Pharmacokinetics and pharmacogenetics of high-dose methotrexate in Chinese adult patients with non-Hodgkin lymphoma: a population analysis.

Cancer Chemother Pharmacol. 2020 Apr 03;:

Authors: Yang L, Wu H, de Winter BCM, Sheng CC, Qiu HQ, Cheng Y, Chen J, Zhao QL, Huang J, Jiao Z, Xie RX

Abstract
PURPOSE: High-dose methotrexate (HD-MTX) is widely used in the treatment of non-Hodgkin lymphoma (NHL), but the pharmacokinetic properties of HD-MTX in Chinese adult patients with NHL have not yet been established through an approach that integrates genetic covariates. The purposes of this study were to identify both physiological and pharmacogenomic covariates that can explain the inter- and intraindividual pharmacokinetic variability of MTX in Chinese adult patients with NHL and to explore a new sampling strategy for predicting delayed MTX elimination.
METHODS: A total of 852 MTX concentrations from 91 adult patients with NHL were analyzed using the nonlinear mixed-effects modeling method. FPGS, GGH, SLCO1B1, ABCB1 and MTHFR were genotyped using the Sequenom MassARRAY technology platform and were screened as covariates. The ability of different sampling strategies to predict the MTX concentration at 72 h was assessed through maximum a posteriori Bayesian forecasting using a validation dataset (18 patients).
RESULTS: A two-compartment model adequately described the data, and the estimated mean MTX clearance (CL) was 6.03 L/h (9%). Creatinine clearance (CrCL) was identified as a covariate for CL, whereas the intercompartmental clearance (Q) was significantly affected by the body surface area (BSA). However, none of the genotypes exerted a significant effect on the pharmacokinetic properties of MTX. The percentage of patients with concentrations below 0.2 µmol/L at 72 h decreased from 65.6 to 42.6% when the CrCL decreased from 90 to 60 ml/min/1.73 m2 with a scheduled dosing of 3 g/m2, and the same trend was observed with dose regimens of 1 g/m2 and 2 g/m2. Bayesian forecasting using the MTX concentrations at 24 and 42 h provided the best predictive performance for estimating the MTX concentration at 72 h after dosing.
CONCLUSIONS: The MTX population pharmacokinetic model developed in this study might provide useful information for establishing personalized therapy involving MTX for the treatment of adult patients with NHL.

PMID: 32246190 [PubMed - as supplied by publisher]

High-Protein Diet Induces Hyperuricemia in a New Animal Model for Studying Human Gout.

Int J Mol Sci. 2020 Mar 20;21(6):

Authors: Hong F, Zheng A, Xu P, Wang J, Xue T, Dai S, Pan S, Guo Y, Xie X, Li L, Qiao X, Liu G, Zhai Y

Abstract
Hyperuricemia is a central risk factor for gout and increases the risk for other chronic diseases, including cardiometabolic disease, kidney disease, and hypertension. Overproduction of urate is one of the main reasons for hyperuricemia, and dietary factors including seafoods, meats, and drinking are contributed to the development of it. However, the lack of a suitable animal model for urate metabolism is one of the main reasons for the delay and limitations of hyperuricemia research. Combining evolutionary biological studies and clinical studies, we conclude that chicken is a preferred animal model for hyperuricemia. Thus, we provided chickens a high-protein diet (HPD) to evaluate the changes in the serum urate levels in chickens. In our study, the HPD increased the serum urate level and maintained it at a long-term high level in chickens. Long-term high serum urate levels induced an abnormal chicken claw morphology and the precipitation of monosodium urate (MSU) in joint synovial fluid. In addition, a long-term HPD also decreased the glomerular filtration rate and induced mild renal injury. Most importantly, allopurinol and probenecid displayed the positive effects in decreasing serum urate and then attenuated hyperuricemia in chicken model. These findings provide a novel model for hyperuricemia and a new opportunity to further investigate the effects of long-term hyperuricemia on other metabolic diseases.

PMID: 32245084 [PubMed - as supplied by publisher]

MAPK14 (p38α) inhibition effects against metastatic gastric cancer cells: A potential biomarker and pharmacological target.

Toxicol In Vitro. 2020 Mar 31;:104839

Authors: Mesquita FP, Moreira-Nunes CA, da Silva EL, Lima LB, Daniel JP, Zuerker WJ, Brayner M, de Moraes MEA, Montenegro RC

Abstract
Gastric cancer has been considering one of the worst cancer types since it is diagnosed in advanced stages, currently in the metastatic stage. Therefore, the challenge is to find out a biomarker and a pharmacology target that would help face this worldwide health issue. In this sense, the mitogen-activated protein kinase (MAPK) signaling pathway has become an important aim of the studies in several cancers. Therefore, we evaluated the role of MAPK14 (p38α) inhibitor SB-245392 in the cellular process, such as proliferation, cell death, and cell migration, and whether MAPK14 gene could be a potential biomarker in gastric cancer models. The results clearly suggest that p38α inhibition significantly impairs the cell proliferation, induces modest apoptosis and strongly inhibits cell migration of gastric cancer cell (AGP-01). Gene expression analysis showed that c-MYC level was decreased and TP53 was increased after SB-245392 treatment. Furthermore, MAPK14 was found in high levels in gastric cancer samples compared to normal samples in the TCGA database, especially in advanced stages (stage 3 and 4), which is significantly associated with low rate survival of the patients. In conclusion, the MAPK14 could be a potential biomarker for advanced gastric cancer as well as a pharmacological target, which could improve the survival rate of patients.

PMID: 32243890 [PubMed - as supplied by publisher]

Precision in cancer pharmacogenomics.

Pharmacogenomics. 2020 Apr 03;:

Authors: Kyrochristos ID, Baltagiannis EG, Mitsis M, Roukos DH

PMID: 32242500 [PubMed - as supplied by publisher]

Tannic acid prevents macrophage-induced pro-fibrotic response in lung epithelial cells via suppressing TLR4-mediated macrophage polarization.

Inflamm Res. 2019 Dec;68(12):1011-1024

Authors: Sivanantham A, Pattarayan D, Rajasekar N, Kannan A, Loganathan L, Bethunaickan R, Mahapatra SK, Palanichamy R, Muthusamy K, Rajasekaran S

Abstract
BACKGROUND: Polarized macrophages induce fibrosis through multiple mechanisms, including a process termed epithelial-to-mesenchymal transition (EMT). Mesenchymal cells contribute to the excessive accumulation of fibrous connective tissues, leading to organ failure. This study was aimed to investigate the effect of tannic acid (TA), a natural dietary polyphenol on M1 macrophage-induced EMT and its underlying mechanisms.
MATERIALS: First, we induced M1 polarization in macrophage cell lines (RAW 264.7 and THP-1). Then, the conditioned-medium (CM) from these polarized macrophages was used to induce EMT in the human adenocarcinomic alveolar epithelial (A549) cells. We also analysed the role of TA on macrophage polarization.
RESULTS: We found that TA pre-treated CM did not induce EMT in epithelial cells. Further, TA pre-treated CM showed diminished activation of MAPK in epithelial cells. Subsequently, TA was shown to inhibit LPS-induced M1 polarization in macrophages by directly targeting toll-like receptor 4 (TLR4), thereby repressing LPS binding to TLR4/MD2 complex and subsequent signal transduction.
CONCLUSION: It was concluded that TA prevented M1 macrophage-induced EMT by suppressing the macrophage polarization possibly through inhibiting the formation of LPS-TLR4/MD2 complex and blockage of subsequent downstream signal activation. Further, our findings may provide beneficial information to develop new therapeutic strategies against chronic inflammatory diseases.

PMID: 31489459 [PubMed - indexed for MEDLINE]

The association of an alpha2C adrenoreceptor gene polymorphism with vasomotor symptoms in African American women.

Menopause. 2019 03;26(3):300-305

Authors: Aharon DA, Friedman EG, Overbey JR, McLaughlin M, Langaee T, Thurston RC

Abstract
OBJECTIVE: The alpha2C adrenoreceptor deletion 322-325 (ADRA2C del 322-325) polymorphism has been associated with autonomic activity and thermoregulation, which are implicated in the vasomotor symptom (VMS) mechanism. The ADRA2C del (322-325) has higher prevalence in African American women, a group known to experience more frequent and bothersome VMS. We assessed whether the ADRA2C del (322-325) genotype is associated with increased frequency of VMS in African American women.
METHODS: DNA samples from African American (N = 400) women participating in the Study of Women's Health Across the Nation (SWAN) were genotyped for the ADRA2C del (322-325) polymorphism. Longitudinal data on VMS were obtained from the SWAN repository. The relation of ADRA2C del (322-325) genotypes (deletion/deletion [D/D]; insertion/deletion [I/D]; insertion/insertion [I/I]) with VMS over the menopausal transition for up to 12 years of follow-up was examined using generalized estimating equations. Primary models considered the outcome of frequent VMS (6 or more days in the prior 2 wk vs VMS <6 d in the prior 2 wk) by stage of menopause.
RESULTS: Four hundred DNA samples from African American women were included. Seventy-five women (18.8%) were found to carry the homozygous variant allele (D/D). There was no significant difference in the trajectory of frequent VMS over the menopausal transition between women with D/D and I/I + I/D genotypes (P = 0.39).
CONCLUSIONS: In this preliminary study among African American women in SWAN, ADRA2C del (322-325) was not significantly related to self-reported VMS. Further studies are warranted to help us understand the role of the adrenergic system in the physiology of VMS to tailor medical therapy to patient needs.

PMID: 30277919 [PubMed - indexed for MEDLINE]

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Relationship among DSB, DSB repair, and transcription prevents genome instability and cancer.

Cancer Sci. 2020 Mar 31;:

Authors: Ui A, Chiba N, Yasui A

Abstract
DNA double-strand break (DSB) is a serious type of DNA damage and is known to trigger multiple responses within cells. In the responses, novel relationships among DSB, DSB repair and transcription machineries are created. First, transcription is repressed if DSB occurs near or at the transcription site, termed DSB-induced transcriptional repression, which contributes to DSB repair with the aid of DNA damage-signaling pathways, ATM- or DNA-PKcs-signaling pathway. DSB-induced transcriptional repression is also regulated by transcriptional factors TLP1, NELF, and ENL, as well as chromatin remodeling and organizing factors ZMYND8, CDYL1, PBAF, and cohesin. Second, transcription and RNA promote DSB repair for genome integrity. Transcription factors such as LEDGF, SETD2, and transcriptionally active histone modification, H3K36, facilitate homologous recombination (HR) to overcome DSB. At transcriptional active sites, DNA:RNA hybrids, termed R-loops, which are formed by DSB, are processed by RAD52 and XPG leading to an activation of the HR pathway. Even in a transcriptionally inactive non-genic site, noncoding RNAs that are produced by RNA polymerase II, DICER, and DROSHA, help to recruit DSB repair proteins at the DSB sites. Third, transcriptional activation itself, however, can induce DSB. Transcriptional activation often generates specific DNA structures such as R-loops and topoisomerase-induced DSBs, which cause genotoxic stress and may lead to genome instability and consequently to cancer. Thus, transcription and DSB repair machineries interact and cooperate to prevent genome instability and cancer.

PMID: 32232911 [PubMed - as supplied by publisher]

Neuroimmunomodulation of tissue injury and disease: an expanding view of the inflammatory reflex pathway.

Bioelectron Med. 2019;5:13

Authors: Tanaka S, Hammond B, Rosin DL, Okusa MD

Abstract
Neuroimmunomodulation through peripheral nerve activation is an important therapeutic approach to various disorders. Central to this approach is the inflammatory reflex pathway in which the cholinergic anti-inflammatory pathway represents the efferent limb. Recent studies provide a framework for understanding this control pathway, however our understanding remains incomplete. Genetically modified mice, using optogenetics and pharmacogenomics, have been invaluable resources that will allow investigators to disentangle neural pathways that provide a unifying mechanism by which vagal nerve stimulation (and other means of stimulating the pathway) leads to an anti-inflammatory and tissue protective effect. In this review we describe disease models that contribute to our understanding of how vagal nerve stimulation attenuates inflammation and organ injury: acute kidney injury, rheumatoid arthritis, and inflammatory gastrointestinal disease. The gut microbiota contributes to health and disease and the potential role of the vagus nerve in affecting the relationship between gut microbiota and the immune system and modifying diseases remains an intriguing opportunity to attenuate local and systemic inflammation that undergird disease processes.

PMID: 32232102 [PubMed]

A Continuing Professional Development Program for Pharmacists Implementing Pharmacogenomics into Practice.

Pharmacy (Basel). 2020 Mar 28;8(2):

Authors: Crown N, Sproule BA, Luke MJ, Piquette-Miller M, McCarthy LM

Abstract
A continuing professional development (CPD) program for pharmacists practicing in community and team-based primary care settings was developed and evaluated using Moore's framework for the assessment of continuing medical education. The program had three components: online lectures, a two-day training workshop, and patient case studies. Knowledge (pre-post multiple choice test); attitudes, readiness, and comfort with applying pharmacogenomics in their practices (pre-post surveys); and experiences of implementing pharmacogenomics in practice (semi-structured interviews) were assessed. Twenty-one of 26 enrolled pharmacists successfully completed the program, and were satisfied with their experience. Almost all achieved a score of 80% or higher on the post-training multiple choice test, with significantly improved scores compared to the pre-training test. Pre- and post-training surveys demonstrated that participants felt that their knowledge and competence increased upon completion of the training. In the follow-up, 15 pharmacists incorporated pharmacogenomics testing into care for 117 patients. Ten pharmacists participated in semi-structured interviews, reporting strong performance in the program, but some difficulty implementing new knowledge in their practices. This multi-component CPD program successfully increased pharmacists' knowledge, readiness, and comfort in applying pharmacogenomics to patient care in the short-term, yet some pharmacists struggled to integrate this new service into their practices.

PMID: 32231164 [PubMed]

Intercalating pyrene with polypeptide as a novel self-assembly nano-carrier for colon cancer suppression in vitro and in vivo.

Mater Sci Eng C Mater Biol Appl. 2020 Apr;109:110593

Authors: Lo PY, Lee GY, Zheng JH, Huang JH, Cho EC, Lee KC

Abstract
Giving patients right dosage is an essential concept of precision medicine. Most of nanocarriers lack of flexible drug capacity and structural stability to be customized for specific treatment, resulting in low therapeutic efficacy and unexpected side effects. Thus, a growing need emerges for fast and rigorous approaches to develop nanoparticles with properties of adjustable dosage and controllable particle size. Poly-l-Lysine is known for its enhanced bioadhesivity and pH-triggered structural swelling effect, which is utilized as the main agent to activate the multistage drug releasing. Inspired by natural bio-assembly system, we report a simple method to self-assemble Poly-l-Lysine-based nanoparticles via supramolecular recognitions of cross-linked pyrenes, which provides noncovalent force to flexibly encapsulate Doxorubincin and to construct robust nanostructures. Pyrene-modified polypeptide self-assemblies are able to adjust drug payload from 1: 10 to 2:1 (drug: polypeptide) without changing its uniform nano-spherical morphology. This nanostructure remained the as-made morphology even after experiencing the long-term (~ 10 weeks) storage at room temperature. Also, the nanoparticles displayed multi-step drug release behaviours and exhibited great in vitro and in vivo cytotoxicity towards colon cancer cells. The as-mentioned nanoparticles provide a novel perspective to compensate the clinical needs of specific drug feedings and scalable synthesis with advantages of simple-synthesis, size-adaptivity, and morphology reversibility.

PMID: 32228904 [PubMed - in process]

An integrated prognosis model of pharmacogenomic gene signature and clinical information for diffuse large B-cell lymphoma patients following CHOP-like chemotherapy.

J Transl Med. 2020 Mar 30;18(1):144

Authors: Hu J, Xu J, Yu M, Gao Y, Liu R, Zhou H, Zhang W

Abstract
BACKGROUND: As the most common form of lymphoma, diffuse large B-cell lymphoma (DLBCL) is a clinical highly heterogeneous disease with variability in therapeutic outcomes and biological features. It is a challenge to identify of clinically meaningful tools for outcome prediction. In this study, we developed a prognosis model fused clinical characteristics with drug resistance pharmacogenomic signature to identify DLBCL prognostic subgroups for CHOP-based treatment.
METHODS: The expression microarray data and clinical characteristics of 791 DLBCL patients from two Gene Expression Omnibus (GEO) databases were used to establish and validate this model. By using univariate Cox regression, eight clinical or genetic signatures were analyzed. The elastic net-regulated Cox regression analysis was used to select the best prognosis related factors into the predictive model. To estimate the prognostic capability of the model, Kaplan-Meier curve and the area under receiver operating characteristic (ROC) curve (AUC) were performed.
RESULTS: A predictive model comprising 4 clinical factors and 2 pharmacogenomic gene signatures was established after 1000 times cross validation in the training dataset. The AUC of the comprehensive risk model was 0.78, whereas AUC value was lower for the clinical only model (0.68) or the gene only model (0.67). Compared with low-risk patients, the overall survival (OS) of DLBCL patients with high-risk scores was significantly decreased (HR = 4.55, 95% CI 3.14-6.59, log-rank p value = 1.06 × 10-15). The signature also enables to predict prognosis within different molecular subtypes of DLBCL. The reliability of the integrated model was confirmed by independent validation dataset (HR = 3.47, 95% CI 2.42-4.97, log rank p value = 1.53 × 10-11).
CONCLUSIONS: This integrated model has a better predictive capability to ascertain the prognosis of DLBCL patients prior to CHOP-like treatment, which may improve the clinical management of DLBCL patients and provide theoretical basis for individualized treatment.

PMID: 32228625 [PubMed - in process]

Functionally Significant Coumarin-Related Variant Alleles and Time to Therapeutic Range in Chilean Cardiovascular Patients.

Clin Appl Thromb Hemost. 2020 Jan-Dec;26:1076029620909154

Authors: Rojo M, Roco AM, Suarez M, Lavanderos MA, Verón G, Bertoglia MP, Arredondo A, Nieto E, Rubilar JC, Tamayo F, Cruz D, Muñoz J, Bravo G, Salas P, Mejías F, Véliz P, Godoy G, Varela NM, Llull G, Quiñones LA

Abstract
Despite the development of new oral agents over the last decade, vitamin K antagonists (VKAs) remain the most widely used anticoagulants for treating and preventing thromboembolism worldwide. In Chile, the Ministry of Health indicates that acenocoumarol should be used in preference to any other coumarin. Complications of inappropriate dosing are among the most frequently reported adverse events associated with this medication. It is well known that polymorphisms in pharmacokinetic and pharmacodynamic proteins related to coumarins (especially warfarin) influence response to these drugs. This work analyzed the impact of CYP2C19*2 (rs4244285), CYP1A2*1F (rs762551), GGCx (rs11676382), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), CYP4F2 (rs2108622), VKORC1 (rs9923231), VKORC1 (rs7294), CYP3A4*1B (rs2740574), and ABCB1 (rs1045642) polymorphisms on time to therapeutic range for oral anticoagulants in 304 Chilean patients. CYP2C9*3 polymorphisms were associated with time to therapeutic range for acenocoumarol in Chilean patients, and the CYP4F2 TT genotype, MDR1 A allele, CYP1A2 A allele, and CYP3A4T allele are promising variants that merit further analysis. The presence of polymorphisms explained only 4.1% of time to therapeutic range for acenocoumarol in a multivariate linear model. These results improve our understanding of the basis of ethnic variations in drug metabolism and response to oral anticoagulant therapy. We hope that these findings will contribute to developing an algorithm for VKA dose adjustment in the Chilean population in the near future, decreasing the frequency of stroke, systemic embolism, and bleeding-related adverse events.

PMID: 32228310 [PubMed - in process]

The CFTR variant profile of Hispanic patients with cystic fibrosis: Impact on access to effective screening, diagnosis, and personalized medicine.

J Genet Couns. 2020 Mar 30;:

Authors: Januska MN, Marx L, Walker PA, Berdella MN, Langfelder-Schwind E

Abstract
Hispanic patients comprise an appreciable and increasing proportion of patients with cystic fibrosis (CF) in the United States (US). Hispanic patients with CF are known to have increased morbidity and mortality compared to non-Hispanic white patients with CF, and ongoing investigations are underway to identify contributing factors amenable to intervention in order to address the disparate health outcomes. One contributing factor is the different CF transmembrane conductance regulator (CFTR) variant profile observed in Hispanic patients with CF. The most common CFTR variant, p.Phe508del (legacy name F508del), is proportionally underrepresented in Hispanic patients with CF. This difference has implications for prenatal screening, newborn screening (NBS), and CFTR variant-specific therapeutic options. In particular, the recent approval of a highly effective CFTR modulator for patients carrying at least one copy of F508del, elexacaftor/tezacaftor/ivacaftor triple combination therapy, underscores the potential for unequal access to personalized treatment for Hispanic patients with CF. We report the CFTR variant profiles of Hispanic patients with CF and non-CF Hispanic infants with a false-positive New York State CF NBS at a single center in New York City over a 5-year study period, as an opportunity to address the racial and ethnic disparities that currently exist in CF screening, diagnosis, and treatment. In addition to the previously documented disparate prevalence of the CFTR variant F508del in Hispanic patients, we observed two CFTR variants, p.His609Arg (legacy name H609R) and p.Thr1036Asn (legacy name T1036N), frequently identified in our Hispanic patients of Ecuadorian and Mexican ancestry, respectively, that are not well-described in the US population. The presence of population-specific and individually rare CFTR variants in Hispanic patients with CF further accentuates the disparity in health outcomes, as these CFTR variants are often absent from prenatal and NBS CFTR variant panels, potentially delaying diagnosis, and without an approved CFTR variant-specific therapy.

PMID: 32227567 [PubMed - as supplied by publisher]

Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer.

Theranostics. 2020;10(9):3939-3951

Authors: Wu Z, Li S, Tang X, Wang Y, Guo W, Cao G, Chen K, Zhang M, Guan M, Yang D

Abstract
Rationale: Loss of DNA damage repair (DDR) in the tumor is an established hallmark of sensitivity to DNA damaging agents such as chemotherapy. However, there has been scant investigation into gain-of-function alterations of DDR genes in cancer. This study aims to investigate to what extent copy number amplification of DDR genes occurs in cancer, and what are their impacts on tumor genome instability, patient prognosis and therapy outcome. Methods: Retrospective analysis was performed on the clinical, genomics, and pharmacogenomics data from 10,489 tumors, matched peripheral blood samples, and 1,005 cancer cell lines. The key discoveries were verified by an independent patient cohort and experimental validations. Results: This study revealed that 13 of the 80 core DDR genes were significantly amplified and overexpressed across the pan-cancer scale. Tumors harboring DDR gene amplification exhibited decreased global mutation load and mechanism-specific mutation signature scores, suggesting an increased DDR proficiency in the DDR amplified tumors. Clinically, patients with DDR gene amplification showed poor prognosis in multiple cancer types. The most frequent Nibrin (NBN) gene amplification in ovarian cancer tumors was observed in 15 out of 31 independent ovarian cancer patients. NBN overexpression in breast and ovarian cancer cells leads to BRCA1-dependent olaparib resistance by promoting the phosphorylation of ATM-S1981 and homology-dependent recombination efficiency. Finally, integration of the cancer pharmacogenomics database of 37 genome-instability targeting drugs across 505 cancer cell lines revealed significant correlations between DDR gene copy number amplification and DDR drug resistance, suggesting candidate targets for increasing patient treatment response. Principal Conclusions: DDR gene amplification can lead to chemotherapy resistance and poor overall survival by augmenting DDR. These amplified DDR genes may serve as actionable clinical biomarkers for cancer management.

PMID: 32226530 [PubMed - in process]

Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?

Front Psychiatry. 2020;11:94

Authors: van Westrhenen R, Aitchison KJ, Ingelman-Sundberg M, Jukić MM

Abstract
In recent decades, very few new psychiatric drugs have entered the market. Thus, improvement in the use of antidepressant and antipsychotic therapy has to focus mainly on enhanced and more personalized treatment with the currently available drugs. One important aspect of such individualization is emphasizing interindividual differences in genes relevant to treatment, an area that can be termed neuropsychopharmacogenomics. Here, we review previous efforts to identify such critical genetic variants and summarize the results obtained to date. We conclude that most clinically relevant genetic variation is connected to phase I drug metabolism, in particular to genetic polymorphism of CYP2C19 and CYP2D6. To further improve individualized pharmacotherapy, there is a need to take both common and rare relevant mutations into consideration; we discuss the present and future possibilities of using whole genome sequencing to identify patient-specific genetic variation relevant to treatment in psychiatry. Translation of pharmacogenomic knowledge into clinical practice can be considered for specific drugs, but this requires education of clinicians, instructive guidelines, as well as full attention to polypharmacy and other clinically relevant factors. Recent large patient studies (n > 1,000) have replicated previous findings and produced robust evidence warranting the clinical utility of relevant genetic biomarkers. To further judge the clinical and financial benefits of preemptive genotyping in psychiatry, large prospective randomized trials are needed to quantify the value of genetic-based patient stratification in neuropsychopharmacotherapy and to demonstrate the cost-effectiveness of such interventions.

PMID: 32226396 [PubMed]

Kinin B1 Receptor Signaling in Skin Homeostasis and Wound Healing.

Yale J Biol Med. 2020 Mar;93(1):175-185

Authors: Matus CE, Bhoola KD, Figueroa CD

Abstract
Kinins are proinflammatory peptides that are formed in the skin by the enzymatic action of tissue kallikrein (KLK1) on kininogens. Tissue kallikrein is produced by eccrine sweat glands and also by cells of the stratum granulosum and other skin appendages. Kinin formation may be favored during inflammatory skin disorders when plasma constituents, including kininogens, extravasate from venules and capillaries, which have increased permeability in response to the plethora of inflammatory mediators generated in the course of acute inflammation. By activating either kinin B1 or B2 receptors, kinins modulate keratinocyte differentiation, which relays on activation of several signaling systems that follows receptor stimulation. Participation of the kinin B1 receptor in wound healing is still a matter of controversy though some studies indicate that B1 receptor stimulation regulates keratinocyte migration by controlling metalloproteases 2 and 9 production and by improving wound closure in a mouse model. Development of more stable kinin B1 receptor agonists may be beneficial to modulate wound healing, especially if we take into account that the B1 receptor is up-regulated by inflammation and by cytokines generated in the inflamed microenvironment.

PMID: 32226346 [PubMed - in process]

Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes.

Int J Mol Sci. 2020 Mar 26;21(7):

Authors: Caspar SM, Schneider T, Meienberg J, Matyas G

Abstract
Although several pharmacogenetic (PGx) predispositions affecting drug efficacy and safety are well established, drug selection and dosing as well as clinical trials are often performed in a non-pharmacogenetically-stratified manner, ultimately burdening healthcare systems. Pre-emptive PGx testing offers a solution which is often performed using microarrays or targeted gene panels, testing for common/known PGx variants. However, as an added value, whole-genome sequencing (WGS) could detect not only disease-causing but also pharmacogenetically-relevant variants in a single assay. Here, we present our WGS-based pipeline that extends the genetic testing of Mendelian diseases with PGx profiling, enabling the detection of rare/novel PGx variants as well. From our in-house WGS (PCR-free 60× PE150) data of 547 individuals we extracted PGx variants with drug-dosing recommendations of the Dutch Pharmacogenetics Working Group (DPWG). Furthermore, we explored the landscape of DPWG pharmacogenes in gnomAD and our in-house cohort as well as compared bioinformatic tools for WGS-based structural variant detection in CYP2D6. We show that although common/known PGx variants comprise the vast majority of detected DPWG pharmacogene alleles, for better precision medicine, PGx testing should move towards WGS-based approaches. Indeed, WGS-based PGx profiling is not only feasible and future-oriented but also the most comprehensive all-in-one approach without generating significant additional costs.

PMID: 32225115 [PubMed - in process]

Implementation of a Renal Precision Medicine Program: Clinician Attitudes and Acceptance.

Life (Basel). 2020 Mar 26;10(4):

Authors: Spiech KM, Tripathy PR, Woodcock AM, Sheth NA, Collins KS, Kannegolla K, Sinha AD, Sharfuddin AA, Pratt VM, Khalid M, Hains DS, Moe SM, Skaar TC, Moorthi RN, Eadon MT

Abstract
A precision health initiative was implemented across a multi-hospital health system, wherein a panel of genetic variants was tested and utilized in the clinical care of chronic kidney disease (CKD) patients. Pharmacogenomic predictors of antihypertensive response and genomic predictors of CKD were provided to clinicians caring for nephrology patients. To assess clinician knowledge, attitudes, and willingness to act on genetic testing results, a Likert-scale survey was sent to and self-administered by these nephrology providers (N = 76). Most respondents agreed that utilizing pharmacogenomic-guided antihypertensive prescribing is valuable (4.0 ± 0.7 on a scale of 1 to 5, where 5 indicates strong agreement). However, the respondents also expressed reluctance to use genetic testing for CKD risk stratification due to a perceived lack of supporting evidence (3.2 ± 0.9). Exploratory sub-group analyses associated this reluctance with negative responses to both knowledge and attitude discipline questions, thus suggesting reduced exposure to and comfort with genetic information. Given the evolving nature of genomic implementation in clinical care, further education is warranted to help overcome these perception barriers.

PMID: 32224869 [PubMed]

Polysaccharides obtained from mycelia of Cordyceps militaris attenuated doxorubicin-induced cytotoxic effects in chemotherapy.

Afr Health Sci. 2019 Jun;19(2):2156-2163

Authors: Lin RK, Choong CY, Hsu WH, Tai CJ, Tai CJ

Abstract
Objectives: Fungus Cordyceps militaris has been used as a herbal tonic in traditional Chinese medicine, which could be surface liquid-cultured for mycelia production. To evaluate the potential of polysaccharides obtained from mycelia of Cordyceps militaris (PS-MCM) for attenuation of side-effects of chemotherapy.
Methods: Doxorubicin was used to induce cytotoxicity in THP-1 monocytes and EL-4 T cells, and the effects of PS-MCM on cell viability and cytokine production were detected on doxorubicin-treated THP-1 and EL-4 cells.
Results: PS-MCM reduced doxorubicin-induced cell death and promoted cell proliferation in THP-1 and EL-4 cells. Moreover, PS-MCM elevated the level of cytokines associated with immune-modulation of THP-1 and EL-4 cells.
Conclusion: These findings indicate that PS-MCM has potential for development as a functional food to counteract side effects of chemotherapy.

PMID: 31656500 [PubMed - indexed for MEDLINE]