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The article discusses lethal capecitabine toxicity in patients with complete dihydropyrimidine dehydrogenase deficiency due to ultra-rare DPYD variants. It emphasizes the importance of preemptive genetic analysis of DPYD to reduce fluoropyrimidine-related adverse events and highlights the need for comprehensive genotyping and phenotyping strategies for identifying patients at risk of severe toxicity. The study presents two cases of patients with complete DPYD deficiency due to ultra-rare DPYD variants and lethal capecitabine toxicity, underscoring the challenges in predicting severe toxicity in patients with rare DPYD variants. The research advocates for a combined genotyping/phenotyping approach to enhance the safety of fluoropyrimidine-based therapy, even in patients with complete DPYD deficiency. [Extracted from the article]

A DPD deficiency should be considered in case of severe toxicity even in the absence of common risk variants in DPYD. [ABSTRACT FROM AUTHOR]

Summary: Background: Atopic dermatitis (AD) is characterized by immune dysregulations and an impaired skin barrier, including abnormalities in lipid organization. In the stratum corneum (SC), β‐glucocerebrosidase (GBA) mediates transformation of glucosylceramide (GlcCER) into ceramide (CER) and cholesterol into glucosylcholesterol (GlcChol). Alteration in GBA activity might contribute to skin barrier defects in AD. Objectives: To investigate GBA activity in the SC of children with AD before and after topical corticosteroid therapy and to compare it with healthy controls; to determine SC levels of GlcCER‐ and CER‐containing hydroxysphingosine base (GlcCER[H] and CER[H], respectively) and GlcChol; and to relate them to disease severity, skin barrier function and the local cytokine milieu. Methods: Lipid markers and cytokines of innate, T helper 1 and T helper 2 immunity were determined in SC collected from healthy children and from clinically unaffected skin of children with AD, before and after 6 weeks of therapy with topical corticosteroids. AD severity was assessed by Scoring Atopic Dermatitis and skin barrier function by transepidermal water loss (TEWL). Results: Baseline GBA activity and GlcChol levels were increased in children with AD but declined after therapy. CER[H] levels and the CER[H] to GlcCER[H] ratio were increased in AD. GBA activity and GlcChol correlated with TEWL and levels of multiple cytokines, especially interleukin‐1α and interleukin‐18. GlcChol was strongly associated with disease severity. Conclusions: We show increased GBA activity and levels of GlcChol in AD. Our data suggest an important role of inflammation in disturbed lipid processing. GBA activity or GlcChol might be useful biomarkers in the monitoring of therapeutic responses in AD. What is already known about this topic?Patients with atopic dermatitis (AD) have a reduced skin barrier, mainly caused by altered lipid organization.The mechanisms underlying these lipid anomalies are not fully understood but likely reflect both genetic abnormalities in AD skin and the local cutaneous inflammatory environment. What does this study add?We show increased activity of the ceramide‐generating enzyme β‐glucocerebrosidase in AD. Activity of this enzyme was correlated with the local cytokine milieu and declined after local corticosteroid therapy.We show that glucosylcholesterol levels in the stratum corneum are increased in AD.The function of glucosylcholesterol and the physiological consequences of increased levels are not clear yet; however, its levels were strongly correlated with skin barrier function: high transepidermal water loss strongly correlated with high levels of glucosylcholesterol. What is the translational message?Correction of cutaneous inflammation largely restores alterations in lipid metabolism in the stratum corneum of infants with AD. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). Genetic analysis of the ARSA gene is important in MLD diagnosis and screening of family members. In addition, more information on genotype prevalence will help interpreting MLD population differences between countries. In this study, we identified 31 different ARSA variants in the patient cohort (n = 67) of the Dutch expertise center for MLD. The most frequently found variant, c.1283C > T, p.(Pro428Leu), was present in 43 (64%) patients and resulted in a high prevalence of the juvenile MLD type (58%) in The Netherlands. Furthermore, we observed in five out of six patients with a non-Caucasian ethnic background previously unreported pathogenic ARSA variants. In total, we report ten novel variants including four missense, two nonsense, and two frameshift variants and one in-frame indel, which were all predicted to be disease causing in silico. In addition, one silent variant was found, c.1200C > T, that most likely resulted in erroneous exonic splicing, including partial skipping of exon 7. The c.1200C > T variant was inherited in cis with the pseudodeficiency allele c.1055A > G, p.(Asn352Ser) + ∗96A > G. With this study we provide a genetic base of the unique MLD phenotype distribution in The Netherlands. In addition, our study demonstrated the importance of genetic analysis in MLD diagnosis and the increased likelihood of unreported, pathogenic ARSA variants in patients with non-Caucasian ethnic backgrounds. [ABSTRACT FROM AUTHOR]

I DPYD i screening showed that the patient was homozygous for I DPYD i *2A; measurement of DPD activity in PBMCs of this patient indicated absence of DPD activity. Pretreatment identification of the patient homozygous for I DPYD i *2A with complete DPD deficiency saved this patient from receipt of a full fluoropyrimidine dose, which most likely would have been fatal. For patients 2 and 3, samples were collected only on C1D1, on the same time points as for patient 1, except for the latest time point (the sample 10 hours after capecitabine intake was not collected for patient 2, and the last sample was collected at 12 hours instead of at 10 hours for patient 3). For patients 2 and 3, uracil levels were increased compared with reference levels (a value of 28.7 ng/mL for patient 2 and of 35.6 ng/mL for patient 3), and both values were within the top 1% of reference values. [Extracted from the article]

The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C. elegans , independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo , via reduction of translation and ATF-4. [Display omitted] • The anti-retroviral zidovudine extends healthy longevity in C. elegans • Lifespan extension with NRTIs zidovudine and didanosine depends on ATF-4 • Zidovudine alters pyrimidine metabolism and reduces cytosolic translation • ATF-4 regulates reduced translation upon zidovudine treatment McIntyre et al. report on the longevity-extending effects of the anti-retroviral pharmaceutical zidovudine in the worm C. elegans. Zidovudine reduces translation in treated worm populations, and both this reduced translation and the lifespan extension are dependent on the transcription factor ATF-4. [ABSTRACT FROM AUTHOR]

Abstract: Histone deacetylase inhibitors (HDACi) have been discovered as potential drugs for cancer treatment. The effect of BL1521, a novel HDACi, on the cell cycle distribution and the induction of apoptosis was investigated in a panel of MYCN single copy and MYCN amplified neuroblastoma cell lines. BL1521 arrested neuroblastoma cells in the G1 phase and induced up to 30% apoptosis. Downregulation of CDK4, upregulation of p21WAF1/CIP1 and an increase of hypophosphorylated retinoblastoma protein were observed, indicating a possible mechanism for the cell-cycle arrest. BL1521 also induced downregulation of p27, which may underlie the observed induction of apoptosis. [Copyright &y& Elsevier]

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). A deficiency of DPD is increasingly being recognized as the cause of an important pharmacogenetic syndrome. The importance of DPD deficiency in the aetiology of unexpected severe 5FU toxicity has been demonstrated by the fact that, in 39–59% of cases, decreased DPD activity could be detected in peripheral blood mononuclear (PBM) cells. It was observed that 55% of the patients with a decreased DPD activity suffered from grade IV neutropenia compared with 13% of the patients with a normal DPD activity (P = 0·01). Furthermore, toxicity developed significantly earlier in patients with low DPD activity than in patients with normal DPD activity (10·0 ± 7·6 versus 19·1 ± 15·3 days, P < 0·05). In patients suffering from severe 5FU-associated toxicity, 11 mutations have been identified in DPYD, including one splice-site mutation (IVS14 + 1G→A), one nonsense mutation (E386X), four missense mutations (M166V, V335L, I560S, D949V) and five polymorphisms (C29R, R21Q, S534N, I543V, V732I). Considering the common use of 5FU in the treatment of cancer patients, the severe 5FU-related toxicities in patients with a low DPD activity and the high prevalence of the IVS14 + 1G→A mutation, analysis of the DPD activity in PBM cells or screening for the IVS14 + 1G→A mutation should be routinely carried out prior to the start of treatment with 5FU. [ABSTRACT FROM AUTHOR]

In this paper, it is demonstrated that all-trans, 9-cis and 13-cis retinoic acid (RA) decreased the sensitivity of SK-N-BE(2)c neuroblastoma cells towards the chemotherapeutic agent cyclopentenyl cytosine (CPEC), a potent inhibitor of cytosine-5′-triphosphate synthetase. Retinoic acid attenuated CPEC-induced apoptosis as reflected by a decreased caspase-3 induction. Retinoic acid decreased the accumulation of CPEC, whereas the salvage of cytidine was strongly increased. Metabolic labeling studies using [3H]uridine showed a strongly decreased biosynthesis of CTP via CTP synthetase. Retinoic acid likely confers resistance of neuroblastoma cells to CPEC in part by slowing down proliferation, and in part by shifting the synthesis of CTP towards the salvage of cytidine, thereby bypassing CTP synthetase. [Copyright &y& Elsevier]

The N-terminal amino acid sequences and the electrophoretic mobilities of the subunits VIIa, VIIb and VIIc of cytochrome c oxidase purified from human heart were investigated and compared with those from human skeletal muscle and from bovine heart. In purified human heart cytochrome c oxidase, both so-called 'heart-type' and 'liver-type' isoforms of subunit VIIa were found. The first 30 residues of the N-terminal amino acid sequences of these 'heart-type' and 'liver-type' subunits VIIa showed nine differences. The two isoforms of subunit VIIa in human heart were present in almost equal amounts, in contrast to the situation in skeletal muscle, where the 'heart-type' subunit VIIa was predominant. Therefore, our results imply that in human heart a cytochrome c oxidase isoform pattern is present that differs from that found in skeletal muscle. Subunits VIIb and Vile purified from human heart oxidase proved to be very similar to their bovine heart counterparts. Our direct demonstration of the presence of subunit VIIb, the sequence of which has only recently been identified in the bovine heart enzyme, suggests that human cytochrome c oxidase also contains 13 subunits. We found no evidence for the presence of different isoforms of subunit VIIc in cytochrome c oxidase from human heart and skeletal muscle. We observed clear differences in the electrophoretic mobility of the subunits VIIa,b,c between bovine and human cytochrome c oxidase. On Tricine/glycerol/SDS/polyacrylamide gels the 'hearttype' and 'liver-type' subunits VIIa present in human heart cytochrome c oxidase migrated with almost the same electrophoretic mobility. Subunit VIIb migrated only slightly faster than subunit VIIa, whereas Vile proved to have the highest electrophoretic mobility on Tricine/SDS/glycerol/ polyacrylamide gels. Our findings may have implications for the elucidation of certain tissue-specific cytochrome c oxidase deficiencies in man. [ABSTRACT FROM AUTHOR]

Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (p = 0.05), higher plasma lysoGb3 at baseline (p < 0.001) and agalsidase beta as first treatment (p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk. [ABSTRACT FROM AUTHOR]

The treatment of cancer patients with 5-fluorouracil (5FU)-based chemotherapy can be accompanied by severe and sometimes lethal toxicity. Dihydropyrimidine dehydrogenase (DPD) plays a pivotal role in the metabolism of 5FU and as such, a deficiency of DPD has been recognized as an important risk factor, predisposing patients to the development of severe 5FU-associated toxicity. To date, screening of patients for the presence of a DPD deficiency prior to the treatment is not yet routinely performed. Taking into account the relatively small impact of adjuvant 5FU-based chemotherapy on survival, patients should be informed about the risks of the therapy and should be offered the possibility of testing for the presence of a DPD deficiency in advance of receiving such treatment. [ABSTRACT FROM AUTHOR]

Presents a correction to the article "Identification of Three Novel Mutations in the Dihydropyrimidine Dehydrogenase Gene Associated With Altered Pre-mRNA Splicing or Protein Function," by B. P. van Kuilenburg André, et al, published in the journal "Biological Chemistry."