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Antoine Desilets William McCarvill Francine Aubin Houda Bahig Olivier Ballivy Danielle Charpentier dith Filion Rahima Jamal Louise Lambert Phuc Felix Nguyen-Tan Charles Vadnais Xiaoduan Weng Denis Soulires 《Current oncology (Toronto, Ont.)》2022,29(2):497
Simple SummaryThe combination of carboplatin and 5-fluorouracil (5-FU) is effective when used concurrently with radiotherapy for locoregionally advanced oropharyngeal carcinomas. DPYD polymorphisms can be associated with an increased risk of severe toxicity to fluoropyrimidines. Upfront screening for the DPYD*2A allele has been available in the province of Québec, Canada, since March 2017. This study aimed to determine the effect of upfront genotyping on the incidence of grade ≥3 toxicities. We included 181 patients in the analysis. Extended screening for three supplemental at-risk DPYD variants was also retrospectively performed in August 2019. The DPYD*2A, c.2846A>T and c.1236G>A polymorphisms were associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can thus identify patients in whom 5-FU-related toxicity should be avoided.AbstractBackground: 5-FU-based chemoradiotherapy (CRT) could be associated with severe treatment-related toxicities in patients harboring at-risk DPYD polymorphisms. Methods: The studied population included consecutive patients with locoregionally advanced oropharyngeal carcinoma treated with carboplatin and 5-FU-based CRT one year before and after the implementation of upfront DPYD*2A genotyping. We aimed to determine the effect of DPYD genotyping on grade ≥3 toxicities. Results: 181 patients were analyzed (87 patients before and 94 patients following DPYD*2A screening). Of the patients, 91% (n = 86) were prospectively genotyped for the DPYD*2A allele. Of those screened, 2% (n = 2/87) demonstrated a heterozygous DPYD*2A mutation. Extended genotyping of DPYD*2A-negative patients later allowed for the retrospective identification of six additional patients with alternative DPYD variants (two c.2846A>T and four c.1236G>A mutations). Grade ≥3 toxicities occurred in 71% of the patients before DPYD*2A screening versus 62% following upfront genotyping (p = 0.18). When retrospectively analyzing additional non-DPYD*2A variants, the relative risks for mucositis (RR 2.36 [1.39–2.13], p = 0.0063), dysphagia (RR 2.89 [1.20–5.11], p = 0.019), and aspiration pneumonia (RR 13 [2.42–61.5)], p = 0.00065) were all significantly increased. Conclusion: The DPYD*2A, c.2846A>T, and c.1236G>A polymorphisms are associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can identify patients in whom 5-FU-related toxicity should be avoided. 相似文献
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Céline Gleizes Andrei Constantinescu Malak Abbas Houda Bouhadja Fatiha Zobairi Florence Toti 《Transplant international》2014,27(7):733-740
Instant Blood‐Mediated Inflammatory Reaction (IBMIR) occurs at the vicinity of transplanted islets immediately after intraportal infusion and is characterized by cytokine secretion, tissue factor (TF) expression, and ß cell loss. Microparticles (MPs) are cellular effectors shed from the plasma membrane of apoptotic cells. Modulation of the properties of ß cell‐derived MPs by liraglutide was assessed in a cellular model designed to mimic IBMIR oxidative and inflammatory conditions. Rin‐m5f rat β cells were stimulated by H2O2 or a combination of IL‐1β and TNF‐α. Cell‐derived MPs were applied to naive Rin‐m5f for 24 h. Apoptosis, MP release, TF activity, P‐IκB expression, and MP‐mediated apoptosis were measured in target cells. Direct protection by liraglutide was shown by a significant decrease in the oxidative stress‐induced apoptosis (18.7% vs. 7.6%, P < 0.0001 at 1 μm liraglutide) and cellular TF activity (?40% at 100 nm liraglutide). Indirect cytoprotection led to 20% reduction in MP generation, thereby lowering MP‐mediated apoptosis (6.3% vs. 3.7%, P = 0.022) and NF‐κB activation (?50%) in target cells. New cytoprotective effects of liraglutide were evidenced, limiting the expression of TF activity by ß cells and the generation of noxious MPs. Altogether, these data suggest that liraglutide could target pro‐apoptotic and pro‐inflammatory MPs in transplanted islets. 相似文献
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The general medicine remains a same survey subject in countries where the debate began since several years. We have led an investigation by questionnaire close to 50 chosen hospitalo-academic physicians by pull to the fate on the list of teachers of the faculty of medicine of Tunis. The majority of our investigated (90%) consider that the physician general practitioner is the physician of the individual in its totality, the counselor and the family's confidant. The formation that receives the future general practitioner currently doesn't prepare it to assure his role. To form the future physician better general practitioner, we think that it's necessary to define the general practitioner role, to adapt the formation to the role of the general practitioner and the specificity of the general medicine. 相似文献
16.
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase 总被引:16,自引:0,他引:16
Selak MA Armour SM MacKenzie ED Boulahbel H Watson DG Mansfield KD Pan Y Simon MC Thompson CB Gottlieb E 《Cancer cell》2005,7(1):77-85
Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha. These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations. 相似文献
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Potassium (K+) requirements have been largely overlooked because severe deficiencies are uncommon due to the ubiquity of this element in foods. However, a transition toward modern ("Westernized") diets has led to a substantial decline of K+ intake compared with traditional food habits, and a large fraction of the population might now have suboptimal K+ intake. A high K+ intake was demonstrated to have protective effects against several pathologic states affecting the cardiovascular system, kidneys, and bones. Additionally, fruits and vegetables contain K/organic anion salts (malate, citrate), which exert alkalinizing effects, through KHCO(3)(-) generation, which serves to neutralize fixed acidity in urine. Low-grade metabolic acidosis, when not properly controlled, may exacerbate various catabolic processes (bone Ca++ mobilization, proteolysis), especially in the elderly. Fruits and vegetables are therefore receiving great attention in a strategy to increase the nutritional value of meals while reducing energy density and intake. The need to ensure a 2.5- to 3.5-g daily K+ supply from fruits and vegetables represents a strong rationale for the "5-10 servings per day" recommendations. 相似文献
19.
Sarciron ME Nebois P Pautet F Pétavy AF Fillion H Walchshofer N 《Parasitology research》2002,88(11):969-971
Quinonic derivatives were tested against a virulent RH strain of Toxoplasma gondii maintained in cell culture in THP-1, a human myelomonocytic cell line. The derivatives were tested at various doses (0.5-4 microg/ml) and compared with the reference molecules clindamycine, sulfadiazine, pyrimethamine and atovaquone. The percentage of parasite growth inhibition was observed after 72 h of incubation. The tested derivatives are bicyclic, tricyclic or tetracyclic quinones. Eight of these compounds exhibit over 70% inhibition of parasite growth; and two were nearly equipotent to pyrimethamine. These data indicate that the most active compounds against the RH strain of T. gondii are bis-heterocyclic quinones. 相似文献
20.
Thameur H Abdelmoula S Chenik S Bey M Ziadi M Mestiri T Mechmeche R Chaouch H 《World journal of surgery》2001,25(1):58-67
apd: 18 December 2000 相似文献