Curr Hypertens Rev. 2023 Jan 9. doi: 10.2174/1573402119666230109142156. Online ahead of print.

ABSTRACT

Cardiac circadian rhythms are an important regulator of body functions, including cardiac activities and blood pressure. Disturbance of circadian rhythm is known to trigger and aggravate various cardiovascular diseases. Thus, modulating the circadian rhythm can be used as a therapeutic approach to cardiovascular diseases. Through this work, we intend to discuss the current understanding of cardiac circadian rhythms, in terms of quantifiable parameters like BP and HR. We also elaborate on the molecular regulators and the molecular cascades along with their specific genetic aspects involved in modulating circadian rhythms, with specific reference to cardiovascular health and cardiovascular diseases. Along with this, we also presented the latest pharmacogenomic and metabolomics markers involved in chronobiological control of the cardiovascular system along with their possible utility in cardiovascular disease diagnosis and therapeutics. Finally, we reviewed the current expert opinions on chronotherapeutic approaches for utilizing the conventional as well as the new pharmacological molecules for antihypertensive chronotherapy.

PMID:36624649 | DOI:10.2174/1573402119666230109142156

J Transl Med. 2023 Jan 9;21(1):11. doi: 10.1186/s12967-022-03819-4.

ABSTRACT

BACKGROUND: Radiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC.

METHODS: This was a large‑scale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC.

RESULTS: After genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10- 6), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy.

CONCLUSION: Our study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients.

TRIAL REGISTRATION NUMBER: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546 .

PMID:36624463 | DOI:10.1186/s12967-022-03819-4

Biomed Pharmacother. 2023 Jan 6;159:114225. doi: 10.1016/j.biopha.2023.114225. Online ahead of print.

ABSTRACT

BACKGROUND: To predict primary failure of infliximab (IFX) therapy in Crohn's disease (CD) and to identify patients who maintain long-term effectiveness to IFX is currently not feasible. Some genetic variations are proposed as potential biomarkers.

AIM: We assessed a set of single nucleotide polymorphisms (SNPs) in genes related to the IFX mechanism of action and the presence of HLA-DQA1 * 05 allele on the primary response and long-term durability in CD patients.

METHODS: A multi-centre cross-sectional study of IFX-exposed adult patients with CD was undertaken. Treatment persistence and time to failure were co-primary endpoints. DNA from the 131 patients was genotyped. Association between SNPs and clinical variables with IFX persistence was assessed.

RESULTS: Failure to IFX was documented in 65 (49.6%) out of 131 patients. IFX persistence was associated either with carrying the TT genotype in ADAM17 rs10929587 (ORa=0.2; 95%CI=0.1-0.8; p = 0.021), or the CC genotype in SLCO1C1 rs3794271 (ORa=0.2; 95%CI=0.1-0.7; p = 0.008), according to multivariate logistic regression. In contrast, previous bowel resection increased the risk of IFX failure (ORa=2.8; 95%CI=1.1-7.3; p = 0.025). Cox regression analysis confirmed these findings and also identified IL23R rs10489629-TT (HRa 0.41; 95%CI=0.22-0.75; p = 0.004) and concomitant immunosuppressants (HRa 0.46; 95%CI=0.27-0.77; p = 0.003) as protection from IFX failure. However, no association between HLA-DQA1 * 05 allele and persistence of IFX therapy was found, with similar failure rates among carriers and non-carriers (52.8% vs. 47.4%, respectively; p = 0.544).

CONCLUSIONS: SNPs rs10929587-TT in ADAM17, rs10489629-TT in IL23R and rs3794271-CC in SLCO1C1, together with no previous bowel surgery and concomitant immunosuppression, were identified as protection from failure to IFX.

PMID:36621146 | DOI:10.1016/j.biopha.2023.114225

Biomed Pharmacother. 2023 Jan 6;159:114210. doi: 10.1016/j.biopha.2022.114210. Online ahead of print.

ABSTRACT

Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ2-test adjusted p-values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ2-test adjusted p-values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study.

PMID:36621142 | DOI:10.1016/j.biopha.2022.114210

Eur J Cancer. 2022 Dec 9;181:3-17. doi: 10.1016/j.ejca.2022.11.028. Online ahead of print.

ABSTRACT

Fluoropyrimidine drugs (FP) are the backbone of many chemotherapy protocols for treating solid tumours. The rate-limiting step of fluoropyrimidine catabolism is dihydropyrimidine dehydrogenase (DPD), and deficiency in DPD activity can result in severe and even fatal toxicity. In this review, we survey the evidence-based pharmacogenetics and therapeutic recommendations regarding DPYD (the gene encoding DPD) genotyping and DPD phenotyping to prevent toxicity and optimize dosing adaptation before FP administration. The French experience of mandatory DPD-deficiency screening prior to initiating FP is discussed.

PMID:36621118 | DOI:10.1016/j.ejca.2022.11.028

Int J Med Sci. 2023 Jan 1;20(1):142-150. doi: 10.7150/ijms.77206. eCollection 2023.

ABSTRACT

Metformin is the most often prescribed drug for people with type 2 diabetes (T2D). More than 120 million patients with T2D use metformin worldwide. However, monotherapy fails to achieve glycemic control in a third of the treated patients. Genetics contribute to some of the inter-individual variations in glycemic response to metformin. Numerous pharmacogenetic studies have demonstrated that variations in genes related to pharmacokinetics and pharmacodynamics of metformin's encoding transporters are mainly associated with metformin response. The goal of this review is to evaluate the current state of metformin pharmacogenetics and metabolomics research, discuss the clinical and scientific issues that need to be resolved in order to increase our knowledge of patient response variability to metformin, and how to improve patient outcomes. Metformin's hydrophilic nature and absorption as well as its action mechanism and effectiveness on T2D initiation are discussed. The impacts of variations associated with various genes are analysed to identify and evaluate the effect of genetic polymorphisms on the therapeutic activity of metformin. The metabolic pattern of T2D and metformin is also indicated. This is to emphasise that studies of pharmacogenetics and metabolomics could expand our knowledge of metformin response in T2D.

PMID:36619226 | PMC:PMC9812811 | DOI:10.7150/ijms.77206

Ann Transl Med. 2022 Dec;10(23):1258. doi: 10.21037/atm-2022-57.

NO ABSTRACT

PMID:36618811 | PMC:PMC9816836 | DOI:10.21037/atm-2022-57

Ann Transl Med. 2022 Dec;10(23):1262. doi: 10.21037/atm-2022-58.

ABSTRACT

BACKGROUND: Oxycodone is a commonly used oral opioid in children for treating postoperative pain. Highly polymorphic gene CYP2D6 metabolizes oxycodone into its more potent metabolite, oxymorphone. We hypothesized that altered activity due to CYP2D6 polymorphisms will influence oxycodone requirements {relative oxycodone use [oxycodone morphine equivalents (MEq)/total MEq] to maintain analgesia} (primary outcome) and risk for oxycodone induced side-effects such as respiratory depression (RD) and emesis (secondary outcomes). We also explored the influence of genotype availability and provider guidance on oral opioid prescription patterns.

METHODS: Patients who underwent Nuss procedure and spine fusion with CYP2D6 genotyping results available preoperatively were included. Data on demographics, genotypes, oral opioids, pain scores, RD and emesis were collected. Univariate and multivariable regression for comparison of CYP2D6 genotype predicted poor, ultrarapid, intermediate metabolizers (PM, UM and IM) phenotype with normal metabolizers (NM) for outcomes were performed. Stratified logistic regression was conducted in low (oxycodone/total MEq <0.5) and high (and oxycodone/total MEq >0.5) oxycodone use groups for RD and emesis, with application of firth correction due to quasi-complete separations. Breslow-Day test was used to evaluate odds ratios for prescribing genotype directed opioid between control group (2012-15) (where providers were alerted to genotyping results availability but not directed to use them while prescribing) and genotype directed groups (2016-18) (where providers were directed to use the genotyping results available to them while prescribing oxycodone after surgery).

RESULTS: Of 193 subjects (age 15.9±0.25 years, 28.5% female, 93.78% White; 101 NM, 76 IM, 10 PM and 6 UM), 77.72% underwent pectus surgery. CYP2D6 phenotype was associated with oxycodone MEq/total MEq requirements (P<0.001). Both PM and UM phenotypes had lower oxycodone requirements compared to NM [-0.316 (SE 0.098), P=0.005 and -0.432 (SE 0.113), P<0.001 respectively]. CYP2D6 phenotype was associated with RD in high use oxycodone group (P=0.018) but not low use oxycodone groups (P=0.634). No phenotype association was found for emesis. Oxycodone was prescribed to 91.24% of NM/IM vs. 66.67% of PM/UM (P=0.129) in control group and 94.64% of NM/IM vs. 28.57% of PM/UM (P<0.001) in the genotype-directed group. PM/UM phenotypes in genotype directed group had a lower chance of being prescribed oxycodone (effect size =-2.775; SE 1.566; P=0.076).

CONCLUSIONS: Our findings suggest CYP2D6 genotypes are associated with oxycodone requirements for analgesia and may influence risk for RD. Genotype availability and guidance likely influence oral opioid prescription pattern after surgery. Our findings are limited by small sample size for UM/PM groups.

PMID:36618804 | PMC:PMC9816853 | DOI:10.21037/atm-2022-58

Ann Transl Med. 2022 Dec;10(23):1259. doi: 10.21037/atm-2022-63.

ABSTRACT

BACKGROUND: Medication reconciliation is recognized as a critically important medication safety element and a key initiative by multiple organizations. Within our precision medicine program, accurate medication lists are essential to our ability to make specific medication recommendations based on pharmacogenetic results. Our study aimed to identify discrepancies within the patient's medication list to improve medication management via genetic factors through a pharmacy team-based approach.

METHODS: A dedicated team of pharmacists and trained student pharmacists conducted telephone interviews to complete medication reconciliation for individuals enrolled in our precision medicine preemptive screening program. Medication list discrepancies were tracked as well as if pharmacogenetic consults were altered by findings during the telephone interviews.

RESULTS: Medication reconciliation was completed on 465 participants who had recently received or were awaiting pharmacogenetic testing. We found similar results to previously described rates of medication list discrepancies with an average of 4.9 medication discrepancies per patient as well as greater than 90% of individuals having at least one medication discrepancy. Pharmacogenetic recommendations for 20 individuals (4.3%) required adjustment following medication reconciliation.

CONCLUSIONS: This pilot program supports the value of a dedicated team for medication reconciliation and the importance of accurate medication lists to optimize precision medicine programs.

PMID:36618791 | PMC:PMC9816821 | DOI:10.21037/atm-2022-63

Ann Transl Med. 2022 Dec;10(23):1261. doi: 10.21037/atm-2022-68.

ABSTRACT

BACKGROUND: This study extended a precision medicine clinical decision support mobile application (app) for use with oncology medications. Two gene variants (CYP2D6 and DPYD) associated with pharmacogenomic dosing algorithms in oncology was added to a prototype app. Usability of the app was evaluated. The use of smartphones and mobile apps for prescribing medications has exponentially increased since the introduction of physician order entry. Decision support apps have improved provider performance and studies have shown broader adoption is crucial for the success of these tools. Therefore, successful use of mobile apps will depend on perceptions of users. Rogers' Diffusion of Innovation theory will be the guiding framework for this study.

METHODS: The main research variable is usability as measured by effectiveness, efficiency, and satisfaction. A mixed method design was used. The setting was inpatient and outpatient oncology practices within North Carolina. The sample included registered nurses and nurse practitioners within the oncology field. A functioning mobile app was extended based on the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines to address the most common gene variants seen in oncology patients. Usability testing is divided into two main categories, inspection and testing methods. Prior to the field study, a heuristic evaluation was conducted. This evaluation inspected the user interface, comparing the elements and aspects of it to a set of principles, heuristics, as a guideline to evaluate the usability of the mobile app.

RESULTS: The testing evaluation was conducted with a sample of 51 health care providers to evaluate usability, measured by the System Usability Scale and open-ended questions. Descriptive statistics was used to summarize usefulness and end-user perceived ease of use. In addition, a thematic analysis of the open-ended questions was conducted.

CONCLUSIONS: The development of this mobile app is relevant to nurses who have prescriptive privileges, as well as an educational tool for nurses to understand the rationale behind prescribing certain medications and alternate dosages by providing specific recommendations. Translation of precision medicine into practice will benefit patients by improving care, reducing adverse reactions, and lowering costs.

PMID:36618784 | PMC:PMC9816840 | DOI:10.21037/atm-2022-68

Curr Top Med Chem. 2023 Jan 6. doi: 10.2174/1568026623666230106144509. Online ahead of print.

ABSTRACT

A sedentary lifestyle has evoked a high risk of cardiovascular (CV) disease, diabetes, and obesity, all of them with high morbimortality rates and with a common denominator, hypertension. Numerous pharmacological drugs have been used for the treatment of hypertension. However, the side effects associated with the use of existing pharmacological therapies have triggered a demand for plant-based medications. In this connection, the aim of this review was to provide an in-depth analysis of the use of plant-derived bioactives for the effective management of hypertension. Phytoconstituents from leaves, bark, stem, roots, seeds, and fruits of medicinal plants grown in our different regions of the globe have been highly searched. Among them, polyphenols (e.g., flavonoids as quercetin, anthocyanins as cyanidin, tannins as ellagic acid, stilbenes as resveratrol, lignans as honokiol and others as hydroxytyrosol or curcumin), organosulfur compounds (e.g. s-allyl cysteine and allicin), fatty acids (e.g. α-lipoic acid, DHA and oleic acid), alkaloids (e.g. berberine or tetrandrine) and some terpenes have been intensively investigated for the management of hypertension, with effective ability being stated in controlling high blood pressure and related health problems both in vivo and in vitro studies. Some of the activities presented by these bioactive compounds are reducing oxidative stress, renin-angiotensin system control, SIRT1 activation, regulating platelet aggregation and COX activity, anti-atherogenic effects, anti-inflammatory properties, vasorelaxation and other results that translate into the prevention or control of hypertension. The knowledge of these bioactive compounds is important in developing countries where traditional medicine is the majority, but it can also give rise to new approaches in hypertension therapy.

PMID:36617707 | DOI:10.2174/1568026623666230106144509

Nutrients. 2022 Dec 29;15(1):169. doi: 10.3390/nu15010169.

ABSTRACT

The coronavirus disease (COVID-19) pandemic represents a global health challenge, particularly considering concomitant diseases. Patients with inflammatory bowel diseases (IBD) can be considered a population at risk. On the other hand, the risk of developing IBD and COVID-19 have both been described as modulated by vitamin D (VD) levels. In this work, a cohort of 106 adult patients affected by IBD was prospectively enrolled, during the second wave of the pandemic in Italy. In these patients, VD plasma levels, demographic, and clinical characteristics were tested for a correlation/an association with the risk of infection with SARS-CoV-2 in the study period (anti-spike IgG positivity) and the severity of COVID-19 symptoms. By multivariate logistic regression analysis, VD supplementation (Odds Ratio; OR 0.116, p = 0.002), therapy with monoclonal antibodies (OR 0.227, p = 0.007), and the use of mesalazine (OR 2.968, p = 0.046) were found to be independent predictors of SARS-CoV-2 positivity. Moreover, hypertension was associated with severe disease (p = 0.019), while a VD level higher than 30 ng/mL (p = 0.031, OR 0.078) was associated with asymptomatic infection. No interplay between IBD activity and COVID-19 risk of infection or symptoms was observed. These results confirm the importance of VD levels in defining the risk of COVID-19 and give encouraging data about the safety of maintaining immunomodulatory treatments for IBD during the COVID-19 pandemic.

PMID:36615826 | DOI:10.3390/nu15010169

Molecules. 2023 Jan 3;28(1):414. doi: 10.3390/molecules28010414.

ABSTRACT

Ewing sarcoma (ES) is a highly malignant carcinoma prevalent in children and most frequent in the second decade of life. It mostly occurs due to t(11;22) (q24;q12) translocation. This translocation encodes the oncogenic fusion protein EWS/FLI (Friend leukemia integration 1 transcription factor), which acts as an aberrant transcription factor to deregulate target genes essential for cancer. Traditionally, flavonoids from plants have been investigated against viral and cancerous diseases and have shown some promising results to combat these disorders. In the current study, representative flavonoid compounds from various subclasses are selected and used to disrupt the RNA-binding motif of EWS, which is required for EWS/FLI fusion. By blocking the RNA-binding motif of EWS, it might be possible to combat ES. Therefore, molecular docking experiments validated the binding interaction patterns and structural behaviors of screened flavonoid compounds within the active region of the Ewing sarcoma protein (EWS). Furthermore, pharmacogenomics analysis was used to investigate potential drug interactions with Ewing sarcoma-associated genes. Finally, molecular dynamics simulations were used to investigate the stability of the best selected docked complexes. Taken together, daidzein, kaempferol, and genistein exhibited a result comparable to ifosfamide in the proposed in silico study and can be further analyzed as possible candidate compounds in biological in vitro studies against ES.

PMID:36615603 | DOI:10.3390/molecules28010414

Int J Mol Sci. 2023 Jan 3;24(1):823. doi: 10.3390/ijms24010823.

ABSTRACT

Modern pharmacotherapy of neurodegenerative diseases is predominantly symptomatic and does not allow vicious circles causing disease development to break. Protein misfolding is considered the most important pathogenetic factor of neurodegenerative diseases. Physiological mechanisms related to the function of chaperones, which contribute to the restoration of native conformation of functionally important proteins, evolved evolutionarily. These mechanisms can be considered promising for pharmacological regulation. Therefore, the aim of this review was to analyze the mechanisms of endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) in the pathogenesis of neurodegenerative diseases. Data on BiP and Sigma1R chaperones in clinical and experimental studies of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are presented. The possibility of neuroprotective effect dependent on Sigma1R ligand activation in these diseases is also demonstrated. The interaction between Sigma1R and BiP-associated signaling in the neuroprotection is discussed. The performed analysis suggests the feasibility of pharmacological regulation of chaperone function, possibility of ligand activation of Sigma1R in order to achieve a neuroprotective effect, and the need for further studies of the conjugation of cellular mechanisms controlled by Sigma1R and BiP chaperones.

PMID:36614266 | DOI:10.3390/ijms24010823

Int J Mol Sci. 2022 Dec 30;24(1):657. doi: 10.3390/ijms24010657.

ABSTRACT

Migraine is a common neurovascular disorder characterized by recurrent episodes of headache and associated neurological symptoms. At present, a significant portion of patients do not obtain a satisfactory response to acute pain-relieving therapies, including NSAIDs and triptans. In this context, pharmacogenetics plays a key role in the understanding of such a diverse response. In order to investigate whether functional polymorphisms in proinflammatory cytokine genes (IL-1α, IL-1β, IL-1RN; IL-6 and TNF-α) may influence the response to acute treatment, 313 consecutive patients with episodic migraine without aura were enrolled. Pain relief by administration of NSAIDs or triptans for three consecutive migraine attacks was evaluated. We found a significant association between A allele of the TNF-α promoter (-308 A/G) and a lack of efficacy after NSAID administration (p &lt; 0.01, OR 2.51, 95% CI: 1.33 &lt; OR &lt; 4.75 compared to the G allele). Remaining polymorphisms had no significant effect on pain relief. Our study showed that a functional polymorphism in the TNF-α gene significantly modulates the clinical response to NSAID administration in acute attacks. Patients with higher production of the active cytokine during stress showed a significantly lower anti-migraine effect. Our results further support a role for TNF-α in the pathophysiological mechanisms of migraine attack.

PMID:36614097 | DOI:10.3390/ijms24010657

Int J Mol Sci. 2022 Dec 28;24(1):497. doi: 10.3390/ijms24010497.

ABSTRACT

Major depressive disorder (MDD) is the leading cause of disability worldwide. Treatment with antidepressant drugs (ATD), which target monoamine neurotransmitters including serotonin (5HT), are only modestly effective. Monoamine oxidase (MAO) metabolizes 5HT to 5-hydroxy indoleacetic acid (5HIAA). Genetic variants in the X-chromosome-linked MAO-encoding genes, MAOA and MAOB, have been associated with clinical improvement following ATD treatment in depressed patients. Our aim was to analyze the association of MAOA and MAOB genetic variants with (1) clinical improvement and (2) the plasma 5HIAA/5HT ratio in 6-month ATD-treated depressed individuals. Clinical (n = 378) and metabolite (n = 148) data were obtained at baseline and up to 6 months after beginning ATD treatment (M6) in patients of METADAP. Mixed-effects models were used to assess the association of variants with the Hamilton Depression Rating Scale (HDRS) score, response and remission rates, and the plasma 5HIAA/5HT ratio. Variant × sex interactions and dominance terms were included to control for X-chromosome-linked factors. The MAOA rs979605 and MAOB rs1799836 polymorphisms were analyzed. The sex × rs979605 interaction was significantly associated with the HDRS score (p = 0.012). At M6, A allele-carrying males had a lower HDRS score (n = 24, 10.9 ± 1.61) compared to AA homozygous females (n = 14, 18.1 ± 1.87; p = 0.0067). The rs1799836 polymorphism was significantly associated with the plasma 5HIAA/5HT ratio (p = 0.018). Overall, CC/C females/males had a lower ratio (n = 44, 2.18 ± 0.28) compared to TT/T females/males (n = 60, 2.79 ± 0.27; p = 0.047). The MAOA rs979605 polymorphism, associated with the HDRS score in a sex-dependent manner, could be a useful biomarker for the response to ATD treatment.

PMID:36613935 | DOI:10.3390/ijms24010497

Int J Mol Sci. 2022 Dec 23;24(1):244. doi: 10.3390/ijms24010244.

ABSTRACT

High cholesterol levels have been linked to a high risk of cardiovascular diseases, and preventative pharmacological care to lower cholesterol levels is critically important. Statins, which are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are drugs used to reduce the endogenous cholesterol synthesis, thus minimizing its pathophysiological effects. Despite the proven benefits, statins therapy is known to cause a number of skeletal muscle disorders, including myalgia, myopathy and myositis. The mechanisms underlying such statin-induced side effects are unknown. Recently, a group of genes and molecular pathways has been described to participate in statin-induced myopathy, caused by either simvastatin or rosuvastatin, although the mechanism by which changes in gene regulation occur was not studied. Transposable Elements (TEs), repetitive elements that move within the genome, are known to play regulatory roles in gene expression; however, their role in statin-induced muscle damage has not been studied. We analyzed the expression of TEs in human skeletal fiber cells treated with either simvastatin or rosuvastatin, as well as their respective controls, and identified TEs that change their expression in response to the treatment. We found that simvastatin resulted in &gt;1000 differentially expressed (DE) TEs, whereas rosuvastatin resulted in only 27 DE TEs. Using network analysis tools, we predicted the impact of the DE TEs on the expression of genes and found that amongst the genes potentially modulated by TEs, there are some previously associated to statin-linked myopathy pathways (e.g., AKT3). Overall, our results indicate that TEs may be a key player in the statin-induced muscle side effects.

PMID:36613689 | DOI:10.3390/ijms24010244

Cancers (Basel). 2022 Dec 24;15(1):117. doi: 10.3390/cancers15010117.

ABSTRACT

Chimeric antigen receptor (CAR)-modified T cell therapy has been rapidly developing in recent years, ultimately revolutionizing immunotherapeutic strategies and providing significant anti-tumor potency, mainly in treating hematological neoplasms. However, graft-versus-host disease (GVHD) and other adverse effects, such as cytokine release syndromes (CRS) and neurotoxicity associated with CAR-T cell infusion, have raised some concerns about the broad application of this therapy. Natural killer (NK) cells have been identified as promising alternative platforms for CAR-based therapies because of their unique features, such as a lack of human leukocyte antigen (HLA)-matching restriction, superior safety, and better anti-tumor activity when compared with CAR-T cells. The lack of CRS, neurotoxicity, or GVHD, in the case of CAR-NK therapy, in addition to the possibility of using allogeneic NK cells as a CAR platform for "off-the-shelf" therapy, opens new windows for strategic opportunities. This review underlines recent design achievements in CAR constructs and summarizes preclinical studies' results regarding CAR-NK therapies' safety and anti-tumor potency. Additionally, new approaches in CAR-NK technology are briefly described, and currently registered clinical trials are listed.

PMID:36612114 | DOI:10.3390/cancers15010117

J Appl Lab Med. 2023 Jan 5:jfac091. doi: 10.1093/jalm/jfac091. Online ahead of print.

ABSTRACT

BACKGROUND: In the US adverse drug reactions (ADRs) are estimated to cause 100 000 fatalities and cost over $136 billion annually. A patient's genes play a significant role in their response to a drug. Pharmacogenomics aims to optimize drug choice and dose for individual patients by characterizing patients' pharmacologically relevant genes to identify variants of known impact.

METHODS: DNA was extracted from randomly selected remnant whole blood samples from Caucasian patients with previously performed complete blood counts. Samples were genotyped by mass spectrometry using a customized pharmacogenomics panel. A third-party result interpretation service used genotypic results to predict likely individual responses to frequently prescribed drugs.

RESULTS: Complete genotypic and phenotypic calls for all tested Cytochrome P450 isoenzymes and other genes were obtained from 152 DNA samples. Of these 152 unique genomic DNA samples, 140 had genetic variants suggesting dose adjustment for at least one drug. Cardiovascular and psychiatry drugs had the highest number of recommendations, which included United States Food and Drug Administration warnings for highly prescribed drugs metabolized by CYP2C19, CYP2C9, CYP2D6, HLA-A, and VKORC1.

CONCLUSIONS: Risk for each drug:gene pairing primarily depends upon the degree of predicted enzyme impairment or activation, width of the therapeutic window, and whether parent compound or metabolite is pharmacologically active. The resulting metabolic variations range from risk of toxicity to therapeutic failure. Pharmacogenomic profiling likely reduces ADR potential by allowing up front drug/dose selection to fit a patient's unique drug-response profile.

PMID:36611001 | DOI:10.1093/jalm/jfac091

J Psychosom Res. 2022 Dec 27;165:111131. doi: 10.1016/j.jpsychores.2022.111131. Online ahead of print.

ABSTRACT

OBJECTIVES: Psychological distress, as defined by elevations in symptoms of depression, anxiety, and/or perceived stress, is frequent in patients with chronic diseases, such as coronary artery disease (CAD). While psychological distress is known to impact disease outcomes, less is known about its influence on health care utilization, or on the factors that may modify these relationships. This prospective study examined whether 1) psychological distress predicts greater use of outpatient care services over a period of up to eight years in middle-aged to older individuals with CAD or other non-cardiovascular chronic diseases; 2) this relationship differs according to sex, presence of CAD, and/or social support.

METHODS: Men and women (N = 1236; aged 60.85 ± 6.95 years) with and without CAD completed validated questionnaires on symptoms of depression, anxiety, perceived stress, and social support. Number of medical outpatient visits was obtained from the Régie de l'assurance maladie du Québec. Analyses included bivariate correlations, hierarchical regressions, and moderation analyses, controlling for sociodemographic and lifestyle variables.

RESULTS: Psychological distress, social support, and yearly outpatient visits were significantly correlated (ps < 0.05). In regression analyses, only depressive symptoms were associated with significantly greater use of outpatient care (b = 0.048, p = .004), particularly among CAD patients (b = 0.085, p < .001). Neither sex nor social support moderated this relation.

CONCLUSION: Depression predicted greater outpatient visits in patients with chronic disease, especially CAD patients. More research is needed to determine whether psychosocial interventions may have an impact on health care utilization.

PMID:36610332 | DOI:10.1016/j.jpsychores.2022.111131