Results of a comprehensive pharmacogenetic analysis of dihydropyrimidine dehydrogenase in patients treated with fluoropyrimidines and patterns of polymorphisms partially related to treatment tolerability.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13057-e13057
Author(s):  
Marzia Del Re ◽  
Marta Schirripa ◽  
Angela Michelucci ◽  
Marta Cubelli ◽  
Silvia Magagna ◽  
...  
Keyword(s):  
Adverse Reactions ◽  
Consensus Sequence ◽  
Dihydropyrimidine Dehydrogenase ◽  
Cytotoxic Agents ◽  
Metabolic Clearance ◽  
Good Tolerability ◽  
Rate Limiting ◽  
Poor Tolerability ◽  
Head Neck ◽  
Dose Delay

e13057 Background: Metabolic clearance of fluoropyrimidines is highly dependent on the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD). Deficiency of DPD is associated with drug accumulation and severe toxicities. The DPD gene (DPYD) is highly polymorphic; however, except the G>A mutation in the splicing consensus sequence of intron 14 (IVS14+1G>A), which is responsible of severe enzyme impairment, the association of other variants with adverse reactions is unclear. Therefore, this study was aimed at examining the prevalence of DPYD variants in patients with toxicities and in subjects with good tolerability to fluoropyrimidine-based regimens. Methods: Patients affected by colorectal, breast and head/neck cancers requiring standard treatment with 5-FU or capecitabine in combination with other cytotoxic agents (irinotecan, oxaliplatin, cyclophosphamide or methotrexate) and/or antibodies (cetuximab or bevacizumab) were enrolled: 224 suffered from grade ≥2 non-hematological and ≥3 hematological toxicities (CTCAE v. 4) and 61 control patients developed adverse events to an extent not requiring dose-delay or reduction (i.e., <2 non-hematological and <3 hematological toxicities). DNA was extracted from blood and used to screen patients for known DPD variants (IVS14+1G>A, 496A>G, 1601G>A, 1627A>G, 1896T>C, 2194G>A and 2846T>C) by automatic sequencing. The study was approved by local Ethics Committee. Results: A complex pattern of DPYD variants was identified in both cohorts; the following genotypes were detected in patients with severe toxicities vs controls: 496AG+GG: 24.1 vs 21.3%; 1601GA: 12.5 vs 1.6%; 1627AG+GG: 37.1 vs 32.8%; 1896TC+TT: 6.25 vs 8.2%; IVS14+1GA: 4.9 vs 0%; 2194GA: 25.9 vs 9.8; 2846AT: 1.3 vs 0%. Conclusions: Although there was a higher prevalence of DPYD variants in patients with severe toxicities, their presence also in subjects with good tolerability suggest that their role needs to be re-evaluated, with the exception of IVS14+1GA and 2846AT which were found only in patients with poor tolerability. This study was supported in part by a grant from AIRC to R. Danesi.

Polyadenylation of Na(+)-K(+)-ATPase beta 1-subunit during early development of Xenopus laevis

1994 ◽  
Vol 266 (1) ◽  
pp. C157-C164 ◽  
Author(s):  
P. Burgener-Kairuz ◽  
I. Corthesy-Theulaz ◽  
A. M. Merillat ◽  
P. Good ◽  
K. Geering ◽  
...  
Keyword(s):  
Consensus Sequence ◽  
Limiting Factor ◽  
Beta Subunits ◽  
Mrna Accumulation ◽  
Oocyte Growth ◽  
Cytoplasmic Polyadenylation ◽  
Midblastula Transition ◽  
Parallel Increase ◽  
Fluid Formation ◽  
Rate Limiting

In fully grown Xenopus oocytes, the synthesis of beta-subunits is limiting for the formation of functional Na(+)-K(+)-adenosinetriphosphatase alpha/beta-complexes (Geering, K. FEBS Lett. 285: 189-193, 1991). In the present study, we show that during oocyte growth (from stage I to stage VI) alpha 1-, but not beta 1- or beta 3-isoform, mRNAs accumulate. In addition, beta-mRNAs are apparently sequestered in an untranslated pool in fully grown oocytes (stage VI). From fertilization to morulation, the total pools of alpha 1-, beta 1-, or beta 3-mRNAs vary little. Whereas polyadenylated [poly(A)+] alpha 1- and beta 3-isoform mRNAs did not change significantly, poly(A)+ beta 1-mRNA abundance increased three- to fourfold at morulation, accompanied by a parallel increase in beta 1-protein synthesis. After midblastula transition (i.e., at early gastrula) and during neurulation, poly(A)+ alpha 1- and beta 3-mRNAs accumulated rapidly, whereas poly(A)+ beta 1-mRNA accumulation was delayed by approximately 2 h, beginning only at early neurula. Our results indicate that 1) the abundance of poly(A)+ beta 1-mRNA is rate limiting during embryonic development for the assembly of alpha 1/beta 1-heterodimers, shown to be involved in the vectorial transport of sodium in kidney cells, and 2) the polyadenylation of beta 1-mRNA is a rate-limiting factor during morulation for the synthesis and assembly of new sodium pumps at the time of blastocoel fluid formation. The 3'-untranslated region of beta 1-mRNA (but not of alpha 1-mRNA) expresses cytoplasmic polyadenylation elements (CPEs) with the consensus sequence AXX-AUUUU(A/U)(A/U)(A/U). A role of CPE in the differential polyadenylation of alpha 1- and beta 1-mRNA is proposed.

scholarly journals DPYD Exome, mRNA Expression and Uracil Levels in Early Severe Toxicity to Fluoropyrimidines: An Extreme Phenotype Approach

2021 ◽  
Vol 11 (8) ◽  
pp. 792
Author(s):  
Priscila Villalvazo ◽  
Belén Marzal-Alfaro ◽  
Pilar García-Alfonso ◽  
José Luis Revuelta-Herrero ◽  
Fabienne Thomas ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Adverse Reactions ◽  
Dehydrogenase Deficiency ◽  
Dihydropyrimidine Dehydrogenase ◽  
Severe Toxicity ◽  
Exon Sequence ◽  
Extreme Phenotypes ◽  
Life Threatening ◽  
Early Toxicity

Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It was carried out in two groups of patients with extreme phenotypes (toxicity versus control) newly treated with a fluoropyrimidine, during the first three cycles of treatment. A novel nonsense gene variant (c.2197insA) was most likely responsible for fluoropyrimidine-induced toxicity in one patient, while neither DPYD mRNA expression nor plasma uracil concentration was globally associated with early toxicity. Our present work may help improve pharmacogenetic testing to avoid severe and undesirable adverse reactions to fluoropyrimidine treatment and it also supports the idea of looking beyond DPYD.

scholarly journals Laser technologies in treatment of cervical intraepithelial neoplasia (review)

2020 ◽  
Vol 9 (3) ◽  
pp. 30-39
Author(s):  
D. A. Tzerkovsky ◽  
V. V. Dunaevskaya
Keyword(s):  
Cervical Intraepithelial Neoplasia ◽  
Adverse Reactions ◽  
High Efficiency ◽  
Aminolevulinic Acid ◽  
Light Exposure ◽  
Intraepithelial Neoplasia ◽  
Laser Vaporization ◽  
Tissue Destruction ◽  
Good Tolerability ◽  
Laser Technologies

This review article discusses the key aspects of the use of laser technologies, namely, laser vaporization (LV) and photodynamic therapy (PDT), in the treatment of patients with cervical intraepithelial neoplasia (CIN). The authors analyzed and systematized the foreign experience of these methods of treatment, their indications and contraindications, as well as the advantages over traditional approaches to the treatment of this pathology. The main advantages of the LV are the possibility of complete evaporation of the pathological focus, visual control over the depth of tissue destruction, the absence of prolonged edema and cicatricial deformities, which allows maintaining the integrity of the cervix and its reproductive function. Despite the low trauma and low frequency of adverse reactions, the data on the effectiveness of LV are quite contradictory and, according to various authors, vary from 50% to 98%. To date, there is a significant amount of accumulated experience in the use of PDT with various photosensitizing agents (5-aminolevulinic acid (5-ALA), hematoporphyrin and chlorin and their derivatives) in the treatment of patients with CIN. The main advantages of the PDT are minimal toxicity to the surrounding normal tissues due to the selective accumulation of photosensitizer in pathological tissues, a low risk of severe pain syndrome, the absence of mechanisms of primary and acquired resistance, the possibility of an outpatient treatment session, the possibility of combining with other methods of therapeutic action, the absence of limiting cumulative doses of photosensitizers and light exposure, the possibility of multiple repetitions of the session, good cosmetic results and the possibility of implementing an organ-preserving method of treatment. The obtained results indicate good tolerability of the method (no severe adverse reactions) and a fairly high efficiency of PDT: the frequency of complete regressions varies from 30% to 67% - for application forms of 5-ALA and from 90% to 98.1% - for hematoporifirin and chlorin photosensitizers. Thus, LV and PDT can be considered safe and effective treatment options for patients with CIN.

scholarly journals Evaluation of the efficiency of perioperative chemotherapy in the complex treatment of gastric cancer

2021 ◽  
Vol 20 (2) ◽  
pp. 17-22
Author(s):  
Е. О. Mantsyrev ◽  
A. V. Privalov ◽  
S. V. Kuvaev ◽  
К. V. Semikopov ◽  
I. A. Gavrishkin
Keyword(s):  
Gastric Cancer ◽  
Postoperative Complications ◽  
Adverse Reactions ◽  
Morphological Structure ◽  
Long Term Results ◽  
R0 Resection ◽  
Perioperative Chemotherapy ◽  
Complex Treatment ◽  
Good Tolerability ◽  
Female Ratio

Introduction. Of greatest interest in the complex treatment of gastric cancer is the assessment of the effect of perioperative chemotherapy on the immediate and long-term results of treatment. Including, the possibility of studying the effectiveness of chemotherapy, its effect on the resectability of the tumor process, determining the possibility of an indirect correlation for intra — and postoperative complications.The aim of the study is to study the effectiveness of perioperative chemotherapy in the treatment of gastric cancer and its direct effect on the results of surgical treatment. Methods. At the base Chelyabinsk Center of Oncology and Nuclear Medicine, studies are being conducted to assess the effectiveness and tolerability of perioperative chemotherapy in the complex treatment of gastric cancer. Based on the inclusion criteria, 80 patients were selected with a diagnosis of gastric cancer T2-3N0-2M0. The first stage of all patients underwent diagnostic laparoscopy with negative peritoneal washings. The male to female ratio was 51% and 49%, respectively. The average age of the patients was 61 years. By morphological structure, gastric adenocarcinoma prevailed — 85%, cricoid cell carcinoma was 9%, adenocarcinoma with a cricoid cell component — 6%. According to the T category, the patients were distributed as follows: cT2 — 5%; sT3 — 59%; cT4 — 36%. In category N, patients of category N1 prevailed — 59%; patients with cN0 and cN1 were represented in approximately equal proportions, 14% and 19%, respectively. Patients with stage II accounted for 33%, with stage III — 67%. The main combination of drugs was FLOT (87%), FolFox (3%), XELOX (5%), PF (5%) were also used.Results. The data obtained clearly demonstrate the good tolerability of the performed preoperative chemotherapy, the absence of significant adverse reactions. Drug therapy did not affect the planned timing of the surgical stage of treatment. Also, no effect of chemotherapy on postoperative complications was noted. R0 resection was performed in 100% of cases. In 49% of cases, stage reduction was performed. Significant medical grade III — IV pathomorphosis was obtained in 26% of cases. Discussion. Interpretation of therapeutic tumor pathomorphosis for evaluating the effectiveness and planning of adjuvant therapy currently requires further study and evaluation. Conclusion. Perioperative chemotherapy is not accompanied by adverse reactions affecting the timing and outcome of treatment. The obtained positive clinical effect according to examination data, intraoperative visual assessment suggests an improvement in overall survival and a decrease in one-year mortality in the complex treatment of gastric cancer.

Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: Experience of 4 years

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2056-2056
Author(s):  
R. Mehra ◽  
L. K. Mattison ◽  
L. Ledbetter ◽  
H. Ezzeldin ◽  
R. B. Diasio ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Memory Loss ◽  
Altered Mental Status ◽  
Heterozygous Mutation ◽  
High Dose ◽  
Dpyd Gene ◽  
Genotypic Analysis ◽  
Grade 3 ◽  
Rate Limiting

2056 Background: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. With DPD deficiency, 5-FU is discontinued. Data regarding safety of capecitabine (CAP) in this population is scarce. Methods: Patients were tested for DPD deficiency after excessive toxicities from 5-FU and CAP at UAB between 2001 and 2005. DPD activity was evaluated by PBMC radio assay, genotyping of DPYD gene by DHPLC, or 2-13C uracil breath test (UraBT). Results: Of 23 patients with GI malignancies (small intestine, gastric, pancreatic, HCC, and colorectal) evaluated, 7 (30%) were DPD deficient. Among these 7 patients, DPD activity ranged from 0.064 - 0.18 nmol/min/mg. Age ranged from 51–75 years, M:F ratio = 1.3:1, and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). Four were treated with 5-FU/LV (2 Roswell; 2 Mayo); 2 CAP (1800mg/m2); and 2 high dose bolus 5-FU (1400mg/m2) + PN401 (tri-acetyluridine). Toxicities included mucositis (71%), diarrhea (43%), nausea (29%), memory loss/altered mental status (43%), cytopenias (43%), hypotension (14%), respiratory distress (14%), acute renal failure (14%), and severe skin rashes (43%). Re-challenge with CAP in 1 patient after the Mayo regimen caused grade 3 HFS only on dorsal surfaces of hands. One patient on PN401 had a grade 3 facial rash as the worst toxicity. Genotypic analysis of the DPYD gene in the second on PN401, who had severe leucopenia, demonstrated a heterozygous mutation (IVS14+1 G>A, DPYP*2A). UraBT in 2 patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4%) and borderline normal values (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths (28%): 1 on CAP and 1 on 5-FU + PN401. Conclusions: DPD deficiency was observed in several ethnicities. Patients with CAP toxicities should also be tested for DPD deficiency. Role of PN401 in rescuing 5-FU toxicity in DPD deficiency is not clear. Screening patients for DPD deficiency prior to administration of 5-FU or CAP, using UraBT, could potentially lower risk of toxicity. Future studies should validate this technique. [Table: see text]

Drug-free Nanotherapies for Cancer Treatment

2020 ◽  
Vol 16 ◽  
Author(s):  
Pravin Shende ◽  
Prashant Saini
Keyword(s):  
Cancer Treatment ◽  
Molecularly Imprinted Polymers ◽  
Adverse Reactions ◽  
The Body ◽  
Grafted Polymer ◽  
Normal Tissues ◽  
Organ Specific ◽  
Tumor Accumulation ◽  
Drug Free ◽  
Head Neck

Background:: In the diagnosis, management and treatment of cancer, numerous technological advancements have been explored in the past few years to find better applications over the conventional treatment approaches. However, their implementation in clinical practice leads to severe and toxic effects to the healthy tissues. Drugs in the form of actives impart cytotoxic effect but concurrently produce undesirable changes on normal tissues. Moreover, serum half-life and intra-tumor accumulation limit an effective cancer treatment for therapeutic agents. Objective:: The objective of this review is to promote the significance of nanotherapy in cancer by strategizing drug-free macromolecules in contrast to conventional methodologies. Methods:: This unique concept covers molecularly-imprinted polymers, nanopolymer complex systems, metal nanoparticles, carbon nanotubes, quantum dots, grafted polymer-based systems and drug-free macromolecular therapeutics for effective and selective therapeutic action. Results:: In advance drug delivery systems, target-specific therapy indicates great potential to improve the efficacy of therapeutics by reducing adverse events to other parts of the body, but is restricted due to adverse reactions at the therapeutic site. To resolve such complications, drug-free nanotherapy approaches act as an alternative system against conventional carriers for treating organ-specific cancers like head, neck, lung, breast, prostate, kidney, etc. Conclusion:: The drug-free approaches in various diseases will provide entirely new perception in order to avoid or reduce the side and adverse effects of drugs.

Safety evaluation of a multiallergen immunotherapy treatment in polyallergic patients. APOLO observational study

Immunotherapy ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 75-87
Author(s):  
Pilar Alba ◽  
Victoria Moreno ◽  
José Arias-Irigoyen ◽  
Mónica Antón ◽  
Antonio Parra ◽  
...  
Keyword(s):  
Allergic Rhinitis ◽  
Adverse Events ◽  
Observational Study ◽  
Adverse Reactions ◽  
Safety Evaluation ◽  
Subjective Assessment ◽  
Clinical Impression ◽  
Good Tolerability ◽  
Systemic Reactions ◽  
Global Clinical Impression

Aim: Assessment of safety, tolerability and changes in global clinical impression with an multiallergen immunotherapy treatment without dilutional effect in polyallergic patients. Patients & methods: This observational prospective study included patients with allergic rhinitis-rhinoconjunctivitis with or without asthma between 5 and 60 years old receiving immunotherapy treatment with a mixture of two allergenic sources. All adverse events were recorded. Global clinical impression, tolerability subjective assessment and satisfaction were also assessed. Results: 130 patients were analyzed. Nine clinically relevant local adverse reactions were reported in six patients (4.6%). Six systemic reactions (grades 0–I) occurred in four patients (3.1%). Patients improved significantly in their global clinical impression. Good tolerability subjective assessment and satisfaction values were also observed. Conclusion: This multiallergen immunotherapy treatment without dilutional effect can be considered as a potential therapeutic alternative for polyallergic patients suffering from allergic rhinitis.

scholarly journals Fluoropyrimidine-Associated Toxicity in Two Gastrointestinal Cancer Patients: Potential Role of Common DPYD Polymorphisms

Chemotherapy ◽  
2017 ◽  
Vol 62 (5) ◽  
pp. 323-326 ◽  
Author(s):  
Felicia Stefania Falvella ◽  
Marco Luoni ◽  
Stefania Cheli ◽  
Sergio Fava ◽  
Massimiliano Cergnul
Keyword(s):  
Genetic Variants ◽  
Drug Toxicity ◽  
Adverse Reactions ◽  
Potential Role ◽  
Dihydropyrimidine Dehydrogenase ◽  
Compound Heterozygous ◽  
Allelic Variants ◽  
Gene Carriers ◽  
Severe Adverse Reactions

While the majority of patients can be treated safely with fluoropyrimidine, some experience severe fluoropyrimidine-associated toxicity. The frequency and severity of these adverse events vary from patient to patient and are partially explained by genetic polymorphism into the dihydropyrimidine dehydrogenase (DPYD) gene. Carriers of the rare allelic variants DPYD*2A, DPYD*13, and DPYD D949V are more likely to experience severe adverse reactions during fluoropyrimidine-based therapy. However, these 3 genetic variants explain only a small percentage of the overall drug toxicity, and more frequent ones such as homozygous or compound heterozygous DPYD V732I can play a key role.

Phase IB Study of the mTOR Inhibitor Ridaforolimus With Capecitabine

2010 ◽  
Vol 28 (30) ◽  
pp. 4554-4561 ◽  
Author(s):  
Antonella Perotti ◽  
Alberta Locatelli ◽  
Cristiana Sessa ◽  
Dagmar Hess ◽  
Lucia Viganò ◽  
...  
Keyword(s):  
Mtor Inhibitor ◽  
Mononuclear Cells ◽  
Prolonged Exposure ◽  
Dihydropyrimidine Dehydrogenase ◽  
Mammalian Target Of Rapamycin ◽  
Pharmacokinetic Interaction ◽  
Erk Signaling ◽  
Prolonged Treatment ◽  
Good Tolerability ◽  
Peripheral Blood Mononuclear

Purpose Synergistic/additive cytotoxicity in tumor models and widespread applicability of fluoropyrimidines in solid tumors prompted the study of the combination of the mammalian target of rapamycin (mTOR) inhibitor, non-prodrug rapamycin analog ridaforolimus, with capecitabine. Patients and Methods Thirty-two adult patients were treated. Intravenous ridaforolimus was given once weekly for 3 weeks and capecitabine was given from days 1 to 14 every 4 weeks. Ridaforolimus was given at 25, 37.5, 50, or 75 mg with capecitabine at 1,650 mg/m2 or 1,800 mg/m2 divided into two daily doses. Pharmacokinetics of both drugs were determined during cycles 1 and 2. Pharmacodynamic studies in peripheral blood mononuclear cells (PBMCs) and wound tissue of the skin characterized pathways associated with the metabolism or disposition of fluoropyrimidines and mTOR and ERK signaling. Results Two recommended doses (RDs) were defined: 75 mg ridaforolimus/1,650 mg/m2 capecitabine and 50 mg ridaforolimus/1,800 mg/m2 capecitabine. Dose-limiting toxicities were stomatitis and skin rash. One patient achieved a partial response lasting 10 months and 10 of 29 evaluable patients had stable disease for ≥ 6 months. The only pharmacokinetic interaction was a ridaforolimus-induced increase in plasma exposure to fluorouracil. PBMC data suggested that prolonged exposure to capecitabine reduced the ridaforolimus inhibition of mTOR. Ridaforolimus influenced the metabolism of fluoropyrimidines and inhibited dihydropyrimidine dehydrogenase, behavior similar to that of rapamycin. Inhibition of the target thymidylate synthase by capecitabine was unaffected. mTOR and ERK signaling was inhibited in proliferating endothelial cells and was more pronounced at the RD with the larger amount of ridaforolimus. Conclusion Good tolerability, feasibility of prolonged treatment, antitumor activity, and favorable pharmacologic profile support further investigation of this combination.

Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency

2003 ◽  
Vol 40 (1) ◽  
pp. 41-45 ◽  
Author(s):  
André B.P. van Kuilenburg ◽  
Ronney A. De Abreu ◽  
Albert H. van Gennip
Keyword(s):  
Dehydrogenase Deficiency ◽  
Dihydropyrimidine Dehydrogenase ◽  
Splice Site Mutation ◽  
Clinical Aspects ◽  
Missense Mutations ◽  
Site Mutation ◽  
Peripheral Blood Mononuclear ◽  
High Prevalence ◽  
The Common ◽  
Rate Limiting

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.

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