Methotrexate overdose in clinical practice.

Curr Drug Metab. 2019;20(9):714-719

Authors: Pannu AK

Abstract
BACKGROUND: A folic-acid antagonist, methotrexate, is one of the most commonly prescribed drugs with its expanding use in clinical practice. The drug requires regular monitoring given its wide range of adverse effects including bone marrow suppression, hepatic or renal dysfunction, gastrointestinal distress, mucocutaneous damage, and neurotoxicity. The toxicity usually occurs rapidly and leads to severe neutropenia, sepsis, and advanced renal failure that are difficult to manage.
METHODS: This review is an update for the clinicians to understand the pharmacology, clinical features, laboratory evaluation, and treatment of patients with methotrexate overdose. High-quality literature of the past six decades was collected and reviewed in this article. Several landmark articles were reviewed using PubMed, EMBASE Ovid, and the Cochrane Library, that have important implications in current clinical practice.
RESULTS: Methotrexate overdose has complex toxicokinetic and produces myriad clinical features mimicking conditions of lesser severity. Organ dysfunction related to bone marrow, kidney or central nervous system is lifethreatening. The management should focus on high-quality supportive care, antidotal therapy (folinic acid and carboxypeptidase- G2) and plasma alkalization.
CONCLUSION: In accordance with the dictum "prevention is better than cure", the author emphasizes on the role of patient education, regular clinical observation, and laboratory monitoring for prompt recognition and diagnosis of methotrexate overdosing at the earliest stage.

PMID: 31385765 [PubMed - indexed for MEDLINE]

Prophylactic use of ketamine reduces postpartum depression in Chinese women undergoing cesarean section✰.

Psychiatry Res. 2019 09;279:252-258

Authors: Ma JH, Wang SY, Yu HY, Li DY, Luo SC, Zheng SS, Wan LF, Duan KM

Abstract
This study aimed to explore the effect of prophylactic ketamine administration on postpartum depression in Chinese woman undergoing cesarean section. This randomized controlled study included 654 Chinese women undergoing cesarean section. At 10 min after child birth, patients in the ketamine group were given 0.5 mg/kg ketamine, whereas patients in the control group received standard postpartum care. At the end of operation, all patients were armed with a patient-controlled intravenous analgesia device. The primary outcome was the prevalence of postpartum depression (PPD), as assessed by the Edinburgh Postnatal Depression Scale (EPDS), and the secondary outcomes included the safety assessment and the Numerical Rating Scale (NRS) of postoperative pain. The prevalence of postpartum blues and postpartum depression were significantly lower in the ketamine group than in the control group. Logistic analysis showed that ketamine administration protected against postpartum depression, and PPD-associated risk factors included stress during pregnancy, antenatal depressive symptom and antenatal suicidal ideation. In addition, the antidepressive effect of prophylactic ketamine was stronger in mothers with a history of moderate stress during pregnancy, antenatal depressive symptom and antenatal suicidal ideation. Our findings suggest that ketamine functions as a prophylactic agent against PPD.

PMID: 31147085 [PubMed - indexed for MEDLINE]

Implications of de novo mutations in guiding drug discovery: A study of four neuropsychiatric disorders.

J Psychiatr Res. 2019 03;110:83-92

Authors: So HC, Wong YH

Abstract
Recent studies have suggested an important role of de novo mutations (DNMs) in neuropsychiatric disorders. As DNMs are not subject to elimination due to evolutionary pressure, they are likely to have greater disruptions on biological functions. While a number of sequencing studies have been performed on neuropsychiatric disorders, the implications of DNMs for drug discovery remain to be explored. In this study, we employed a gene-set analysis approach to address this issue. Four neuropsychiatric disorders were studied, including schizophrenia (SCZ), autistic spectrum disorders (ASD), intellectual disability (ID) and epilepsy. We first identified gene-sets associated with different drugs, and analyzed whether the gene-set pertaining to each drug overlaps with DNMs more than expected by chance. We also assessed which medication classes are enriched among the prioritized drugs. We discovered that neuropsychiatric drug classes were indeed significantly enriched for DNMs of all four disorders; in particular, antipsychotics and antiepileptics were the most strongly enriched drug classes for SCZ and epilepsy respectively. Interestingly, we revealed enrichment of several unexpected drug classes, such as lipid-lowering agents for SCZ and anti-neoplastic agents. By inspecting individual hits, we also uncovered other interesting drug candidates or mechanisms (e.g. histone deacetylase inhibition and retinoid signaling) that might warrant further investigations. Taken together, this study provided evidence for the usefulness of DNMs in guiding drug discovery or repositioning.

PMID: 30597425 [PubMed - indexed for MEDLINE]

Harmonization of Next-Generation Sequencing Procedure in Italian Laboratories: A Multi-Institutional Evaluation of the SiRe® Panel.

Front Oncol. 2020;10:236

Authors: Malapelle U, Pepe F, Pisapia P, Sgariglia R, Nacchio M, De Luca C, Lacalamita R, Tommasi S, Pinto R, Palomba G, Palmieri G, Vacirca D, Barberis M, Bottillo I, Grammatico P, Grillo LR, Costa V, Smeraglio R, Bruzzese D, Troncone G

Abstract
Background: Next-generation sequencing (NGS) needs to be validated and standardized to ensure that cancer patients are reliably selected for target treatments. In Italy, NGS is performed in several institutions and harmonization of wet and dry procedures is needed. To this end, a consortium of five different laboratories, covering the most part of the Italian peninsula, was constituted. A narrow gene panel (SiRe®) covering 568 clinically relevant mutations in six different genes (EGFR, KRAS, NRAS, BRAF, cKIT, and PDGFRα) with a predictive role for therapy selection in non-small cell lung cancer (NSCLC), gastrointestinal stromal tumor, colorectal carcinoma (CRC), and melanoma was evaluated in each participating laboratory. Methods: To assess the NGS inter-laboratory concordance, the SiRe® panel, with a related kit and protocol for library preparation, was used in each center to analyze a common set of 20 NSCLC and CRC routine samples. Concordance rate, in terms of mutation detected and relative allelic frequencies, was assessed. Then, each institution prospectively analyzed an additional set of 40 routine samples (for a total of 160 specimens) to assess the reproducibility of the NGS run parameters in each institution. Results: An inter-laboratory agreement of 100% was reached in analyzing the data obtained from the 20 common sample sets; the concordance rate of allelic frequencies distribution was 0.989. The prospective analysis of the run metric parameters obtained by each center locally showed that the analytical performance of the SiRe® panel in the different institutions was highly reproducible. Conclusions: The SiRe® panel represents a robust diagnostic tool to harmonize the NGS procedure in different Italian laboratories.

PMID: 32219061 [PubMed - as supplied by publisher]

Associations of CYP2C9 and CYP2C19 pharmacogenetic variation with phenytoin-induced cutaneous adverse drug reactions.

Clin Transl Sci. 2020 Mar 26;:

Authors: Fohner AE, Rettie AE, Thai KK, Ranatunga DK, Lawson BL, Liu VX, Schaefer CA

Abstract
The role of CYP2C9 and CYP2C19 genetic variation in risk for phenytoin-induced cutaneous adverse drug events is not well understood independently of the HLA-B*15:02 risk allele. In the multiethnic Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we identified 382 participants who filled a phenytoin prescription between 2005-2017. These participants included 21 (5%) people who self-identified as Asian, 18 (5%) as Black, 29 (8%) as White, Hispanic, and 308 (81%) as White, Non-Hispanic. We identified 264 (69%) CYP2C9*1/*1, 77 (20%) CYP2C9*1/*2, and 29 (8%) CYP2C9*1/*3. We also determined CYP2C19 genotypes, including 112 with the increased activity CYP2C19*17 allele. Using electronic clinical notes, we identified 32 (8%) participants with phenytoin-induced cutaneous adverse events recorded within 100 days of first phenytoin dispensing. Adjusting for age, sex, daily dose, and race/ethnicity, participants with CYP2C9*1/*3 or CYP2C9*2/*2 genotypes were more likely to develop cutaneous adverse events compared to CYP2C9*1/*1 participants (odds ratio: 4.47; 95% confidence interval: 1.64 - 11.69; p < 0.01). Among participants with low-intermediate and poor CYP2C9 metabolizer genotypes, 8 (22%) who also had extensive and rapid CYP2C19 metabolizer genotypes experienced cutaneous adverse events, compared to none of those who also had intermediate CYP2C19 metabolizer genotypes (p = 0.17). Genetic variation reducing CYP2C9 metabolic activity may increase risk for phenytoin-induced cutaneous adverse events in the absence of the HLA-B*15:02 risk allele.

PMID: 32216088 [PubMed - as supplied by publisher]

Sex Differences in Associations Between CYP2D6 Phenotypes and Response to Opioid Analgesics.

Pharmgenomics Pers Med. 2020;13:71-79

Authors: Lopes GS, Bielinski SJ, Moyer AM, Black Iii JL, Jacobson DJ, Jiang R, Larson NB, St Sauver JL

Abstract
Background: Several small studies have previously investigated associations between the cytochrome P450 2D6 (CYP2D6) metabolism and response to opioids. We used a large sample of patients to study associations between CYP2D6 phenotypes and estimated CYP2D6 enzymatic activity scores with pain control and adverse reactions related to codeine and tramadol use. We conducted additional analyses to determine whether our results were consistent among men and women.
Methods: We used data from 2,877 participants in the RIGHT Protocol who were prescribed codeine and/or tramadol between 01/01/2005 and 12/31/2017 and who were not prescribed CYP2D6 inhibitors within 1 year prior to the opioid prescription. CYP2D6 phenotype categories were condensed into four groups: (1) Ultra-rapid and Rapid (n = 61), (2) Normal and Intermediate to Normal (n = 1,448), (3) Intermediate and Intermediate to Poor (n = 1,175), and (4) Poor metabolizer status (n = 193). Opioid-related outcomes included indications of poor pain control or adverse reactions related to medication use. We modeled the risk of each outcome using logistic regression, adjusting for age, sex, race, and ethnicity.
Results: The results revealed a trend from poor to ultra-rapid and rapid CYP2D6 phenotypes in which the risk of adverse reactions incrementally increased and the risk of poor pain control incrementally decreased. This trend reached statistical significance among female (but not male) participants. Among normal and intermediate to normal metabolizers, a larger proportion of women experienced adverse reactions relative to men.
Discussion: We replicated and extended the findings of previous research indicating associations between CYP2D6 phenotypes and response to opioids. In addition, the observed associations were stronger in women than in men. We recommend sex differences to be factored in future research investigating associations between pharmacogenomics and response to medications.

PMID: 32214840 [PubMed]

Therapeutic drug monitoring and pharmacogenetics of antipsychotics and antidepressants in real life settings: a 5-year single center experience.

World J Biol Psychiatry. 2020 Mar 26;:1-31

Authors: Baldelli S, Cheli S, Montrasio C, Cattaneo D, Clementi E

Abstract
Introduction: Exposure and clinical response to CNS drugs are largely variable. AGNP guidelines suggest therapy individualization with therapeutic drug monitoring of plasma concentrations and pharmacogenetic testing. We present the retrospective analysis of the last 5 years' data collected in real life settings as indirect evidence of the applications of the AGNP guidelines in the routine clinical management of psychiatric patients requiring pharmacologic treatments.Methods: Plasma concentrations were quantified using a liquid chromatography/tandem mass spectrometry method. Genomic DNA was isolated using an automatic DNA extraction system. All genotypes were determined by Real-Time PCR.Results: We collected a total of 4582 requests for TDM and 212 requests for pharmacogenetic analysis. A wide distribution in the trough concentrations was observed for most drugs indicating a high interpatient variability. Nearly 45% of the samples had trough levels below the minimum effective drug concentrations set by the AGNP guidelines; only 8% of the samples had high concentrations. For pharmacogenetics analysis, among antipsychotics, clozapine, haloperidol and aripiprazole were the most requested (78%); while for antidepressants SSRIs were the most frequently prescribed.Conclusions: These data suggest that physicians are becoming more confident with the laboratory pharmacologic tools to optimize treatments and/or that the pharmacological treatment of patients with psychiatric disorders is becoming more challenging. TDM and PGx might significantly contribute to the rational selection of the best drug and best dose in individual cases.

PMID: 32212950 [PubMed - as supplied by publisher]

Cisplatin Resistance in Osteosarcoma: In vitro Validation of Candidate DNA Repair-Related Therapeutic Targets and Drugs for Tailored Treatments.

Front Oncol. 2020;10:331

Authors: Fanelli M, Tavanti E, Patrizio MP, Vella S, Fernandez-Ramos A, Magagnoli F, Luppi S, Hattinger CM, Serra M

Abstract
Treatment of high-grade osteosarcoma, the most common malignant tumor of bone, is largely based on administration of cisplatin and other DNA damaging drugs. Altered DNA repair mechanisms may thus significantly impact on either response or resistance to chemotherapy. In this study, by using a panel of human osteosarcoma cell lines, either sensitive or resistant to cisplatin, we assessed the value as candidate therapeutic targets of DNA repair-related factors belonging to the nucleotide excision repair (NER) or base excision repair (BER) pathways, as well as of a group of 18 kinases, which expression was higher in cisplatin-resistant variants compared to their parental cell lines and may be indirectly involved in DNA repair. The causal involvement of these factors in cisplatin resistance of human osteosarcoma cells was validated through gene silencing approaches and in vitro reversal of CDDP resistance. This approach highlighted a subgroup of genes, which value as promising candidate therapeutic targets was further confirmed by protein expression analyses. The in vitro activity of 15 inhibitor drugs against either these genes or their pathways was then analyzed, in order to identify the most active ones in terms of inherent activity and ability to overcome cisplatin resistance. NSC130813 (NERI02; F06) and triptolide, both targeting NER factors, proved to be the two most active agents, without evidence of cross-resistance with cisplatin. Combined in vitro treatments showed that NSC130813 and triptolide, when administered together with cisplatin, were able to improve its efficacy in both drug-sensitive and resistant osteosarcoma cells. This evidence may indicate an interesting therapeutic future option for treatment of osteosarcoma patients who present reduced responsiveness to cisplatin, even if possible effects of additive collateral toxicities must be carefully considered. Moreover, our study also showed that targeting protein kinases belonging to the mitogen-activated protein kinase (MAPK) or fibroblast growth factor receptor (FGFR) pathways might indicate new promising therapeutic perspectives in osteosarcoma, demanding for additional investigation.

PMID: 32211337 [PubMed]

Perception of the association between erectile dysfunction and cardiovascular disease among Chinese physicians: an online survey.

J Int Med Res. 2020 Mar;48(3):300060519894187

Authors: Li DJ, Liao ZC, Zhang XB, Tang YX, Zu XB, Wang L, Yang Y, Peng H, Li XC, Tang ZY, Chen XP

PMID: 32208935 [PubMed - in process]

Extramedullary leukemia behaving as solid cancer: clinical, histologic, and genetic clues to chemoresistance in organ sites.

Am J Hematol. 2019 11;94(11):1200-1207

Authors: Cunningham I, Hamele-Bena D, Guo Y, Shiomi T, Papp AC, Chakravarti B, Yang J, Shyr Y, Fisher RA

Abstract
Recent studies of leukemic tumors in individual extramedullary sites showed they adopt the clinical and metastatic behavior of solid cancers originating in those sites. To elucidate features of leukemic tumors that render them resistant to agents effective against marrow leukemia, we analyzed a series of AML breast tumors by histology, immunohistochemistry, and RNA sequencing. Striking histologic similarities to solid cancers were found: a single-filing architectural pattern virtually identical to that of invasive lobular breast carcinoma and dense desmoplastic keloid-like fibrosis similar to colon, gallbladder, and pancreas carcinomas. Sequencing found 2157 genes significantly downregulated in AML breast tumors compared to normal breast. Comparison to triple-negative breast cancer found 859 genes similarly downregulated. At least 30 of these genes have been associated with poor prognosis in breast cancers. Five were reported in AML marrow studies to correlate with poor prognosis. The findings of this pilot study suggest the seed-and-soil interaction recognized in solid cancer growth may help explain how leukemic cells, in some patients, adopt solid tumor behavior in non-marrow sites. Transformed cells that metastasize from tumor to marrow can impart chemoresistance and be an unrecognized cause of treatment failure and death. Further studies comparing leukemic tumor to simultaneous marrow could potentially identify biomarkers that predict extramedullary resistance and lead to new therapeutic targets. Recognizing the potential for leukemia to adopt solid tumor phenotype, and implementation of body scanning and ablative tumor treatment, could decrease the persistently high rates of marrow resistance and treatment failure.

PMID: 31353508 [PubMed - indexed for MEDLINE]

Pharmacogenomic response of low dose haloperidol in critically ill adults with delirium.

J Crit Care. 2020 Mar 04;57:203-207

Authors: Trogrlić Z, van der Jagt M, Osse RJ, Devlin JW, Nieboer D, Koch BCP, van Schaik RHN, Hunfeld NGM

Abstract
PURPOSE: To characterize the pharmacogenomic response of low-dose haloperidol for delirium treatment in critically ill adults.
MATERIALS AND METHODS: Single-center, pilot study of a convenience sample of ICU adults with delirium treated with low-dose IV haloperidol. Patients were evaluated for delirium with the ICDSC every 8 h. Serum haloperidol concentrations were collected on ICU days 2-6, CYP2D6 and CYP3A4 genotypes were characterized and patients were categorized as extensive (EM), intermediate (IM) or poor metabolizers (PM).
RESULTS: The 22 patients (median age 67 [IQR 48,77] years; median APACHE III 81[IQR 54,181]; CYP2D6 [EM = 12, IM = 7, PM = 3], CYP3A [EM = 18, IM = 4]) received a median [IQR] daily haloperidol dose of 3.0 [2.4, 4.5] mg. After adjusting for age, SOFA, and ICU day, neither an association between CYP2D6 (IM p = .67/PM p = .25) or CYP3A4 (IM p = .44) metabolizer status and serum haloperidol concentrations was found. After adjusting for age, SOFA, and ICU day, neither an association between daily haloperidol dose (p = .77) or ICDSC score (p = .13) and serum haloperidol concentrations was found. No patient experienced QTc interval prolongation (≥500 ms).
CONCLUSIONS: This pilot study, the first to evaluate the pharmacogenomic response of low-dose haloperidol when used to treat delirium in the ICU, suggests CYP2D6/CYP3A4 metabolizer status does not affect the serum haloperidol concentrations.

PMID: 32208328 [PubMed - as supplied by publisher]

Clinical Characteristics, Molecular Phenotyping, and Management of Isolated Adrenal Metastases From Lung Cancer.

Clin Lung Cancer. 2019 11;20(6):405-411

Authors: Mazzella A, Loi M, Mansuet-Lupo A, Bobbio A, Blons H, Damotte D, Alifano M

Abstract
INTRODUCTION: Adrenal gland metastases occur in up to 20% of patients with non-small-lung cancer. In selected cases with limited burden of disease, surgery may be offered to improve patient outcome; furthermore, tissue analysis would provide useful information on genotype of primary and secondary neoplasms.
MATERIALS AND METHODS: We report our experience in the management of adrenal metastasis by retrospectively reviewing data of 21 consecutive patients treated with curative intent to the primary tumor followed by adrenalectomy in a 15-year time span. Targeted next generation sequencing was performed to compare molecular profile of primary lung cancers and adrenal metastases. Patient overall survival was assessed by Kaplan-Meier method, using adrenalectomy as time zero. Survival rates were compared by log rank test.
RESULTS: No surgery-related mortality or morbidity was observed. Median survival was 50 months; 5-year overall survival was 34.5% (95% confidence interval, 12%-66%). No significant survival difference was observed with respect to timing of onset (synchronous vs. metachronous) or side (homolateral vs. contralateral) of adrenal metastasis, T or N status of primary lung cancer, mutational asset, and histologic type. Mutations in TP53 genes were found in 61% and 85% of primary and metastatic tumors, respectively. In 3 of 15 cases, we found differences between molecular mutation patterns in primary lung cancer and corresponding adrenal metastasis.
CONCLUSIONS: Adrenalectomy is a safe and effective approach in selected cases. Discordance between primary and secondary tumor mutational profile was found in 20% of assessable patients.

PMID: 31281051 [PubMed - indexed for MEDLINE]

Spotlight on the fetus: how physical activity during pregnancy influences fetal health: a narrative review.

BMJ Open Sport Exerc Med. 2020;6(1):e000658

Authors: Bauer I, Hartkopf J, Kullmann S, Schleger F, Hallschmid M, Pauluschke-Fröhlich J, Fritsche A, Preissl H

Abstract
Before and during pregnancy, women often aim to improve their lifestyle so as to provide a healthier environment for their developing child. It remains unresolved, however, as to whether physical activity (PA) during pregnancy poses a possible risk or whether it might even have beneficial effects on the developing child. There is increasing evidence that PA during pregnancy is indeed beneficial to maternal physiological and psychological health and that it is generally not detrimental to the fetal cardiovascular system and neuronal function in the developing child. This also led to international recommendations for PAs during pregnancy. In the current review, we aimed to comprehensively assess the evidence of beneficial and harmful effects of maternal PA, including high-performance sports, on fetal development. The different mental and body-based relaxation techniques presented here are frequently performed during pregnancy. We found a considerable number of studies addressing these issues. In general, neither low key, moderate maternal PA nor relaxation techniques were observed to have a harmful effect on the developing child. However, we identified some forms of PA which could have at least a transient unfavourable effect. Notably, the literature currently available does not provide enough evidence to enable us to make a general conclusive statement on this subject. This is due to the lack of longitudinal studies on the metabolic and cognitive effects of regular PA during pregnancy and the wide diversity of methods used. In particular, the kind of PA investigated in each study differed from study to study.

PMID: 32206341 [PubMed]

DNA methylation of MMPs and TIMPs in atherothrombosis process in carotid plaques and blood tissues.

Oncotarget. 2020 Mar 10;11(10):905-912

Authors: Gallego-Fabrega C, Cullell N, Soriano-Tárraga C, Carrera C, Torres-Aguila NP, Muiño E, Cárcel-Márquez J, de Moura MC, Fernández-Sanlés A, Esteller M, Elosua R, Jiménez-Conde J, Roquer J, Montaner J, Krupinski J, Fernandez-Cadenas I

Abstract
BACKGROUND AND PURPOSE: Polymorphisms and serum levels of Matrix Metalloproteinases (MMP) and Tissue Inhibitor of Metalloproteinases (TIMP) have been studied with regard to atheromatous plaques and ischemic stroke, while no studies of DNA methylation (DNAm) patterns of MMP or TIMP have been performed to that end. Here, we evaluate DNAm levels of the MMP and TIMP gene families in human carotid plaques and blood samples of atherothrombotic stroke patients.
METHODS: We profiled the DNAm status of stable and ulcerated atherosclerotic plaques obtained as pair sets from three patients who underwent carotid endarterectomy surgery. We selected 415 CpG sites, mapping into MMPs and TIMPs genes for further study. Secondly, the statistically associated CpG sites were analyzed in blood samples from two separate atherothrombotic stroke cohorts (total sample size = 307), ischemic stroke-cohort 1 (ISC-1): 37 atherothrombotic patients and 6 controls, ischemic stroke-cohort 2 (ISC-2): 80 atherothrombotic patients and 184 controls. DNAm levels from plaque tissue and blood samples were evaluated using a high-density microarray Infinium, HumanMethylation450 BeadChip and Infinium MethylationEPIC BeadChip.
RESULTS: Three CpG sites were statistically significantly associated with unstable plaque portions; cg02969624, q-value = 0.035 (TIMP2), and cg04316754, q-value = 0.037 (MMP24) were hypermethylated, while cg24211657 q-value = 0.035 (TIMP2) was hypomethylated. Association of cg04316754 (MMP24) methylation levels with atherothrombotic risk was also observed in blood tissue: ISC-1 p-values = 0.03, ISC-2 p-value = 1.9 × 10-04.
CONCLUSIONS: The results suggest different DNAm status of MMP24 between stable and unstable atherothrombotic carotid plaques, and between atherothrombotic stroke and controls in blood samples.

PMID: 32206187 [PubMed]

Ethnogeographic and inter-individual variability of human ABC transporters.

Hum Genet. 2020 Mar 23;:

Authors: Xiao Q, Zhou Y, Lauschke VM

Abstract
ATP-binding cassette (ABC) transporters constitute a superfamily of 48 structurally similar membrane transporters that mediate the ATP-dependent cellular export of a plethora of endogenous and xenobiotic substances. Importantly, genetic variants in ABC genes that affect gene function have clinically important effects on drug disposition and can be predictors of the risk of adverse drug reactions and efficacy of chemotherapeutics, calcium channel blockers, and protease inhibitors. Furthermore, loss-of-function of ABC transporters is associated with a variety of congenital disorders. Despite their clinical importance, information about the frequencies and global distribution of functionally relevant ABC variants is limited and little is known about the overall genetic complexity of this important gene family. Here, we systematically mapped the genetic landscape of the entire human ABC superfamily using Next-Generation Sequencing data from 138,632 individuals across seven major populations. Overall, we identified 62,793 exonic variants, 98.5% of which were rare. By integrating five computational prediction algorithms with structural mapping approaches using experimentally determined crystal structures, we found that the functional ABC variability is extensive and highly population-specific. Every individual harbored between 9.3 and 13.9 deleterious ABC variants, 76% of which were found only in a single population. Carrier rates of pathogenic variants in ABC transporter genes associated with autosomal recessive congenital diseases, such as cystic fibrosis or pseudoxanthoma elasticum, closely mirrored the corresponding population-specific disease prevalence, thus providing a novel resource for rare disease epidemiology. Combined, we provide the most comprehensive, systematic, and consolidated overview of ethnogeographic ABC transporter variability with important implications for personalized medicine, clinical genetics, and precision public health.

PMID: 32206879 [PubMed - as supplied by publisher]

Pharmacogenetics of antitumor necrosis factor therapy in severe sarcoidosis.

Curr Opin Pulm Med. 2020 Mar 19;:

Authors: Crommelin H, Vorselaars A, van der Vis J, Deneer V, van Moorsel C

Abstract
PURPOSE OF REVIEW: Antitumor necrosis factor (TNF) treatment is an effective third-line treatment option in severe sarcoidosis. But not all patients respond to treatment. Pharmacogenetics studies the influence of genetic variations on treatment response.
RECENT FINDINGS: In sarcoidosis, only one study reported on a relationship between genetic variation in TNF and response to anti-TNF therapy. In immune-mediated inflammatory diseases (IMIDs) other than sarcoidosis, several genetic variants were associated with response to anti-TNF therapy. Genes related to TNF, the target of this group of drugs, and the pathway by which TNF exerts its effect, TNF receptor, were studied most extensively. Recent findings related genetic variations in the human leukocyte antigen region to development of antidrug antibodies.We also included new original data on genetic variations and response to anti-TNF therapy in severe sarcoidosis. We found that TNFRSF1A rs1800693 AA genotype, TNFRSF1B 196T and absence of HLA-DRB103 associate with better response after infliximab treatment in severe sarcoidosis.
SUMMARY: Data on pharmacogenetics of anti-TNF therapy in severe sarcoidosis are scarce. Findings in other IMIDs indicate there may be a role for pharmacogenetics in predicting response and adverse events in anti-TNF therapy, also in sarcoidosis. Future studies are needed to evaluate pharmacogenetics as a predicting marker in anti-TNF therapy in sarcoidosis.

PMID: 32205584 [PubMed - as supplied by publisher]

Exosomes in Prostate Cancer Diagnosis, Prognosis and Therapy.

Int J Mol Sci. 2020 Mar 19;21(6):

Authors: Lorenc T, Klimczyk K, Michalczewska I, Słomka M, Kubiak-Tomaszewska G, Olejarz W

Abstract
Prostate cancer (PCa) is the second most common cause of cancer-related mortality among men in the developed world. Conventional anti-PCa therapies are not effective for patients with advanced and/or metastatic disease. In most cases, cancer therapies fail due to an incomplete depletion of tumor cells, resulting in tumor relapse. Exosomes are involved in tumor progression, promoting the angiogenesis and migration of tumor cells during metastasis. These structures contribute to the dissemination of pathogenic agents through interaction with recipient cells. Exosomes may deliver molecules that are able to induce the transdifferentiation process, known as "epithelial to mesenchymal transition". The composition of exosomes and the associated possibilities of interacting with cells make exosomes multifaceted regulators of cancer development. Extracellular vesicles have biophysical properties, such as stability, biocompatibility, permeability, low toxicity and low immunogenicity, which are key for the successful development of an innovative drug delivery system. They have an enhanced circulation stability and bio-barrier permeation ability, and they can therefore be used as effective chemotherapeutic carriers to improve the regulation of target tissues and organs. Exosomes have the capacity to deliver different types of cargo and to target specific cells. Chemotherapeutics, natural products and RNA have been encapsulated for the treatment of prostate cancers.

PMID: 32204455 [PubMed - in process]

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Unexpected overdose blood concentration of tacrolimus: keep in mind the role of inflammation.

Br J Clin Pharmacol. 2020 Mar 21;:

Authors: Bonneville E, Gautier-Veyret E, Ihl C, Hilleret MN, Baudrant M, Fonrose X, Stanke-Labesque F

PMID: 32199027 [PubMed - as supplied by publisher]

Oncology Pharmacists Can Reduce the Projected Shortfall in Cancer Patient Visits: Projections for Years 2020 to 2025.

Pharmacy (Basel). 2020 Mar 18;8(1):

Authors: Knapp K, Ignoffo R

Abstract
Based on the projected need for a larger oncology care workforce, we estimated the patient care visits and care activities that Board Certified oncology pharmacists (BCOPs) could contribute to oncology care from 2020-2025. Using projected counts for BCOPs through 2025, we estimated that 2.9-4.1 million 30-min BCOP patient visits were possible at 50% workforce capacity. BCOPs' clinical activities overlapped strongly with those of nurse practitioners (NPs) and physician assistants (PAs) in patient education and treatment management. BCOPs could help reduce provider stress and burnout concerns by spreading these activities across a broader set of providers. BCOPs were more active than NPs and PAs in clinical trials research. Recent advances in immunotherapy, pharmacogenetics, pharmacogenomics, and oral oncolytic agents make the medication-focused training of OPs particularly useful to care teams. Comparison also showed that BCOPs were less active in providing follow-up visits and prescribing. Fulfilling the projected BCOP numbers through 2025 will require continued growth in Postgraduate Year 2 (PGY2) oncology pharmacy resident programs and on-the-job training programs. Our review of the trends in cancer incidence, mortality, and survivorship suggest a sustained need for the activities of BCOPs and other oncology care providers.

PMID: 32197351 [PubMed - as supplied by publisher]