Pharmacogenetics of anticancer drugs in non-Hodgkin lymphomas

The variability of tumour responses to chemotherapeutic agents is a topic of major interest in current oncology research. Advances in the knowledge of molecular pathology of cancer make available strategies by which tumour cells can be profiled for their genetic background in order to select anticancer agents that might selectively kill cells in a molecular context that matches the mechanism of action of drugs. The next generation of anticancer treatments might thus be tailored on the basis of the numerous molecular alterations identified in tumour cells of a particular patient. However, to exploit these alterations, it is necessary to understand how they influence the cellular pathways that control the sensitivity or, conversely, resistance to chemotherapeutic agents. The aim of this article is to outline major genetic abnormalities in non-Hodgkin lymphomas that can be used to streamline anticancer drug selection and to underscore the major role of pharmacogenetics, which studies the interactions between genetic background and drug activity, to the prediction of likelihood of response and identification of potential new targets for pharmacological intervention. © 2001 Cancer Research Campaign  http://www.bjcancer.co

Fructose-1,6-diphosphate reduces acute ECG changes due to doxorubicin in isolated rat heart

Doxorubicin (DXR) (0.17 x 10(-4) M) induces an acute cardiotoxicity in isolated rat heart; there is a progressive widening of the S alpha T segment, with a decrease in force derivatives and in the coronary flow. Concurrent perfusion with fructose-1,6-diphosphate (FDP) (10(-5)-10(-4) M) dose-dependently reduces the S alpha T enlargement but fails to affect the reduction in force derivatives and coronary flow. The target of cardiac protection by FDP might be the ionic mechanisms underlying the action potential configuration

Geranylgeraniol overcomes the block of cell proliferation by lovastatin in C6 glioma cells

It is well documented that 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors prevent cultured mammalian cells from progressing through the cell cycle, suggesting a critical role for a mevalonate-derived product. Recently, it has been shown that free geranylgeraniol (GG-OH) and farnesol (F-OH) can be utilized by C6 glioma cells for protein isoprenylation. The ability of CC-OH and F-OH to restore protein geranylgeranylation or farnesylation selectively has enabled us to examine the possibility that mevalonate is essential for cell proliferation because it is a precursor of farnesyl pyrophosphate or geranylgeranyl pyrophosphate, the isoprenyl donors involved in the posttranslational modification of key regulatory proteins. In this study we report that CC-OH, as well as mevalonate, overcomes the arrest of cell proliferation of C6 glioma cells treated with lovastatin, as assessed by increased cell numbers and a stimulation in [H-3]thymidine incorporation. The increase in cell number and [H-3]thymidine incorporation were significantly lower when F-OH was added. Under these conditions [H-3]mevalonate and [H-3]GG-OH are actively incorporated into a set of isoprenylated proteins in the size range of small, GTP-binding proteins (19-27 kDa) and a polypeptide with the molecular size (46 kDa) of the smaller isoform of 2',3'-cyclic nucleotide 3'-phosphodiesterase. Analysis of the proteins metabolically labeled by [H-3]mevalonate and [H-3]GG-OH reveals the presence of labeled proteins containing geranylgeranylated cysteinyl residues. Consistent with geranylgeranylated proteins playing a critical role in the entry of C6 cells into the cell cycle, a (phosphonoacetamido) oxy derivative of GG-OH, a drug previously shown to interfere with protein geranylgeranylation, prevented the increase in cell number when mevalonate or GG-OH was added to lovastatin-treated cells. These results strongly suggest that geranylgeranylated proteins are essential for progression of C6 cells into the S phase of the cell cycle and provide the first evidence that the "salvage" pathway for the utilization of the free isoprenols is physiologically significant in the CNS

Synergistic cytotoxicity and pharmacogenetics of gemcitabine and pemetrexed combination in pancreatic cancer cell lines

PURPOSE: Gemcitabine is an inhibitor of ribonucleotide reductase (RR) and DNA synthesis and is an effective agent in the treatment of pancreas cancer. The present study investigates whether the multitargeted antifolate pemetrexed would be synergistic with gemcitabine against MIA PaCa-2, PANC-1, and Capan-1 pancreatic cancer cell lines. EXPERIMENTAL DESIGN: Cells were treated with gemcitabine and pemetrexed, and the type of drug interaction was assessed using the combination index. Cytotoxicity of gemcitabine was examined with inhibitors of (a) deoxycytidine kinase (dCK), which activates gemcitabine by phosphorylation, and (b) 5'-nucleotidase (drug dephosphorylation) and cytidine deaminase (drug deamination), the main inactivating enzymes. The effects of gemcitabine and pemetrexed on cell cycle were analyzed by flow cytometry, and apoptosis was examined by fluorescence microscopy. Finally, quantitative, real-time PCR was used to study the pharmacogenetics of the drug combination. RESULTS: Synergistic cytotoxicity and enhancement of apoptosis was demonstrated, mostly with the sequence pemetrexed-->gemcitabine. Pemetrexed increased cells in S phase, the most sensitive to gemcitabine, and a positive correlation was found between the expression ratio of dCK:RR and gemcitabine sensitivity. Indeed, pemetrexed significantly enhanced dCK gene expression (+227.9, +86.0, and +135.5% in MIA PaCa-2, PANC-1, and Capan-1 cells, respectively), and the crucial role of this enzyme was confirmed by impairment of gemcitabine cytotoxicity after dCK saturation with 2'-deoxycytidine. CONCLUSIONS: These data demonstrate that the gemcitabine and pemetrexed combination displays schedule-dependent synergistic cytotoxic activity, favorably modulates cell cycle, induces apoptosis, and enhances dCK expression in pancreatic cancer cells

Enamel interproximal reduction during treatment with clear aligners: digital planning versus OrthoCAD analysis

Background The aim of the study was to compare the amount of interproximal enamel reduction (IPR) provided on ClinCheck software with the amount of IPR carried out by the orthodontist during treatment with clear aligners. Methods 30 subjects (14 males, 16 females; mean age of 24.53 +/- 13.41 years) randomly recruited from the Invisalign account of the Department of Orthodontics at the University of Rome "Tor Vergata" from November 2018 to October 2019, were collected according to the following inclusion criteria: mild to moderate dento-alveolar discrepancy (1.5-6.5 mm); Class I canine and molar relationship; full permanent dentition (excluding third molars); both arches treated only using Comprehensive Package by Invisalign system; treatment plan including IPR. Pre- (T0) and post-treatment (T1) digital models (.stl files), created from an iTero scan, were collected from all selected patients. The OrthoCAD digital software was used to measure tooth mesiodistal width in upper and lower arches before (T0) and at the end of treatment (T1) before any refinement. The widest mesio-distal diameter was measured for each tooth excluding molars by "Diagnostic" OrthoCAD tool. The total amount of IPR performed during treatment was obtained comparing the sum of mesio-distal widths of all measured teeth at T0 and T1. Significant T1-T0 differences were tested with dependent sample t-test (P < 0.05). Results In the upper arch, IPR was digitally planned on average for 0.62 mm while in the lower arch was on average for 1.92 mm. As for the amount of enamel actually removed after IPR performing, it was on average 0.62 mm in the maxillary arch. In the mandibular arch, the mean of IPR carried out was 1.93 mm. The difference between planned IPR and performed IPR is described: this difference was on average 0.00 mm in the upper arch and 0.01 in the lower arch. Conclusions The amount of enamel removed in vivo corresponded with the amount of IPR planned by the Orthodontist using ClinCheck software

<b><i>Topoisomerase 1</i></b> Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients

Objective: Topoisomerase 1 (topo-1) is an important target for the treatment of metastatic colorectal cancer (CRC). The aim of the present study was to evaluate the correlation between topo-1 single-nucleotide polymorphisms (SNPs) and clinical outcome in metastatic CRC (mCRC) patients. Methods: With the use of specific software (PROMO 3.0), we performed an in silico analysis of topo-1 promoter SNPs; the rs6072249 and rs34282819 SNPs were included in the study. DNA was extracted from 105 mCRC patients treated with FOLFIRI ± bevacizumab in the first line. SNP genotyping was performed by real-time PCR. Genotypes were correlated with clinical parameters (objective response rate, progression-free survival, and overall survival). Results: No single genotype was significantly associated with clinical variables. The G allelic variant of rs6072249 topo-1 SNP is responsible for GC factor and X-box-binding protein transcription factor binding. The same allelic variant showed a nonsignificant trend toward a shorter progression-free survival (GG, 7.5 months; other genotypes, 9.3 months; HR 1.823, 95% CI 0.8904-3.734; p = 0.1). Conclusion: Further analyses are needed to confirm that the topo-1 SNP rs6072249 and transcription factor interaction could be a part of tools to predict clinical outcome in mCRC patients treated with irinotecan-based regimens

Low-cost carriers and airports: a complex relationship

In the last decades, low-cost carriers have generated several changes in the air market for both passengers and airports. Mainly for regional airports, low-cost carriers have represented an important opportunity to improve their connectivity levels and passenger traffic. Furthermore, many regional airports have become key factors to regenerate the local economy by improving accessibility and stimulating several markets, such as tourism. However, the relationship between low-cost carriers and airports is rather complex and the outcomes not always predictable. In order to analyse and understand better such relationship and its outcomes, this chapter discusses the main underlying factors identified in: relation with the regional air market (secondary/primary airports), balance of power (dominated/non-dominated airports) and industrial organisation (bases/non-bases). Starting from the proposed Relative Closeness Index, which combines yearly airport passengers and distance between airport pairs, a large sample of European airports is analysed. Then, a smaller sub-sample – which includes selected, significant case studies referring to mid-sized airports – is discussed in detail. Among the main findings, airports sharing their catchment area with others are in a very risky position, due to the potential mobility of LCCs, while geographically isolated airports in good catchment areas can better counterbalance the power of carriers

Posttransplant lymphoproliferative disorders in neuronal xenotransplanted macaques

Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations that occur in the setting of depressed T-cell function due to immunosuppressive therapy used following solid organ transplantation, hematopoietic stem cell transplantation, and also xenotransplantation. In the present study, 28 immunosuppressed parkinsonian Macaca fascicularis were intracerebrally injected with wild-type or CTLA4-Ig transgenic porcine xenografts to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Nine of 28 (32%) immunosuppressed primates developed masses compatible with PTLD, located mainly in the gastrointestinal tract and/or nasal cavity. The masses were classified as monomorphic PTLD according to the World Health Organization classification. Immunohistochemistry and polymerase chain reaction (PCR) analyses revealed that the PTLDs were associated with macaca lymphocryptovirus as confirmed by double-labeling immunohistochemistry for CD20 and Epstein-Barr nuclear antigen 2 (EBNA-2), where the viral protein was located within the CD20+ neoplastic B cells. In sera from 3 distinct phases of the experimental life of the primates, testing by quantitative PCR revealed a progression of the viral load that paralleled the PTLD progression and no evidence of zoonotic transmission of porcine lymphotropic herpesvirus through xenoneuronal grafts. These data suggest that monitoring the variation of macaca lymphocryptovirus DNA in primates could be used as a possible early diagnostic tool for PTLD progression, allowing preemptive treatment such as immunosuppression therapy reduction

A comparative study of EEG abnormalities among subjects with inter-ictal psychosis and those with schizophrenia

Background: Electrophysiological investigation is an integral part in the management of neuropsychiatric disorders; but this is rare in developing countries including Nigeria.Objectives: The study aims to determine EEG abnormalities among subjects with inter-ictal psychosis in comparison to those with schizophrenia.Methods: A cross-sectional study of subjects with inter-ictal psychosis and those with schizophrenia. Each of the subjects that met the inclusion criteria had an awake EEG recording that lasted 45 minutes.Results: For PWEIP, the mean age was 23.9 (±13.8) years; and made up of 53 (53.0%) males; and for PWS, the mean age was 24.2 (±13.5) years; and there were 51 (51.0%) males. The EEG was normal in 53 (53.0%) of PWEIP and in 83 (83.0%) of PWS. EEG was abnormal in 47 (47.0%) of PWEIP, and 17 (17.0%) in those with PWS, and these were all ‘epileptiform’ activities, and the difference was statistically significant with X2 =20.7 (Fisher’s exact test), df=1 and p=0.00**. Conclusion: A number of subjects in our sample with inter-ictal psychosis and PWS had EEG epileptiform activities reflecting cerebral insults in early life. Thus, preventive measures such as good antenatal care are advocated to minimize the occurrence of these neuro-psychiatric disorders.Keywords: EEG abnormalities, inter-ictal psychosis, schizophreni

Can we improve the treatment of congestion in heart failure?

INTRODUCTION: Dyspnoea and peripheral oedema, caused by fluid redistribution to the lungs and/or by fluid overload, are the main causes of hospitalization in patients with heart failure and are associated with poor outcomes. Treatment of fluid overload should relieve symptoms and have a neutral or favorable effect on outcomes. AREAS COVERED: We first consider the results obtained with furosemide administration, which is still the mainstay of treatment of congestion in patients with heart failure. We then discuss important shortcomings of furosemide treatment, including the development of resistance and side effects (electrolyte abnormalities, neurohormonal activation, worsening renal function), as well as the relationship of furosemide - and its doses - with patient prognosis. Finally, the results obtained with potential alternatives to furosemide treatment, including different modalities of loop diuretic administration, combined diuretic therapy, dopamine, inotropic agents, ultrafiltration, natriuretic peptides, vasopressin and adenosine antagonists, are discussed. EXPERT OPINION: Relief of congestion is a major objective of heart failure treatment but therapy remains based on the administration of furosemide, an agent that is often not effective and is associated with poor outcomes. The results of the few controlled studies aimed at the assessment of new treatments to overcome resistance to furosemide and/or to protect the kidney from its untoward effects have been mostly neutral. Better treatment of congestion in heart failure remains a major unmet need