Cells. 2022 Mar 19;11(6):1049. doi: 10.3390/cells11061049.

ABSTRACT

Mitochondrial dynamics encompass mitochondrial fusion, fission, and movement. Mitochondrial fission and fusion are seemingly ubiquitous, whereas mitochondrial movement is especially important for organelle transport through neuronal axons. Here, we review the roles of different mitochondrial dynamic processes in mitochondrial quantity and quality control, emphasizing their impact on the neurological system in Charcot-Marie-Tooth disease type 2A, amyotrophic lateral sclerosis, Friedrich's ataxia, dominant optic atrophy, and Alzheimer's, Huntington's, and Parkinson's diseases. In addition to mechanisms and concepts, we explore in detail different technical approaches for measuring mitochondrial dynamic dysfunction in vitro, describe how results from tissue culture studies may be applied to a better understanding of mitochondrial dysdynamism in human neurodegenerative diseases, and suggest how this experimental platform can be used to evaluate candidate therapeutics in different diseases or in individual patients sharing the same clinical diagnosis.

PMID:35326500 | DOI:10.3390/cells11061049

Cancer Med. 2022 Mar 23. doi: 10.1002/cam4.4644. Online ahead of print.

ABSTRACT

PURPOSE: Cisplatin is a critical component of first-line chemotherapy for several cancers, but causes peripheral sensory neuropathy, hearing loss, and tinnitus. We aimed to identify comorbidities for cisplatin-induced neurotoxicities among large numbers of similarly treated patients without the confounding effect of cranial radiotherapy.

METHODS: Utilizing linear and logistic regression analyses on 1680 well-characterized cisplatin-treated testicular cancer survivors, we analyzed associations of hearing loss, tinnitus, and peripheral neuropathy with nongenetic comorbidities. Genome-wide association studies and gene-based analyses were performed on each phenotype.

RESULTS: Hearing loss, tinnitus, and peripheral neuropathy, accounting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension and poorer self-reported health. In addition, hearing loss was positively associated with BMIs at clinical evaluation and nonwork-related noise exposure (>5 h/week). Tinnitus was positively associated with tobacco use, hypercholesterolemia, and noise exposure. We observed positive associations between peripheral neuropathy and persistent vertigo, tobacco use, and excess alcohol consumption. Hearing loss and TXNRD1, which plays a key role in redox regulation, showed borderline significance (p = 4.2 × 10-6 ) in gene-based analysis. rs62283056 in WFS1 previously found to be significantly associated with hearing loss (n = 511), was marginally significant in an independent replication cohort (p = 0.06; n = 606). Gene-based analyses identified significant associations between tinnitus and WNT8A (p = 2.5 × 10-6 ), encoding a signaling protein important in germ cell tumors.

CONCLUSIONS: Genetics variants in TXNRD1 and WNT8A are notable risk factors for hearing loss and tinnitus, respectively. Future studies should investigate these genes and if replicated, identify their potential impact on preventive strategies.

PMID:35322580 | DOI:10.1002/cam4.4644

BMC Geriatr. 2022 Mar 23;22(1):242. doi: 10.1186/s12877-022-02942-7.

ABSTRACT

BACKGROUND: In older patients with polypharmacy and multiple comorbidities, even low grades of statin-associated muscle symptoms may have clinical implications. The aim of this study was therefore to investigate the potential associations between statin use and measures of physical performance and muscle function.

METHODS: Participants were aged 70+, treated with at least seven regular systemic medications, and not expected to die or become institutionalized within 6 months. Physical performance measured as gait speed and Short Physical Performance Battery (SPPB) score, and muscle function measured as grip strength, were compared between users and non-users of statins. In the subgroup of statin users, the dose-response relationship was assessed using harmonized simvastatin equivalents adjusted for statin potency, pharmacokinetic interactions and SLCO1B1 c.521 T > C genotype. Multiple linear regression analyses were applied to investigate potential associations between stain use and exposure as independent variables, and physical performance and muscle function as outcomes, adjusted for age, gender, body mass, comorbidity, disability and dementia.

RESULTS: 174 patients (87 users and 87 non-users of statins) with a mean (SD) age of 83.3 (7.3) years were included. In analyses adjusted only for gender, grip strength was significantly higher in users than in non-users of statins [regression coefficient (B) 2.7, 95% confidence interval (CI) 1.0 to 4.4]. When adjusted for confounders, the association was no longer statistically significant (B 1.1, 95% CI - 0.5 to 2.7). SPPB and gait speed was also better in statin users than in non-users, but the differences were not statistically significant. In dose-response analyses adjusted for confounders, we found a statistically significant increase in SPPB score (B 0.01, 95% CI 0.00 to 0.02) and gait speed (B 0.001, 95% CI 0.000 to 0.002) per mg increase in simvastatin equivalents.

CONCLUSIONS: In contrast to our hypothesis, statin use and exposure was associated with better measures of physical performance and muscle function in older patients with complex drug treatment. The unexpected findings of this cross-sectional, observational study should be further investigated by comparing physical performance before and after statin initiation or statin withdrawal in prospective studies.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02379455 , registered March 5, 2015.

PMID:35321652 | DOI:10.1186/s12877-022-02942-7

Front Pharmacol. 2022 Mar 7;13:797032. doi: 10.3389/fphar.2022.797032. eCollection 2022.

ABSTRACT

Special Thai oolong tea is oolong tea (Camellia sinensis (L.) Kuntze) steamed with selected Thai botanical drugs. Oolong tea steamed with ginger (Zingiber officinale), lemongrass (Cymbopogon citratus), and celery (Anathallis graveolens L.) is called eternity tea (EN), whereas peaceful rest (PR) tea is made of oolong tea leaves steamed with Indian gooseberry (Phyllanthus emblica), Turkey berry (Solanum torvum), and wild betel leaf bush leaves (Piper sarmentosum). Oolong tea is known for its numerous biological activities including antidiabetic properties. However, the effect of the additional botanical drugs on the biological activities of special oolong teas has not yet been explored. From the results, the PR extract exhibited the best activity in the in vitro assays relevant to antidiabetic properties such as chemical antioxidant, anti-inflammation, anti-adipogenesis, enzyme inhibition, and glucose uptake and consumption. The UHPLC-QTOF-MS/MS profiles of PR and EN extracts indicated chemical profiles different from oolong tea. For instance, gingerdiol and gingerol were detected in EN, whereas piperettine I was detected in PR. Therefore, it was inferred that among the three tea extracts, the additional compounds in PR contributed to good activities compared to oolong and EN. It is also important to highlight that the PR extract inhibited glucose uptake and consumption by adipocytes and skeletal muscles at concentrations of 500 and 100 μg/ml, respectively, as well as metformin activity (p < 0.05). Findings from this study support the antidiabetic potential of PR tea.

PMID:35321328 | PMC:PMC8936575 | DOI:10.3389/fphar.2022.797032

Pharmacogenomics J. 2022 Mar 22. doi: 10.1038/s41397-022-00272-w. Online ahead of print.

ABSTRACT

The major challenges that delay the implementation of pharmacogenomics based clinical practice in the developing countries, primarily the low- and middle-income countries need to be recognized. This review was conducted to systematically review evidence of the cost-effectiveness for the conduct of pharmacogenomics testing in the developing countries. Studies that evaluated the cost-effectiveness of pharmacogenomics testing in the developing countries as defined by the United Nations were included in this study. Twenty-seven articles met the criteria. Pharmacogenomics effectiveness were evaluated for drugs used in the treatment of cancers, cardiovascular diseases and severe cutaneous adverse reactions in gout and epilepsy. Most studies had reported pharmacogenomics testing to be cost-effective (cancers, cardiovascular diseases, and tuberculosis) and economic models were evaluated from multiple perspectives, different cost categories and time horizons. Additionally, most studies used a single gene, rather than a gene panel for the pharmacogenomics testing. Genotyping cost and frequency of risk alleles in the populations influence the cost-effectiveness outcome. Further studies are warranted to examine the clinical and economic validity of pharmacogenomics testing in the developing countries.

PMID:35319010 | DOI:10.1038/s41397-022-00272-w

Hu Li Za Zhi. 2022 Apr;69(2):4-6. doi: 10.6224/JN.202204_69(2).01.

ABSTRACT

Individualizing healthcare and treatment is a core value of the healthcare sector because of the professional importance of accurately diagnosing, treating, and caring for people who are ill (Ho et al., 2020). Although clinicians may have been working to personalize care to the individual health needs of their patients throughout the history of medicine, predicting how specific individuals will respond to specific treatments or healthcare interventions has long been a goal impossible to achieve. Precision health, a broad concept that includes precision medicine, is a term that refers to personalized healthcare based on a person's unique genetic composition as well as related lifestyle, social, economic, cultural and environmental influences that is designed to help individuals achieve well-being and optimal health (Fu et al., 2019). The term "personal medicine" is frequently used in the healthcare sector to describe a population-based approach. However, this approach is less-individualized than precision medicine. Several rising trends in healthcare are providing doctors and nurses with the tools necessary to better access and manage the vast amounts of data needed to provide individualized care in a manner that both improves outcomes and lowers costs. By focusing on health and wellness, nurses can have a meaningful impact on reducing healthcare cost. One way to support the development of precision health initiatives within the nursing context is to develop interventions that match patients' complex phenomena. Tailoring intervention is an intervention method that selects and applies strategies to treat each patient based on her / his specific characteristics (Salmond & Echevarria, 2017). Furthermore, continuous-tuning interventions are one class of tailoring that adjusts and tunes interventions to the changing needs of individuals based on their data (Hekler et al., 2020). Precision health links health-related research and practice as well as medicine, population health, and public health. Nursing roles are important in the implementation of precision health. They provide precision delivery of medications based on knowledge of pharmacogenetics, patient and family education related to the meaning of genomics, health and family assessments, and critical feedback and insights on the feasibility of implementing new technologies into clinical point-of-care or community workflows. Therefore, the domain knowledge of precision health is critical to clinical practice. In line with the rapid pace of development in digital health technologies, the role of medical informatics in advancing personalized healthcare and precision healthcare has been increasingly emphasized (Hussein, 2020). As medical care and healthcare have entered the information era, digital health technologies provide significant opportunities to optimize clinical care. Using digital health technology should provide opportunities to better generate evidence and provide evidence-based medical care and healthcare. To share more information related to clinical trends in precision health and digital care, we have invited expert groups to share their related expertise and experiences. We do hope nurse professionals and healthcare providers are inspired by this topic and the articles in this issue of the journal.

PMID:35318626 | DOI:10.6224/JN.202204_69(2).01

BMC Health Serv Res. 2022 Mar 22;22(1):378. doi: 10.1186/s12913-022-07730-y.

ABSTRACT

INTRODUCTION: Pharmacogenomics (PGx) testing services have been delivered through community pharmacies across the globe, though not yet in the UK. This paper is reporting a focus group study, the first stage of a participatory co-design process to increase the chance of a successful implementation of a PGx service through community pharmacy in the UK.

AIM: To identify the barriers and enablers to implementing a community pharmacy based PGx service in the UK.

METHOD: Three focus groups were conducted with community pharmacists (n = 10), prescribers (n = 8) and patients (n = 8) in England. The focus groups were recorded, transcribed and thematically analysed using the Braun and Clarke six phase reflexive thematic analysis approach.

RESULTS: The analysis identified five themes about PGx testing in community pharmacies: (1) In- principle receptiveness, (2) Appreciation of the benefits, (3) Lack of implementation resources (4) Ambiguity about implications for implementation and (5) Interprofessional relationship challenges.

CONCLUSION: The identified enablers for implementation of a PGx service were at a macro health system strategic level; the concerns were more at a granular operational procedural level. Overall receptiveness was noted by all three participant groups, and both prescriber and pharmacist groups appreciated the potential benefits for patients and the healthcare system. Prior to implementation in the UK, there is a need to disambiguate health professional's concerns of the guidance, resources, and knowledge required to set up and deliver the service and to resolve patient concerns about the nature of genomics.

PMID:35317803 | DOI:10.1186/s12913-022-07730-y

Research (Wash D C). 2022 Mar 4;2022:9805932. doi: 10.34133/2022/9805932. eCollection 2022.

ABSTRACT

Flowrate control in flexible bioelectronics with targeted drug delivery capabilities is essential to ensure timely and safe delivery. For neuroscience and pharmacogenetics studies in small animals, these flexible bioelectronic systems can be tailored to deliver small drug volumes on a controlled fashion without damaging surrounding tissues from stresses induced by excessively high flowrates. The drug delivery process is realized by an electrochemical reaction that pressurizes the internal bioelectronic chambers to deform a flexible polymer membrane that pumps the drug through a network of microchannels implanted in the small animal. The flowrate temporal profile and global maximum are governed and can be modeled by the ideal gas law. Here, we obtain an analytical solution that groups the relevant mechanical, fluidic, environmental, and electrochemical terms involved in the drug delivery process into a set of three nondimensional parameters. The unique combinations of these three nondimensional parameters (related to the initial pressure, initial gas volume, and microfluidic resistance) can be used to model the flowrate and scale up the flexible bioelectronic design for experiments in medium and large animal models. The analytical solution is divided into (1) a fast variable that controls the maximum flowrate and (2) a slow variable that models the temporal profile. Together, the two variables detail the complete drug delivery process and control using the three nondimensional parameters. Comparison of the analytical model with alternative numerical models shows excellent agreement and validates the analytic modeling approach. These findings serve as a theoretical framework to design and optimize future flexible bioelectronic systems used in biomedical research, or related medical fields, and analytically control the flowrate and its global maximum for successful drug delivery.

PMID:35316891 | PMC:PMC8917966 | DOI:10.34133/2022/9805932

Biocontrol Sci. 2022;27(1):31-39. doi: 10.4265/bio.27.31.

ABSTRACT

Calcineurin (CN) is a conserved Ca2+-calmodulin activated protein phosphatase, which plays important roles in immune regulation, cardiac hypertrophy, and apoptosis in humans. In pathogenic fungi, CN is essential for stress survival, sexual development, and virulence. The immunosuppressant tacrolimus (FK506) is a specific inhibitor of CN in humans and fungi including nonpathogenic fission yeast. Although calcineurin inhibition by FK506 or CN deletion in fission yeast does not induce growth defects, treatment with some anti-fungal drugs such as micafungin and valproic acid, induced synthetic lethality with calcineurin inhibition. Here, we searched for the compounds that induce synthetic growth defects with CN inhibition in fission yeast. We found that ellagic acid (EA) preferentially induced growth inhibition in CN deletion cells. Consistently, co-treatment with EA and FK506 induced severe growth inhibition in the wild-type cells, whereas neither of the single treatment with each compound did so. Moreover, deletion of the calcineurin-regulated transcription factor Prz1 also induced a marked EA sensitivity. Intriguingly, EA also enhanced the growth inhibitory effect of other anti-fungal drugs, including micafungin and miconazole. Thus, our data suggesting the synergistic growth inhibitory effect of the calcineurin inhibitor FK506 and EA may be useful to understand the mechanism to overcome the antifungal resistance.

PMID:35314558 | DOI:10.4265/bio.27.31

Eur Neuropsychopharmacol. 2022 Mar 18;58:80-85. doi: 10.1016/j.euroneuro.2022.03.001. Online ahead of print.

ABSTRACT

Recently, Salagre and Vieta commented on the complexity of implementing precision medicine in psychiatry. For 25 years, this author has focused on a circumscribed type of precision medicine: personalized dosing using pharmacokinetic mechanisms to stratified patients. This short communication focuses on personalized dosing of three oral antipsychotics (clozapine, risperidone and paliperidone) and presents their maintenance dosing in a table which provides dose-correction factors generated by pharmacokinetic studies. Inhibitors need dose-correction factors < 1 and inducers need correction factors >1. Clozapine maintenance dosing is based on the dose needed to reach 350 ng/ml (the minimum plasma therapeutic concentration in treatment-resistant schizophrenia). Clozapine maintenance dosing is influenced by 3 levels of complexity: 1) ancestry groups (Asians/Native Americans; Europeans and Blacks), 2) sex-smoking subgroups (lowest dose in female non-smokers and highest in male smokers) and 3) presence/absence of poor metabolizer status (due to genetic and non-genetic causes including co-prescription of inhibitors, obesity or inflammation). Risperidone and paliperidone maintenance dosing are based on the dose needed to reach plasma concentrations of 20-60 ng/ml. Risperidone PMs need approximately half the dose, which can be explained by genetics (CYP2D6 PMs) or co-prescription of CYP2D6 inhibitors. Fluoxetine co-prescription may require one fourth the risperidone maintenance dose. Carbamazepine co-prescription may require twice the risperidone maintenance dose. Although not well studied, two groups may need higher doses of oral paliperidone: Koreans may need 1.5 times higher doses while those taking carbamazepine may need 3 times higher paliperidone maintenance doses. Precision dosing in psychiatry requires using blood levels of individuals.

PMID:35314415 | DOI:10.1016/j.euroneuro.2022.03.001

J Alzheimers Dis. 2022 Mar 14. doi: 10.3233/JAD-215735. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenetic effects of statins on clinical changes in Alzheimer's disease (AD) could be mediated by epistatic interactions among relevant genetic variants involved in cholesterol metabolism.

OBJECTIVE: To investigate associations of HMGCR (rs3846662), NR1H2 (rs2695121), or CETP (rs5882&rs708272) with cognitive and functional changes in AD, with stratification according to APOEɛ4 carrier status and lipid-lowering treatment with lipophilic statins.

METHODS: Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and global ratings, with prospective neurotranslational associations documented for one year.

RESULTS: Considering n = 190:142 had hypercholesterolemia, 139 used lipophilic statins; minor allele frequencies were 0.379 (rs2695121-T:46.3% heterozygotes), 0.368 (rs5882-G:49.5% heterozygotes), and 0.371 (rs708272-A:53.2% heterozygotes), all in Hardy-Weinberg equilibrium. For APOEɛ4 carriers: rs5882-GG protected from cognitive decline; rs5882-AA caused faster cognitive decline; carriers of rs2695121-CC or rs5882-AA were more susceptible to harmful cognitive effects of lipophilic statins; carriers of rs5882-GG or rs708272-AG had functional benefits when using lipophilic statins. APOEɛ4 non-carriers resisted any cognitive or functional effects of lipophilic statins, while invariability of rs3846662 (all AA) prevented the assessment of HMGCR effects. When assessing CETP haplotypes only: rs5882-GG protected from cognitive and functional decline, regardless of lipophilic statin therapy; lipophilic statins usually caused cognitive and functional harm to carriers of rs5882-A and/or rs708272-A; lipophilic statins benefitted cognition and functionality of carriers of rs5882-G and/or rs708272-G.

CONCLUSION: Reportedly protective variants of CETP and NR1H2 also slowed cognitive and functional decline particularly for APOEɛ4 carriers, and regardless of cholesterol variations, while therapy with lipophilic statins might affect carriers of specific genetic variants.

PMID:35311709 | DOI:10.3233/JAD-215735

Pharmacogenomics. 2022 Mar 21. doi: 10.2217/pgs-2022-0006. Online ahead of print.

ABSTRACT

Clozapine (CLZ) is an atypical antipsychotic reserved for patients with refractory psychosis, but it is associated with a significant risk of severe adverse reactions (ADRs) that are potentiated with the concomitant use of alcohol. Additionally, pharmacogenetic studies have explored the influence of several genetic variants in CYP450, receptors and transporters involved in the interindividual response to CLZ. Herein, we systematically review the current multiomics knowledge behind the interaction between CLZ and alcohol intake, and how its concomitant use might modulate the pharmacogenetics. CYP1A2*1F, *1C and other alleles not yet discovered could support a precision medicine approach for better therapeutic effects and fewer CLZ ADRs. CLZ monitoring systems should be amended and include alcohol intake to protect patients from severe CLZ ADRs.

PMID:35311547 | DOI:10.2217/pgs-2022-0006

Pharmacogenomics. 2022 Mar 21. doi: 10.2217/pgs-2021-0154. Online ahead of print.

ABSTRACT

Aim: To examine the association between variant rs163184 in the type 2 diabetes mellitus (T2DM) susceptibility gene KCNQ1 and exenatide glycemic response in the Chinese population. Patients & methods: We included 100 T2DM patients from the CONFIDENCE study and investigated the association between rs163184 and glycemic response to exenatide, by using a multivariate linear model with adjustment for baseline glucose status and other covariates. Results: The G allele of rs163184 was associated with a 0.34% (p = 0.016) lower glycosylated hemoglobin reduction after 48 weeks of exenatide treatment. Similar significant associations were observed when glycemic response to exenatide was evaluated with fasting blood glucose or postprandial blood glucose reduction. Conclusion: We found that rs163184 in the gene KCNQ1 was associated with reduced glycemic response to exenatide in T2DM patients. The effect size observed in this study was large enough to be considered clinically relevant in stratified medicine.

PMID:35311356 | DOI:10.2217/pgs-2021-0154

Pharmacogenomics. 2022 Mar 21. doi: 10.2217/pgs-2022-0002. Online ahead of print.

ABSTRACT

Aim: This study explores parental understanding and attitudes around pharmacogenomic results in their child(ren). Patients and methods: In-depth interviews with parents whose child(ren) had received a pharmacogenomic testing panel for management of neuropsychiatric medications were completed. Interviews were analyzed for themes and accuracy of understanding of results. Results: In 18 parents interviewed, 49/63 (78%) of statements made regarding results were accurate. Differences in understanding were seen by clinic, number of medications and result type. Parents expected results to guide prescribing and perceived the greatest utility in results that could impact current care. Results predicting normal drug metabolism may create mixed feelings. Conclusion: Parents perceive utility in pharmacogenomic testing for their children. Challenges exist in understanding probabilistic and multifactorial information about pharmacogenomic results.

PMID:35311353 | DOI:10.2217/pgs-2022-0002

Pharmacogenomics. 2022 Mar 21. doi: 10.2217/pgs-2022-0009. Online ahead of print.

ABSTRACT

Global migration trends are accelerating population admixture. Increasing population diversity met with minority health disparities necessitates thoughtful training of health professional students. Health professional accreditation standards emphasize pharmacogenomics and clinical cultural competency (CCC); however, published studies focus on students' knowledge in pharmacogenomics alone. This report reviews considerations for integrating CCC into required pharmacogenomic education in pharmacy and other health disciplines. By coupling both topics during didactic training and active learning exercises repeated throughout the existing curriculum, students can become adept at these individualized patient care skills and retain their knowledge into their careers. Moving beyond race as a proxy for healthcare decision-making, the CCC of clinicians coupled with patients' genetic test results could empower clinicians to address health disparities and facilitate discussions about the role of race in clinical practice. Ultimately, an integrated approach of teaching pharmacogenomics and CCC could dismantle race-norming or race-based clinical practices.

PMID:35311348 | DOI:10.2217/pgs-2022-0009

Gen Psychiatr. 2022 Feb 23;35(1):e100685. doi: 10.1136/gpsych-2021-100685. eCollection 2022.

ABSTRACT

BACKGROUND: Schizophrenia is a serious mental illness affecting approximately 20 million individuals globally. Both genetic and environmental factors contribute to the illness. If left undiagnosed and untreated, schizophrenia results in impaired social function, repeated hospital admissions, reduced quality of life and decreased life expectancy. Clinical diagnosis largely relies on subjective evidence, including self-reported experiences, and reported behavioural abnormalities followed by psychiatric evaluation. In addition, psychoses may occur along with other conditions, and the symptoms are often episodic and transient, posing a significant challenge to the precision of diagnosis. Therefore, objective, specific tests using biomarkers are urgently needed for differential diagnosis of schizophrenia in clinical practice.

AIMS: We aimed to provide evidence-based and consensus-based recommendations, with a summary of laboratory measurements that could potentially be used as biomarkers for schizophrenia, and to discuss directions for future research.

METHODS: We searched publications within the last 10 years with the following keywords: 'schizophrenia', 'gene', 'inflammation', 'neurotransmitter', 'protein marker', 'gut microbiota', 'pharmacogenomics' and 'biomarker'. A draft of the consensus was discussed and agreed on by all authors at a round table session.

RESULTS: We summarised the characteristics of candidate diagnostic markers for schizophrenia, including genetic, inflammatory, neurotransmitter, peripheral protein, pharmacogenomic and gut microbiota markers. We also proposed a novel laboratory process for diagnosing schizophrenia in clinical practice based on the evidence summarised in this paper.

CONCLUSIONS: Further efforts are needed to identify schizophrenia-specific genetic and epigenetic markers for precise diagnosis, differential diagnosis and ethnicity-specific markers for the Chinese population. The development of novel laboratory techniques is making it possible to use these biomarkers clinically to diagnose disease.

PMID:35309241 | PMC:PMC8867318 | DOI:10.1136/gpsych-2021-100685

Front Med (Lausanne). 2022 Mar 3;9:811326. doi: 10.3389/fmed.2022.811326. eCollection 2022.

ABSTRACT

Vitamin D deficiency or insufficiency is common in obese people, with some studies suggesting that low vitamin D level might be an independent predictor of obesity. Thus, the purpose of the present randomized, double-blind, placebo-controlled study was to investigate the effect of oral spray vitamin D3 3000 IU supplementation along with personalized weight-loss diet on obesity markers in overweight and obese Caucasians with vitamin d deficiency or insufficiency. The impact of vitamin D receptor (VDR) and adrenergic receptors (ADRs) genetic variants on vitamin D levels and weight loss diet outcomes was also investigated. After signing informed consent, a total of 125 eligible volunteers were randomly assigned into vitamin D (vitamin D3 3000 IU/d oral spray supplementation, n = 76) or placebo (xylitol, water, mint, n = 49) group following a weight loss program (600 calories less than the total energy expenditure of each volunteer) for 3 months. Fat mass, BMI, REE and 25(OH)D serum level were monitored on baseline and each month. DNA samples were extracted from buccal swabs and genotyped for the rs2228570 (VDR), rs1544410 (VDR), rs731236 (VDR), rs1800544 (ADRA2A), rs1801252 (ADRB1), rs1042713 (ADRB2), and rs4994 (ADRB3) polymorphisms. Statistical analysis was performed using SPSS package (v.23). Between group comparisons revealed significant improvement in serum 25(OH)D level and greater reduction in weight, BMI and fat percentage in the vitamin D group compared to placebo group (p < 0.05). In the vitamin D group, carriers of the rs2228570 T allele tended to have greater vitamin D level improvement compared with the homozygous C allele (p = 0.067). Furthermore, heterozygous (CT) for the rs731236 tended to have lesser weight loss (p = 0.068) and for the rs1042713, a lower decline in fat percentage was observed for homozygous AA carriers compared to the heterozygous (p = 0.051). In the control group, differences in weight loss (p = 0.055) and BMI (p = 0.045) were observed between rs1544410 AA and GG homozygous. In conclusion, vitamin D oral spray supplementation seems to improve vitamin D status and decrease obesity markers during a weight-loss intervention in overweight/obese Caucasians with vitamin D deficiency or insufficiency. Also, the results of the present study indicate that VDR and ADRs genetic polymorphisms seem to influence vitamin D supplementation response and obesity markers.

PMID:35308505 | PMC:PMC8928870 | DOI:10.3389/fmed.2022.811326

Diabetologia. 2022 Mar 21. doi: 10.1007/s00125-022-05681-x. Online ahead of print.

ABSTRACT

Data generated over nearly two decades clearly demonstrate the importance of epigenetic modifications and mechanisms in the pathogenesis of type 2 diabetes. However, the role of pharmacoepigenetics in type 2 diabetes is less well established. The field of pharmacoepigenetics covers epigenetic biomarkers that predict response to therapy, therapy-induced epigenetic alterations as well as epigenetic therapies including inhibitors of epigenetic enzymes. Not all individuals with type 2 diabetes respond to glucose-lowering therapies in the same way, and there is therefore a need for clinically useful biomarkers that discriminate responders from non-responders. Blood-based epigenetic biomarkers may be useful for this purpose. There is also a need for a better understanding of whether existing glucose-lowering therapies exert their function partly through therapy-induced epigenetic alterations. Finally, epigenetic enzymes may be drug targets for type 2 diabetes. Here, I discuss whether pharmacoepigenetics is clinically relevant for type 2 diabetes based on studies addressing this topic.

PMID:35307762 | DOI:10.1007/s00125-022-05681-x

Br J Cancer. 2022 Mar 19. doi: 10.1038/s41416-022-01779-6. Online ahead of print.

ABSTRACT

BACKGROUND: Serious and potentially life-threatening toxicities can occur following 5-fluorouracil/capecitabine exposure. Patients carrying Dihydropyrimidine Dehydrogenase (DPYD) variant alleles associated with decreased enzymatic function are at a greater risk of early/severe 5-fluorouracil/capecitabine toxicity. The objective of this systematic review/meta-analysis was to evaluate treatment outcomes between Pharmacogenetics Guided Dosing (PGD) versus non-PGD and within PGD (DPYD variant allele carriers versus wild type).

METHODS: A systematic review/meta-analysis of original publications indexed in Ovid Medline, Ovid Embase, and the Cochrane CENTRAL (Wiley) library from inception to 7-Dec-2020. Eligible studies evaluated at least one pre-defined treatment outcome measures (toxicity/hospitalisations/survival/overall response/quality of life).

RESULTS: Of 1090 identified publications, 17 met predefined eligibility criteria. The meta-analysis observed reduced incidence of grade 3/4 overall toxicity (Risk Ratio [RR] 0.32 [95% Cl 0.27-0.39], p < 0.00001) and grade 3/4 diarrhoea (RR 0.38 [95% Cl 0.24-0.61], p < 0.0001) among PGD versus non-PGD cohorts. Within PGD cohorts, there was no statistical differences for overall response rates (complete/partial) (RR 1.31 [95% Cl 0.93-1.85], p = 0.12). Similar results were found with stable disease (RR 1.27 [95% Cl 0.66-2.44], p = 0.47).

CONCLUSION: PGD improves patient outcomes in terms of grade 3/4 toxicity, in particular overall toxicity and diarrhoea, without impacting on treatment response.

REGISTRATION NUMBER: The study is registered with PROSPERO, registration number CRD42020223768.

PMID:35306539 | DOI:10.1038/s41416-022-01779-6

Gene. 2022 Mar 16:146398. doi: 10.1016/j.gene.2022.146398. Online ahead of print.

ABSTRACT

PURPOSE: To explore the associations between FANC (FANCA, FANCC, FANCE, FANCF, and FANCJ) single nucleotide polymorphisms (SNPs) and prognosis of non-small cell lung cancer (NSCLC) patients with platinum-based chemotherapy.

METHODS: According to the inclusion criteria, we selected 395 DNA samples from NSCLC patients for genotyping and combined with clinical data for Cox regression analysis and stratification analyses to assess relationships between overall survival (OS) and progression free survival (PFS) with SNPs genotypes.

RESULTS: The results revealed that patients with FANCE rs6907678 TT genotype have a longer OS than TC and CC genotype (Additive model: P=0.004, HR =1.696, 95% CI =1.186-2.425). In stratification analyses, Longer PFS is found in female, age ≤55 years old and non-smoking patients with FANCE rs6907678 TT genotype, and patients with TT genotypes were significantly had longer OS in male, age ＞55 years old, non-smoking, squamous cell carcinoma and stage IV stratification.

CONCLUSION: Our data demonstrates that patients with FANCE rs6907678 TT genotype are contributed to better prognosis. FANCE rs6907678 may be used as a clinical biomarker for predicting the prognosis of NSCLC patients with platinum-based chemotherapy.

PMID:35306114 | DOI:10.1016/j.gene.2022.146398