J Transl Med. 2021 Sep 8;19(1):384. doi: 10.1186/s12967-021-03062-3.

ABSTRACT

Tumor heterogeneity is a primary cause of treatment failure. However, changes in drug sensitivity over time are not well mapped in cancer. Patient-derived organoids (PDOs) may predict clinical drug responses ex vivo and offer an opportunity to evaluate novel treatment strategies in a personalized fashion. Here we have evaluated spatio-temporal functional and molecular dynamics of five PDO models established after hepatic re-resections and neoadjuvant combination chemotherapies in a patient with microsatellite stable and KRAS mutated metastatic rectal cancer. Histopathological differentiation phenotypes of the PDOs corresponded with the liver metastases, and ex vivo drug sensitivities generally reflected clinical responses and selection pressure, assessed in comparison to a reference data set of PDOs from metastatic colorectal cancers. PDOs from the initial versus the two recurrent metastatic settings showed heterogeneous cell morphologies, protein marker expression, and drug sensitivities. Exploratory analyses of a drug screen library of 33 investigational anticancer agents showed the strongest ex vivo sensitivity to the SMAC mimetic LCL161 in PDOs of recurrent disease compared to those of the initial metastasis. Functional analyses confirmed target inhibition and apoptosis induction in the LCL161 sensitive PDOs from the recurrent metastases. Gene expression analyses indicated an association between LCL161 sensitivity and tumor necrosis factor alpha signaling and RIPK1 gene expression. In conclusion, LCL161 was identified as a possible experimental therapy of a metastatic rectal cancer that relapsed after hepatic resection and standard systemic treatment.

PMID:34496878 | DOI:10.1186/s12967-021-03062-3

Braz J Biol. 2021 Sep 6;83:e248746. doi: 10.1590/1519-6984.248746. eCollection 2021.

ABSTRACT

Colorectal cancer (CRC) is one of the most common cancers leading to comorbidities and mortalities globally. The rational of current study was to evaluate the combined epigallocatechin gallate and quercetin as a potent antitumor agent as commentary agent for therapeutic protocol. The present study investigated the effect of epigallocatechin Gallate (EGCG) (150mg) and quercetin (200mg) at different proportions on proliferation and induction of apoptosis in human colon cancer cells (HCT-116). Cell growth, colonogenic, Annexin V in addition cell cycle were detected in response to phytomolecules. Data obtained showed that, the colony formation was inhibited significantly in CRC starting from the lowest concentration tested of 10 µg/mL resulting in no colonies as visualized by a phase-contrast microscope. Data showed a significant elevation in the annexin V at 100 µg/mL EGCG(25.85%) and 150 µg/mL quercetin (48.35%). Moreover, cell cycle analysis showed that this combination caused cell cycle arrest at the G1 phase at concentration of 100 µg/mL (72.7%) and 150 µg/mL (75.25%). The combined effect of epigallocatechin Gallate and quercetin exert antiproliferative activity against CRC, it is promising in alternative conventional chemotherapeutic agent.

PMID:34495165 | DOI:10.1590/1519-6984.248746

Expert Rev Hematol. 2021 Sep 7. doi: 10.1080/17474086.2021.1977117. Online ahead of print.

NO ABSTRACT

PMID:34490838 | DOI:10.1080/17474086.2021.1977117

Front Psychiatry. 2021 Aug 19;12:724170. doi: 10.3389/fpsyt.2021.724170. eCollection 2021.

ABSTRACT

Introduction: Polypharmacy and genetic variants that strongly influence medication response (pharmacogenomics, PGx) are two well-described risk factors for adverse drug reactions. Complexities arise in interpreting PGx results in the presence of co-administered medications that can cause cytochrome P450 enzyme phenoconversion. Aim: To quantify phenoconversion in a cohort of acute aged persons mental health patients and evaluate its impact on the reporting of medications with actionable PGx guideline recommendations (APRs). Methods: Acute aged persons mental health patients (N = 137) with PGx and medication data at admission and discharge were selected to describe phenoconversion frequencies for CYP2D6, CYP2C19 and CYP2C9 enzymes. The expected impact of phenoconversion was then assessed on the reporting of medications with APRs. Results: Post-phenoconversion, the predicted frequency at admission and discharge increased for CYP2D6 intermediate metabolisers (IMs) by 11.7 and 16.1%, respectively. Similarly, for CYP2C19 IMs, the predicted frequency at admission and discharge increased by 13.1 and 11.7%, respectively. Nineteen medications with APRs were prescribed 120 times at admission, of which 50 (42%) had APRs pre-phenoconversion, increasing to 60 prescriptions (50%) post-phenoconversion. At discharge, 18 medications with APRs were prescribed 122 times, of which 48 (39%) had APRs pre-phenoconversion, increasing to 57 prescriptions (47%) post-phenoconversion. Discussion: Aged persons mental health patients are commonly prescribed medications with APRs, but interpretation of these recommendations must consider the effects of phenoconversion. Adopting a collaborative care model between prescribers and clinical pharmacists should be considered to address phenoconversion and ensure the potential benefits of PGx are maximised.

PMID:34489765 | PMC:PMC8416898 | DOI:10.3389/fpsyt.2021.724170

Curr Opin Pharmacol. 2021 Sep 3;60:275-280. doi: 10.1016/j.coph.2021.08.004. Online ahead of print.

ABSTRACT

Genetic testing for Alzheimer's disease offers a molecular diagnosis to patients and their relatives and provides information on personal risk, reproductive choices, clinical trial eligibility, and treatment options. In the past, molecular testing was limited to detecting single variations in single genes. Currently, with the advent of next-generation sequencing, simultaneous analysis of more than 100 genes using the same DNA sample is possible. This approach allows the determination of gene mutations, genetic risk factors, genotypes at many pharmacogenomic loci, and the determination of a polygenic risk scores for stratification of risk. This article reviews the diagnostic genetic testing of Alzheimer's disease, from the first molecular approaches to recent advances in NGS, focusing on a precision medicine approach.

PMID:34487952 | DOI:10.1016/j.coph.2021.08.004

Curr Hypertens Rep. 2021 Sep 6;23(8):40. doi: 10.1007/s11906-021-01157-2.

ABSTRACT

PURPOSE OF HEADING: To review the relationship between intestinal microbes and hypertension and its impact on the efficacy of antihypertensive drugs, and help to address some of these knowledge gaps.

RECENT FINDINGS: Hypertension is associated with cardiovascular diseases and is the most important modifiable risk factor for all-cause morbidity and mortality worldwide. The pathogenesis of hypertension is complex, including factors such as dietary, environmental and genetics. Recently, the studies have shown that the gut microbiota influences the occurrence and development of hypertension through a variety of ways, including affecting the production of short-chain fatty acids, dysfunction of the brain-gut axis, and changes in serotonin content that cause the imbalance of vagus and sympathetic nerve output associated with hypertension. However, patients with hypertension typically take antihypertensive drugs orally on a long-term basis, and most antihypertensive drugs are absorbed by the gastrointestinal tract. Studies have shown that the pharmacokinetics and metabolism of antihypertensive drugs may be influenced by microbiota, or antihypertensive drugs act directly on the intestinal flora to exert efficacy, including regulation of intestinal microbial metabolism, intestinal inflammation, and intestinal sympathetic nervous system disorders. The intestinal flora can affect the pharmacokinetics and metabolism of antihypertensive drugs in the rats, and intestinal microbiota also can be the target "organ" by antihypertensive drugs.

PMID:34487269 | DOI:10.1007/s11906-021-01157-2

Am J Health Syst Pharm. 2021 Sep 6:zxab339. doi: 10.1093/ajhp/zxab339. Online ahead of print.

NO ABSTRACT

PMID:34487145 | DOI:10.1093/ajhp/zxab339

Expert Opin Drug Metab Toxicol. 2021 Sep 6:1-7. doi: 10.1080/17425255.2021.1974397. Online ahead of print.

ABSTRACT

INTRODUCTION: Irinotecan is a cytotoxic agent that is widely used in the treatment of several types of solid tumors. However, although it is generally well tolerated, approximately 20% to 35% of patients develop severe toxicity, particularly delayed-type diarrhea and neutropenia. As the incidence of such toxicities is often associated with the UGT1A1 *28/*28, *6/*28 and *6/*6 genotypes, individualized dosing could reduce these adverse events. Furthermore, prospective trials have shown that patients harboring the UGT1A1 *1/*1 and *1/*28 genotypes can tolerate higher doses of irinotecan, which may in turn impact on a better outcome. Upfront UGT1A1 genotyping could therefore be a usefulness strategy in order to individualize irinotecan dosing, but consensus on the recommended dose based on the UGT1A1 genotype is still lacking.

AREAS COVERED: This review summarizes the results of the main pharmacogenetic studies focused on irinotecan. We provide an overview of current evidence and recommendations for individualized dosing of irinotecan in metastatic colorectal cancer patients.

EXPERT OPINION: Implementation of UGT1A1*28 and UGT1A1*6 genotyping in clinical practice is a first step toward personalizing irinotecan therapy. This approach is likely to improve patient care and reduce healthcare costs. Future large and prospective studies will help to clarify the clinical value of other genetic markers in irinotecan treatment personalization.

PMID:34486919 | DOI:10.1080/17425255.2021.1974397

Pharmacogenomics. 2021 Sep 6. doi: 10.2217/pgs-2021-0041. Online ahead of print.

ABSTRACT

Antiepileptic-mood stabilizers (AED-MS) are often used to treat bipolar disorder (BD). Similar to other mood disorder medications, AED-MS treatment response varies between patients. Identification of biomarkers associated with treatment response may ultimately help with the delivery of individualized treatment and lead to improved treatment efficacy. Here, we conducted a narrative review of the current knowledge of the pharmacogenomics of AED-MS (valproic acid, lamotrigine and carbamazepine) treatment response in BD, including genetic contributions to AED-MS pharmacokinetics. Genes involved in neurotransmitter systems and drug transport have been shown to be associated with AED-MS treatment response. As more studies are conducted, and experimental and analytical methods advance, knowledge of AED-MS pharmacogenomics is expected to grow and contribute to precision medicine in BD.

PMID:34486896 | DOI:10.2217/pgs-2021-0041

Epilepsia Open. 2021 Sep 6. doi: 10.1002/epi4.12536. Online ahead of print.

ABSTRACT

Mesial temporal lobe epilepsy (MTLE) is the most common type of focal epilepsy in adults, and hippocampal sclerosis (HS) is a frequent histopathological feature in patients with MTLE. Pharmacoresistance is present in at least one third of patients with MTLE with HS (MTLE+HS). Several hypotheses have been proposed to explain the mechanisms of pharmacoresistance in epilepsy, including the effect of genetic and molecular factors. In recent years, the increased knowledge generated by high-throughput omic technologies has significantly improved the power of molecular genetic studies to discover new mechanisms leading to disease and response to treatment. In this review, we present and discuss the contribution of different omic modalities to understand the basic mechanisms determining pharmacoresistance in patients with MTLE+HS. We provide an overview and a critical discussion of the findings, limitations, new approaches, and future directions of these studies to improve the understanding of pharmacoresistance in MTLE+HS. However, it is important to point out that, as with other complex traits, pharmacoresistance to anti-seizure medications is likely a multifactorial condition in which gene-gene and gene-environment interactions play an important role. Thus, studies using multidimensional approaches are more likely to unravel these intricate biological processes.

PMID:34486831 | DOI:10.1002/epi4.12536

Front Cardiovasc Med. 2021 Aug 16;8:704175. doi: 10.3389/fcvm.2021.704175. eCollection 2021.

ABSTRACT

Several studies show that statin therapy improves endothelial function by cholesterol-independent mechanisms called "pleiotropic effects." These are due to the inhibition of the RhoA/ROCK kinase pathway, its inhibition being an attractive atheroprotective treatment. In addition, recent work has shown that microRNAs, posttranscriptional regulators of gene expression, can affect the response of statins and their efficacy. For this reason, the objective of this study was to identify by bioinformatic analysis possible new microRNAs that could modulate the pleiotropic effects exerted by statins through the inhibition of ROCK kinases. A bioinformatic study was performed in which the differential expression of miRNAs in endothelial cells was compared under two conditions: Control and treated with simvastatin at 10 μM for 24 h, using a microarray. Seven miRNAs were differentially expressed, three up and four down. Within the up group, the miRNAs hsa-miR-618 and hsa-miR-297 present as a predicted target to ROCK2 kinase. Also, functional and enriched pathway analysis showed an association with mechanisms associated with atheroprotective effects. This work shows an in-silico approach of how posttranscriptional regulation mediated by miRNAs could modulate the pleiotropic effects exerted by statins on endothelial cells, through the inhibition of ROCK2 kinase and its effects.

PMID:34485404 | PMC:PMC8415262 | DOI:10.3389/fcvm.2021.704175

Sci Bull (Beijing). 2021 Aug 28. doi: 10.1016/j.scib.2021.08.017. Online ahead of print.

NO ABSTRACT

PMID:34484849 | PMC:PMC8400453 | DOI:10.1016/j.scib.2021.08.017

Ont Health Technol Assess Ser. 2021 Aug 12;21(13):1-214. eCollection 2021.

ABSTRACT

BACKGROUND: Major depression is a substantial public health concern that can affect personal relationships, reduce people's ability to go to school or work, and lead to social isolation. Multi-gene pharmacogenomic testing that includes decision-support tools can help predict which depression medications and dosages are most likely to result in a strong response to treatment or to have the lowest risk of adverse events on the basis of people's genes.We conducted a health technology assessment of multi-gene pharmacogenomic testing that includes decision-support tools for people with major depression. Our assessment evaluated effectiveness, safety, cost-effectiveness, the budget impact of publicly funding multi-gene pharmacogenomic testing, and patient preferences and values.

METHODS: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane Risk of Bias Tool and the Risk of Bias Assessment Tool for Nonrandomized studies (RoBANS) and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria.We performed a systematic literature search of the economic evidence to review published cost-effectiveness studies on multi-gene pharmacogenomic testing that includes a decision-support tool in people with major depression. We developed a state-transition model and conducted a probabilistic analysis to determine the incremental cost of multi-gene pharmacogenomic testing versus treatment as usual per quality-adjusted life-year (QALY) gained for people with major depression who had inadequate response to one or more antidepressant medications. In the reference case (with GeneSight-guided care), we considered a 1-year time horizon with an Ontario Ministry of Health perspective. We also estimated the 5-year budget impact of publicly funding multi-gene pharmacogenomic testing for people with major depression in Ontario.To contextualize the potential value of multi-gene pharmacogenomic testing that includes decision-support tools, we spoke with people who have major depression and their families.

RESULTS: We included 14 studies in the clinical evidence review that evaluated six multi-gene pharmacogenomic tests. Although all tests included decision-support tools, they otherwise differed greatly, as did study design, populations included in studies, and outcomes reported. Little or no improvement was observed on change in HAM-D17 depression score compared with treatment as usual for any test evaluated (GRADE: Low-Very Low). GeneSight- and NeuroIDgenetix-guided medication selection led to statistically significant improvements in response (GRADE: Low-Very Low) and remission (GRADE: Low-Very Low), while treatment guided by CNSdose led to significant improvement in remission rates (GRADE: Low), but the study did not report on response. Results were inconsistent and uncertain for the impact of Neuropharmagen, and no significant improvement was observed for Genecept or another unspecified test for either response or remission (GRADE: Low-Very Low). Neuropharmagen may reduce adverse events and CNSDose may reduce intolerability to medication, while no difference was observed in adverse events with GeneSight, Genecept, or another unspecified test (GRADE: Moderate-Very Low). No studies reported data on suicide, treatment adherence, relapse, recovery, or recurrence of depression symptoms.Our review included four model-based economic studies and found that multi-gene pharmacogenomic testing was associated with greater effectiveness and cost savings than treatment as usual, over long-term (i.e., 3-,5-year and lifetime) time horizons. Since none of the included studies was fully applicable to the Ontario health care system, we conducted a primary economic evaluation.Our reference case analysis over the 1-year time horizon found that multi-gene pharmacogenomic testing (with GeneSight) was associated with additional QALYs (0.03, 95% credible interval [CrI]: 0.005; 0.072) and additional costs ($1,906, 95% Crl: $688; $3,360). An incremental cost-effectiveness ratio was $60,564 per QALY gained. The probability of the intervention being cost-effective (vs. treatment as usual) was 36.8% at a willingness-to-pay amount of $50,000 per QALY (i.e., moderately likely not to be cost-effective), rising to 70.7% at a willingness-to-pay amount of $100,000 per QALY (i.e., moderately likely to be cost-effective). Evidence informing economic modeling of the reference case with GeneSight and other multi-gene pharmacogenomic tests was of low to very low quality, implying considerable uncertainty or low confidence in the effectiveness estimates. The price of the test, efficacy of the intervention on remission, time horizon, and analytic perspective were major determinants of the cost-effectiveness results. If the test price were assumed to be $2,162 (compared with $2,500 in the reference case), the intervention would be cost-effective at a willingness-to-pay amount of $50,000 per QALY; moreover, if the price decreased to $595, the intervention would be cost saving (or dominant) compared with treatment as usual.At an increasing uptake of 1% per year and a test price of $2,500, the annual budget impact of publicly funding multi-gene pharmacogenomic testing in Ontario over the next 5 years ranged from an additional $3.5 million in year 1 (at uptake of 1%) to $16.8 million in year 5. The 5-year budget impact was estimated at about $52 million.People with major depression and caregivers generally supported multi-gene pharmacogenomic testing because they believed it could provide guidance that fit their values. They hoped such guidance would speed symptom relief, would reduce side effects and help inform their medication choices. Some patients expressed concerns over maintaining confidentiality of test results and the possibility that physicians would sacrifice patient-centred care to follow pharmacogenomic guidance.

CONCLUSIONS: Multi-gene pharmacogenomic testing that includes decision-support tools to guide medication selection for depression varies widely. Differences between individual tests must be considered, as clinical utility observed with one test might not apply to other tests. Overall, effectiveness was inconsistent among the six multi-gene pharmacogenomic tests we identified. Multi-gene pharmacogenomic tests may result in little or no difference in improvement in depression scores compared with treatment as usual, but some tests may improve response to treatment or remission from depression. The impact on adverse events is uncertain. The evidence, however, is uncertain, and therefore our confidence that these observed effects reflect the true effects is low to very low.For the management of major depression in people who had inadequate response to at least one medication, some multi-gene pharmacogenomic tests that include decision support tools are associated with additional costs and QALYs over the 1-year time horizon, and maybe be cost-effective at the willingness-to-pay amount of $100,000 per QALY. Publicly funding multi-gene pharmacogenomic testing in Ontario would result in additional annual costs of between $3.5 million and $16.8 million, with a total budget impact of about $52 million over the next 5 years.People with major depression and caregivers generally supported multi-gene pharmacogenomic testing because they believed it could provide guidance that fit their values. They hoped such guidance would speed symptom relief, would reduce side and help inform their medication choices. Some patients expressed concerns over maintaining confidentiality of test results and the possibility that physicians would sacrifice patient-centred care to follow pharmacogenomic guidance.

PMID:34484487 | PMC:PMC8382305

Front Genet. 2021 Aug 17;12:698825. doi: 10.3389/fgene.2021.698825. eCollection 2021.

ABSTRACT

Background: The triad of drug efficacy, toxicity and resistance underpins the risk-benefit balance of all therapeutics. The application of pharmacogenomics has the potential to improve the risk-benefit balance of a given therapeutic via the stratification of patient populations based on DNA variants. A growth in the understanding of the particulars of the mitochondrial genome, alongside the availability of techniques for its interrogation has resulted in a growing body of literature examining the impact of mitochondrial DNA (mtDNA) variation upon drug response. Objective: To critically evaluate and summarize the available literature, across a defined period, in a systematic fashion in order to map out the current landscape of the subject area and identify how the field may continue to advance. Methods: A systematic review of the literature published between January 2009 and December 2020 was conducted using the PubMed database with the following key inclusion criteria: reference to specific mtDNA polymorphisms or haplogroups, a core objective to examine associations between mtDNA variants and drug response, and research performed using human subjects or human in vitro models. Results: Review of the literature identified 24 articles reporting an investigation of the association between mtDNA variant(s) and drug efficacy, toxicity or resistance that met the key inclusion criteria. This included 10 articles examining mtDNA variations associated with antiretroviral therapy response, 4 articles examining mtDNA variants associated with anticancer agent response and 4 articles examining mtDNA variants associated with antimicrobial agent response. The remaining articles covered a wide breadth of medications and were therefore grouped together and referred to as "other." Conclusions: Investigation of the impact of mtDNA variation upon drug response has been sporadic to-date. Collective assessment of the associations identified in the articles was inconclusive due to heterogeneous methods and outcomes, limited racial/ethnic groups, lack of replication and inadequate statistical power. There remains a high degree of idiosyncrasy in drug response and this area has the potential to explain variation in drug response in a clinical setting, therefore further research is likely to be of clinical benefit.

PMID:34484295 | PMC:PMC8416105 | DOI:10.3389/fgene.2021.698825

Front Pharmacol. 2021 Aug 13;12:729474. doi: 10.3389/fphar.2021.729474. eCollection 2021.

ABSTRACT

Antipsychotics (APs) are associated with weight gain and other metabolic abnormalities such as hyperglycemia, dyslipidemia and metabolic syndrome. This translational study aimed to uncover the underlying molecular mechanisms and identify the key genes involved in AP-induced metabolic effects. An integrative gene expression analysis was performed in four different mouse tissues (striatum, liver, pancreas and adipose) after risperidone or olanzapine treatment. The analytical approach combined the identification of the gene co-expression modules related to AP treatment, gene set enrichment analysis and protein-protein interaction network construction. We found several co-expression modules of genes involved in glucose and lipid homeostasis, hormone regulation and other processes related to metabolic impairment. Among these genes, EP300, which encodes an acetyltransferase involved in transcriptional regulation, was identified as the most important hub gene overlapping the networks of both APs. Then, we explored the genetically predicted EP300 expression levels in a cohort of 226 patients with first-episode psychosis who were being treated with APs to further assess the association of this gene with metabolic alterations. The EP300 expression levels were significantly associated with increases in body weight, body mass index, total cholesterol levels, low-density lipoprotein cholesterol levels and triglyceride concentrations after 6 months of AP treatment. Taken together, our analysis identified EP300 as a key gene in AP-induced metabolic abnormalities, indicating that the dysregulation of EP300 function could be important in the development of these side effects. However, more studies are needed to disentangle the role of this gene in the mechanism of action of APs.

PMID:34483940 | PMC:PMC8414590 | DOI:10.3389/fphar.2021.729474

Focus (Am Psychiatr Publ). 2021 Jan;19(1):76-85. doi: 10.1176/appi.focus.19107. Epub 2021 Jan 25.

ABSTRACT

(Reprinted with permission from Am J Geriatr Psychiatry 2020; 28:933-945).

PMID:34483773 | PMC:PMC8412149 | DOI:10.1176/appi.focus.19107

Pharmgenomics Pers Med. 2021 Aug 28;14:1069-1080. doi: 10.2147/PGPM.S322743. eCollection 2021.

ABSTRACT

BACKGROUND: Annually, 10% of warfarin patients will likely need to stop warfarin prior to elective surgery to achieve a baseline international normalization ratio (INR) level (INR ≤ 1.2) at the time of the procedure. This study explores the influence of genetic and non-genetic factors on INR normalization in the Arab (major part of Near Eastern) population in preprocedural warfarin management.

METHODS: An observational prospective cohort study was designed to recruit Arab patients taking warfarin and scheduled for an elective procedure. Two INR readings were recorded. DNA extraction and genotyping of variants in CYP2C9*2, CYP2C9*3, CYP4F2*3, VKORC1*2, and FII (rs5896) and FVII (rs3093229) genes using real-time polymerase chain reaction were performed.

RESULTS: Data from 116 patients were included in the analysis. CYP2C9 and VKORC1 genetic variants carriers required lower maintenance dose compared to non-carriers. The analysis showed that ciprofloxacin, antiplatelet medications, and INR index (INR at visit 1) are the only factors associated with the INR decline rate. Also, the proportion of CYP2C9*3 carriers with normal INR (≤1.2) on the day of surgery was significantly lower than those with wild-type genotype (28% vs 60%, p=0.013). In addition, heparin bridging, INR target, and Sudanese nationality are significant predictors of INR normalization (≤1.2) on the day of the procedure.

CONCLUSION: Despite the confirmed effect of genetic factors on warfarin maintenance dose, the study was not able to find a significant effect of any genetic factor on the rate of INR normalization possibly due to the small sample size. Index INR and interacting medications showed to be significant predictors of INR decline rate.

PMID:34483679 | PMC:PMC8409603 | DOI:10.2147/PGPM.S322743

Ind Psychiatry J. 2021 Jan-Jun;30(1):4-5. doi: 10.4103/ipj.ipj_119_21. Epub 2021 Jun 24.

NO ABSTRACT

PMID:34483516 | PMC:PMC8395549 | DOI:10.4103/ipj.ipj_119_21

Anal Chim Acta. 2021 Sep 15;1178:338829. doi: 10.1016/j.aca.2021.338829. Epub 2021 Jul 5.

ABSTRACT

Rapid, convenient, sensitive and simultaneous detection of distinct enzymes is urgently needed for diagnosis, therapeutics and prognostic of related diseases. Here, a new strategy for simultaneous monitoring γ-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) activity has been fabricated based on dual-emission carbon dots (CDs). CDs were prepared by solvothermal treatment of Actinidia chinensis, which presents two fluorescent emissions at 471 nm (blue channel) and 671 nm (red channel). GGT and ALP activity can be detected based on inner filter effect (IFE) and static quenching effect (SQE) of blue and red channels of CDs, respectively. Linear ranges were 2.5-90 U L-1 and 5-200 U L-1, and limit of detection (LOD) were 0.71 U L-1 and 1.2 U L-1 for GGT and ALP, respectively. Developed CDs can monitor GGT and ALP activity in human serum samples with satisfied recoveries (99.3%-108.6% for GGT, 98.4%-105.4% for ALP). Furthermore, the combination of CDs to sense GGT and ALP activity with OR logic gate can predict human health status. The design and application of dual-emission CDs can also be extended as promising tools to detect multianalytes using different channel signals.

PMID:34482874 | DOI:10.1016/j.aca.2021.338829

Mol Oncol. 2021 Sep 4. doi: 10.1002/1878-0261.13096. Online ahead of print.

ABSTRACT

Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin-based chemotherapy. Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5-aza deoxy-cytosine (5-aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5-aza resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5-aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5-aza and 5-aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5-aza resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin resistant cells which upregulated polycomb target genes. This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5-aza resistant cells, the exact opposite changes seen in cisplatin resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2 and BMI1, conferred 5-aza resistance and cisplatin sensitization, and mediated genome-wide repression of polycomb target gene expression. Finally, genome-wide analysis revealed that 5-aza resistant, cisplatin resistant and DNMT3B knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5-aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs.

PMID:34482638 | DOI:10.1002/1878-0261.13096