J Pers Med. 2022 Aug 22;12(8):1353. doi: 10.3390/jpm12081353.

ABSTRACT

The CYP2D6 gene encodes an enzyme responsible for the metabolism of ~20% of clinically prescribed drugs. In this study, 18 SNPs from the enhancer and promoter regions of CYP2D6 in 323 Roma from Croatia were genotyped, to find out whether the demographic history of Roma affected the distribution of the studied SNPs and their linkage disequilibrium (LD) values, with the major SNPs defining the CYP2D6 star alleles. No differences were found between the three Roma groups in allele and genotype frequencies. The distribution of LD values of Roma was compared with LD values of European and Asian populations. Regulatory CYP2D6 SNPs (rs5758550, rs28624811, rs1080985 and rs1080983) showed similar distribution and the highest LDs with rs16947 from the gene-coding region in all populations. In the promoter region, a complete LD between rs1080989 and rs28588594, and between rs1080983 and rs28624811, was found in Croatian Roma and investigated populations from 1000 genomes. A high LD was also found between rs1080985 from the promoter and rs5758550 from the enhancer region. SNP rs28735595 from the gene promoter region had the highest LD, with two gene region SNPs, rs1058164 and rs1135840. To conclude, the Croatian Roma population shows an LD pattern of the CYP2D6 gene region similar to the 1000 Genomes European and Asian populations.

PMID:36013302 | DOI:10.3390/jpm12081353

J Pers Med. 2022 Aug 21;12(8):1348. doi: 10.3390/jpm12081348.

ABSTRACT

(1) Background: Uptake of pharmacogenomic testing in routine clinical practices is currently slow in China. Pharmacists might play an important role in leveraging care through applying pharmacogenomics, therefore, it is important to better understand clinical pharmacists' knowledge of and attitudes toward pharmacogenomic testing, which has not been well-studied. (2) Methods: A self-administered survey was developed based on previous knowledge of pharmacogenomic testing and its uptake in China. Participants were recruited through the Committee of Pharmaceutical Affairs Management under the Chinese Hospital Association. (3) Results: A total of 1005 clinical pharmacists completed the questionnaire, among whom 996 (99.10%) had heard of pharmacogenomic testing before participation. More than half of respondents (60.0%, n = 597) rated their knowledge of pharmacogenomic testing as "average", while 25% rated it "good" or "excellent". "Guidelines, consensus and treatment paths for disease diagnosis and treatment" (78.7%) were the most preferred sources of information about pharmacogenomic testing. Most respondents (77.0%) believed that pharmacogenomics could "help to improve efficacy and reduce the incidence of adverse reactions". Our participants also believed that patients would benefit most from pharmacogenomic testing through better prediction of individual drug responses and thus informed treatment decisions. The top challenge for the uptake of pharmacogenomic testing was its high cost or lack of insurance coverage (76.7%). (4) Conclusions: Most Chinese clinical pharmacists who participated in our study had a positive attitude toward pharmacogenomic testing, while the knowledge of pharmacogenomic testing was generally self-assessed as average.

PMID:36013297 | DOI:10.3390/jpm12081348

J Pers Med. 2022 Aug 13;12(8):1313. doi: 10.3390/jpm12081313.

ABSTRACT

Using a patient's genetic information to inform medication prescriptions can be clinically effective; however, the practice has not been widely implemented. Health systems need guidance on how to engage with providers to improve pharmacogenetic test utilization. Approaches from the field of implementation science may shed light on the complex factors affecting pharmacogenetic test use in real-world settings and areas to target to improve utilization. This paper presents an approach to studying the application of precision medicine that utilizes mixed qualitative and quantitative methods and implementation science frameworks to understand which factors or combinations consistently account for high versus low utilization of pharmocogenetic testing. This approach involves two phases: (1) collection of qualitative and quantitative data from providers-the cases-at four clinical institutions about their experiences with, and utilization of, pharmacogenetic testing to identify salient factors; and (2) analysis using a Configurational Comparative Method (CCM), using a mathematical algorithm to identify the minimally necessary and sufficient factors that distinguish providers who have higher utilization from those with low utilization. Advantages of this approach are that it can be used for small to moderate sample sizes, and it accounts for conditions found in real-world settings by demonstrating how they coincide to affect utilization.

PMID:36013262 | DOI:10.3390/jpm12081313

J Pers Med. 2022 Aug 8;12(8):1297. doi: 10.3390/jpm12081297.

ABSTRACT

Hereditary factors contribute to disease development and drug pharmacokinetics. The risk of hereditary disease development can be attenuated or eliminated by early screening or risk reducing interventions. The purpose of this study was to assess the clinical utility of germline medical exome sequencing in patients recruited from a family medicine clinic and compare the mutation frequency of hereditary predisposition genes to established general population frequencies. At the University of Kentucky, 205 family medicine patients underwent sequencing in a Clinical Laboratory Improvement Amendments of 1988-compliant laboratory to identify clinically actionable genomic findings. The study identified pathogenic or likely pathogenic genetic variants-classified according to the American College of Medical Genetics and Genomics variant classification guidelines-and actionable pharmacogenomic variants, as defined by the Clinical Pharmacogenetics Implementation Consortium. Test results for patients with pharmacogenomic variants and pathogenic or likely pathogenic variants were returned to the participant and enrolling physician. Hereditary disease predisposition gene mutations in APOB, BRCA2, MUTYH, CACNA1S, DSC2, KCNQ1, LDLR, SCN5A, or SDHB were identified in 6.3% (13/205) of the patients. Nine of 13 (69.2%) underwent subsequent clinical interventions. Pharmacogenomic variants were identified in 76.1% (156/205) of patients and included 4.9% (10/205) who were prescribed a medication that had pharmacogenomic implications. Family physicians changed medications for 1.5% (3/205) of patients to prevent toxicity. In this pilot study, we found that with systemic support, germline genetic screening initiatives were feasible and clinically beneficial in a primary care setting.

PMID:36013246 | DOI:10.3390/jpm12081297

J Pers Med. 2022 Jul 31;12(8):1267. doi: 10.3390/jpm12081267.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) testing is increasingly used in clinical practice to optimize drug therapies. This study aims to understand the involvement of clinical pharmacists in PGx testing at tertiary hospitals in China and their self-assessed capacity to deliver such services.

METHODS: We developed a questionnaire exploring clinical pharmacists' involvement and self-assessed level of capacity of performing PGx tests. A random sample was obtained from the Pharmaceutical Affairs Management Professional Committee of the Chinese Hospital Association.

RESULTS: A total of 1005 clinical pharmacists completed the survey. Of these, 996 (99.1%) had heard of PGx tests and 588 (59.0%) had been involved in PGx testing and related services. Some clinical pharmacists (28.9%) provided PGx services at the rate of "1-5 cases/year" while 21.9% of clinical pharmacists provided PGx services at the rate of ">30 cases/year". Clinical pharmacists most frequently provided PGx testing for cardiovascular diseases. "Consult relevant guidelines/literature" (90.1%) was the most frequently used method to familiarize oneself with PGx testing. About 60% of the pharmacists considered themselves to have poor or fair capacity to provide PGx testing and related services.

CONCLUSIONS: More than half of the pharmacists had been involved in PGx testing and related services. However, pharmacists generally had little confidence in their knowledge level of and capacity to provide PGx-related services.

PMID:36013216 | DOI:10.3390/jpm12081267

J Pers Med. 2022 Jul 31;12(8):1265. doi: 10.3390/jpm12081265.

ABSTRACT

Precision medicine refers to a highly individualized and personalized approach to patient care. Pharmacogenomics is the study of how an individual's genomic profile affects their drug response, enabling stable and effective drug selection, minimizing side effects, and maximizing therapeutic efficacy. Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation in the joints. It mainly starts in peripheral joints, such as the hands and feet, and progresses to large joints, which causes joint deformation and bone damage due to inflammation of the synovial membrane. Here, we review various pharmacogenetic studies investigating the association between clinical response to monoclonal antibody therapy and their target genetic polymorphisms. Numerous papers have reported that some single nucleotide polymorphisms (SNPs) are related to the therapeutic response of several monoclonal antibody drugs including adalimumab, infliximab, rituximab, and tocilizumab, which target tumor necrosis factor (TNF), CD20 of B-cells, and interleukin (IL)-6. Additionally, there are some pharmacogenomic studies reporting on the association between the clinical response of monoclonal antibodies having various mechanisms, such as IL-1, IL-17, IL-23, granulocyte-macrophage colony-stimulating factor (GM-CSF) and the receptor activator of nuclear factor-kappa B (RANK) inhibition. Biological therapies are currently prescribed on a "trial and error" basis for RA patients. If appropriate drug treatment is not started early, joints may deform, and long-term treatment outcomes may worsen. Pharmacogenomic approaches that predict therapeutic responses for RA patients have the potential to significantly improve patient quality of life and reduce treatment costs.

PMID:36013214 | DOI:10.3390/jpm12081265

Int J Mol Sci. 2022 Aug 15;23(16):9124. doi: 10.3390/ijms23169124.

ABSTRACT

Resistance to Immune Checkpoint Blockade (ICB) constitutes the current limiting factor for the optimal implementation of this novel therapy, which otherwise demonstrates durable responses with acceptable toxicity scores. This limitation is exacerbated by a lack of robust biomarkers. In this study, we have dissected the basal TME composition at the gene expression and cellular levels that predict response to Nivolumab and prognosis. BCR, TCR and HLA profiling were employed for further characterization of the molecular variables associated with response. The findings were validated using a single-cell RNA-seq data of metastatic melanoma patients treated with ICB, and by multispectral immunofluorescence. Finally, machine learning was employed to construct a prediction algorithm that was validated across eight metastatic melanoma cohorts treated with ICB. Using this strategy, we have unmasked a major role played by basal intratumoral Plasma cells expressing high levels of IGKC in efficacy. IGKC, differentially expressed in good responders, was also identified within the Top response-related BCR clonotypes, together with IGK variants. These results were validated at gene, cellular and protein levels; CD138+ Plasma-like and Plasma cells were more abundant in good responders and correlated with the same RNA-seq-defined fraction. Finally, we generated a 15-gene prediction model that outperformed the current reference score in eight ICB-treated metastatic melanoma cohorts. The evidenced major contribution of basal intratumoral IGKC and Plasma cells in good response and outcome in ICB in metastatic melanoma is a groundbreaking finding in the field beyond the role of T lymphocytes.

PMID:36012390 | DOI:10.3390/ijms23169124

Int J Environ Res Public Health. 2022 Aug 17;19(16):10173. doi: 10.3390/ijerph191610173.

ABSTRACT

TTN encodes the third myofilament, titin, which plays structural, mechanical, regulatory, and developmental roles in sarcomeres. The aim of this research was to determine the interaction between novel and previously described TTN variants and athletic performance, as well as competition level, in Caucasians. Firstly, 100 athletes and 47 controls were recruited, and whole-genome sequencing was performed. Secondly, 348 athletes (108 endurance, 100 sprint/power, 140 mixed-sport athletes) and 403 volunteers were included, and real-time PCR was performed. We found a significant overrepresentation of the rs10497520 CT and TT genotypes in the sprint/power athlete group (95% CI, 1.41-3.66, p = 0.0013). The rs10497520 T carriers were 2.17 times more likely to become sprint/power athletes (95% CI 1.35-3.49, p = 0.0021). We also found that the likelihood of having the TT genotype was higher for the highly elite and sub-elite sprint/power athletes. Possessing at least one TAA (rs10497520, rs55837610, rs72648256) haplotype resulted in an increase in the log-odds ratio by 0.80 (p = 0.0015), 1.42 (p = 0.003), and 0.77 (p = 0.044) for all, highly elite, and sub-elite sprint/power athletes, respectively. We demonstrated that harbouring the rs10497520 T allele, individually and in a haplotype combination, increased the chance of being an elite sprint/power athlete, indicating that this allele may be favourable for sprint/power performance.

PMID:36011809 | DOI:10.3390/ijerph191610173

Int J Environ Res Public Health. 2022 Aug 15;19(16):10073. doi: 10.3390/ijerph191610073.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) and personalized medicine embrace the potential to optimize drug treatment and improve the patient's quality of life. Pharmacists' roles include contributing to genetic testing, patient counseling, and pharmacotherapies selection for superior treatment outcomes. The aim of this study is to assess the pharmacists' knowledge, insight, and self-confidence toward PGx testing, identify their future preferred education patterns, and determine the barriers to pharmacogenomic testing implementation.

METHOD: A cross-sectional study was conducted using a previously validated questionnaire among pharmacists working in the Kingdom of Saudi Arabia (KSA). The questionnaire was designed in seven major categories, consisting of 26 questions.

RESULTS: A total of 671 pharmacists participated in this survey. As for knowledge, only 29.8% of pharmacists had good knowledge regarding PGx, while 42.9% had poor knowledge levels. Respectable PGx knowledge was significantly higher among outpatient dispensing pharmacists (33.6%; p = 0.049) and among pharmacists who had completed PGx testing-related training or education (40.3%; p = 0.001). Considering perception, it was positive among 50% of pharmacists and negative among 19.8%. With regard to self-confidence, it was high among 39.2% of male pharmacists (p = 0.042), among 43% of clinical pharmacists (p = 0.006), and among 44.8% of pharmacists who had extra credentials (p = 0.001). The utmost favored continuing-education learning approaches were workshops or seminars. The barriers to the implementation of PGx testing included a lack of testing devices, clinical guidelines, training or education, and personnel.

CONCLUSION: The present study revealed that pharmacists in KSA had inadequate knowledge and understanding of PGx. Nevertheless, the majority established that PGx is a valuable tool for augmenting drug efficacy and safety.

PMID:36011723 | DOI:10.3390/ijerph191610073

Genes (Basel). 2022 Aug 5;13(8):1394. doi: 10.3390/genes13081394.

ABSTRACT

OBJECTIVE: This study describes the single nucleotide polymorphisms (SNPs) in amlodipine-associated genes and assesses their correlation with blood pressure control among South African adults with hypertension.

METHODS: In total, 304 hypertensive patients on amlodipine treatment belonging to the indigenous Swati, Xhosa and Zulu population groups of South Africa were recruited between June 2017 and June 2019. Participants were categorized into: controlled (blood pressure < 140/90 mmHg) and uncontrolled (blood pressure ≥ 140/90 mmHg) hypertension. Thirteen SNPs in amlodipine pharmacogenes with a high PharmGKB evidence base were selected and genotyped using MassArray (Agena BioscienceTM). Logistic regression was fitted to identify significant associations between the SNPs and blood pressure control with amlodipine.

RESULTS: The majority of the participants were females (76.6%), older than 45 years (89.1%) and had uncontrolled hypertension (52.3%). Of the 13 SNPs genotyped, five SNPs, rs1042713 (minor allele frequency = 45.9%), rs10494366 (minor allele frequency = 35.3%), rs2239050 (minor allele frequency = 28.7%), rs2246709 (minor allele frequency = 51.6%) and rs4291 (minor allele frequency = 34.4%), were detected among the Xhosa participants, while none were detected among the Swati and Zulu tribal groups. Variants rs1042713 and rs10494366 demonstrated an expression frequency of 97.5% and 79.5%, respectively. Variant TA genotype of rs4291 was significantly associated with uncontrolled hypertension. No association was established between blood pressure response to amlodipine and the remaining four SNPs.

CONCLUSIONS: This study reports the discovery of five SNPs in amlodipine genes (rs2239050, rs2246709, rs4291, rs1042713 and rs10494366) among the indigenous Xhosa-speaking tribe of South Africa. In addition, the TA genotype of rs4291 was associated with blood pressure control in this cohort. These findings might open doors for more pharmacogenomic studies, which could inform innovations to personalised anti-hypertensive treatment in the ethnically diverse population of South Africa.

PMID:36011305 | DOI:10.3390/genes13081394

Cancers (Basel). 2022 Aug 14;14(16):3922. doi: 10.3390/cancers14163922.

ABSTRACT

Despite the fact that the incidence of gastric cancer has declined over the last decade, it is still the world's leading cause of cancer-related death. The diagnosis of early gastric cancer is difficult, as symptoms of this cancer only manifest at a late stage of cancer progression. Thus, the prognosis of gastric cancer is poor, and the current treatment for improving patients' outcomes involves the application of surgery and chemotherapy. Immunotherapy is one of the most recent therapies for gastric cancer, whereby the immune system of the host is programmed to combat cancer cells, and the therapy differs based upon the patient's immune system. However, an understanding of the role of immune cells, namely the cell-mediated immune response and the humoral immune response, is pertinent for applications of immunotherapy. The roles of immune cells in the prognosis of gastric cancer have yielded conflicting results. This review discusses the roles of immune cells in gastric cancer pathogenesis, specifically, T cells, B cells, macrophages, natural killer cells, and dendritic cells, as well as the evidence presented thus far. Understanding how cancer cells interact with immune cells is of paramount importance in designing treatment options for gastric cancer immunotherapy.

PMID:36010915 | DOI:10.3390/cancers14163922

Cells. 2022 Aug 19;11(16):2586. doi: 10.3390/cells11162586.

ABSTRACT

Despite the general awareness of the need to reduce air pollution, the efforts were undertaken in Poland to eliminate the pollutants and their harmful effect on human health seem to be insufficient. Moreover, the latest data indicate that the city of Krakow is at the forefront of the most polluted cities worldwide. Hence, in this report, we investigated the impact of particulate matter isolated from the air of Krakow (PM KRK) on the gene expression profile of peripheral blood mononuclear cells (PBMCs) in healthy donors (HD) and patients with atherosclerosis (AS), rheumatoid arthritis (RA) and multiple sclerosis (MS), after in vitro exposure. Blood samples were collected in two seasons, differing in the concentration of PM in the air (below or above a daily limit of 50 µg/m3 for PM 10). Data show that PBMCs exposed in vitro to PM KRK upregulated the expression of genes involved, among others, in pro-inflammatory response, cell motility, and regulation of cell metabolism. The transcriptional effects were observed predominantly in the group of patients with AS and MS. The observed changes seem to be dependent on the seasonal concentration of PM in the air of Krakow and may suggest their important role in the progression of AS, MS, and RA in the residents of Krakow.

PMID:36010662 | DOI:10.3390/cells11162586

Diagnostics (Basel). 2022 Aug 22;12(8):2025. doi: 10.3390/diagnostics12082025.

ABSTRACT

Preterm premature rupture of the membranes (PPROM) at the limit of viability is associated with low neonatal survival rates and a high rate of neonatal complications in survivors. It carries a major risk of maternal morbidity and mortality. The limit of viability can be defined as the earliest stage of fetal maturity when a fetus has a reasonable chance, although not a high likelihood, for extra-uterine survival. The study reviews available data on preventing preterm delivery caused by the previable PPROM, pregnancy latency, therapeutic options including the use of antibiotics and steroids, neonatal outcomes, and future directions and opportunities.

PMID:36010375 | DOI:10.3390/diagnostics12082025

Antioxidants (Basel). 2022 Aug 19;11(8):1609. doi: 10.3390/antiox11081609.

ABSTRACT

The coronavirus disease (COVID-19) pandemic is a leading global health and economic challenge. What defines the disease's progression is not entirely understood, but there are strong indications that oxidative stress and the defense against reactive oxygen species are crucial players. A big influx of immune cells to the site of infection is marked by the increase in reactive oxygen and nitrogen species. Our article aims to highlight the critical role of oxidative stress in the emergence and severity of COVID-19 and, more importantly, to shed light on the underlying molecular and genetic mechanisms. We have reviewed the available literature and clinical trials to extract the relevant genetic variants within the oxidative stress pathway associated with COVID-19 and the anti-oxidative therapies currently evaluated in the clinical trials for COVID-19 treatment, in particular clinical trials on glutathione and N-acetylcysteine.

PMID:36009328 | DOI:10.3390/antiox11081609

Antioxidants (Basel). 2022 Aug 19;11(8):1602. doi: 10.3390/antiox11081602.

ABSTRACT

Repetitive seizures, a common phenomenon in diverse neurologic conditions such as epilepsy, can undoubtedly cause neuronal injury and our prior work reveals that ferroptosis is a contributing factor of neuronal damage post seizure. However, there is no drug available in clinical practice for ameliorating seizure-induced neuronal impairment via targeting ferroptosis. Our present work aimed to explore whether D-penicillamine (DPA), an originally approved drug for treating Wilson's disease, inhibited neuronal ferroptosis and alleviated seizure-associated brain damage. Our findings revealed that DPA remarkably improved neuronal survival in kainic acid (KA)-treated mouse model. Furthermore, ferroptosis-associated indices including acyl-coA synthetase long chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (Ptgs2) gene and lipid peroxide (LPO) level were significantly decreased in KA mouse model after DPA treatment. In a ferroptotic cell death model induced by glutamate or erastin, DPA was also validated to evidently suppress neuronal ferroptosis. The results from RNA-seq analysis indicated that Aqp11, a gene coding previously reported channel protein responsible for transporting water and small solutes, was identified as a molecular target by which DPA exerted anti-ferroptotic potential in neurons. The experimental results from in vivo Aqp11 siRNA transfer into the brain also confirmed that knockdown of Aqp11 abrogated the inhibitory effect of seizure-induced ferroptosis after DPA treatment, suggesting that the effects of DPA on ferroptosis process are dependent upon Aqp11. In conclusion, DPA can be repurposed to cure seizure disorders such as epilepsy.

PMID:36009321 | DOI:10.3390/antiox11081602

Trends Pharmacol Sci. 2022 Aug 22:S0165-6147(22)00171-7. doi: 10.1016/j.tips.2022.07.002. Online ahead of print.

ABSTRACT

Recent advances in next-generation sequencing (NGS) have resulted in the identification of tens of thousands of rare pharmacogenetic variations with unknown functional effects. However, although such pharmacogenetic variations have been estimated to account for a considerable amount of the heritable variability in drug response and toxicity, accurate interpretation at the level of the individual patient remains challenging. We discuss emerging strategies and concepts to close this translational gap. We illustrate how massively parallel experimental assays, artificial intelligence (AI), and machine learning can synergize with population-scale biobank projects to facilitate the interpretation of NGS data to individualize clinical decision-making and personalized medicine.

PMID:36008164 | DOI:10.1016/j.tips.2022.07.002

Prog Mol Biol Transl Sci. 2022;190(1):147-188. doi: 10.1016/bs.pmbts.2022.04.001. Epub 2022 May 23.

ABSTRACT

Epilepsy is a common neurological disorder affecting over 50 million people worldwide. Although more than 20 new anti-seizure medications have been developed in the past three decades, about one-third of patients still experience recurrent seizures. The heterogeneity of epilepsy types and the highly variable inter-individual response to the therapies makes disease management challenging. A precision medicine approach of treatment for epilepsy patients that considers individual patient characteristics has long been advocated. With advances in DNA sequencing technology, it has been estimated than >30% of all epilepsy syndromes have genetic components. Here we summarize recent approaches in genetic testing and current personalized treatments that are already applicable in genetic epilepsy syndromes. We also discuss current precision therapy utilized in personalized pharmacogenomics, as well as tailored treatment with neuromodulation for epilepsy patients. In the near future, we envision precision medicine in epilepsy will be applicable on a large scale involving not only targeted therapies, but also diagnosis, prognosis, and comorbidity management.

PMID:36007998 | DOI:10.1016/bs.pmbts.2022.04.001

Aging (Albany NY). 2022 Aug 24;14(undefined). doi: 10.18632/aging.204244. Online ahead of print.

ABSTRACT

BACKGROUND: Recent studies identified correlations between splicing factors (SFs) and tumor progression and therapy. However, the potential roles of SFs in immune regulation and the tumor microenvironment (TME) remain unknown.

METHODS: We used UpSet plots to screen for prognostic-related alternative splicing (AS) events. We evaluated SF patterns in specific immune landscapes. Single sample gene set enrichment analysis (ssGSEA) algorithms were used to quantify relative infiltration levels in immune cell subsets. Principal component analysis (PCA) algorithm-based SFscore were used to evaluate SF patterns in individual tumors with an immune response.

RESULTS: From prognosis-related AS events, 16 prognosis-related SFs were selected to construct three SF patterns. Further TME analyses showed these patterns were highly consistent with immune-inflamed, immune-excluded, and immune-desert landscapes. Based on SFscore constructed using differentially expressed genes (DEGs) between SF patterns, patients were classified into two immune-subtypes associated with differential pharmacogenomic landscapes and cell features. A low SFscore was associated with high immune cell infiltration, high tumor mutation burden (TMB), and elevated expression of immune check points (ICPs), indicating a better immune response.

CONCLUSIONS: SFs are significantly associated with TME remodeling. Evaluating different SF patterns enhances our understanding of the TME and improves effective immunotherapy strategies.

PMID:36006412 | DOI:10.18632/aging.204244

Pharmacy (Basel). 2022 Aug 5;10(4):95. doi: 10.3390/pharmacy10040095.

ABSTRACT

Currently, metastatic colon cancer is treated with monotherapeutic regimens such as folinic acid, fluorouracil, and oxaliplatin (FOLFOX), capecitabine and oxaliplatin (CapeOX), and leucovorin, fluorouracil, and irinotecan hydrochloride (FOLFIRI). Other treatments include biological therapies and immunotherapy with drugs such as bevacizumab, panitumumab, cetuximab, and pembrolizumab. After the research, it was found that some mutations make those treatments not as effective in all patients. In this bibliographic review, we investigated the pharmacogenetic explanations for how mutations in the genes coding for rat sarcoma virus (RAS) and rapidly accelerated fibrosarcoma (RAF) reduce the effectiveness of these treatments and allow the continued proliferation of tumors. Furthermore, we note that patients with mutations in the dihydropyrimidine dehydrogenase (DPDY) gene usually require lower doses of therapies such as 5-fluorouracyl (5-FU) and capecitabine to avoid severe adverse effects. Some other mutations in the thymidylate synthase gene (TSYM), methylenetetrahydrofolate reductase gene (MTHFR), and ATP binding cassette transporter B (ABCB1 and ABCB2) affect efficacy and security of the treatments. It is important to address the clinical implication of the oncologist in the study of gene mutations than can influence in the antitumoral response and safety of colon cancer treatments.

PMID:36005935 | DOI:10.3390/pharmacy10040095

Immunol Cell Biol. 2022 Aug 25. doi: 10.1111/imcb.12581. Online ahead of print.

ABSTRACT

Alloreactive CD4+ T cells play a central role in allograft rejection. However, the post-transcriptional regulation of the effector program in alloreactive CD4+ T cells is unclear. N6 -methyladenosine (m6 A) RNA modification is involved in various physiological and pathological processes. Herein, we investigated whether m6 A methylation plays a role in the allogeneic T-cell effector program. m6 A levels of CD4+ T cells from spleens, draining lymph nodes and skin allografts were determined in a skin transplantation model. The effects of a METTL3 inhibitor STM2457 on CD4+ T-cell characteristics including proliferation, cell cycle, cell apoptosis and effector differentiation were determined after stimulation of polyclonal and alloantigen-specific (TEa; TCR transgenic) CD4+ T cells with α-CD3/α-CD28 mAbs and cognate CB6F1 alloantigen, respectively. We found that graft-infiltrating CD4+ T cells expressed high m6 A levels. Administration of STM2457 reduced m6 A levels, inhibited T-cell proliferation, and suppressed effector differentiation of polyclonal CD4+ T cells. Alloreactive TEa cells challenged with 40μM STM2457 exhibited deficits in T-cell proliferation and Th1 cell differentiation, a cell cycle arrest in the G0 phase, and elevated cell apoptosis. Moreover, these impaired T-cell responses were associated with the diminished expression levels of transcription factors Ki67, c-Myc and T-bet. Therefore, METTL3 inhibition reduces the expression of several key transcriptional factors for the T-cell effector program and suppresses alloreactive CD4+ T-cell effector function and differentiation. Targeting m6 A-related enzymes and molecular machinery in CD4+ T-cells represents an attractive therapeutic approach to prevent allograft rejection.

PMID:36005900 | DOI:10.1111/imcb.12581