Genes (Basel). 2023 Jan 23;14(2):296. doi: 10.3390/genes14020296.

ABSTRACT

A limited number of studies are devoted to regulating TRIP6 expression in cancer. Hence, we aimed to unveil the regulation of TRIP6 expression in MCF-7 breast cancer cells (with high TRIP6 expression) and taxane-resistant MCF-7 sublines (manifesting even higher TRIP6 expression). We found that TRIP6 transcription is regulated primarily by the cyclic AMP response element (CRE) in hypomethylated proximal promoters in both taxane-sensitive and taxane-resistant MCF-7 cells. Furthermore, in taxane-resistant MCF-7 sublines, TRIP6 co-amplification with the neighboring ABCB1 gene, as witnessed by fluorescence in situ hybridization (FISH), led to TRIP6 overexpression. Ultimately, we found high TRIP6 mRNA levels in progesterone receptor-positive breast cancer and samples resected from premenopausal women.

PMID:36833223 | DOI:10.3390/genes14020296

Cancers (Basel). 2023 Feb 18;15(4):1306. doi: 10.3390/cancers15041306.

ABSTRACT

ESR1 mutations contribute to endocrine resistance and occur in a high percentage of hormone-receptor-positive (HR+) metastatic breast cancer (mBC) cases. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) changed the treatment landscape of HR+ mBC, as they are able to overcome estrogen resistance. The present retrospective study investigates the clinical benefit of CDK4/6i in ESR1 mutant HR+ mBC patients treated with a CDK4/6i as first- or second-line therapy. Plasma was collected at baseline prior to CDK4/6i plus hormone therapy as a first- or second-line treatment. Circulating free DNA (cfDNA) was extracted from plasma, and ESR1 mutation analysis was performed on a ddPCR. Statistical analyses were performed to investigate the predictive power of ESR1 mutations and any association with clinical factors. A total of 42 patients with mBC treated with CDK4/6i plus endocrine therapy as first- (n = 35) or second-line (n = 7) were enrolled. Twenty-eight patients received hormonal therapy (AI or tamoxifen) in the adjuvant setting. ESR1 mutation status in blood was associated with shorter median disease-free survival (DFS) (30 vs. 110 months; p = 0.006). Multivariate analysis confirmed ESR1 mutations as independent factors of resistance in adjuvant hormone therapy. On the contrary, no difference in progression-free survival (PFS) was observed in the presence or absence of an ESR1 mutation in patients treated with CDK4/6i as first-line treatment (p = 0.29). No statistically significant correlation between the best response to CDK4/6i and ESR1 mutation was found (p = 0.46). This study indicates that the ESR1 mutation detected in cfDNA is an independent predictive factor of clinical recurrence in the adjuvant setting and that CDK4/6i can overcome ESR1-dependent resistance.

PMID:36831647 | DOI:10.3390/cancers15041306

Cancers (Basel). 2023 Feb 8;15(4):1087. doi: 10.3390/cancers15041087.

ABSTRACT

Molecular diagnostic tests help clinicians understand the underlying biological mechanisms of their patients' breast cancer (BC) and facilitate clinical management. Several tissue-based mRNA tests are used routinely in clinical practice, particularly for assessing the BC recurrence risk, which can guide treatment decisions. However, blood-based mRNA assays have only recently started to emerge. This review explores the commercially available blood mRNA diagnostic assays for BC. These tests enable differentiation of BC from non-BC subjects (Syantra DX, BCtect), detection of small tumours <10 mm (early BC detection) (Syantra DX), detection of different cancers (including BC) from a single blood sample (multi-cancer blood test Aristotle), detection of BC in premenopausal and postmenopausal women and those with high breast density (Syantra DX), and improvement of diagnostic outcomes of DNA testing (variant interpretation) (+RNAinsight). The review also evaluates ongoing transcriptomic research on exciting possibilities for future assays, including blood transcriptome analyses aimed at differentiating lymph node positive and negative BC, distinguishing BC and benign breast disease, detecting ductal carcinoma in situ, and improving early detection further (expression changes can be detected in blood up to eight years before diagnosing BC using conventional approaches, while future metastatic and non-metastatic BC can be distinguished two years before BC diagnosis).

PMID:36831426 | DOI:10.3390/cancers15041087

Cells. 2023 Feb 20;12(4):667. doi: 10.3390/cells12040667.

ABSTRACT

Members of the activator protein 2 (AP-2) transcription factor (TF) family are known to play a role in both physiological processes and cancer development. The family comprises five DNA-binding proteins encoded by the TFAP2A to TFAP2E genes. Numerous scientific reports describe differential expression of these TF and their genes in various types of cancer, identifying among them a potential oncogene or suppressor like TFAP2A or TFAP2C. Other reports suggest their influence on disease development and progression, as well as response to treatment. Not all members of this AP-2 family have been comprehensively studied thus far. The aim of the present article is to gather and discuss knowledge available in bioinformatics databases regarding all five members of this family and to differentiate them in relation to the two most common lung cancer subtypes: adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). In addition, to assess the difference in levels depending on a number of clinicopathological factors, the impact on patient survival and interactions with tumor-infiltrating immune cells. This article may help to identify the target for further original research that may contribute to the discovery of new diagnostic biomarkers and define the molecular differences between LUAD and LUSC, which may affect the therapy effectiveness improvement and longer survival.

PMID:36831334 | DOI:10.3390/cells12040667

Cells. 2023 Feb 8;12(4):547. doi: 10.3390/cells12040547.

ABSTRACT

Glioblastoma's (GBM) aggressive growth is driven by redundant activation of a myriad of signaling pathways and genomic alterations in tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), which is altered in over 50% of cases. Single agents targeting EGFR have not proven effective against GBM. In this study, we aimed to identify an effective anti-tumor regimen using pharmacogenomic testing of patient-derived GBM samples, in culture and in vivo. High-throughput pharmacological screens of ten EGFR-driven GBM samples identified the combination of erlotinib (EGFRi) and MLN0128 (a mammalian target of rapamycin inhibitor, or MTORi) as the most effective at inhibiting tumor cell viability. The anti-tumor activity of erlonitib+MLN0128 was synergistic and produced inhibition of the p-EGFR, mitogen-activated protein kinase (MAPK), and Phosphoinositide 3-kinase (PI3K) pathways in culture. Using an orthotopic murine model of GBM, we show that erlotinib+MLN0128 inhibited tumor growth in vivo and significantly prolonged the survival of tumor-bearing mice. Expression profiling of tumor tissues from treated mice revealed a unique gene signature induced by erlotinib+MLN0128, consisting of downregulation of immunosuppressive chemokines in the tumor microenvironment, including C-C motif chemokine ligand 2 (CCL2) and periostin. Lower periostin levels resulted in the inhibition of Iba1+ (tumor-promoting) macrophage infiltration of GBM xenografts. Taken together, our results demonstrate that pharmacological co-targeting of EGFR and MTOR using clinically available drugs represents an effective treatment paradigm for EGFR-driven GBMs, acting both by inhibiting tumor cell growth and modulating the immune tumor microenvironment.

PMID:36831214 | DOI:10.3390/cells12040547

Antioxidants (Basel). 2023 Jan 29;12(2):316. doi: 10.3390/antiox12020316.

ABSTRACT

Oxidative stress and neuroinflammation are important processes involved in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Numerous risk factors, including genetic background, can affect the complex interplay between those mechanisms in the aging brain and can also affect typical AD hallmarks: amyloid plaques and neurofibrillary tangles. Our aim was to evaluate the association of polymorphisms in oxidative stress- and inflammation-related genes with cerebrospinal fluid (CSF) biomarker levels and cognitive test results. The study included 54 AD patients, 14 MCI patients with pathological CSF biomarker levels, 20 MCI patients with normal CSF biomarker levels and 62 controls. Carriers of two polymorphic IL1B rs16944 alleles had higher CSF Aβ1-42 levels (p = 0.025), while carriers of at least one polymorphic NFE2L2 rs35652124 allele had lower CSF Aβ1-42 levels (p = 0.040). Association with IL1B rs16944 remained significant in the AD group (p = 0.029). Additionally, MIR146A rs2910164 was associated with Aβ42/40 ratio (p = 0.043) in AD. Significant associations with cognitive test scores were observed for CAT rs1001179 (p = 0.022), GSTP1 rs1138272 (p = 0.005), KEAP1 rs1048290 and rs9676881 (both p = 0.019), as well as NFE2L2 rs35652124 (p = 0.030). In the AD group, IL1B rs1071676 (p = 0.004), KEAP1 rs1048290 and rs9676881 (both p = 0.035) remained associated with cognitive scores. Polymorphisms in antioxidative and inflammation genes might be associated with CSF biomarkers and cognitive test scores and could serve as additional biomarkers contributing to early diagnosis of dementia.

PMID:36829875 | DOI:10.3390/antiox12020316

Bioengineering (Basel). 2023 Jan 23;10(2):153. doi: 10.3390/bioengineering10020153.

ABSTRACT

Mass detection in mammograms has a limited approach to the presence of a mass in overlapping denser fibroglandular breast regions. In addition, various breast density levels could decrease the learning system's ability to extract sufficient feature descriptors and may result in lower accuracy performance. Therefore, this study is proposing a textural-based image enhancement technique named Spatial-based Breast Density Enhancement for Mass Detection (SbBDEM) to boost textural features of the overlapped mass region based on the breast density level. This approach determines the optimal exposure threshold of the images' lower contrast limit and optimizes the parameters by selecting the best intensity factor guided by the best Blind/Reference-less Image Spatial Quality Evaluator (BRISQUE) scores separately for both dense and non-dense breast classes prior to training. Meanwhile, a modified You Only Look Once v3 (YOLOv3) architecture is employed for mass detection by specifically assigning an extra number of higher-valued anchor boxes to the shallower detection head using the enhanced image. The experimental results show that the use of SbBDEM prior to training mass detection promotes superior performance with an increase in mean Average Precision (mAP) of 17.24% improvement over the non-enhanced trained image for mass detection, mass segmentation of 94.41% accuracy, and 96% accuracy for benign and malignant mass classification. Enhancing the mammogram images based on breast density is proven to increase the overall system's performance and can aid in an improved clinical diagnosis process.

PMID:36829647 | DOI:10.3390/bioengineering10020153

Pharmacy (Basel). 2023 Feb 5;11(1):29. doi: 10.3390/pharmacy11010029.

ABSTRACT

Non-vitamin K antagonist oral anticoagulants' interindividual trough concentration variability affects efficacy and safety, especially in bleeding events. Rivaroxaban is metabolised via CYP3A4/5-, CYP2J2-, and CYP-independent mechanisms and is a substrate of two transporter proteins: ABCB1 (MDR1, P-glycoprotein) and ABCG2 (BCRP; breast-cancer-resistance protein). The polymorphisms of these genes may possibly affect the pharmacokinetics of rivaroxaban and, consequently, its safety profile. Rivaroxaban variability may be associated with age, liver and kidney function, concomitant illness and therapy, and pharmacogenetic predisposition. This case series is the first, to our knowledge, that presents multiple risk factors for rivaroxaban-related bleeding (RRB) including age, renal function, concomitant diseases, concomitant treatment, and pharmacogenetic data. It presents patients with RRB, along with their complete clinical and pharmacogenetic data, as well as an evaluation of possible risk factors for RRB. Thirteen patients were carriers of ABCB1, ABCG2, CYP2J2, and/or CYP3A4/5 gene polymorphisms. Possible drug-drug interactions with increased bleeding risk were identified in nine patients. Six patients had eGFR <60 mL/min/1.73 m2. Our data suggest a possible role of multiple factors and their interactions in predicting RRB; however, they also indicate the need for further comprehensive multidisciplinary research to enable safer use of this product based on a personalised approach.

PMID:36827667 | DOI:10.3390/pharmacy11010029

PLoS One. 2023 Feb 24;18(2):e0274339. doi: 10.1371/journal.pone.0274339. eCollection 2023.

ABSTRACT

We present allele frequencies of pharmacogenomics relevant variants across multiple ancestry in a sample representative of the US population. We analyzed 658,582 individuals with genotype data and extracted pharmacogenomics relevant single nucleotide variant (SNV) alleles, human leukocyte antigens (HLA) 4-digit alleles and an important copy number variant (CNV), the full deletion/duplication of CYP2D6. We compiled distinct allele frequency tables for European, African American, Hispanic, and Asian ancestry individuals. In addition, we compiled allele frequencies based on local ancestry reconstruction in the African-American (2-way deconvolution) and Hispanic (3-way deconvolution) cohorts.

PMID:36827430 | DOI:10.1371/journal.pone.0274339

Pediatr Allergy Immunol. 2023 Feb;34(2):e13919. doi: 10.1111/pai.13919.

ABSTRACT

BACKGROUND: Uncontrolled asthma can lead to severe exacerbations and reduced quality of life. Research has shown that the microbiome may be linked with asthma characteristics; however, its association with asthma control has not been explored. We aimed to investigate whether the gastrointestinal microbiome can be used to discriminate between uncontrolled and controlled asthma in children.

METHODS: 143 and 103 feces samples were obtained from 143 children with moderate-to-severe asthma aged 6 to 17 years from the SysPharmPediA study. Patients were classified as controlled or uncontrolled asthmatics, and their microbiome at species level was compared using global (alpha/beta) diversity, conventional differential abundance analysis (DAA, analysis of compositions of microbiomes with bias correction), and machine learning [Recursive Ensemble Feature Selection (REFS)].

RESULTS: Global diversity and DAA did not find significant differences between controlled and uncontrolled pediatric asthmatics. REFS detected a set of taxa, including Haemophilus and Veillonella, differentiating uncontrolled and controlled asthma with an average classification accuracy of 81% (saliva) and 86% (feces). These taxa showed enrichment in taxa previously associated with inflammatory diseases for both sampling compartments, and with COPD for the saliva samples.

CONCLUSION: Controlled and uncontrolled children with asthma can be differentiated based on their gastrointestinal microbiome using machine learning, specifically REFS. Our results show an association between asthma control and the gastrointestinal microbiome. This suggests that the gastrointestinal microbiome may be a potential biomarker for treatment responsiveness and thereby help to improve asthma control in children.

PMID:36825736 | DOI:10.1111/pai.13919

Oxid Med Cell Longev. 2022 Feb 3;2022:2041769. doi: 10.1155/2022/2041769. eCollection 2022.

ABSTRACT

The genus Papaver is highly esteemed in the pharmacy industry, in the culinary field, and as ornamental plants. These plants are also valued in traditional medicine. Among all Papaver species, Papaver somniferum L. (opium poppy) is the most important species in supplying phytochemicals for the formulation of drugs, mainly alkaloids like morphine, codeine, rhoeadine, thebaine, and papaverine. In addition, Papaver plants present other types of phytochemicals, which altogether are responsible for its biological activities. Therefore, this review covers the phytochemical composition of Papaver plants, including alkaloids, phenolic compounds, and essential oils. The traditional uses are reviewed along with their pharmacological activities. Moreover, safety aspects are reported to provide a deep overview of the pharmacology potential of this genus. An updated search was carried out in databases such as Google Scholar, ScienceDirect, and PubMed to retrieve the information. Overall, this genus is a rich source of alkaloids of different types and also contains interesting phenolic compounds, such as anthocyanins, flavonols, and the characteristic indole derivatives nudicaulins. Among other pharmacological properties, numerous preclinical studies have been published about the analgesic, anticancer, antimicrobial, antioxidant, and antidiabetic activities of Papaver plants. Although it highlights the significant impact of this genus for the treatment of a variety of diseases and conditions, as a future prospect, characterization works accompanying preclinical studies are required along with clinical and toxicology studies to establish a correlation between the scientific and traditional knowledge.

PMID:36824615 | PMC:PMC9943628 | DOI:10.1155/2022/2041769

Front Oncol. 2023 Feb 3;13:1010132. doi: 10.3389/fonc.2023.1010132. eCollection 2023.

ABSTRACT

Cervical cancer (CC) remains one of the leading causes of cancer-related deaths worldwide. However, cervical cancer is preceded by the pre-malignant cervical intraepithelial neoplasia (CIN) that can last for up to 20 years before becoming malignant. Therefore, early screening is the key to prevent the progression of cervical lesions into invasive cervical cancer and decrease the incidence. The genes, down-regulated and hypermethylated in cancers, may provide potential drug targets for cervical cancer. In our current study, using the datasets from Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases, we found that endothelin 3 (EDN3) was downregulated and hypermethylated in cervical squamous cell carcinoma (CSCC). The further analysis in GSE63514 (n=128) dataset and in our samples (n=221) found that the expression of EDN3 was decreased with the degree of cervical lesions. Pyrosequencing was performed to evaluate 4 CpG sites of the EDN3 promoter region in our samples (n=469). The data indicated that the methylation level of EDN3 was increased with the degree of cervical lesions. EDN3 silencing mediated by methylation can be blocked by 5-Azacytidine (5-Aza), a DNA methyltransferase 1 (DNMT1) inhibitor, treatment in cervical cancer cell lines. Ethynyldeoxyuridine (EdU) assay, would-healing assay, clone formation assay and transwell assay were conducted to investigate the biological function of EDN3 in cervical cancer cell lines. The results of these experiments confirmed that overexpression of EDN3 could inhibit the proliferation, clone formation, migration and invasion of cervical cancer cells. EDN3 may provide potential biomarker and therapeutic target for CSCC.

PMID:36824133 | PMC:PMC9942821 | DOI:10.3389/fonc.2023.1010132

Obstet Gynecol Clin North Am. 2023 Mar;50(1):1-15. doi: 10.1016/j.ogc.2022.10.012.

ABSTRACT

Since the recognition of pregnancy as a special pharmacokinetic population in the late 1990s, investigations have expanded our understanding of obstetric pharmacology. Many of the basic physiologic changes that occur during pregnancy impact on drug absorption, distribution, or clearance. Activities of hepatic metabolizing enzymes are variably altered by pregnancy, resulting in concentrations sufficiently different for some drugs that efficacy or toxicity may be affected. Understanding these unique pharmacologic changes will better inform our use of medications for our pregnant patients.

PMID:36822695 | DOI:10.1016/j.ogc.2022.10.012

Cancer Treat Rev. 2023 Feb 14;115:102525. doi: 10.1016/j.ctrv.2023.102525. Online ahead of print.

ABSTRACT

Non-metastatic castration resistant prostate cancer (nmCRPC) is a clinical setting defined as confirmed rising levels of PSA in patients treated with ADT but without detectable metastases on conventional imaging with computerized tomography (CT) and technetium-99 m scintigraphy. Men with nmCRPC and a PSA doubling time (PSADT) ≤ 10 months are considered at high risk of rapidly developing metastases with a consequent possible impact on survival. Three recent phase III trials have demonstrated, in this setting, the efficacy of adding a next-generation androgen receptor targeted agent (ARTA) to ADT in respect to ADT only, in delaying the development of metastases (metastasis-free survival, MFS) and prolong overall survival. The magnitude of clinical benefit of these agents was even more meaningful if considering the low incidence of drug related adverse events. Our review described the latest advances in the management of nmCRPC, deriving from the pivotal clinical trials, SPARTAN, PROSPER and ARAMIS, in order to support clinicians to optimally manage these patients. Of note, the emergence of novel, more accurate, next-generation imaging techniques (including Ga PSMA-PET/CT), as well as eventual future tumor biomarkers, is modifying the entity and definition of the nmCRPC setting, with a consequent impact on patient's diagnosis and management.

PMID:36822009 | DOI:10.1016/j.ctrv.2023.102525

Aging Dis. 2023 Feb 1;14(1):63-83. doi: 10.14336/AD.2022.0621. eCollection 2023 Feb 1.

ABSTRACT

Glia cells are essential for brain functioning during development, aging and disease. However, the role of astroglia plays during brain development is quite different from the role played in the adult lesioned brain. Therefore, a deeper understanding of pathomechanisms underlying astroglia activity in the aging brain and cerebrovascular diseases is essential to guide the development of new therapeutic strategies. To this end, this review provides a comparison between the transcriptomic activity of astroglia cells during development, aging and neurodegenerative diseases, including cerebral ischemia. During fetal brain development, astrocytes and microglia often affect the same developmental processes such as neuro-/gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis, and synaptic pruning. In the adult brain astrocytes are a critical player in the synapse remodeling by mediating synapse elimination while microglia activity has been associated with changes in synaptic plasticity and remove cell debris by constantly sensing the environment. However, in the lesioned brain astrocytes proliferate and play essential functions with regard to energy supply to the neurons, neurotransmission and buildup of a protective scar isolating the lesion site from the surroundings. Inflammation, neurodegeneration, or loss of brain homeostasis induce changes in microglia gene expression, morphology, and function, generally referred to as "primed" microglia. These changes in gene expression are characterized by an enrichment of phagosome, lysosome, and antigen presentation signaling pathways and is associated with an up-regulation of genes encoding cell surface receptors. In addition, primed microglia are characterized by upregulation of a network of genes in response to interferon gamma. Conclusion. A comparison of astroglia cells transcriptomic activity during brain development, aging and neurodegenerative disorders might provide us with new therapeutic strategies with which to protect the aging brain and improve clinical outcome.

PMID:36818562 | PMC:PMC9937697 | DOI:10.14336/AD.2022.0621

Front Pharmacol. 2023 Feb 2;14:1110460. doi: 10.3389/fphar.2023.1110460. eCollection 2023.

ABSTRACT

Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study was to evaluate the impact of 29 alleles in 12 candidate genes (e.g., CYP enzymes like CYP2D6, CYP3A4, or CYP2C19; ABC transporters like ABCB1; SLCO1B1; and UGT enzymes like UGT1A1) on desvenlafaxine pharmacokinetic variability and tolerability. Pharmacokinetic parameters and adverse drug reaction (ADR) incidence obtained from six bioequivalence clinical trials (n = 98) evaluating desvenlafaxine formulations (five with single dose administration and one with multiple-dose administration) were analyzed. No genetic polymorphism was related to pharmacokinetic variability or ADR incidence. Volunteers enrolled in the multiple-dose clinical trial also showed a higher incidence of ADRs, e.g., xerostomia or appetite disorders. Volunteers experiencing any ADR showed a significantly higher area under the time-concentration curve (AUC) than those not experiencing any ADR (5115.35 vs. 4279.04 ng*h/mL, respectively, p = 0.034). In conclusion, the strong dose-dependent relationship with the occurrence of ADRs confirms that the mechanism of action of desvenlafaxine is essentially dose-dependent.

PMID:36817149 | PMC:PMC9934922 | DOI:10.3389/fphar.2023.1110460

Rev Med Suisse. 2023 Feb 22;19(815):380-387. doi: 10.53738/REVMED.2023.19.815.380.

ABSTRACT

Despite the progress in cure rates for pediatric cancers, several challenges remain, such as the management of diseases with poor prognosis. The efficacy of intensified chemotherapies is also accompanied by increased risks of severe acute and chronic toxicities. Thus, therapies specifically targeting tumor cells, or inhibiting oncogenic molecular aberrations, could provide more effective and less toxic treatments for pediatric cancers. Personalization of chemotherapies through pharmacogenetics and precision dosing could also improve the efficacy and toxicity of chemotherapies. In this review, we describe precision medicine strategies implemented or undergoing clinical evaluation in the treatment of pediatric cancers.

PMID:36815329 | DOI:10.53738/REVMED.2023.19.815.380

Front Neurosci. 2023 Feb 6;17:1126970. doi: 10.3389/fnins.2023.1126970. eCollection 2023.

ABSTRACT

INTRODUCTION: Prader-Willi Syndrome (PWS) is a rare genetic condition, which affects one in 25,000 births and results in various phenotypes. It leads to a wide range of metabolic and endocrine disorders including growth delay, hypogonadism, narcolepsy, lack of satiety and compulsive eating, associated with mild to moderate cognitive impairment. Prognosis is especially determined by the complications of obesity (diabetes, cardiorespiratory diseases) and by severe behavioral disorders marked by impulsivity and compulsion. This heterogeneous clinical picture may lead to mis- or delayed diagnosis of comorbidities. Moreover, when diagnosis is made, treatment remains limited, with high interindividual differences in drug response. This may be due to the underlying genetic variability of the syndrome, which can involve several different genetic mutations, notably deletion or uniparental disomy (UPD) in a region of chromosome 15. Here, we propose to determine whether subjects with PWS differ for clinical phenotype and treatment response depending on the underlying genetic anomaly.

METHODS: We retrospectively included all 24 PWS patients who were referred to the Reference Center for Rare Psychiatric Disorders (GHU Paris Psychiatrie and Neurosciences) between November 2018 and July 2022, with either deletion (N = 8) or disomy (N = 16). The following socio-demographic and clinical characteristics were recorded: age, sex, psychiatric and non-psychiatric symptoms, the type of genetic defect, medication and treatment response to topiramate, which was evaluated in terms of eating compulsions and impulsive behaviors. We compared topiramate treatment doses and responses between PWS with deletion and those with disomy. Non-parametric tests were used with random permutations for p-value and bootstrap 95% confidence interval computations.

RESULTS: First, we found that disomy was associated with a more severe clinical phenotype than deletion. Second, we observed that topiramate was less effective and less tolerated in disomy, compared to deletion.

DISCUSSION: These results suggest that a pharmacogenomic-based approach may be relevant for the treatment of compulsions in PWS, thus highlighting the importance of personalized medicine for such complex heterogeneous disorders.

PMID:36814790 | PMC:PMC9939745 | DOI:10.3389/fnins.2023.1126970

Nat Rev Endocrinol. 2023 Feb 17:1-12. doi: 10.1038/s41574-023-00807-6. Online ahead of print.

ABSTRACT

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.

PMID:36805052 | PMC:PMC9936492 | DOI:10.1038/s41574-023-00807-6

Farm Hosp. 2023 Feb 20:S1130-6343(22)00026-5. doi: 10.1016/j.farma.2022.12.017. Online ahead of print.

ABSTRACT

OBJECTIVE: Capecitabine, an antineoplastic drug used in the treatment of breast and colon cancer, can cause severe, even fatal toxicity in some patients. The interindividual variability of this toxicity is largely due to genetic variations in target genes and enzymes of metabolism of this drug, such as thymidylate synthase and dihydropyrimidine dehydrogenase. The enzyme cytidine deaminase (CDA), involved in the activation of capecitabine, also has several variants associated with an increased risk of toxicity to treatment, although its role as a biomarker is not yet clearly defined. Therefore, our main objective is to study the association between the presence of genetic variants in CDA gen, CDA enzymatic activity and the development of severe toxicity in patients treated with capecitabine whose initial dose was adjusted based on the genetic profile of the dihydropyrimidine dehydrogenase gen (DPYD).

METHOD: Prospective multicenter observational cohort study, focused on the analysis of the genotype-phenotype association of the CDA enzyme. After the experimental phase, an algorithm will be developed to determine the dose adjustment needed to reduce the risk of treatment toxicity according to CDA genotype, developing a clinical guide for capecitabine dosing according to genetic variants in DPYD and CDA. Based on this guide, a Bioinformatics Tool will be created to generate the pharmacotherapeutic report automatically, facilitating the implementation of pharmacogenetic advice in clinical practice. This tool will be a great support in making pharmacotherapeutic decisions based on the patient's genetic profile, incorporating precision medicine into clinical routine. Once the usefulness of this tool has been validated, it will be offered free of charge to facilitate the implementation of pharmacogenetics in hospital centers and equitably benefit all patients on capecitabine treatment.

PMID:36813623 | DOI:10.1016/j.farma.2022.12.017