Ahmed M. L. Bedewy

Do SLCO1B3 (T334G) and CYP3A5*3 polymorphisms affect response in Egyptian chronic myeloid leukemia patients receiving imatinib therapy?

Abstract Background Imatinib has so far been the first-choice treatment in chronic myeloid leukemia (CML) with excellent results. However, only a proportion of patients achieve major molecular response. Hence, the need to find whether there are some factors that affect the response to treatment is essential. This study aimed to investigate the allele and genotype frequencies of single nucleotide polymorphisms (SNPs) of SLCO1B3 (T334G) and CYP3A5*3 in CML patients undergoing imatinib treatment and to determine whether SNPs of these two genes could predict the response of imatinib therapy in CML patients. Subjects and methods We investigated SLCO1B3 (T334G) and CYP3A5*3 polymorphisms by Polymerase Chain Reaction-restriction fragment length polymorphism in 86 Philadelphia positive newly diagnosed Egyptian CML patients (78 patients in chronic phase and 8 patients in accelerated phase). All patients received imatinib therapy and were followed for at least one and half years. The response to imatinib therapy was evaluated by recording the hematological response, cytogenetic response, and molecular response according to the European Leukemia Net criteria. Results This study included 86 Philadelphia positive newly diagnosed CML patients, 78 in the early chronic phase and 8 in the accelerated phase. In the chronic phase patients, no association between SLCO1B3 (T334G) exon 3 polymorphism and response to imatinib therapy was detected (P = 0.938) while CYP3A5*3 gene polymorphism was associated with inferior outcome (P < 0.001). In the group of accelerated phase patients, the SLCO1B3 polymorphic variants (TG) and (GG) were detected equally with none of the patients in this group having the homozygous wild form (TT). The homozygous state for the CYP3A5*3 allele was the most frequent (50%) and the homozygous state for the CYP3A5*1 allele was the least frequent (12.5%) in this group. Conclusion CYP3A5*3 polymorphism was associated with imatinib efficacy while the SNP SLCO1B3 (T334G) was not associated with the response to imatinib treatment in Egyptian patients with CML in chronic phase. These results prompt us to explore the effect of CYP3A5*3 in CML patients taking imatinib in a larger scale study.

Do baseline Cereblon gene expression and IL-6 receptor expression determine the response to thalidomide–dexamethasone treatment in Multiple myeloma patients?

Immunomodulatory drugs (IMiDs) are key components of treatment for hematologic malignancies, especially multiple myeloma (MM). Cereblon (CRBN) expression was described to be essential for the activity of thalidomide. Furthermore, IMiD binding to CRBN is cytotoxic to multiple myeloma cells and absence of CRBN confers IMiDs resistance. Interleukin‐6 (IL‐6) is a potent pleiotropic cytokine that regulates plasma cell (PC) growth via the IL‐6 receptor (IL‐6R). IL‐6/IL‐6R autocrine activity is implicated in the development and progression of cancers including cervical cancer, prostate cancer, and multiple myeloma. The aim of the study was to evaluate CRBN and IL‐6R expressions and their impact on clinical efficacy of dexamethasone–thalidomide therapy in multiple myeloma (MM) patients, in addition to their association with other clinical and prognostic parameters. Forty‐six newly diagnosed MM patients were enrolled in the study. We measured CRBN expression prior to therapy initiation by real‐time polymerase chain reaction in 46 bone marrow (BM) aspiration samples of patients and controls. In addition, IL‐6R expression was evaluated on BM biopsies of patients and controls by immunohistochemistry (IHC). Twenty‐eight males (60.9%) and 18 females (39.1%) were enrolled. The mean age was 65.11 ± 7.3 yr (range 39–77 yr). Median CRBN expression in 46 BM samples of MM patients was significantly higher than in controls (P < 0.001). Among established prognostic parameters, international staging system (ISS), serum beta‐2‐microglobulin (B2M), and serum albumin correlated reversely with CRBN expression. IL‐6R expression was significantly higher in patients than in controls. IL‐6R expression was significantly associated with response to treatment (P < 0.001), B2M (P = 0.032), and ISS (P = 0.028). Strong intensity expression was associated with low CRBN expression (P = 0.001).In conclusion, CRBN expression may provide a biomarker to predict response to IMiD in patients with MM and its high expression can serve as a marker of good prognosis. Strong IL‐6R expression is associated with poor response to therapy in multiple myeloma patients and may be used as a prognostic marker.

XPD gene polymorphisms and the effects of induction chemotherapy in cytogenetically normal de novo acute myeloid leukemia patients

Abstract Background Cytogenetically normal acute myeloid leukemia (AML) represents nearly half of newly diagnosed de novo AML cases. XPD is one of the DNA repair proteins, whose genetic polymorphisms are thought to affect their function as regards response to chemotherapeutic drugs and chemotherapy-induced toxicities. Subjects and methods We investigated the XPD Asp312Asn and Lys751Gln polymorphisms by polymerase chain reaction-restriction fragment length polymorphism in 51 newly diagnosed cytogenetically normal de novo AML patients. The response to the standard induction chemotherapy protocol and chemotherapy-induced toxicities were monitored. Results The XPD Asp312Asn GG genotype was the most frequent (57%) followed by the GA variant (37%), and the AA variant was the least frequent (6%). As regards the XPD Lys751Gln polymorphism, the AA genotype was the most frequent (49%), followed by the AC (39%) and CC (12%) variants. These variants were not associated with age, sex, FAB subtype, CNS infiltration, chemotherapy-induced hepatotoxicity, nephrotoxicity, or metabolic toxicity. The XPD Lys751Gln CC polymorphic variant was associated with chemotherapy-induced cardiotoxicity and lower chance to achieve response to induction chemotherapy. Conclusion XPD Lys751Gln and not Asp312Asn polymorphism was associated with chemotherapy-induced cardiotoxicity and response to induction chemotherapy in newly diagnosed cytogenetically normal AML patients. Pretreatment assay of XPD Lys751Gln may help to anticipate cardiotoxicity in those at risk. Moreover, it may be considered a prognostic marker in AML cases. However, further large scale research is needed to verify its usefulness.

On the stability of random access with energy harvesting and collision resolution

This paper studies the queues stability in a random access network in which the nodes have finite energy sources. The network consists of two nodes, each having a battery for energy storage. Each transmission consumes a fixed amount of energy, and the batteries are replenished through energy harvesting. Moreover, the nodes leverage the feedback information for collision resolution. In case of a collision, the destination stores the collided packets, and sends negative acknowledgement (NACK). Once the NACK is heard, one of the nodes retransmits its collided packet. The destination uses the retransmitted packet and the stored collided packets to recover the two packets involved in the collision. Therefore, the two nodes are served in two transmissions, but the retransmitting node has used more energy in the process. To characterize the stability region of this system, each node is modeled with two queues, the first for storing packets and the second models the energy in the battery. The random access nature of the network, as well as the interdependence between the battery and packet queues in each node, result in an interacting system of queues. To decouple this interaction, and characterize the stability region, we resort to a dominant system approach for the analysis. The stability region obtained is compared with the stability region of the system without energy constraints, and the losses due to finite energy are identified.

Cooperative MAC for Cognitive Radio Network with Energy Harvesting and Randomized Service Policy

This paper studies the queues stability and delay in cooperative multiple access for cognitive radio systems in which the secondary user (SU) has finite energy sources. The SU has two queues with a battery for energy storage. One of the SUs queues is used to store the relayed packets from the primary user (PU) queue. While the other one is used to store its own packets. Each transmission consumes a fixed amount of energy, and the battery is replenished through energy harvesting. A PUs packet is admitted to the relay queue with an admission probability. Moreover, the SU serves either the queue of its own data or the queue of the PU relayed data with certain service probabilities. The finiteness of energy has an effect on the system throughput and how it is affected by varying the service and admission probabilities. The analysis of this system is non- trivial due to the interdependence between the battery and SUs packet queues. This results in an interacting system of queues. To decouple this interaction, and characterize the stability region, we resort to a dominant system approach for the analysis. The obtained stability region is compared with the stability region of the system without energy constraints, and the losses due to finite energy are identified. Furthermore, the average delay encountered by the packets of both PU and SU is shown not to be affected by the finiteness of the energy within the stability region.

What Determines the Response to Immunomodulatory Therapy in Multiple Myeloma

Zhu et al. demonstrated that cereblon (CRBN) is essential for IMiDs activity, and low levels of CRBN correlate with poor drug response, and CRBN expression in MM cells may help to distinguish MM patients that will or will not benefit from thalidomide [2]. In the present study we evaluated CRBN and IL-6R expressions and their impact on clinical efficacy of dexamethasone–thalidomide therapy in Multiple Myeloma (MM) patients, in addition to their association with other clinical and prognostic parameters. Forty-six newly diagnosed MM patients were enrolled in the study. We measured CRBN expression prior to therapy initiation by real-time polymerase chain reaction in 46 Bone Marrow (BM) aspiration samples of patients and 15 controls. In addition, IL-6R expression was evaluated on BM biopsies of patients and controls by Immunohistochemistry (IHC). Median CRBN expression in 46 BM samples of MM patients was significantly higher than in controls (P < 0.001).Among established prognostic parameters, International Staging System (ISS), serum Beta-2-Microglobulin (B2M), and serum albumin correlated reversely with CRBN expression. Strong IL-6R expression was significantly higher in patients than in controls.IL-6R expression was significantly associated with poor response to treatment (P < 0.001), B2M(P = 0.032),and ISS(P = 0.028).Strong intensity expression was associated with low CRBN expression(P = 0.001).In conclusion, CRBN expression may provide a biomarker to predict response to IMiDs in patients with MM and its high expression can serve as a marker of good prognosis. Strong IL-6R expression is associated with poor response to therapy in multiple myeloma patients and can be used as a prognostic marker [3].

Correction to: The Influence of CYP2C9 and VKORC1 Gene Polymorphisms on the Response to Warfarin in Egyptians

The aim of this erratum is to acknowledge that the original version of this article was inadvertently published with incorrect author name and affiliation for a co-author.

Prognostic value of miRNA-155 expression in B-cell Non-Hodgkin's lymphoma.

Objective: MicroRNA-155 (miRNA-155) resides within the B-cell integration cluster gene on chromosome 21. It can act either as an oncogene or as a tumor-suppressor gene, depending on the cell background in which miRNA-155 is performing its specific target gene controlling function. Therefore, the aim of this study was to investigate miRNA-155 expression in patients with B-cell non-Hodgkin lymphoma (NHL) and its relation to disease prognosis in diffuse large B-cell lymphoma (DLBCL) patients. Materials and Methods: Reverse transcription-polymerase chain reaction assay was performed to evaluate the expression levels of miRNA-155 in 84 patients with newly diagnosed B-cell NHL and 15 normal controls. Results: Compared with normal controls, miRNA-155 expression was significantly upregulated in patients. Moreover, higher levels of miRNA-155 were associated with the presence of B symptoms, involvement of extranodal sites, and high Eastern Cooperative Oncology Group (ECOG) score. Higher levels of miRNA-155 in DLBCL were associated with non-germinal B-cell-like type, the presence of B symptoms, involvement of extranodal sites, and higher International Prognostic Index (IPI) and ECOG scores. Only the high IPI score and high miRNA-155 expression indicated a higher risk of lower event-free survival using multivariate Cox regression analysis. Our data demonstrated that the expression of miRNA-155 was upregulated in newly diagnosed B-cell NHL patients. miRNA-155 is expressed at a lower level in GCB-subtype DLBCL. Low IPI score and miRNA-155 expression were predictors of longer event-free survival. Conclusion: Despite contradicting literature reports, the current findings suggest the potential value of miRNA-155 as a biomarker of prognosis and monitoring in B-cell NHL, and especially that of the DLBCL type.

The prognostic value of glucocorticoid receptors for adult acute lymphoblastic leukemia.

Background Therapeutic protocols used in adult acute lymphoblastic leukemia (ALL) are widely variable, and glucocorticoids (GCs) are essential components in ALL treatment. Therefore, this study aimed to evaluate the distribution of prominent glucocorticoid receptor (GR) gene polymorphic variants among adult ALL patients. We also investigated the association between GR messenger ribonucleic acid (mRNA) isoform expressions and the response to chemotherapy. Methods Fifty-two newly diagnosed Philadelphia-negative adult ALL patients and 30 healthy control subjects were enrolled in this study. Genotyping was carried out using a polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. GR mRNA isoform expressions were assayed by quantitative real-time PCR. Results ALL patients in this study had a median age of 34 years (range, 18-75). GRα expression was associated with complete remission (P=0.03), while GRγ mRNA expression was significantly higher in GC resistant patients (P=0.032) and in non-responders (P=0.019). However, there were no significant associations with GC resistance. The BclI polymorphic variant of the GR gene was the most frequent in adult ALL patients and was not associated with the GC response. Both higher GRα expression and lower GRγ expression were associated with achievement of complete remission, while higher GRγ expression was associated with GC-resistance. Conclusion Our data suggest that the level of GR isoform expression may be useful in predicting GC response, achievement of complete remission, and better event-free survival in ALL patients. However, further evaluation with a larger cohort of patients is warranted.