Pain Ther. 2022 Apr 16. doi: 10.1007/s40122-022-00374-0. Online ahead of print.

ABSTRACT

The abuse of opioids has become one of the most serious concerns in the world. Opioid use can cause serious adverse reactions, including respiratory depression, postoperative nausea and vomiting, itching, and even death. These adverse reactions are also important complications of clinical application of opioid drugs that may affect patient safety and recovery. Due to the fear of adverse reactions of opioids, clinicians often do not dare to use opioids in an adequate or appropriate amount, thus affecting the clinical medication strategy and the quality of treatment for patients. The prediction of adverse reactions to opioids is one of the most concerned problems in clinical practice. At present, the correlation between gene polymorphism and the efficacy of opiates has been widely studied and preliminarily confirmed, but the research on the effect of gene polymorphism on the adverse reactions of opiates is relatively limited. Existing studies have made encouraging progress in predicting the incidence and severity of adverse opioid reactions and clinical management by using genetic testing, but most of these studies are single-center, small-sample clinical studies or animal experiments, which have strong limitations. When the same receptor or enzyme is studied by different experimental methods, different or even opposite conclusions can be drawn. These phenomena indicate that the correlation between gene polymorphism and adverse opioid reaction still needs further research and demonstration. At present, it is still too early to use genetic testing to predict opioid adverse reactions in clinic. In this paper, the correlation between gene polymorphism and adverse opioid reactions and a small number of clinical applications were reviewed in terms of pharmacokinetics and pharmacodynamics, in order to provide some suggestions for future research and clinical drug decision making.

PMID:35429333 | DOI:10.1007/s40122-022-00374-0

Pharmacotherapy. 2022 Apr 16. doi: 10.1002/phar.2684. Online ahead of print.

ABSTRACT

Dexmedetomidine is titrated to achieve sedation in the pediatric and cardiovascular intensive care units (PICU, CVICU). In adults, dexmedetomidine response has been associated with an ADRA2A polymorphism (rs1800544); CC genotype is associated with an increased sedative response compared to GC and GG. To date, this has not been studied in children. We conducted a pilot study to determine if ADRA2A genotype is associated with dexmedetomidine response in critically ill children. Forty intubated PICU or CVICU patients who received dexmedetomidine as a continuous infusion for at least 2 days were genotyped for ADRA2A with a custom designed TaqMan® Assay. Ten (25%) patients were wildtype (GG), 15 (37.5%) were heterozygous (GC), and 15 (37.5%) were homozygous variant (CC). The maximum dexmedetomidine doses (mCg/kg/hr) were not different between genotype groups CC (1, range 0.3-1.2), GC (1, 0.3-1.3), and GG (0.8, 0.3-1.2), (p=0.37); mean dexmedetomidine doses also were not different for these respective genotype groups CC (0.68, 0.24-1.07), GC (0.72, 0.22-0.98), and GG (0.58, 0.3-0.94), (p=0.67). These findings did not confirm results from adult studies where ADRA2A polymorphisms correlate with dexmedetomidine response, therefore highlighting the need for pediatric studies to validate pharmacogenomics (PGx) findings in adults prior to implementation in pediatrics.

PMID:35429176 | DOI:10.1002/phar.2684

Clin Pharmacol Ther. 2022 Apr 16. doi: 10.1002/cpt.2612. Online ahead of print.

ABSTRACT

The ABCD-GENE score was developed to identify patients at risk for diminished antiplatelet effects with clopidogrel after percutaneous coronary intervention (PCI) and utilizes Age, Body mass index, Chronic kidney disease, Diabetes and CYP2C19 GENEtic variants. The objective of this study was to validate the ability of ABCD-GENE score to predict risk for atherothrombotic events in a diverse, real-world population of clopidogrel-treated PCI patients who received clinical CYP2C19 genotyping to guide antiplatelet therapy. A total of 2341 adult patients who underwent PCI, were genotyped for CYP2C19, and received treatment with clopidogrel across four institutions were included (mean age 64±12 years, 35% female, 20% Black). The primary outcome was major atherothrombotic events, defined as the composite of all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina within 12 months following PCI. Major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, myocardial infarction, ischemic stroke, or stent thrombosis, was assessed as the secondary outcome. Outcomes were compared between patients with an ABCD-GENE score ≥10 versus <10. The risk of major atherothrombotic events was higher in patients with an ABCD-GENE score ≥10 (n=505) versus <10 (n=1836; 24.6 versus 14.7 events per 100 patient-years, adjusted hazard ratio (HR), 1.66; 95% CI, 1.23-2.25; p<0.001). The risk for MACE was also higher among patients with a score ≥10 versus <10 (16.7 versus 10.1 events per 100 patient-years, adjusted HR, 1.59; 95% CI, 1.11-2.30; p=0.013). Our diverse, real-world data demonstrate diminished clopidogrel effectiveness in PCI patients with an ABCD-GENE score ≥10.

PMID:35429163 | DOI:10.1002/cpt.2612

Res Social Adm Pharm. 2022 Apr 9:S1551-7411(22)00123-1. doi: 10.1016/j.sapharm.2022.04.002. Online ahead of print.

ABSTRACT

INTRODUCTION: Pharmacogenomics (PGx) uses DNA to predict an individual's response to a medicine. Internationally, the delivery of PGx is frequently via community pharmacies, who can take a saliva sample, send it off for analysis and contribute to the final clinical decision making. No similar service has been set up in England.

AIM: To identify the barriers, enablers and Behaviour Change Techniques (BCTs) to inform a service specification for delivery of a community pharmacy based PGx service in England.

METHOD: This qualitative co-design research study was designed in three stages using action-orientated theory-based frameworks and tools. The first stage mapped perceptions, barriers to, and enablers for, implementing a community pharmacy based PGx service, derived from a previous qualitative study onto the Theoretical Domains Framework (TDF). The second stage utilised the Theory and Techniques Tool (TTT) to link the identified TDF domain with corresponding BCTs. The final stage used a Delphi survey followed by a Nominal Group Technique session to facilitate community pharmacists selecting their preferred BCTs to include in a service specification.

RESULTS: The existing qualitative data were mapped onto six TDF domains: Knowledge, Skills, Social/professional role and identity, Optimism, Beliefs about Consequences, and Environmental context and resources. Forty-six BCTs were identified using the TTT and the consensus methods resulted in nine selected BCTs: Review outcome goal(s), Feedback on behaviour, Instruction on how to perform behaviour, Demonstration of the behaviour, Credible source and Adding objects to the environment.

CONCLUSION: Using a range of action-orientated theoretical frameworks and tools, pragmatic BCTs have been identified as part of a co-design process, which can now be used as the basis to develop a service specification for the implementation of a PGx testing service in a community pharmacy setting in England.

PMID:35428579 | DOI:10.1016/j.sapharm.2022.04.002

Drug Resist Updat. 2022 Apr 5;62:100832. doi: 10.1016/j.drup.2022.100832. Online ahead of print.

ABSTRACT

Small-molecule kinase inhibitors (SMKIs) represent the cornerstone in the treatment of non-small cell lung cancer (NSCLC) patients harboring genetic driver mutations. Because of the introduction of SMKIs in the last decades, treatment outcomes have drastically improved. Their treatment efficacy, the development of drug resistance as well as untoward toxicity, all suffer from large patient variability. This variability can be explained, at least in part, by their oral route of administration, which leads to a large inter- and intra-patient variation in bioavailability based on differences in absorption. Additionally, drug-drug and food-drug interactions are frequently reported. These interactions could modulate SMKI efficacy and/or untoward toxicity. Furthermore, the large patient variability could be explained by the presence of germline variations in target receptor domains, metabolizing enzymes, and drug efflux transporters. Knowledge about these predictor variations is crucial for handling SMKIs in clinical practice, and for selecting the most optimal therapy. In the current review, the literature search included all SMKIs registered for locally-advanced and metastatic NSCLC by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) until March 24th, 2022. The BIM deletion showed a significantly decreased PFS and OS for East-Asian patients treated with gefitinib, and has the potential to be clinically relevant for other SMKIs as well. Furthermore, we expect most relevance from the ABCG2 34 G>A and CYP1A1 variations during erlotinib and gefitinib treatment. Pre-emptive CYP2D6 testing before starting gefitinib treatment can also be considered to prevent severe drug-related toxicity. These and other germline variations are summarized and discussed, in order to provide clear recommendations for clinical practice.

PMID:35427871 | DOI:10.1016/j.drup.2022.100832

Semin Cancer Biol. 2022 Apr 12:S1044-579X(22)00096-7. doi: 10.1016/j.semcancer.2022.04.002. Online ahead of print.

ABSTRACT

Epidermal Growth Factor Receptor (EGFR) enacts major roles in the maintenance of epithelial tissues. However, when EGFR signaling is altered, it becomes the grand orchestrator of epithelial transformation, and hence one of the most world-wide studied tyrosine kinase receptors involved in neoplasia, in several tissues. In the last decades, EGFR-targeted therapies shaped the new era of precision-oncology. Despite major advances, the dream of converting solid tumors into a chronic disease is still unfulfilled, and long-term remission eludes us. Studies investigating the function of this protein in solid malignancies have revealed numerous ways how tumor cells dysregulate EGFR function. Starting from preclinical models (cell lines, organoids, murine models) and validating in clinical specimens, EGFR-related oncogenic pathways, mechanisms of resistance, and novel avenues to inhibit tumor growth and metastatic spread enriching the therapeutic portfolios, were identified. Focusing on non-small cell lung cancer (NSCLC), where EGFR mutations are major players in the adenocarcinoma subtype, we will go over the most relevant discoveries that led us to understand EGFR and beyond, and highlight how they revolutionized cancer treatment by expanding the therapeutic arsenal at our disposal.

PMID:35427766 | DOI:10.1016/j.semcancer.2022.04.002

Toxicol In Vitro. 2022 Apr 12:105357. doi: 10.1016/j.tiv.2022.105357. Online ahead of print.

ABSTRACT

Gastric cancer (GC) is among the deadliest cancers worldwide despite available therapies, highlighting the need for novel therapies and pharmacological agents. Metabolic deregulation is a potential study area for new anticancer targets, but the in vitro metabolic studies are controversial, as different ranges of glucose used in the culture medium can influence results. In this study, we evaluated cellular viability, glucose uptake, and LDH activity in gastric cell lines when exposed to different glucose concentrations: high (HG, 25 mM), low (LG, 5.5 mM), and free (FG, 0 mM) glucose mediums. Moreover, we evaluated how glucose variations may influence cellular phenotype and the expression of genes related to epithelial-mesenchymal transition (EMT), metabolism, and cancer development in metastatic GC cells (AGP-01). Results showed that in the FG metastatic cells evidenced higher viability when compared with other cell lines and that when exposed to either LG or HG mediums most of the phenotypic assays did not differ. However, cells exposed to LG increased colony formation and mRNA levels of metabolic-related genes when compared to HG medium. Our results recommend LG medium to metabolic studies once glucose concentration is closer to physiological levels. These findings are important to point out new relevant targets in metabolic reprogramming that can be alternatives to current chemotherapies in patients with metastatic GC.

PMID:35427737 | DOI:10.1016/j.tiv.2022.105357

J Biomol Struct Dyn. 2022 Apr 15:1-12. doi: 10.1080/07391102.2022.2062785. Online ahead of print.

ABSTRACT

CYP2A6 is a very important enzyme that plays a crucial role in nicotine compounds and is responsible for the metabolism of more than 3% drugs of total metabolized drugs by the CYP family and reported as one of very important pharmacogenes. CYP2A6 is highly polymorphic in nature and reported with more than 40 variants, most of these variants are SNPs originated and population specific. It has been well observed and reported that the presence of these population-specific non-synonymous SNPs in CYP2A6 alters the rate of drug metabolism and as a functional consequence, drugs produce an abnormal response. Though genomics and pharmacogenomics studies are there, very less is known about the structural effects of these SNPs on molecular-interaction and folding of CYP2A6. To fill the knowledge gap, SNPs based four variants, i.e., CYP2A6*2, CYP2A6*18, CYP2A6*21, and CYP2A6*35, which are frequently reported in the South Asian population, were considered for the study. Coumarin (DB04665), a well reported drug, is considered as a model substance, and the effect of all four variants on 'CYP2A6*-coumarin' complex was studied. MD simulation-based analysis (at 200 ns) was performed and comparative analysis with respect to wild type 'CYP2A6-coumarin' complex was done. Though observation didn't find any global effect on complete complex but found some crucial minor-local alteration in interaction and folding process. It is assumed that the change due to SNPs in the single amino acid did not bring global change in physiochemical properties of CYP2A6* but caused local-trivial changes which are very crucial for its metabolic activity.Communicated by Ramaswamy H. Sarma.

PMID:35427216 | DOI:10.1080/07391102.2022.2062785

Front Pharmacol. 2022 Mar 29;13:833174. doi: 10.3389/fphar.2022.833174. eCollection 2022.

ABSTRACT

Background: It is imperative to identify drugs that allow treating symptoms of severe COVID-19. Respiratory failure is the main cause of death in severe COVID-19 patients, and the host inflammatory response at the lungs remains poorly understood. Methods: Therefore, we retrieved data from post-mortem lungs from COVID-19 patients and performed in-depth in silico analyses of single-nucleus RNA sequencing data, inflammatory protein interactome network, and shortest pathways to physiological phenotypes to reveal potential therapeutic targets and drugs in advanced-stage COVID-19 clinical trials. Results: Herein, we analyzed transcriptomics data of 719 inflammatory response genes across 19 cell types (116,313 nuclei) from lung autopsies. The functional enrichment analysis of the 233 significantly expressed genes showed that the most relevant biological annotations were inflammatory response, innate immune response, cytokine production, interferon production, macrophage activation, blood coagulation, NLRP3 inflammasome complex, and the TLR, JAK-STAT, NF-κB, TNF, oncostatin M signaling pathways. Subsequently, we identified 34 essential inflammatory proteins with both high-confidence protein interactions and shortest pathways to inflammation, cell death, glycolysis, and angiogenesis. Conclusion: We propose three small molecules (baricitinib, eritoran, and montelukast) that can be considered for treating severe COVID-19 symptoms after being thoroughly evaluated in COVID-19 clinical trials.

PMID:35422702 | PMC:PMC9002106 | DOI:10.3389/fphar.2022.833174

Endocr Pract. 2022 Apr 11:S1530-891X(22)00480-3. doi: 10.1016/j.eprac.2022.04.002. Online ahead of print.

ABSTRACT

OBJECTIVE: We aimed to assess treatment outcomes and disease control status in patients with acromegaly by patient- and clinician-reported outcome tools and to analyse correlations among different components of both tools.

METHODS: Cross-sectional study included 72 patients from the national referral centre with a median follow up of 8 (5-12) years. Baseline SAGIT at the diagnosis was determined retrospectively, while the follow up SAGIT and AcroQoL results were assessed at the most recent visit and by additional telephone interviews.

RESULTS: All SAGIT subscores significantly lowered from baseline to follow up (global score from 14 to 4 (P<0.001)). SAGIT at baseline did not discriminate the current disease control status. However, higher baseline SAGIT score and subscore T were associated with uncontrolled disease after the first-line treatment. Diagnostic delay correlated with baseline S, A, G, and global SAGIT scores. At follow up, global SAGIT score discriminated between cured/controlled and uncontrolled groups (4 vs. 6 (P=0.007)). AcroQoL score was 69.3, with »Personal relations subscale« being the least and »Physical scale« the most affected. There was no difference in AcroQoL between patients classified as uncontrolled or cured/controlled. At baseline and follow up, there were significant negative correlations between S and A subscores and AcroQoL. Higher BMI, presence of swelling, joint symptoms, headaches, sleep apnea, and hypertension significantly impaired QoL.

CONCLUSION: Our results emphasised the complementary nature of patient- and clinician-reported outcome tools in acromegaly management. We identified modifiable signs, symptoms, and comorbidities as treatment targets that might help clinicians improve QoL in this population.

PMID:35421593 | DOI:10.1016/j.eprac.2022.04.002

PLoS One. 2022 Apr 14;17(4):e0266590. doi: 10.1371/journal.pone.0266590. eCollection 2022.

ABSTRACT

BACKGROUND: Antidepressant use has been associated with increased fall risk. Antidepressant-related adverse drug reactions (e.g. orthostatic hypotension) depend partly on genetic variation. We hypothesized that candidate genetic polymorphisms are associated with fall risk in older antidepressant users.

METHODS: The association between antidepressant use and falls was cross-sectionally investigated in a cohort of Dutch older adults by logistic regression analyses. In case of significant interaction product term of antidepressant use and candidate polymorphism, the association between the variant genotype and fall risk was assessed within antidepressant users and the association between antidepressant use and fall risk was investigated stratified per genotype. Secondly, a look-up of the candidate genes was performed in an existing genome-wide association study on drug-related falls in antidepressant users within the UK Biobank. In antidepressant users, genetic associations for our candidate polymorphisms for fall history were investigated.

RESULTS: In antidepressant users(n = 566), for rs28371725 (CYP2D6*41) fall risk was decreased in TC/variant allele carriers compared to CC/non-variant allele carriers (OR = 0.45, 95% CI 0.26-0.80). Concerning rs1057910 (CYP2C9*3), fall risk was increased in CA/variant allele carriers compared to AA/non-variant allele carriers (OR = 1.95, 95% CI 1.17-3.27). Regarding, rs1045642 (ABCB1), fall risk was increased in AG/variant allele carriers compared to GG/non-variant allele carriers (OR = 1.69, 95% CI 1.07-2.69). Concerning the ABCB1-haplotype (rs1045642/rs1128503), fall risk was increased in AA-AA/variant allele carriers compared to GG-GG/non-variant allele carriers (OR = 1.86, 95% CI 1.05-3.29). In the UK Biobank, in antidepressant users(n = 34,000) T/variant-allele of rs28371725 (CYP2D*41) was associated with increased fall risk (OR = 1.06, 95% CI 1.01-1.12). G/non-variant-allele of rs4244285 (CY2C19*2) was associated with decreased risk (OR = 0.96, 95% CI 0.92-1.00).

CONCLUSION: This is the first study showing that certain genetic variants modify antidepressant-related fall risk. The results were not always consistent across the studies and should be validated in a study with a prospective design. However, pharmacogenetics might have value in antidepressant (de)prescribing in falls prevention.

PMID:35421149 | DOI:10.1371/journal.pone.0266590

Br J Clin Pharmacol. 2022 Apr 14. doi: 10.1111/bcp.15353. Online ahead of print.

ABSTRACT

AIM: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy in humans, can cause acute hemolysis resulting from exposure to certain medications, chemicals, infections and fava beans. Rasburicase, used to manage elevated uric acid levels in the oncologic emergency of tumor lysis syndrome, is one such drug. The Food & Drug Administration (FDA) recommends testing of G6PD status prior to rasburicase administration for patients at higher risk for G6PD deficiency.

METHODS: We performed a retrospective chart review of all oncology patients for whom a semi-quantitative biochemical test for detecting G6PD deficiency was performed prior to rasburicase administration over a 2.5 year period, in a large academic metropolitan hospital.

RESULTS: We identified 16 out of 260 tested individuals as G6PD-deficient (6.1%), including six females. On average, test results were electronically available to health-care providers within 4 hours of sample collection, with most results available within 2-3 hours. Four G6PD-deficient patients developed elevated uric acid levels. Two of the G6PD-deficient patients were treated with rasburicase, and subsequently developed hemolysis, which was appropriately managed.

CONCLUSION: In summary, by providing information about G6PD status with a rapid turnaround time, we have taken a significant step towards personalized medicine in our institution. In spite of the test implementation, two out of four G6PD deficient patients, who were no longer candidates for rasburicase use, still received the drug, highlighting the need for improved provider education.

PMID:35419830 | DOI:10.1111/bcp.15353

Transl Clin Pharmacol. 2022 Mar;30(1):24-36. doi: 10.12793/tcp.2022.30.e4. Epub 2022 Mar 9.

ABSTRACT

Pediatric patients with coronavirus disease 2019 (COVID-19) are increasing, and severe cases such as multisystem inflammatory syndrome are being reported. Nafamostat, a repurposing drug, is currently being explored for the treatment of COVID-19 in adults. However, the data supporting its exposure in pediatrics remains scarce. Physiologically-based pharmacokinetic (PBPK) modeling enables the prediction of drug exposure in pediatrics based on ontogeny of metabolic enzymes and age dependent anatomical and physiological changes. The study aimed to establish a PBPK model of nafamostat in adults, then scale the adult PBPK model to children for predicting pediatric exposures of nafamostat and an optimal weight-based nafamostat dose in pediatric population. The developed model adequately described adult exposure data in healthy volunteers following i.v. administration with three doses (10, 20, and 40 mg). Scaling adult PBPK models to five pediatric groups predicted that as age advances from neonate to adult, the exposure of nafamostat slightly increased from neonate to infant, steadily decreased from infant to child, and then increased from child to adult after the administration of 0.2 mg/kg/h for 14 days, a dosing regimen being conducted in a clinical trial for COVID-19. Based on the fold change of predicted area under the curve for the respective pediatric group over those of adults, weight-based dosages for each pediatric group may be suggested. The novel PBPK model described in this study may be useful to investigate nafamostat pharmacokinetics in a pediatric subgroup further.

PMID:35419314 | PMC:PMC8979760 | DOI:10.12793/tcp.2022.30.e4

Anal Chem. 2022 Apr 13. doi: 10.1021/acs.analchem.2c00446. Online ahead of print.

ABSTRACT

The clinical actionability of circulating tumor DNA requires sensitive detection methods with a short turnaround time. In the PADA-1 phase 3 trial (NCT03079011), metastatic breast cancer patients treated with an aromatase inhibitor and palbociclib were screened every 2 months for activating ESR1 mutations in blood (bESR1mut). We report the feasibility of the droplet digital polymerase chain reaction (ddPCR) and cross-validation with next-generation sequencing (NGS). bESR1mut testing was centralized in two platforms using the same ddPCR assay. Results were reported as copies/mL of plasma and mutant allele frequency (MAF). We analyzed 200 positive ddPCR samples with an NGS assay (0.5-1% sensitivity). Overall, 12,552 blood samples were collected from 1017 patients from 83 centers. Among the 12,525 available samples with ddPCR results, 11,533 (92%) were bESR1mut-negative. A total of 267 patients newly displayed bESR1mut (26% patients/2% samples) with a median copy number of 14/mL (range: 4-1225) and a median MAF of 0.83% (0.11-35), 648 samples (20% patients/5% samples) displayed persistent bESR1mut, and 77 (<1%) samples encountered a technical failure. The median turnaround time from blood drawing to result notification was 13 days (Q1:9; Q3:21 days). Among 200 ddPCR-positive samples tested, NGS detected bESR1mut in 168 (84%); 25 of the 32 cases missed by NGS had low MAF and/or low coverage. In these 200 samples, bESR1mut MAF by both techniques had an excellent intraclass correlation coefficient (ICC = 0.93; 95% CI [0.85; 0.97]). These results from a large-scale trial support the feasibility and accuracy of real-time bESR1mut tracking by ddPCR, opening new opportunities for therapeutic interventions.

PMID:35416669 | DOI:10.1021/acs.analchem.2c00446

Biochem Biophys Res Commun. 2022 Apr 6;609:62-68. doi: 10.1016/j.bbrc.2022.04.007. Online ahead of print.

ABSTRACT

RNF213, a susceptibility gene for moyamoya disease, is associated with stress responses to various stressors. We previously reported that Rnf213 knockout (KO) mitigated endoplasmic reticulum (ER) stress-induced diabetes in the Akita mouse model of diabetes. However, the role of RNF213 in ER stress regulation remains unknown. In the present study, RNF213 knockdown significantly inhibited the upregulation of ER stress markers (CHOP and spliced XBP1) by chemical ER stress-inducers in HeLa cells. Levels of SEL1L, a critical molecule in ER-associated degradation (ERAD), were increased by RNF213 knockdown, and SEL1L knockdown prevented the inhibitory effect of RNF213 suppression on ER stress in HeLa cells, indicating SEL1L involvement in this inhibition of ER stress. SEL1L upregulation was also confirmed in pancreatic islets of Rnf213 KO/Akita mice and in Rnf213 KO mouse embryonic fibroblasts. Additionally, RNF213 suppression increased levels of HRD1, which forms a complex with SEL1L to degrade misfolded protein in cells under ER stress. In conclusion, we demonstrate that RNF213 depletion inhibits ER stress possibly through elevation of the SEL1L-HRD1 complex, thereby promoting ERAD in vitro and in vivo.

PMID:35413541 | DOI:10.1016/j.bbrc.2022.04.007

Curr Neuropharmacol. 2022 Apr 11. doi: 10.2174/1570159X20666220411095508. Online ahead of print.

ABSTRACT

In this Editorial we discuss the neurobiological processes underlying early emergence of awareness that we term the "when" and "how" the mind comes to live inside the body. We describe an accumulative developmental process starting during embryonic life and continuing to fetal and postnatal development, of coupling of heart rate, body movements and sleep states on the behavioral level with underlying mechanisms on the structural, functional, cellular and molecular levels. A developmental perspective is proposed based on Perceptual Control Theory (PCT). This includes a developing sequence of modules starting from early sensing of neural intensities to early manifestation of human mindful capacities. We also address pharmacological treatments administered to preterm infants, which may interfere with this development and highlight the need to consider this potential "side effect" of current pharmaceuticals when developing novel pharmacogenomic treatments.

PMID:35410607 | DOI:10.2174/1570159X20666220411095508

Curr Med Res Opin. 2022 Apr 12:1-24. doi: 10.1080/03007995.2022.2061710. Online ahead of print.

ABSTRACT

BACKGROUND: The role of personalised treatment approaches, including those based on genetic testing are increasingly enabling informed decision making to improve health outcomes. Research involving Indigenous Australians has been lagging behind, although this population experiences higher prevalence of chronic disease and mental health disorders.

METHODS: Using community-based participatory research principles, this study purposefully interviewed participants with a diagnosed common mental disorder and a comorbid chronic disease condition. Inductive thematic analysis on semi-structured interviews with consenting participants (n = 48). Common themes and analytical domains were identified that provided a semantic understanding shared by participants.

RESULTS: Five emerging themes were identified, primarily focusing on: 1. the perceptions and understanding of genetics research; 2. culturally appropriate conduct of genetics research; 3. the role of indigenous-led genetics research; 4. future prospects of genetics research; and 5. the importance of genetics research for patients with mental and physical health comorbidities.

CONCLUSION: Indigenous Australians are under-represented in pharmacogenomics research despite well-documented epidemiological research demonstrating that Indigenous people globally experience greater risk of developing certain chronic diseases and more severe disease progression. Positive outcomes from this study highlight the importance of not only involving Indigenous participants, but providing leadership and governance opportunities for future genetics research.

PMID:35410562 | DOI:10.1080/03007995.2022.2061710

Mol Cancer. 2022 Apr 11;21(1):98. doi: 10.1186/s12943-022-01561-5.

ABSTRACT

The tumor microenvironment (TME) is essential for immune escape by tumor cells. It plays essential roles in tumor development and metastasis. The clinical outcomes of tumors are often closely related to individual differences in the patient TME. Therefore, reprogramming TME cells and their intercellular communication is an attractive and promising strategy for cancer therapy. TME cells consist of immune and nonimmune cells. These cells need to be manipulated precisely and safely to improve cancer therapy. Furthermore, it is encouraging that this field has rapidly developed in recent years with the advent and development of gene editing technologies. In this review, we briefly introduce gene editing technologies and systematically summarize their applications in the TME for precision cancer therapy, including the reprogramming of TME cells and their intercellular communication. TME cell reprogramming can regulate cell differentiation, proliferation, and function. Moreover, reprogramming the intercellular communication of TME cells can optimize immune infiltration and the specific recognition of tumor cells by immune cells. Thus, gene editing will pave the way for further breakthroughs in precision cancer therapy.

PMID:35410257 | DOI:10.1186/s12943-022-01561-5

Int J Mol Sci. 2022 Apr 4;23(7):4003. doi: 10.3390/ijms23074003.

ABSTRACT

The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine-threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, we showed that arginine increased Pkcδ phosphorylation at Thr505, which is critical for Pkcδ activation. Interestingly, the knockdown of Pkcδ in InR1G9 cells reduced arginine-induced glucagon secretion. Moreover, arginine-induced glucagon secretions were decreased in αPkcδKO mice and islets from αPkcδKO mice. Pkcδ is essential for arginine-induced glucagon secretion in pancreatic α-cells. Therefore, this study may contribute to the elucidation of the molecular mechanism of amino acid-induced glucagon secretion and the development of novel antidiabetic drugs targeting Pkcδ and glucagon.

PMID:35409362 | DOI:10.3390/ijms23074003

Int J Mol Sci. 2022 Mar 30;23(7):3830. doi: 10.3390/ijms23073830.

ABSTRACT

The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients' prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones' survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host's immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.

PMID:35409190 | DOI:10.3390/ijms23073830