Cancer Lett. 2021 Nov 22:S0304-3835(21)00589-9. doi: 10.1016/j.canlet.2021.11.022. Online ahead of print.

ABSTRACT

The cancer cell mitochondrion is functionally different from that in normal cells and could be targeted to develop novel experimental therapeutics. The aryl-ureido fatty acid CTU (16({[4-chloro-3-(trifluoromethyl)phenyl]-carbamoyl}amino)hexadecanoic acid) is the prototype of a new class of mitochondrion-targeted agents that kill cancer cells. Here we show that CTU rapidly depolarized the inner mitochondrial membrane, selectively inhibited complex III of the electron transport chain and increased reactive oxygen species (ROS) production. From RNA-seq analysis, endoplasmic reticulum (ER)-stress was a major activated pathway in CTU-treated cells and in MDA-MB-231 tumor xenografts from CTU-treated nu/nu mice. Mitochondrion-derived ROS activated the PERK-linked ER-stress pathway and induced the BH3-only protein NOXA leading to outer mitochondrial membrane (OMM) disruption. The lipid peroxyl scavenger α-tocopherol attenuated CTU-dependent ER-stress and apoptosis which confirmed the critical role of ROS. Oleic acid protected against CTU-mediated apoptosis by activating Mcl-1 expression, which increased NOXA sequestration and prevented OMM disruption. Taken together, CTU both uncouples mitochondrial electron transport and activates ROS production which promotes ER-stress-dependent OMM disruption and tumor cell death. Dual-mitochondrial targeting agents like CTU offer a novel approach for development of new anti-cancer therapeutics.

PMID:34822928 | DOI:10.1016/j.canlet.2021.11.022

Toxics. 2021 Nov 4;9(11):292. doi: 10.3390/toxics9110292.

ABSTRACT

Pharmacogenetics analyzes the individual behavior of DNA genes after the administration of a drug. Pharmacogenetic research has been implemented in recent years thanks to the improvement in genome sequencing techniques and molecular genetics. In addition to medical purposes, pharmacogenetics can constitute an important tool for clarifying the interpretation of toxicological data in post-mortem examinations, sometimes crucial for determining the cause and modality of death. The purpose of this systematic literature review is not only to raise awareness among the forensic community concerning pharmacogenetics, but also to provide a workflow for forensic toxicologists to follow in cases of unknown causes of death related to drug use/abuse. The scientific community is called on to work hard in order to supply evidence in forensic practice, demonstrating that this investigation could become an essential tool both in civil and forensic contexts. The following keywords were used for the search engine: (pharmacogenetics) AND (forensic toxicology); (pharmacogenetics) AND (post-mortem); (pharmacogenetics) AND (forensic science); and (pharmacogenetics) AND (autopsy). A total of 125 articles were collected. Of these, 29 articles were included in this systematic review. A total of 75% of the included studies were original articles (n = 21) and 25% were case reports (n = 7). A total of 78% (n = 22) of the studies involved deceased people for whom a complete autopsy was performed, while 22% (n = 6) involved people in good health who were given a drug with a subsequent pharmacogenetic study. The most studied drugs were opioids (codeine, morphine, and methadone), followed by antidepressants (tricyclic antidepressants and venlafaxine). Furthermore, all studies highlighted the importance of a pharmacogenetics study in drug-related deaths, especially in cases of non-overdose of drugs of abuse. This study highlights the importance of forensic pharmacogenetics, a field of toxicology still not fully understood, which is of great help in cases of sudden death, deaths from overdose, deaths after the administration of a drug, and also in cases of complaint of medical malpractice.

PMID:34822683 | DOI:10.3390/toxics9110292

Pharmacogenomics. 2021 Nov 25. doi: 10.2217/pgs-2021-0142. Online ahead of print.

ABSTRACT

Tweetable abstract Warfarin will remain in use for a long time to come, thus inclusion of African populations in pharmacogenomics is essential to be able to identify all possible biomarkers that are potential predictors for warfarin drug response.

PMID:34821506 | DOI:10.2217/pgs-2021-0142

Drug Metab Pers Ther. 2021 Jun 7;36(4):289-294. doi: 10.1515/dmpt-2021-0121.

ABSTRACT

OBJECTIVES: Pharmacogenomics (PGx) testing optimizes pharmacotherapy and reduces interindividual variation in drug responses. However, it is still not implemented in clinical practice in the West Bank of Palestine (WBP). The aim of this study was to determine the need for PGx education and testing among physicians from different specialties in WBP.

METHODS: This study used a cross-sectional survey that was administered to 381 physicians from different cities in WBP. The questionnaire consisted of 27 closed-ended questions that evaluate the exposure and attitude toward PGx education, the role of PGx testing in clinical practice, and the capabilities of physicians in PGx testing.

RESULTS: It was found that exposure to PGx education is low, with most of the respondents (81.1%) answering that PGx was not an integral part of their medical education. The majority (>90%) of the participants agreed that PGx should be included in the medical school curriculum. It was also found that 58.5% of the participants agreed that PGx testing is relevant to their current clinical practice. In addition, most of the participant physicians (>60%) think that they are currently not capable of prescribing and making decisions for pharmacotherapy based on PGx testing.

CONCLUSIONS: It is concluded that there is a high need for PGx education and implementation in clinical practice in WBP. We recommend adding PGx courses to the curricula of medical schools and going forward with the implementation of PGx testing in clinical practice in WBP.

PMID:34821126 | DOI:10.1515/dmpt-2021-0121

Front Oncol. 2021 Nov 8;11:686308. doi: 10.3389/fonc.2021.686308. eCollection 2021.

ABSTRACT

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer whose incidence is growing parallel to the lengthening of the average lifespan. Cemiplimab, an antiPD-1 monoclonal antibody, is the first approved immunotherapy for patients with locally advanced CSCC (laCSCC) or metastatic CSCC (mCSCC) thanks to phase I and II studies showing high antitumor activity and good tolerability. Nevertheless, at present, very few data are available regarding cemiplimab in real-life experience and in frail, elderly, and immunosuppressed patients as well as regarding biomarkers able to predict response so as to guide therapeutic choices.

PATIENTS AND METHODS: We built a retroprospective cohort study including 30 non-selected patients with laCSCC (25) and mCSCC (five) treated with cemiplimab from August 2019 to November 2020. Clinical outcomes, toxicity profile, and correlations with disease, patients, and peripheral blood parameters are explored.

RESULTS: The median age was 81 years (range, 36-95), with 24 males and five patients having an immunosuppressive condition, while the frailty prevalence was 83% based on index derived from age, Eastern Cooperative Oncology Group performance status, and Charlson Comorbidity Index. We reported 23 responses (76.7%) with nine complete responses (30%). A statistically significant higher response rate was observed in head and neck primary tumors and in patients with hemoglobin level >12 g/dl. No difference was observed with respect to frailty, median age, sex, and body mass index. The baseline low neuthophil/lymphocyte ratio and low platelet/lymphocyte ratio resulted to be also correlated with a better response. Moreover, lymphocyte, neutrophil, and monocyte behaviors had an opposite trend in responders and non-responders. An overall response was reported in four of five immunosuppressed patients. Seventeen patients (57.6%) have an ongoing response and are still alive. Six responders had interrupted treatment (two for toxicity and four for personal choice) but maintained their response. The treatment was well tolerated by the majority of patients. The most common adverse events were fatigue in seven patients (23.3%) and skin toxicity in 10 patients (33.3%), including pruritus in six patients, rash in three patients, and bullous erythema in one patient.

CONCLUSIONS: In our real-life experience, cemiplimab showed a high antitumor activity with acceptable safety profile similar to those in trials with selected patients. Moreover, its antitumor activity resulted to be not impaired in very elderly patients and in those with immunocompromised status.

PMID:34820323 | PMC:PMC8606572 | DOI:10.3389/fonc.2021.686308

Sex Med. 2021 Nov 21;10(1):100455. doi: 10.1016/j.esxm.2021.100455. Online ahead of print.

ABSTRACT

INTRODUCTION: Patients with erectile dysfunction induced by diabetes mellitus (DMED) show a poor effect rate for oral phosphodiesterase type 5 inhibitors (PDE5is). Therefore, the new therapeutic strategy is necessary in patients with DMED.

AIM: To investigate whether Tetrathiomolybdate (TM) supplementation could ameliorate DMED by activation of eNOS.

METHODS: Twenty-four diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ) and the other 6 normal rats constituted the control group. Eight weeks later, the erectile function of rats was assessed with an apomorphine test. Only some rats with DMED were treated with TM orally every day for 4 weeks; the other rats remained in the same condition for 4 weeks. After 1 week washout, the erectile function of rats in each group was evaluated. Then, the serum concentration of IL-6 and histologic changes of corpus cavernosum were measured.

MAIN OUTCOME MEASURE: Erectile function was measured after DMED rats treated with TM. The cavernosum level of Ceruloplasmin (Cp), eNOS, endothelial cell content, corporal fibrosis, apoptosis rate and the serum level of IL-6 were also assayed.

RESULTS: Erectile function in the DMED group was significantly impaired compared with the control group and was partly, but significantly, improved in the DMED+TM group. The DMED group showed upregulation of Cp and inhibition of eNOS, but the inhibition was partly reversed in the DMED+TM group. The DMED group showed serious corporal fibrosis. However, TM supplementation partly increased the ratio of smooth muscle to collagen, decreased the ratio of apoptosis. What's more, gavage administration of TM profoundly decreased the serum level of IL-6 in DMED rats.

CONCLUSION: TM supplementation inhibits endothelial dysfunction, corporal fibrosis, and systemic inflammation, ultimately leading to partial improvement of DMED in rats. Yin Y, Peng J, Zhou J, et al., Tetrathiomolybdate Partially Alleviates Erectile Dysfunction of Type 1 Diabetic Rats Through Affecting Ceruloplasmin/eNOS and Inhibiting Corporal Fibrosis and Systemic Inflammation. Sex Med 2021;XX:XXXXXX.

PMID:34818604 | DOI:10.1016/j.esxm.2021.100455

Pharmacogenomics. 2021 Nov 24. doi: 10.2217/pgs-2021-0126. Online ahead of print.

ABSTRACT

Aim: Phenytoin (PHT) is a common anticonvulsant agent known for inducing severe cutaneous adverse reactions (SCARs). HLA-B*15:02 as a risk factor of PHT-induced SCARs was reported in numerous studies with inconsistent results. This meta-analysis aimed to establish pooling evidence of this association. Materials & methods: Pooled odds ratios (ORs) with 95% CIs were estimated using a random-effects model. Results: A total of 11 studies on 1389 patients, were included for the analyses. There was a significant association between HLA-B*15:02 and PHT-induced SCAR (pooled OR = 2.29, 95% CI: 1.25-4.19, p = 0.008). Furthermore, there was a significant association regarding Stevens-Johnson syndrome/toxic epidermal necrolysis (OR = 3.63, 95% CI: 2.15-6.13, p < 0.001) but no association regarding drug reaction with eosinophilia and systemic symptom. Conclusion: The results supported the recommendations of HLA-B*15:02 screening before treatment with PHT.

PMID:34816768 | DOI:10.2217/pgs-2021-0126

Heliyon. 2021 Nov 9;7(11):e08353. doi: 10.1016/j.heliyon.2021.e08353. eCollection 2021 Nov.

ABSTRACT

The growing interest in the possibilities of modulating macrophages in inflammatory diseases with therapeutic purpose has prompted the development of new approaches for the treatment of periodontitis. This randomized add-on open preliminary clinical study evaluated the short-term effects of L-arginine or L-ornithine as an adjuvant to scaling and root planing (SRP) in patients with chronic periodontitis.

MATERIALS AND METHODS: Seventy-five periodontitis patients were recruited and monitored clinically and immunologically at baseline (before SRP) and 30 ± 5 days after SRP. All patients were assigned by stratified randomization to SRP (SRP only, n = 25), Arg (SRP + L-arginine, n = 25) or Control (SRP + L-ornithine, n = 25) Group. The medicines were used according to available instructions for 10 and 15 days, respectively. During the study, all patients were on a stable diet, without changing their rations and regiments. As immunological monitoring immunohistochemical study of CD68+ and CD163 + single positive gingival macrophages for 5 patients per group in the same time-point was conducted. The data were statistically analyzed.

RESULTS: Reduction of periodontal pocket depth (PPD) and bleeding on probing (BoP) was observed in all groups, with significant between-group differences for BoP in the Arg Group (p < 0.0001) at 30 days. The SRP and Arg groups demonstrated nonsignificantly increased density of CD68+ and CD163 + cells. The Orn Group showed an increase in the density of CD68+ and CD163 + macrophages at intragroup (p = 0.0066 and p < 0.0001) and between-group levels (p = 0.001 and p < 0.0001), and these changes corresponded to clinical PPD and BoP reduction. In the Arg and Orn groups at 30 days, CD163 + macrophages significantly predominated over CD68+ (p = 0.013, p < 0.0001).

CONCLUSION: The use of L-arginine and L-ornithine as an adjunct to SRP promotes additional limited immunological benefit in the treatment of periodontitis. Metabolic stimulation with L-ornithine, but not L-arginine, is preferable for CD163+ Mφs subpopulation in periodontitis-affected gingiva.

PMID:34816043 | PMC:PMC8593455 | DOI:10.1016/j.heliyon.2021.e08353

Exp Ther Med. 2022 Jan;23(1):12. doi: 10.3892/etm.2021.10934. Epub 2021 Oct 28.

ABSTRACT

Long non-coding RNA (lncRNA) H19 is associated with proliferation, invasion and metastasis in numerous types of cancer. H19 lncRNA has been demonstrated to be an estrogen-inducible gene, the expression of which is significantly increased in tamoxifen (TAM)-resistant MCF-7 breast cancer cells. The aim of the present study was to investigate the role and molecular mechanism of lncRNA H19 in the development of TAM resistance. TAM-resistant MCF-7 (MCF-7R) cells were developed by the treatment of wild-type MCF-7 cells with 4-hydroxytamoxifen. Analysis of H19 expression in the cells indicated that upregulation of H19 contributed to the resistance of the MCF-7R cell line. Furthermore, when H19 was knocked down in the MCF-7R cells, the sensitivity to 4-hydroxytamoxifen was markedly restored. The results further demonstrated that N-acetyltransferase 1 (NAT1) may serve an important role in TAM-resistant cells, as NAT1 expression was notably downregulated in the MCF-7R cells but significantly elevated following the knockdown of H19. In addition, lower expression of NAT1 and higher expression of H19 were indicated to be associated with poor prognosis in patients with breast cancer treated with TAM. The results of bisulfite genomic sequencing PCR analysis indicated that the methylation rate of NAT1 in MCF-7R cells was significantly higher compared with that in MCF-7 cells, while the methylation rate of NAT1 in TAM-resistant cells transfected with small interfering RNA against H19 was significantly lower than that in the corresponding untransfected cells. Therefore, the present study suggests that the H19 gene regulates NAT1 expression in TAM-resistant cells via the mediation of NAT1 promoter methylation.

PMID:34815764 | PMC:PMC8593873 | DOI:10.3892/etm.2021.10934

Mol Cancer Ther. 2021 Nov 23:molcanther.MCT-21-0136-A.2021. doi: 10.1158/1535-7163.MCT-21-0136. Online ahead of print.

ABSTRACT

The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I interferon production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent anti-tumor activity. To exploit this mechanism, we synthesized a novel STING agonist, MSA-1, that activates both mouse and human STING with higher in vitro potency than cGAMP. Following intratumoral (IT) administration of MSA-1 to a panel of syngeneic mouse tumors on immune-competent mice, cytokine upregulation and its exposure were detected in plasma, other tissues, injected tumors, and noninjected tumors. This was accompanied by effective anti-tumor activity. Mechanistic studies in immune-deficient mice suggested that anti-tumor activity of IT-dosed STING agonists is in part due to necrosis and/or innate immune responses such as tumor necrosis factor α (TNF-α) activity, but development of a robust adaptive anti-tumor immunity is necessary for complete tumor elimination. Combination with PD-1 blockade in anti-PD-1-resistant murine models demonstrated that MSA-1 may synergize with checkpoint inhibitors but can also provide superior tumor control as a single agent. We show for the first time that potent cyclic dinucleotides can promote a rapid and stronger induction of the same genes eventually regulated by PD-1 blockade. This may have contributed to the relatively early tumor control observed with MSA-1. Taken together, these data strongly support the development of STING agonists as therapy for patients with aggressive tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 treatment by enhancing the anti-PD-1 immune profile.

PMID:34815361 | DOI:10.1158/1535-7163.MCT-21-0136

Trials. 2021 Nov 23;22(1):831. doi: 10.1186/s13063-021-05752-1.

ABSTRACT

BACKGROUND: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir.

METHODS: This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion.

DISCUSSION: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04385719 . Registered 13 May 2020.

PMID:34814933 | DOI:10.1186/s13063-021-05752-1

J Obstet Gynaecol Res. 2021 Nov 23. doi: 10.1111/jog.15105. Online ahead of print.

ABSTRACT

OBJECTIVE(S): This prospective observational cohort study aimed to evaluate whether women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the first trimester of pregnancy are at higher risk of adverse obstetric and neonatal outcomes compared to negative patients.

STUDY DESIGN: Seromolecular testing for SARS-CoV-2 was performed at 12, 16, 21 weeks, and at delivery; the cohort was then subdivided into a first-trimester SARS-CoV-2-positive (case) group and a SARS-CoV-2-negative (control) group. The primary outcome was a composite adverse obstetric outcome, defined as the presence of either abortion, preterm delivery, preterm prelabor rupture of membranes, preeclampsia, intrauterine growth restriction, stillbirth; and a composite measure of adverse neonatal events, including either 1- and 5-min Apgar score ≤ 7, neonatal intensive care unit admission and congenital birth defects. Maternal symptoms and antibody titer were secondarily assessed.

RESULTS: A total of 17 of 164 women tested positive for SARS-CoV-2 (10.3%) in the first trimester. One SARS-CoV-2-positive patient who gave birth at another hospital was excluded. Composite adverse obstetric outcome was observed in 6.2% (1/16) SARS-CoV-2-positive and 10.5% (11/105) SARS-CoV-2-negative women; composite adverse neonatal outcome in 12.5% (2/16) and 7.6% (8/105), respectively. In the newborns of women who had developed IgG antibodies, the same antibodies were detected in arterial cord blood and the nasopharyngeal swab tested negative for SARS-CoV-2. No maternal pneumonia or hospital admission due to coronavirus disease-19 were recorded.

CONCLUSION: Asymptomatic or mildly symptomatic women during the first trimester of pregnancy did not experience significantly more adverse events than SARS-CoV-2-negative women.

PMID:34814234 | DOI:10.1111/jog.15105

Biomed Pharmacother. 2021 Nov 20;145:112436. doi: 10.1016/j.biopha.2021.112436. Online ahead of print.

ABSTRACT

Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer's disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular pathways. Here, we have used a combined systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, next generation pharmacogenomic analysis identified the PI3K/Akt modulator LY294002 as the most highly ranked small molecule with both pro- and anti-oligodendroglial concentration-dependent effects. We validated these in silico findings using multidisciplinary approaches to reveal a profoundly bipartite effect of LY294002 on the generation of OPCs and their differentiation into myelinating oligodendrocytes in both postnatal and adult contexts. Finally, we employed transcriptional profiling and signalling pathway activity assays to determine cell-specific mechanisms of action of LY294002 on oligodendrocytes and resolve optimal in vivo conditions required to promote myelin repair. These results demonstrate the power of multidisciplinary strategies in determining the therapeutic potential of small molecules in neurodegenerative disorders.

PMID:34813998 | DOI:10.1016/j.biopha.2021.112436

Crit Rev Oncol Hematol. 2021 Nov 20:103525. doi: 10.1016/j.critrevonc.2021.103525. Online ahead of print.

ABSTRACT

AIMS: The KWAY project aims to investigate the economic sustainability of the up-front NGS technologies adoption in the analysis of clinically relevant molecular alterations in NSCLC patients.

METHODS: The diagnostic workflow and the related sustained costs of five Italian referral centers were assessed in four different evolving scenarios were analyzed. For each scenario, two alternative testing strategies were evaluated: the Maximized Standard strategy and the Maximized NGS strategy.

RESULTS: For each center, the robustness of obtained results was verified through a deterministic sensitivity analysis, observing the variation of total costs based on a variation of ±20 % of the input parameters and ensuring that results would present a consistent behavior compared to the original ones.

CONCLUSIONS: our project, highlighted that the adoption of NGS allows to save personnel time dedicated to testing activities and to reduce the overall cost of testing per patient.

PMID:34813925 | DOI:10.1016/j.critrevonc.2021.103525

Chem Biol Interact. 2021 Nov 20:109747. doi: 10.1016/j.cbi.2021.109747. Online ahead of print.

ABSTRACT

Our recent study demonstrated eIF3a loss contributes to vemurafenib resistance in melanoma by activating ERK. However, overexpression of eIF3a in the clinic is not feasible to produce vemurafenib re-sensitization, and ERK inhibitors combined with vemurafenib still exhibit limited effectiveness in the treatment of melanoma. Here, using the human receptor tyrosine kinase phosphorylation antibody array, we observed that silencing eIF3a could activate BMX, a tyrosine kinase. The BMX inhibitor CHMFL-BMX-078 could significantly suppress proliferation and induce cell cycle arrest in vemurafenib resistant melanoma cell line A375 (A375R), however, it was hypotoxic in immortal keratinocytes, melanoma cells, and other solid cancer cells such as glioma and breast cancer cells. Furthermore, the combined treatment of CHMFL-BMX-078 and vemurafenib synergistically reduced cell viability and restored the sensitivity of resistant cells to vemurafenib. The reversal of the resistant phenotype by CHMFL-BMX-078 was associated with the AKT signaling pathway, as co-treatment with the AKT activator SC-79 or up-regulation of AKT attenuated the anti-proliferation effect of CHMFL-BMX-078 and vemurafenib. Lastly, we demonstrated that CHMFL-BMX-078 could significantly enhance vemurafenib efficacy in a xenograft model of A375R cells without producing additive toxicity. In conclusion, these findings reveal that the BMX inhibitor CHMFL-BMX-078 may reverse vemurafenib resistance in melanoma by suppressing the AKT signaling pathway, implying that CHMFL-BMX-078 may be a promising compound for overcoming vemurafenib resistance.

PMID:34813779 | DOI:10.1016/j.cbi.2021.109747

Obes Surg. 2021 Nov 23. doi: 10.1007/s11695-021-05789-w. Online ahead of print.

ABSTRACT

PURPOSE: Fatty acids (FA), particularly polyunsaturated (PUFA) ones, are involved in the regulation of glycemic control, lipid metabolism, and inflammation. The aim of the study was to assess patient FA profile in relation to obesity, lipid and carbohydrate metabolism disturbances, and weight loss.

MATERIALS AND METHODS: The studied group consisted of 51 patients with extreme obesity, 23 of whom achieved radical weight reduction within 1 year after a laparoscopic sleeve gastrectomy (LSG). FA levels were determined using gas chromatography with flame ionization detection.

RESULTS: Patients with extreme obesity and higher serum PUFA content have lower serum levels of SFA and MUFA (especially myristic, palmitic, lignoceric acids and palmitoleic, oleic acids), as well as lower triglyceride and higher HDL-cholesterol concentrations and it was not influenced by CEPT Taq1B variant. At baseline, the fatty acid profile of patients with type II diabetes differ from patients with dyslipidemia. In patients who had lost weight, significantly lower levels of selected saturated FA and major trans-fatty acid, elaidic, were found. Moreover, the proportion of PUFA was increased.

CONCLUSION: In extreme obesity, higher PUFA exert their favorable effects on serum lipids. Significant weight reduction after the bariatric surgery is associated with beneficial changes in the fatty acid profile.

PMID:34813039 | DOI:10.1007/s11695-021-05789-w

J Med Chem. 2021 Nov 23. doi: 10.1021/acs.jmedchem.1c01547. Online ahead of print.

ABSTRACT

To fight COVID-19, much effort has been directed toward in vitro drug repurposing. Here, we investigate the impact of colloidal aggregation, a common screening artifact, in these repurposing campaigns. We tested 56 drugs reported as active in biochemical assays for aggregation by dynamic light scattering and by detergent-based enzyme counter screening; 19 formed colloids at concentrations similar to their literature IC50's, and another 14 were problematic. From a common repurposing library, we further selected another 15 drugs that had physical properties resembling known aggregators, finding that six aggregated at micromolar concentrations. This study suggests not only that many of the drugs repurposed for SARS-CoV-2 in biochemical assays are artifacts but that, more generally, at screening-relevant concentrations, even drugs can act artifactually via colloidal aggregation. Rapid detection of these artifacts will allow the community to focus on those molecules that genuinely have potential for treating COVID-19.

PMID:34812616 | DOI:10.1021/acs.jmedchem.1c01547

Transl Psychiatry. 2021 Nov 22;11(1):596. doi: 10.1038/s41398-021-01717-9.

ABSTRACT

Many antidepressants, atomoxetine, and several antipsychotics are metabolized by the cytochrome P450 enzymes CYP2D6 and CYP2C19, and guidelines for prescribers based on genetic variants exist. Although some laboratories offer such testing, there is no consensus regarding validated methodology for clinical genotyping of CYP2D6 and CYP2C19. The aim of this paper was to cross-validate multiple technologies for genotyping CYP2D6 and CYP2C19 against each other, and to contribute to feasibility for clinical implementation by providing an enhanced range of assay options, customizable automated translation of data into haplotypes, and a workflow algorithm. AmpliChip CYP450 and some TaqMan single nucleotide variant (SNV) and copy number variant (CNV) data in the Genome-based therapeutic drugs for depression (GENDEP) study were used to select 95 samples (out of 853) to represent as broad a range of CYP2D6 and CYP2C19 genotypes as possible. These 95 included a larger range of CYP2D6 hybrid configurations than have previously been reported using inter-technology data. Genotyping techniques employed were: further TaqMan CNV and SNV assays, xTAGv3 Luminex CYP2D6 and CYP2C19, PharmacoScan, the Ion AmpliSeq Pharmacogenomics Panel, and, for samples with CYP2D6 hybrid configurations, long-range polymerase chain reactions (L-PCRs) with Sanger sequencing and Luminex. Agena MassARRAY was also used for CYP2C19. This study has led to the development of a broader range of TaqMan SNV assays, haplotype phasing methodology with TaqMan adaptable for other technologies, a multiplex genotyping method for efficient identification of some hybrid haplotypes, a customizable automated translation of SNV and CNV data into haplotypes, and a clinical workflow algorithm.

PMID:34811360 | DOI:10.1038/s41398-021-01717-9

Front Pharmacol. 2021 Nov 5;12:750433. doi: 10.3389/fphar.2021.750433. eCollection 2021.

ABSTRACT

Tacrolimus (TAC) is a first-choice immunosuppressant for solid organ transplantation, characterized by high potential for drug-drug interactions, significant inter- and intra-patient variability, and narrow therapeutic index. Therapeutic drug monitoring (TDM) of TAC concentrations in whole blood (WB) is capable of reducing the incidence of adverse events. Since TAC acts within lymphocytes, its monitoring in peripheral blood mononuclear cells (PBMC) may represent a valid future alternative for TDM. Nevertheless, TAC intracellular concentrations and their variability are poorly described, particularly in the pediatric context. Therefore, our aim was describing TAC concentrations in WB and PBMC and their variability in a cohort of pediatric patients undergoing constant immunosuppressive maintenance therapy, after liver transplantation. TAC intra-PBMCs quantification was performed through a validated UHPLC-MS/MS assay over a period of 2-3 months. There were 27 patients included in this study. No significant TAC changes in intracellular concentrations were observed (p = 0.710), with a median percent change of -0.1% (IQR -22.4%-+46.9%) between timings: this intra-individual variability was similar to the one in WB, -2.9% (IQR -29.4-+42.1; p = 0.902). Among different patients, TAC weight-adjusted dose and age appeared to be significant predictors of TAC concentrations in WB and PBMC. Intra-individual seasonal variation of TAC concentrations in WB, but not in PBMC, have been observed. These data show that the intra-individual variability in TAC intracellular exposure is comparable to the one observed in WB. This opens the way for further studies aiming at the identification of therapeutic ranges for TAC intra-PBMC concentrations.

PMID:34803692 | PMC:PMC8602893 | DOI:10.3389/fphar.2021.750433

Pharmgenomics Pers Med. 2021 Nov 13;14:1441-1455. doi: 10.2147/PGPM.S329787. eCollection 2021.

ABSTRACT

Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, and is rising in incidence with widespread prevalence. Multiple gene variants are associated with glucose homeostasis, complex T2DM pathogenesis, and its complications. Exploring more effective therapeutic strategies for patients with diabetes is crucial. Pharmacogenomics has made precision medicine possible by allowing for individualized drug therapy based on a patient's genetic and genomic information. T2DM is treated with various classes of oral hypoglycemic agents, such as biguanides, sulfonylureas, thiazolidinediones, meglitinides, DPP4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, and GLP1 analogues, which exhibit various pharmacogenetic variants. Although genomic interventions in monogenic diabetes have been implemented in clinical practice, they are still in the early stages for complex polygenic disorders, such as T2DM. Precision DM medicine has the potential to be effective in personalized therapy for those suffering from various forms of DM, such as T2DM. With recent developments in genetic techniques, the application of candidate-gene studies, large-scale genotyping investigations, genome-wide association studies, and "multiomics" studies has begun to produce results that may lead to changes in clinical practice. Enhanced knowledge of the genetic architecture of T2DM presents a bigger translational potential. This review summarizes the genetics and pathophysiology of T2DM, candidate-gene approaches, genome-wide association studies, personalized medicine, clinical relevance of pharmacogenetic variants associated with oral hypoglycemic agents, and paths toward personalized diabetology.

PMID:34803393 | PMC:PMC8598203 | DOI:10.2147/PGPM.S329787