scholarly journals TYMS 3′-UTR Polymorphism: A Novel Association with FOLFIRINOX-Induced Neurotoxicity in Pancreatic Cancer Patients

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 77
Author(s):  
Marina Emelyanova ◽  
Ilya Pokataev ◽  
Igor Shashkov ◽  
Elena Kopantseva ◽  
Vladimir Lyadov ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Recessive Model ◽  
Ductal Adenocarcinoma ◽  
Hematological Toxicity ◽  
Drug Induced ◽  
Novel Association ◽  
Substantial Risk ◽  
The Common ◽  
Grade 3 ◽  
The Impact

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy that has the worst 5-year survival rate of all of the common malignant tumors. Surgery, chemotherapy, and/or chemoradiation remain the main tactics for PDAC treatment. The efficacy of chemotherapy is often compromised because of the substantial risk of severe toxicities. In our study, we focused on identification of polymorphisms in the genes involved in drug metabolism, DNA repair and replication that are associated with inter-individual differences in drug-induced toxicities. Using the microarray, we genotyped 12 polymorphisms in the DPYD, XPC, GSTP1, MTHFR, ERCC1, UGT1A1, and TYMS genes in 78 PDAC patients treated with FOLFIRINOX. It was found that the TYMS rs11280056 polymorphism (6 bp-deletion in TYMS 3′-UTR) predicted grade 1–2 neurotoxicity (p = 0.0072 and p = 0.0019, according to co-dominant (CDM) and recessive model (RM), respectively). It is the first report on the association between TYMS rs11280056 and peripheral neuropathy. We also found that PDAC patients carrying the GSTP1 rs1695 GG genotype had a decreased risk for grade 3–4 hematological toxicity as compared to those with the AA or AG genotypes (p = 0.032 and p = 0.014, CDM and RM, respectively). Due to relatively high p-values, we consider that the impact of GSTP1 rs1695 requires further investigation in a larger sample size.

Clinical Outcomes and Safety of Patients Treated with NAb-Paclitaxel Plus Gemcitabine in Metastatic Pancreatic Cancer: The NAPA Study

2020 ◽  
Vol 20 (11) ◽  
pp. 887-895 ◽  
Author(s):  
Martina Catalano ◽  
Giandomenico Roviello ◽  
Raffaele Conca ◽  
Alberto D’Angelo ◽  
Valeria Emma Palmieri ◽  
...  
Keyword(s):  
Performance Status ◽  
Real Life ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Hematological Toxicity ◽  
Free Survival ◽  
Grade 3 ◽  
Ecog Ps ◽  
Prognostic And Predictive Markers

Background: The phase III MPACT trial demonstrated the superiority of gemcitabine (Gem) combined with Nab-paclitaxel (Nab-P) versus gemcitabine alone in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to evaluate the effect of Gem/Nab-P in routine clinical practice. Methods: From January 2015 to December 2018, patients with metastatic PDAC receiving firstline treatment with a combination of gemcitabine and Nab-paclitaxel were included in a multicentre retrospective observational study. Exploratory analyses of efficacy, and prognostic and predictive markers, were performed. Results: The cohort comprised 115 patients (median age 65 [range 50-84] years) with good performance status (ECOG PS 0-1). The median overall survival (OS) was 11 months (95% CI; 9-13) and the median progression-free survival (PFS) was 6 months (95% CI 5-7). Partial response and stable disease were achieved in 44 and 30 patients, respectively, yielding an overall disease control rate (DCR) of 64.3%. Grade 3-4 hematological toxicity frequency was 22.61% for neutropenia, 5.22% for anemia, and 3.48% for thrombocytopenia. Grade 3 asthenia was recorded in 2.61% of patients. No grade 4 non-hematological events were reported. Dose reduction was necessary in 51.3% of the patients. Conclusions: Our results confirm the efficacy and safety of a first-line regimen comprising gemcitabine and Nab-paclitaxel in metastatic PDAC in a real-life population.

scholarly journals The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 565
Author(s):  
Sona Ciernikova ◽  
Maria Novisedlakova ◽  
Danka Cholujova ◽  
Viola Stevurkova ◽  
Michal Mego
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Malignant Tumors ◽  
Current Knowledge ◽  
Early Stage ◽  
Poor Response ◽  
Response To Therapy ◽  
Oral Microbiome ◽  
Ductal Adenocarcinoma ◽  
The Impact

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant tumors due to the absence of biomarkers for early-stage detection and poor response to therapy. Since mounting evidence supports the role of microbiota composition in tumorigenesis and cancer treatment, the link between microbiome and PDAC has been described. In this review, we summarize the current knowledge regarding the impact of the gut and oral microbiome on the risk of PDAC development. Microenvironment-driven therapy and immune system interactions are also discussed. More importantly, we provide an overview of the clinical trials evaluating the microbiota role in the risk, prognosis, and treatment of patients suffering from PDAC and solid tumors. According to the research findings, immune tolerance might result from the microbiota-derived remodeling of pancreatic tumor microenvironment. Thus, microbiome profiling and targeting represent the potential trend to enhance antitumor immunity and improve the efficacy of PDAC treatment.

scholarly journals The Impact of Liposomal Irinotecan on the Treatment of Advanced Pancreatic Adenocarcinoma: Real-World Experience in a Taiwanese Cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yung-Yeh Su ◽  
Nai-Jung Chiang ◽  
Hui-Jen Tsai ◽  
Chia-Jui Yen ◽  
Yan‐Shen Shan ◽  
...  
Keyword(s):  
Real World ◽  
Performance Status ◽  
University Hospital ◽  
Ductal Adenocarcinoma ◽  
Hematological Toxicity ◽  
Free Base ◽  
Gemcitabine Refractory ◽  
Liposomal Irinotecan ◽  
Ecog Ps ◽  
The Impact

AbstractLiposomal irinotecan plus 5-fluorouracil/leucovorin (nal-IRI + 5-FU/LV) has shown to provide survival benefits for patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) in NAPOLI-1 trial, in which Asian patients experienced more hematological toxicity and subsequent dose modification. A retrospective chart review to investigate the administration pattern, therapeutic efficacy and safety profile of nal-IRI + 5-FU/LV in 44 consecutive patients with gemcitabine-refractory advanced PDAC treated between December 2016 and December 2018 in National Cheng Kung University Hospital, Taiwan. Most of them had metastatic diseases (88.6%), one-line of prior treatment (72.7%), ECOG PS 0-1 (72.7%) and starting dose of nal-IRI at 60 mg/m2 (≈52 mg/m2 irinotecan free-base) in 65.9%. The overall response rate was 9.1%. The median OS was 6.6 months for the entire cohort, and 7.8 and 2.7 months for patients of ECOG PS 0-1 and>2, respectively. The median OS of ECOG PS 0-1 patients with nal-IRI starting doses at 80 mg/m2 (≈70 mg/m2 irinotecan free-base, n = 13) and 60 mg/m2 (n = 19) were 7.5 and 8.4 months, respectively. Thirty-four percent of patients experienced manageable grade 3-4 hematological toxicity. Our results confirm the clinical benefit of nal-IRI + 5-FU/LV for patients of gemcitabine-refractory advanced PDAC with good performance status in a real-world setting.

The impact of genetic variability on severe toxicity of (neo-) adjuvant chemotherapy in breast cancer patients receiving 5-fluorouracil, epirubicin, and cyclofosfamide (FEC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1020-1020
Author(s):  
Christof Vulsteke ◽  
Diether Lambrechts ◽  
Anne-Sophie Dieudonné ◽  
Sigrid Hatse ◽  
Barbara Brouwers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Variability ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Multi Drug Resistance ◽  
Hematological Toxicity ◽  
Severe Toxicity ◽  
Wild Type ◽  
Grade 3 ◽  
The Impact

1020 Background: We assessed the impact of single nucleotide polymorphisms (SNP) of potential genes of interest in germline DNA on severe adverse events in breast cancer (bc) patients receiving (neo-) adjuvant FEC chemotherapy. Methods: Cases were retrospectively evaluated through electronic chart review for febrile neutropenia (primary endpoint), febrile neutropenia first cycle, prolonged grade 4 or deep (<100/µl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events. The panel of genes, genotyped using iPLEX technology on a MALDI-TOF based MassARRAY Compact Analyser (Sequenom Inc., CA, USA), included ABCBI, ABCC1, ABCC2, ABCG2, ALDH3A1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, DPYD, FGFR4, GPX4, GSTA1, GSTP1, MTHFR, NQ01, TYMS, XPD/ERCC2, XRCC1, UGT1A1, UGT1A6 and UGT2B7. These genes are involved in the metabolization of the studied chemotherapeutics. Because of multiple testing the false discovery rate (FDR) was calculated. Results: We identified 1089 patients treated between 2000-2010 with 3-6 cycles of FEC, for whom germline DNA was available.Homozygous (TT, 0.5%) and heterozygous (GT,11%) genotypes for rs4148350 in the Multi Drug Resistance Protein I (ABCC1/MRP1), compared to wild-type (GG, 88.5%), were associated with febrile neutropenia, febrile neutropenia in first cycle, prolonged grade 4 or deep neutropenia and thrombocytopenia (80 vs 25 vs 15.7%, 40 vs 17.6 vs 9.5%, 100 vs 41.7 vs 33.8% and 20 vs 2.8 vs 0.34% respectively; p 0.0006, 0.01, 0.002 and 0.008 FDR 0.03, 0.65, 0.06 and 0.2). Variant genotypes for rs45511401 (GT/TT, 12%) in ABCC1, compared to wild-type (GG, 88%), were associated with febrile neutropenia, febrile neutropenia in first cycle and thrombocytopenia (26.5 vs 15,8%, 17.1 vs 9.7% and 3.4 vs 0.3%, respectively; p 0.007, 0.03 and 0.005, FDR 0.2, 0.75 and 0.2). Conclusions: Genetic variation in the ABCC1 gene was strongly associated with severe hematological toxicity of FEC. Other previously described SNP were not validated. This is the largest bc study in which the impact of genetic variability on the adverse events of FEC chemotherapy was investigated.

Drug Induced Changes in Cell Organelles

1968 ◽  
Vol 26 ◽  
pp. 110-111
Author(s):  
Sarah A. Luse
Keyword(s):  
Clinical Medicine ◽  
Cell Organelles ◽  
Riboflavin Deficiency ◽  
Drug Induced ◽  
New Era ◽  
Health And Disease ◽  
In The Beginning ◽  
Cellular Pathology ◽  
Induced Changes ◽  
The Impact

In the mid-nineteenth century Virchow revolutionized pathology by introduction of the concept of “cellular pathology”. Today, a century later, this term has increasing significance in health and disease. We now are in the beginning of a new era in pathology, one which might well be termed “organelle pathology” or “subcellular pathology”. The impact of lysosomal diseases on clinical medicine exemplifies this role of pathology of organelles in elucidation of disease today.Another aspect of cell organelles of prime importance is their pathologic alteration by drugs, toxins, hormones and malnutrition. The sensitivity of cell organelles to minute alterations in their environment offers an accurate evaluation of the site of action of drugs in the study of both function and toxicity. Examples of mitochondrial lesions include the effect of DDD on the adrenal cortex, riboflavin deficiency on liver cells, elevated blood ammonia on the neuron and some 8-aminoquinolines on myocardium.

The impact of applying the Common Customs Tariff on the armenian export of Cut and Polished Gems to Russia

2019 ◽  
pp. 33-41
Author(s):  
V. L. Harutyunyan ◽  
S. V. Dokholyan ◽  
A. R. Makaryan
Keyword(s):  
Manufacturing Sector ◽  
Practical Implication ◽  
Dominant Role ◽  
New Technology ◽  
Manufacturing Companies ◽  
Medium Term ◽  
Diamond Cutting ◽  
Global Trends ◽  
The Common ◽  
The Impact

The presented study discusses the issues of applying the Common Customs Tariff (CCT) rates of the Eurasian Economic Union (EAEU) on rough diamonds and the impact thereof on the exports of stones cut and polished inArmeniaand then exported toRussia.Aim. The study aims to identify the possible strategies Armenian diamond cutting and polishing companies could adopt as a response to the application of the CCT rates on rough diamonds and how it would affect exports to various destinations, namely to Russia.Tasks. The authors analyze the current state of the gems and jewelry sector and substantiate the need to either integrate it into the jewelry manufacturing sector or to apply various strategies to facilitate exports to either Russia or other destinations in the medium term in response to the application of the CCT rates.Methods. This study uses general scientific methods of cognition, including analytical and methodological approaches and elements of forecasting. Possible strategies the Armenian diamond cutting and polishing companies could adopt in the medium term in response to the application of the EAEU CCT rates are determined using the analytical research method, forecasts in the context of the developments in the Armenian gem processing and jewelry market and global trends, statistical data on the imports and exports of cut and polished gems and jewelry for 2014–2018 published by the UN Comtrade Statistics.Results. Statistics on the exports of processed diamonds from 2014 to 2018 highlights the issue associated with the loss of competitiveness suffered by Armenian companies (mainly in comparison with Indian diamond cutters). The major global trends in the diamond cutting and polishing business indicate that it could be virtually impossible for Armenian cutters and polishers to compete with Indian companies in the medium term if they do not comes to investing in new technology to achieve operational efficiency. For these companies, it is important not to lose the Russian market due to an increase in the tariff rate and concentrate on the processing of gems that are larger than 1 carat. Another strategy to avoid an increase in the customs tariff rates would depend on the Armenian government’s ability to negotiate with Russia in respect of direct imports of diamond stones from Russian manufactures. Two other options for Armenian cutters involve focusing on cutting and polishing of rubies, sapphires, emeralds, etc. or integrating into the jewelry sector either by being the primary supplier or by considering this business as a channel to sell processed diamond stones by setting up their own jewelry manufacturing companies.Conclusions. With CCT going into effect in January 2021 and India’s dominant role in the diamond cutting and polishing business, Armenia needs to carefully consider all of the strategies the Armenian companies could adopt, as discussed above. As a member state of the EAEU, Armenia freely exports to Russia, however, further exports to Russia would depend on Armenia’s ability to ensure that cost-effective operations are in place, or to concentrate on the processing of precious gems rather than diamonds, or to switch to the manufacturing of jewelry items as a major export item.Practical Implication. The findings of this study could be of interest to the Ministry of Economy of the Republic of Armenia and Business Armenia that could be used in elaborating the strategy for the development of Armenian gems and jewelry sector of the economy.

The Impact of Applying the Common Customs Tariff on Armenian Exports of Tobacco Products

2020 ◽  
Vol 26 (4) ◽  
pp. 358-365
Author(s):  
V. L. Harutyunyan ◽  
S. V. Dokholyan ◽  
A. R. Makaryan
Keyword(s):  
Tobacco Products ◽  
The Common ◽  
The Impact

Marine Quality Standards: Their Derivation and Application in the United Kingdom

1985 ◽  
Vol 17 (6-7) ◽  
pp. 1187-1198 ◽  
Author(s):  
G. Mance ◽  
A. R. O'Donnell
Keyword(s):  
Coastal Waters ◽  
Sublethal Effects ◽  
Quality Standards ◽  
Toxicity Data ◽  
Marine Life ◽  
Nickel Zinc ◽  
The United Kingdom ◽  
The Common ◽  
Lead Nickel ◽  
The Impact

This paper discusses the derivation of environmental quality standards for coastal waters and the difficulties of using such standards for controlling industrial discharges. Attention is focused on the common List II substances, copper, chromium, lead, nickel, zinc and arsenic - and their effects on marine life. The adequacy of existing toxicity data is discussed and it is concluded that long exposure tests are required to provide information on sublethal effects. Such data are currently limited. It is also important that consideration be given to the effects that reducing salinities and increasing temperatures have in increasing the toxicity of these substances. The complexity of interpreting the results of laboratory toxicity data to coastal waters is discussed with reference to a study of the impact of an industrial discharge.

Larvae of the blow fly Caiusa testacea (Diptera: Calliphoridae) as egg predators of Polypedates cruciger Blyth, 1852 (Amphibia: Anura: Rhacophoridae)

2020 ◽  
Vol 12 (17) ◽  
pp. 17374-17379
Author(s):  
W.G.D. Chathuranga ◽  
K. Kariyawasam ◽  
Anslem De Silva ◽  
W.A.Priyanka P. De Silva
Keyword(s):  
Sri Lanka ◽  
High Impact ◽  
Tree Frog ◽  
Blow Fly ◽  
Breeding Habitats ◽  
The Family ◽  
Water Container ◽  
The Common ◽  
Natural Breeding ◽  
The Impact

We investigated the impact of dipteran predators on eggs in foam nests of the Common Hour-glass Tree Frog Polypedates cruciger Blyth, 1852 (Anura: Rhacophoridae) in central Sri Lanka.  Foam nests (n=24) of P. cruciger were examined at their natural breeding habitats and infected (n=8) and uninfected spawns (n=16) were identified.  Emerging tadpoles were collected in a water container hung under each spawn and the average number of tadpoles (N) hatched from infected spawns (N=0) was compared with that of uninfected spawns (N=354 ± 67).  Three severely infected spawns were brought to the laboratory and the fly larvae were reared until they metamorphosed to adults.  Morphological and molecular identification of the flies confirmed them as belonging to Caiusa testacea Senior-White, 1923 of the family Calliphoridae.  The infected spawns were completely destroyed and an estimated average of 400 P. cruciger eggs per spawn were lost.  The results revealed a high impact of Caiusa testacea on egg and embryo mortality of P. cruciger.

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