIPP-Lausanne]. Body Mass Index [BMI], Weight Gain [WG] and Waist Circumference [WC] were measured prospectively at baseline and after 1, 2, 3, 6 and 12 months of weight gain inducing psychotropic treatment. Patients were classified as Early-Trauma and Late-Trauma if the exposure had occurred before age 12 or between ages 12 and 16 respectively. Generalized Linear Mixed-Models were adjusted for age, sex, socioeconomic status, baseline BMI, medication and for diagnosis of depression.
RESULTS: Late-Trauma patients, when compared to Non-Trauma patients showed greater WCs during the follow-up [p = 0.013]. No differences were found in any of the other follow-up measures.
CONCLUSIONS: Exposition to CT during adolescence in EP-patients treated with psychotropic medication is associated with greater WC during the early phase of the disease. Further investigation exploring mechanisms underlying the interactions between peripubertal stress, corticoids responsiveness and a subsequent increase of abdominal adiposity is warranted.

PMID: 33270646 [PubMed - as supplied by publisher]

Flype: Software for enabling personalized medicine.

Am J Med Genet C Semin Med Genet. 2020 Dec 03;:

Authors: Helseth DL, Gulukota K, Miller N, Yang M, Werth T, Sabatini LM, Bouma M, Dunnenberger HM, Wake DT, Hulick PJ, Kaul KL, Khandekar JD

Abstract
The advent of next generation DNA sequencing (NGS) has revolutionized clinical medicine by enabling wide-spread testing for genomic anomalies and polymorphisms. With that explosion in testing, however, come several informatics challenges including managing large amounts of data, interpreting the results and providing clinical decision support. We present Flype, a web-based bioinformatics platform built by a small group of bioinformaticians working in a community hospital setting, to address these challenges by allowing us to: (a) securely accept data from a variety of sources, (b) send orders to a variety of destinations, (c) perform secondary analysis and annotation of NGS data, (d) provide a central repository for all genomic variants, (e) assist with tertiary analysis and clinical interpretation, (f) send signed out data to our EHR as both PDF and discrete data elements, (g) allow population frequency analysis and (h) update variant annotation when literature knowledge evolves. We discuss the multiple use cases Flype supports such as (a) in-house NGS tests, (b) in-house pharmacogenomics (PGX) tests, (c) dramatic scale-up of genomic testing using an external lab, (d) consumer genomics using two external partners, and (e) a variety of reporting tools. The source code for Flype is available upon request to the authors.

PMID: 33270363 [PubMed - as supplied by publisher]

Effect of Pharmacogenetic Testing for Statin Myopathy Risk vs Usual Care on Blood Cholesterol: A Randomized Clinical Trial.

JAMA Netw Open. 2020 Dec 01;3(12):e2027092

Authors: Vassy JL, Gaziano JM, Green RC, Ferguson RE, Advani S, Miller SJ, Chun S, Hage AK, Seo SJ, Majahalme N, MacMullen L, Zimolzak AJ, Brunette CA

Abstract
Importance: Nonadherence to statin guidelines is common. The solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotype is associated with simvastatin myopathy risk and is proposed for clinical implementation. The unintended harms of using pharmacogenetic information to guide pharmacotherapy remain a concern for some stakeholders.
Objective: To determine the impact of delivering SLCO1B1 pharmacogenetic results to physicians on the effectiveness of atherosclerotic cardiovascular disease (ASCVD) prevention (measured by low-density lipoprotein cholesterol [LDL-C] levels) and concordance with prescribing guidelines for statin safety and effectiveness.
Design, Setting, and Participants: This randomized clinical trial was performed from December 2015 to July 2019 at 8 primary care practices in the Veterans Affairs Boston Healthcare System. Participants included statin-naive patients with elevated ASCVD risk. Data analysis was performed from October 2019 to September 2020.
Interventions: SLCO1B1 genotyping and results reporting to primary care physicians at baseline (intervention group) vs after 1 year (control group).
Main Outcomes and Measures: The primary outcome was the 1-year change in LDL-C level. The secondary outcomes were 1-year concordance with American College of Cardiology-American Heart Association and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for statin therapy and statin-associated muscle symptoms (SAMS).
Results: Among 408 patients (mean [SD] age, 64.1 [7.8] years; 25 women [6.1%]), 193 were randomized to the intervention group and 215 were randomized to the control group. Overall, 120 participants (29%) had a SLCO1B1 genotype indicating increased simvastatin myopathy risk. Physicians offered statin therapy to 65 participants (33.7%) in the intervention group and 69 participants (32.1%) in the control group. Compared with patients whose physicians did not know their SLCO1B1 results at baseline, patients whose physicians received the results had noninferior reductions in LDL-C at 12 months (mean [SE] change in LDL-C, -1.1 [1.2] mg/dL in the intervention group and -2.2 [1.3] mg/dL in the control group; difference, -1.1 mg/dL; 90% CI, -4.1 to 1.8 mg/dL; P < .001 for noninferiority margin of 10 mg/dL). The proportion of patients with American College of Cardiology-American Heart Association guideline-concordant statin prescriptions in the intervention group was noninferior to that in the control group (12 patients [6.2%] vs 14 patients [6.5%]; difference, -0.003; 90% CI, -0.038 to 0.032; P < .001 for noninferiority margin of 15%). All patients in both groups were concordant with CPIC guidelines for safe statin prescribing. Physicians documented 2 and 3 cases of SAMS in the intervention and control groups, respectively, none of which was associated with a CPIC guideline-discordant prescription. Among patients with a decreased or poor SLCO1B1 transporter function genotype, simvastatin was prescribed to 1 patient in the control group but none in the intervention group.
Conclusions and Relevance: Clinical testing and reporting of SLCO1B1 results for statin myopathy risk did not result in poorer ASCVD prevention in a routine primary care setting and may have been associated with physicians avoiding simvastatin prescriptions for patients at genetic risk for SAMS. Such an absence of harm should reassure stakeholders contemplating the clinical use of available pharmacogenetic results.
Trial Registration: ClinicalTrials.gov Identifier: NCT02871934.

PMID: 33270123 [PubMed - as supplied by publisher]

Inactivating PTH/PTHrP signaling disorders (iPPSDs): evaluation of the new classification in a multicenter large series of 544 molecularly characterized patients.

Eur J Endocrinol. 2020 Dec 01;:

Authors: Pereda A, Elli FM, Thiele S, de Sanctis L, Rothenbuhler A, Hanna P, Francou B, Ertl DA, Perez de Nanclares G, Linglart A, Mantovani G

Abstract
OBJECTIVE: Pseudohypoparathyroidism and related disorders belong to group of heterogeneous rare diseases that share an impaired signaling downstream of Gsα-protein coupled receptors. Affected patients may present with various combination of symptoms including resistance to PTH and/or to other hormones, ectopic ossifications, brachydactyly type E, early onset obesity, short stature and cognitive difficulties. Several years ago we proposed a novel nomenclature under the term of inactivating PTH/PTHrP signaling disorders (iPPSD). It is now of utmost importance to validate these criteria and/or improve the basis of this new classification.
DESIGN: Retrospective study of a large international series of 459 probands and 85 relatives molecularly characterized.
METHODS: Information on major and minor criteria associated with iPPSD and genetic results was retrieved from patient files. We compared the presence of each criteria according to the iPPSD subtype, age and gender of the patients.
RESULTS: More than 98% of the probands met the proposed criteria for iPPSD classification. Noteworthy, most patients (85%) presented a combination of symptoms rather than a single sign suggestive of iPPSD and the overlap among the different genetic forms of iPPSD was confirmed. The clinical and molecular characterization of relatives identified familial history as an additional important criterion predictive of the disease.
CONCLUSIONS: The phenotypic analysis of this large cohort confirmed the utility of the major and minor criteria and their combination to diagnose iPPSD. This report shows the importance of having simple and easily recognizable signs to diagnose with confidence these rare disorders and supports a better management of patients.

PMID: 33270042 [PubMed - as supplied by publisher]

TRAILR1 (rs20576) and GRIA3 (rs12557782) are not associated with interferon-β response in multiple sclerosis patients.

Mol Biol Rep. 2020 Dec 02;:

Authors: Jazireian P, Sasani ST, Assarzadegan F, Azimian M

Abstract
Multiple sclerosis (MS) is an autoimmune-type inflammatory disorder in human central nervous system. Recombinant interferon beta (IFN-β) decreases the number of relapses and postpones disability progression in MS. However, up to 50% of patients treated with interferon beta continue experiencing relapses and/or worsening disability. Single nucleotide polymorphisms in different genes have been known to show significant associations with response to IFN-β in MS patients. In the present work, we examined the potential role of TRAILR1 and GRIA3 genes polymorphisms on response to IFN-β therapy in Iranian MS patients. The DNA was extracted from blood samples by standard procedures from 73 patients diagnosed with Multiple Sclerosis that were either responded to IFN-β or did not. We carried out RFLP -PCR and tetra-primer ARMS-PCR methods to study of rs20576 and rs12557782, respectively. All results were analyzed using the SPSS software. TRAILR1 rs20576 genotype frequencies in responders and non-responders were similar (χ2 = 0.26, P = 0.87, Fisher, s Exact test). Our results showed that response to IFN-β has not association with sex (p = 0.73). Also, genotypic frequencies of GRIA3 rs12557782 had no significant differences between two groups of female population (χ2 = 3.75, p = 0.15). Furthermore, it had not been any statistical differences between responder and non-responder males (χ2 = 0.7, p = 0.4) related to the SNP. Our results analysis revealed no significant association between the studied SNPs (TRAILR1 rs20576 and GRIA3rs 12,557,782) and response to IFN-β in Iranian MS patients.

PMID: 33269432 [PubMed - as supplied by publisher]

Pharmacogenomic Biomarkers and Their Applications in Psychiatry.

Genes (Basel). 2020 Nov 30;11(12):

Authors: Kam H, Jeong H

Abstract
Realizing the promise of precision medicine in psychiatry is a laudable and beneficial endeavor, since it should markedly reduce morbidity and mortality and, in effect, alleviate the economic and social burden of psychiatric disorders. This review aims to summarize important issues on pharmacogenomics in psychiatry that have laid the foundation towards personalized pharmacotherapy and, in a broader sense, precision medicine. We present major pharmacogenomic biomarkers and their applications in a variety of psychiatric disorders, such as depression, attention-deficit/hyperactivity disorder (ADHD), narcolepsy, schizophrenia, and bipolar disorder. In addition, we extend the scope into epilepsy, since antiepileptic drugs are widely used to treat psychiatric disorders, although epilepsy is conventionally considered to be a neurological disorder.

PMID: 33266292 [PubMed - in process]

Using Personal Genomic Data within Primary Care: A Bioinformatics Approach to Pharmacogenomics.

Genes (Basel). 2020 Nov 30;11(12):

Authors: Overkleeft R, Tommel J, Evers AWM, den Dunnen JT, Roos M, Hoefmans MJ, Schrader WE, Swen JJ, Numans ME, Houwink EJF

Abstract
One application of personalized medicine is the tailoring of medication to the individual, so that the medication will have the highest chance of success. In order to individualize medication, one must have a complete inventory of all current pharmaceutical compounds (a detailed formulary) combined with pharmacogenetic datasets, the genetic makeup of the patient, their (medical) family history and other health-related data. For healthcare professionals to make the best use of this information, it must be visualized in a way that makes the most medically relevant data accessible for their decision-making. Similarly, to enable bioinformatics analysis of these data, it must be prepared and provided through an interface for controlled computational analysis. Due to the high degree of personal information gathered for such initiatives, privacy-sensitive implementation choices and ethical standards are paramount. The Personal Genetic Locker project provides an approach to enable the use of personal genomic data in primary care. In this paper, we provide a description of the Personal Genetic Locker project and show its utility through a use case based on open standards, which is illustrated by the 4MedBox system.

PMID: 33266138 [PubMed - in process]

The Development of Maillard Reaction, and Advanced Glycation End Product (AGE)-Receptor for AGE (RAGE) Signaling Inhibitors as Novel Therapeutic Strategies for Patients with AGE-Related Diseases.

Molecules. 2020 Nov 27;25(23):

Authors: Shen CY, Lu CH, Wu CH, Li KJ, Kuo YM, Hsieh SC, Yu CL

Abstract
Advanced glycation end products (AGEs) are generated by nonenzymatic modifications of macromolecules (proteins, lipids, and nucleic acids) by saccharides (glucose, fructose, and pentose) via Maillard reaction. The formed AGE molecules can be catabolized and cleared by glyoxalase I and II in renal proximal tubular cells. AGE-related diseases include physiological aging, neurodegenerative/neuroinflammatory diseases, diabetes mellitus (DM) and its complications, autoimmune/rheumatic inflammatory diseases, bone-degenerative diseases, and chronic renal diseases. AGEs, by binding to receptors for AGE (RAGEs), alter innate and adaptive immune responses to induce inflammation and immunosuppression via the generation of proinflammatory cytokines, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI). These pathological molecules cause vascular endothelial/smooth muscular/connective tissue-cell and renal mesangial/endothelial/podocytic-cell damage in AGE-related diseases. In the present review, we first focus on the cellular and molecular bases of AGE-RAGE axis signaling pathways in AGE-related diseases. Then, we discuss in detail the modes of action of newly discovered novel biomolecules and phytochemical compounds, such as Maillard reaction and AGE-RAGE signaling inhibitors. These molecules are expected to become the new therapeutic strategies for patients with AGE-related diseases in addition to the traditional hypoglycemic and anti-hypertensive agents. We particularly emphasize the importance of "metabolic memory", the "French paradox", and the pharmacokinetics and therapeutic dosing of the effective natural compounds associated with pharmacogenetics in the treatment of AGE-related diseases. Lastly, we propose prospective investigations for solving the enigmas in AGE-mediated pathological effects.

PMID: 33261212 [PubMed - in process]

An Automated Functional Annotation Pipeline That Rapidly Prioritizes Clinically Relevant Genes for Autism Spectrum Disorder.

Int J Mol Sci. 2020 Nov 27;21(23):

Authors: Veatch OJ, Butler MG, Elsea SH, Malow BA, Sutcliffe JS, Moore JH

Abstract
Human genetic studies have implicated more than a hundred genes in Autism Spectrum Disorder (ASD). Understanding how variation in implicated genes influence expression of co-occurring conditions and drug response can inform more effective, personalized approaches for treatment of individuals with ASD. Rapidly translating this information into the clinic requires efficient algorithms to sort through the myriad of genes implicated by rare gene-damaging single nucleotide and copy number variants, and common variation detected in genome-wide association studies (GWAS). To pinpoint genes that are more likely to have clinically relevant variants, we developed a functional annotation pipeline. We defined clinical relevance in this project as any ASD associated gene with evidence indicating a patient may have a complex, co-occurring condition that requires direct intervention (e.g., sleep and gastrointestinal disturbances, attention deficit hyperactivity, anxiety, seizures, depression), or is relevant to drug development and/or approaches to maximizing efficacy and minimizing adverse events (i.e., pharmacogenomics). Starting with a list of all candidate genes implicated in all manifestations of ASD (i.e., idiopathic and syndromic), this pipeline uses databases that represent multiple lines of evidence to identify genes: (1) expressed in the human brain, (2) involved in ASD-relevant biological processes and resulting in analogous phenotypes in mice, (3) whose products are targeted by approved pharmaceutical compounds or possessing pharmacogenetic variation and (4) whose products directly interact with those of genes with variants recommended to be tested for by the American College of Medical Genetics (ACMG). Compared with 1000 gene sets, each with a random selection of human protein coding genes, more genes in the ASD set were annotated for each category evaluated (p ≤ 1.99 × 10-2). Of the 956 ASD-implicated genes in the full set, 18 were flagged based on evidence in all categories. Fewer genes from randomly drawn sets were annotated in all categories (x = 8.02, sd = 2.56, p = 7.75 × 10-4). Notably, none of the prioritized genes are represented among the 59 genes compiled by the ACMG, and 78% had a pathogenic or likely pathogenic variant in ClinVar. Results from this work should rapidly prioritize potentially actionable results from genetic studies and, in turn, inform future work toward clinical decision support for personalized care based on genetic testing.

PMID: 33261099 [PubMed - in process]

Repression of PPARγ reduces the ABCG2-mediated efflux activity of M2 macrophages.

Int J Biochem Cell Biol. 2020 Nov 28;:105895

Authors: Kim CE, Park HY, Won HJ, Kim M, Kwon B, Lee SJ, Kim DH, Shin JG, Seo SK

Abstract
Even though subclasses of macrophage have distinct roles during progression of infectious diseases, it remains poorly understood whether there is a subset-specific difference in drug responses. Here, we report that ABCG2 was expressed specifically in M2-like macrophages and that it controlled their efflux activities. Abcg2 expression is markedly induced during polarization of PMA-primed macrophages toward an M2 type. IL-4 and IL-13 induced Pparg expression through STAT6 and PPARγ in turn acted on the Abcg2 promoter for its transcription activation. Once polarized to M2-like macrophages, these cells had sustained PPARγ transcription activation of Abcg2 gene. Accordingly, interruption of this machinery by T0070907, an inverse agonist of PPARγ, was shown to be effective in Abcg2 downregulation and its efflux activity in M2-like macrophages. Taken together, our results implicate that ABCG2 of M2 macrophages may function as an important pump that plays a potential role in drug efflux and that T0070907 may be used to increase the efficacy of M2 macrophage-targeting drugs such as antibiotics.

PMID: 33259947 [PubMed - as supplied by publisher]

Observed concentrations of amikacin and gentamycin in the setting of burn patients with gram-negative bacterial infections: Preliminary data from a prospective study.

Therapie. 2020 Oct 23;:

Authors: Corcione S, De Nicolò A, Lupia T, Segala FV, Pensa A, Corgiat Loia R, Romeo MR, Di Perri G, Stella M, D'Avolio A, De Rosa FG

Abstract
AIM OF THE STUDY: Critically ill populations often have shown subtherapeutic aminoglycosides' concentrations mostly because of unavoidable changes in drug volume distribution and clearance. We present a real life prospective study evaluating plasma concentrations for once-daily dosing for amikacin and gentamycin among a population of severe burn adults.
METHODS: We conducted a real life prospective study on the plasma observed concentrations of amikacin and gentamycin among severe burn patients, using aminoglycoside as combination therapy. Antibiotics were prescribed at the standard doses of 15-20mg/kg/day for amikacin and 3-5mg/kg/day for gentamycin.
RESULTS: Eight patients (4 in amikacin and 4 in gentamycin groups, respectively) were enrolled in the study. All subjects were admitted for severe burns. The most common site of infection was bloodstream (5; 62.5%) and pneumonia (4; 50%). Pseudomonas aeruginosa, followed by Klebsiella pneumoniae and multi-drug resistant Acinetobacter baumannii were the most prevalent agents isolated. Amikacin and gentamycin never achieved the target peak concentration of 60mg/L and 30mg/L: in our study Cmax, for amikacin, was 33.1±15.6mg/L (SD), while for gentamycin was 14.3mg/L±9. Cmax and total body surface area have shown a strong negative correlation with borderline statistical significance (amikacin: ρ=0.922, P=0.078; gentamycin: ρ=0.937, P=0.063). At the standard dosage, the pharmacokinetic/pharmacodynamic (PK/PD) target of Cmax>8×highest MIC was reached for 8 (53.3%) out of 15 isolated pathogens.
CONCLUSIONS: The present study found that, in a population of septic burn patients, standard doses of gentamycin and amikacin most often lead to plasma concentrations under the PK/PD target.

PMID: 33257012 [PubMed - as supplied by publisher]

Pharmacogenomics and ALL treatment: How to optimize therapy.

Semin Hematol. 2020 Jul;57(3):130-136

Authors: Karol SE, Yang JJ

Abstract
Inherited genetic variations may alter drug sensitivity in patients with acute lymphoblastic leukemia, predisposing to adverse treatment side effects. In this review, we discuss evidence from children and young adults with acute lymphoblastic leukemia to review the available pharmacogenomic data with an emphasis on clinically actionable and emerging discoveries, for example, genetic variants in thiopurine methyltransferase and NUDT15 that alter 6-mercaptopurine dosing. We also highlight the need for ongoing pharmacogenomic research to validate the significance of recent findings. Further research in young adults, as well as with novel therapeutics, is needed to provide optimal therapy in future trials.

PMID: 33256902 [PubMed - in process]

Multiple Effects of Ascorbic Acid against Chronic Diseases: Updated Evidence from Preclinical and Clinical Studies.

Antioxidants (Basel). 2020 Nov 26;9(12):

Authors: Berretta M, Quagliariello V, Maurea N, Di Francia R, Sharifi S, Facchini G, Rinaldi L, Piezzo M, Manuela C, Nunnari G, Montopoli M

Abstract
Severe disease commonly manifests as a systemic inflammatory process. Inflammation is associated withthe enhanced production of reactive oxygen and nitrogen species and with a marked reduction in the plasma concentrations of protective antioxidant molecules. This imbalance gives rise to oxidative stress, which is greater in patients with more severe conditions such as sepsis, cancer, cardiovascular disease, acute respiratory distress syndrome, and burns. In these patients, oxidative stress can trigger cell, tissue, and organ damage, thus increasing morbidity and mortality. Ascorbic acid (ASC) is a key nutrient thatserves as an antioxidant and a cofactor for numerous enzymatic reactions. However, humans, unlike most mammals, are unable to synthesize it. Consequently, ASC must be obtained through dietary sources, especially fresh fruit and vegetables. The value of administering exogenous micronutrients, to reestablish antioxidant concentrations in patients with severe disease, has been recognized for decades. Despite the suggestion that ASC supplementation may reduce oxidative stress and prevent several chronic conditions, few large, randomized clinical trials have tested it in patients with severe illness. This article reviews the recent literature on the pharmacological profile of ASC and the role of its supplementation in critically ill patients.

PMID: 33256059 [PubMed]