bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lyn Kinase Overexpression Is One of the Mechanisms of Resistance to Nilotinib In Chronic Myeloid Leukemia
Authors: Mahon Francois-Xavi er , Hayette Sandrine , Lagarde Valerie , Nicolini Franck E , Belloc Francis , Leroy Cedric , Roche Serge , Manley Paul , Belanger Coralie , Etienne Gabriel , Pasquet Jean-Max 
Published: April 2020

Abstract
Targeting the tyrosine kinase activity of Bcr-Abl is an attractive therapeutic strategy in Chronic Myeloid Leukemia (CML) and in Bcr-Abl positive Acute Lymphoblastic Leukemia. Whereas imatinib, a selective inhibitor of Bcr-Abl tyrosine kinase, is now used in frontline therapy for CML, second generation inhibitors of Bcr-Abl tyrosine kinase such as nilotinib or dasatinib have been developed. In the current study, we generated nilotinib-resistant cell lines and investigated their mechanism of resistance. Three nilotinib-resistant cell lines were obtained from the Ph-positive cell lines AR230, LAMA84 and K562. Over expression of the BCR-ABL gene was found in two nilotinib-resistant cell lines and the multidrug resistance gene (MDR-1) was found overexpressed in one of them, i.e, LAMA84 nilotinib resistant cell. The K562/DOX cell line, that displays resistance to several drugs by over expressing Pgp, was resistant to nilotinib, and this was reversed by simultaneous incubation with either verapamil or PSC833 confirming that nilotinib is a substrate of the Pgp. In one nilotinib-resistant cell line (K562-rn), we found over expression of p53/56 Lyn kinase, both at the mRNA and protein level (10- fold), and these cells were compared to their sensitive counterpart. Lyn silencing by siRNA restored sensitivity to nilotinib. Two Src kinase inhibitors (PP1 and PP2) partially restored sensitivity to nilotinib, but did not significantly inhibit Bcr-Abl tyrosine kinase activity. In contrast, dasatinib, an inhibitor of Abl and Src-family kinases, inhibited phosphorylation of both BCR-ABL and Lyn, and induced apoptosis of the Bcr-Abl cell line which over expressed p53/56 Lyn. Of 7 nilotinib-resistant CML patients, failure of nilotinib treatment was accompanied by mutations in Bcr-Abl kinase domain in 2 patients and an increase of Lyn mRNA expression (RQ-PCR) in 2 other patients. As an approach to confirm the involvement of the Lyn signalling pathway in nilotinib-resistance, we have used the Stable Isotope Labeling with Amino acids in Cell culture (SILAC) technique. The tyrosine phosphorylated protein fraction was analyzed by tandem mass spectrometry. Peptide sequencing and quantification in the nilotinib-resistant cell line identified &gt;350 proteins, of which several were hyper-phosphorylated; functional analysis of the different candidates is in progress.
In conclusion, mechanisms of resistance to nilotinib in imatinib-resistant cell lines resemble those operating in CML patients, and up-regulated Lyn kinase signalling can play an important role in nilotinib resistance.
Aberrant p53 Signaling Pathways in RPL11 Mutant Zebrafish
Authors: Danilova Nadia , Morimoto Kenji , Sakamoto Kathleen M , Lin Shuo 
Published: April 2020

Abstract
Diamond Blackfan Anemia (DBA) is a congenital syndrome characterized by decreased production of red blood cells and developmental abnormalities. This syndrome is caused by mutations in ribosomal genes (RPs), most frequently in RPS19, RPL11, and RPL5. Previously, we created RPS19 deficient zebrafish using morpholinos and demonstrated that p53 family members mediate the effects of RPS19 deficiency on development and hematopoiesis through upregulation of p53-related proteins. In this study, we found that RPL11 mutations, similar to RPS19 deficiency, leads to dysregulation of p53, its related family members, and downstream signaling pathways in zebrafish. Expression of both total p53 and Δ113Np53 is strongly upregulated in mutants with more modest upregulation of ΔNp63. The p53 protein also induced p21 and G1 cyclin expression, which resulted in cell cycle arrest. The pro-apoptotic genes, puma and bax, were also upregulated. We observed that the expression of several genes involved in hematopoiesis was altered, for example, globin gene expression was decreased. The ΔNp63 protein, which increases expression of adenosine deaminase (ADA) and is upregulated in &gt;70% of DBA patients, was also upregulated in RPL11 zebrafish mutants. Interestingly, we also observed increased expression of the proto-oncogenes c-fos, c-jun, and c-myc in RPL11 mutants. Increased expression of proto-oncogenes may contribute to the mechanisms of transcriptional activation by p53 family members in response to ribosomal protein deficiency. Furthermore, aberrant expression of oncogenes could provide a possible mechanism for the increased risk of malignancies in DBA patients. We propose that the zebrafish is a model system to study developmental and hematologic defects in addition to signaling pathways in the pathogenesis of DBA.
Acute Kidney Injury in Patients Receiving Subcutaneous Deferoxamine Therapy.
Authors: Ponnampalam Arjuna , Houston Donald S 
Published: April 2020

Abstract
Iron chelation is an important modality in treating patients with iron overload syndromes to minimize end-organ damage. The greatest experience has been in young patients with thalassemia, but there is growing use of chelation therapy in patients with acquired transfusion-dependent disorders such as myelodysplastic syndrome. Deferoxamine is a clinically proven and effective therapy for long term chelation, but the standard mode of administration by subcutaneous pump-driven infusion is burdensome for patients and leads to poor adherence. Intermittent bolus injection (1g in 10ml of water injected subcutaneously twice daily) has been advocated as an alternative protocol that may facilitate compliance. Acute kidney injury has been described previously in patients receiving high dose intravenous deferoxamine, but not in patients receiving subcutaneous therapy, and nephrotoxicity is not listed as an adverse effect in the product monograph. Here we report a series of three patients who developed acute kidney injury when receiving subcutaneous deferoxamine by intermittent bolus injection.
CASES: All three patients were elderly adults. The first was a 64 year old man who developed iron overload secondary to hemoglobin H disease, the second was a 78 year old woman with transfusion-dependent myelodysplastic syndrome (refractory anemia with ring sideroblasts), and the third was an 83 year old man with transfusion-dependent smoldering multiple myeloma. These patients had preexisting mild renal impairment: the first was a kidney transplant recipient taking cyclosporine, the second had a prior nephrectomy for renal carcinoma, and the third had longstanding renal impairment from renovascular disease. All three patients had resolution of their acute kidney injury on discontinuation of therapy and have had stable creatinine values subsequently. Rechallenge with deferoxamine led again to a reversible rise in creatinine in the first patient. The most striking effect was in the second patient: her creatinine level rose from a baseline of 154μmol/l to 280μmol/l one month after starting deferoxamine, and fell to 138μmol/l two weeks after discontinuing the drug.
DISCUSSION: We conclude that renal dysfunction can be an important side effect of deferoxamine chelation. The toxicity appears to be reversible on discontinuation of therapy. Older patients and patients with pre-existing renal impairment may be more susceptible to this effect, and subcutaneous bolus dosing may increase the risk, possibly due to higher peak drug levels. Careful monitoring of creatinine values and minimization of other nephrotoxic agents is appropriate and prudent when managing iron overload syndromes with deferoxamine chelation therapy.
Bone Marrow Necrosis: Clinical and Pathological Characteristics of 30 Patients
Authors: Sanchez-Guerrero Sergio , Agreda Gladys , Gutiérrez Ruth , Buitrón Nathalie , Montante Daniel , Lome Carmen 
Published: April 2020

Abstract
Background: Bone marrow necrosis (BMN) affects both stromal tissue and hematopoietic precursors and its prevalence ranges from 0.3–37%, being the hematologic malignancies the most frequent cause.
Aim: To describe the clinical and pathological characteristics of 30 patients with BMN diagnosed and treated at our institution.
Methodology: We included all adult patients diagnosed during the last 8 years (2000– 2007) via bone marrow aspiration and biopsy.
Results: Median age was 44 years (range 14–78); 53.3% were females. 42.2% of the patients died within a month mainly due to adult respiratory distress syndrome (ARDS) and septic shock. Just 5 (16.7%) of them are still alive. In all cases, BMN was of coagulative type, and extense in 23 (76.6%) of the patients. The main symptoms were: bone pain (53%), anemia (53%) and fever (50%), whereas the main underlying diseases were: acute lymphoblastic leukemia (ALL) in 26.7%, non-Hodgkin lymphoma (NHL) in 13.3% and multiple myeloma (MM) in 10% of the patients.
Conclusions: BMN is associated to a fatal course and to hematologic malignancies in most of our patients.
Investigation of Epidemiologic Factors in Children with Acute Lymphoblastic Leukemia
Authors: Yilmaz Oznur , Timur Cetin , Yoruk Asim , Erguven Muferet , Aktekin Elif , Kavakli Kaan 
Published: April 2020

Abstract
In this study, we aimed to investigate epidemiologic factors in children with Acute Lymphoblastic leukemia (ALL). The parents of 105 children diagnosed and treated as ALL between the years 1997 –2007 in our Clinic of Pediatric Hematology-Oncology were questioned and results were compared with control group that consisted of 102 healthy children with similar age and gender. The mean age of the patients was 8.57 ± 3.95 years. The mean age at diagnosis was 5.87 ± 3.73 years. There was no significant difference between the groups in terms of type of delivery, birth weight, asphyxia at birth, resuscitation with high-concentration oxygen and ventilatory support (p&gt;0.05). There was also no significant difference between the groups in terms of duration of breast feeding. The rate of exposure to infections prior to diagnosis was higher in control group (p:0.003). Besides that, the rate of going to nursery was also significantly higher in control group (p:0.014). There was no difference between the groups in terms of X-ray exposure (p&gt;0.05). In conclusion over-protection from infectious agents in and delay in meeting with some specific agents seems to increase ALL risk. Infections in early infantile period can be protective against leukemia. There has to be more extended studies on this subject.
GST T1 and GST M1 Polymorphisms Are Associated with the Risk of Acute Myeloid Leukemia
Authors: Kim Hee Nam , Yu Li , Kim Nan Young , Lee Il-Kwon , Kim Yeo-Kyeoung , Yang Deok-Hwan , Lee Je-Jung , Kim Hee-Je , Min Woo- Sung , Park Moo-Rim , Jo Deog-Yeon , Won Jong-Ho , Kwak Jae-Yong , Kim Hyeoung Joon 
Published: April 2020

Abstract
Xenobiotic-metabolizing enzymes influence the susceptibility to malignancies as well as prognosis by causing chemotherapy resistance. We analyzed genetic polymorphisms of glutathione S-transferases T1 and M1 (del GSTT1 and del GSTM1) and NAD(P)H quinone-oxoreductase (NQO1 C609T) to evaluate the association and risk of acute myeloid leukemia (AML). A large-scale population-based, case-control study of 1700 controls and 663 cases was conducted in Chonnam National University Hwasun Hospital, Korea.
GST T1 null genotype was associated with increased risk for AML [odds ratio (OR) = 1.20; 95% confidence interval (CI) = 1.003–1.45, p=0.047]. GST M1 null genotype was highly associated with a decreased risk for AML (OR= 0.38; 95%CI = 0.31–0.46, p&lt; 0.0001). Analysis of the NQO1 C609T polymorphism failed to show an association with AML, although a near significant increase was also found in NQO1 609GG genotype (OR= 1.30; 95%CI = 0.54–4.77, p=0.06)
Our results suggest an association of extensive GST with an increased or decreased risk for AML, possibly by an increase in the metabolic activation of chemical carcinogens or linkage to another cancer-causing gene. Inconsistent result in other studies may be due to geographical differences in the type of environmental carcinogens to which different populations are exposed.
Can Decrease in Smoking Incidence Reduce Leukemia Mortality?
Authors: Varadarajan Ramya , Cummings Michael K , Hyland Andrew J , Wang Eunice S. , Wetzler Meir 
Published: April 2020

Abstract
Smoking is the leading preventable cause of death in the Western world. There is substantial evidence that smokers are approximately 1.5 times more likely to develop acute myeloid leukemia (AML) than non smokers. We were interested to know if there is a relationship between smoking and treatment outcome in AML. We searched the Centers for Disease Control and Prevention (CDC) and Surveillance Epidemiology and End Results (SEER) databases for data about smoking incidence and AML mortality. We collected AML mortality data for the United States (US) from SEER and state leukemia mortality data from CDC. CDC data are lumped for all types of leukemia. Since AML is the most common leukemia, and no significant improvement in AML treatment, as compared to chronic myeloid leukemia, occurred in the last two decades, we used the collective leukemia data. We compared smoking incidence and age-adjusted leukemia mortality between overall US and states with either a high (Alabama, Indiana, Ohio, Oklahoma, Kentucky) or a low (California, Connecticut, New York, Utah, Rhode Island) smoking incidence. SEER data revealed a statistically significant correlation (r=0.88) between smoking incidence and AML mortality for the different US regions (Figure 1). The correlation was significant whether we included a 10-year lag period (r= 0.75) for leukemia mortality or not. The correlation between smoking incidence and mortality rates for individual states was much more variable; data from two representative states, California (CA) with low smoking incidence (r=0.74) and Indiana (IN) with high smoking incidence (r=0.03) are shown (Figure 2). Possible causes for decreased mortality can include less pulmonary infections, less aggressive leukemia [reports of more frequent chromosomal aberrations involving chromosome 5, 7 and 8 in smokers] and better transplant outcome in non-smokers. To date, we did not find any data on association between leukemia incidence and smoking prevalence. These data suggest a possible association between smoking and leukemia mortality, and additional research is needed to determine if smoking cessation can be a tool to decrease leukemia mortality.
Figure 1 Figure 1. Figure 2: Figure 2:.
Antibody- and Cell-Mediated Immune Thrombocytopenia Are Differentially Sensitive to Intravenous Gammaglobulin Therapy
Authors: Chow Leola , Kim Michael , Speck Edwin R. , Aslam Rukhsana , Webster Michelle Lee , Chen Pingguo , Ni Heyu , Freedman John , Semple John W. 
Published: April 2020

Abstract
Immune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by IgG autoantibody-opsonized platelets prematurely being destroyed in the spleen although recent evidence suggests that thrombocytopenia in perhaps as many as 40% of patients with ITP can be mediated by CD8+ T cells. Although several animal models of immune thrombocytopenia have been developed, few are induced by platelet-specific autoimmune mechanisms nor have any demonstrated cell-mediated platelet destruction. We developed a murine model of ITP by first immunizaing GPIIIa (CD61) knockout (KO) mice against wildtype (WT) CD61+ platelet transfusions and subsequently transferring their splenocytes (5×104 cells/transfer) intraperitonealy into irradiated SCID mouse recipients. The SCID mice developed significant bleeding mortality and thrombocytopenia within 2 weeks post-transfer. Lower doses (&lt;104) of immune splenocytes transferred induced thrombocytopenia in the SCID mouse recipients with no mortality. Depletion of lymphocyte subsets in the splenocytes before transfer showed that both CD19+ B cell (antibody)- and CD8+ T cell (cell)-mediated thrombocytopenia existed and that bleeding mortality was particularly associated with antibody-mediated thrombocytopenia. Treatment of the SCID mouse recipients bi-weekly with 2g/kg intravenous gammaglobulins (IVIg) demonstrated that IVIg was beneficial in eliminating bleeding mortality and thrombocytopenia only in the recipients displaying the antibody-mediated form of ITP. Cell-mediated bleeding mortality and thombocytopenia was completely resistant to IVIg therapy. This model suggests a potential reason why some patients with ITP fail IVIg therapy and may aid in the development of new therapeutics for individuals inflicted with cell mediated thrombocytopenia.
Timed Sequential Therapy Induction and Consolidation in Newly Diagnosed AML: Achievement of Leukemia-Free Survival in Patients Using Two Cycles of Therapy Alone
Authors: Mihelic Ronald , LaPorte Justin , Carmichael Charlene , Morris Lawrence E. , Holland H. Kent , Solomon Scott R. , Bashey Asad 
Published: April 2020

Abstract
Long term outcomes for patients with AML are unsatisfactory following induction and consolidation chemotherapy alone except in patients with favorable–risk cytogenetics. The additional administration of the same or different agents starting 8–10 days after start of initial chemotherapy (timed sequential therapy, TST) may enable the killing of leukemic cells synchronized into cell cycling by the initial chemotherapy. However, it is unclear if patients with intermediate and unfavorable cytogenetics achieve improved outcomes using this approach. Sixty-nine unselected patients with AML (42M, 27F; median age = 53, range 16–74; cytogenetic risk group favorable =2, intermediate = 37, unfavorable = 23; 10 with an antecedent hematologic disorder) referred to a tertiary leukemia center received initial chemotherapy with a regimen of cytarabine 667mg/m2/d by 24 hour infusion on d1–3, idarubicin 12mg (age &lt;60) or 8 mg (age &gt;60)/m2/d on d1–3 and etoposide 100mg/m2 on d 8–10. Induction death occurred in 7 patients (10%). Complete remission was achieved following one cycle of induction therapy in 30 patients (43.5%). The corresponding complete response (CR) rates by cytogenetic subgroup were100%, 48.6% and 26% in the favorable, intermediate and unfavorable cytogenetic groups respectively. In patients who achieved CR, median time to ANC &gt; 1000/mm3 and platelets &gt; 100,000/mm3 were 29 d (range 21–76d) and 26d (range 17–83d). Mucositis was the most common non-hematologic toxicity. Of the 69 patients treated, 30 (43%) and 4 (6%) patients proceeded to allogeneic and autologous hematopoietic stem cell transplantation respectively. Of the patients who did not receive stem cell transplantation, eleven patients (median age 54, range 23–72; median WBC 27.1, range 1–250; cytogenetics -9 normal, 1 t(9;22); 1 11q23 abnormality) underwent consolidation with TST–consisting of a single cycle of cytarabine 667mg/m2/d (continuous infusion) on d1–3 and 10–12, and idarubicin (same dose as induction). Two year estimated probabilities of overall survival and relapse in this group were 65% and 26% respectively. In summary, TST as administered in these patients can be safe in patients with newly diagnosed AML, including those patients aged between 60 and 70. However, the regimen does not appear to improve CR rates over that seen using conventional induction regimens. Patients with intermediate risk cytogenetics who achieve CR and are not candidates for stem cell transplantation may receive consolidation with a single additional cycle of TST.
Dose Escalation of Low Molecular Weight Heparin to Manage VTE Treatment Failure in Cancer Patients
Authors: Carrier Marc , Le Gal Gregoire , Tierney Sarah , Do Kimberley , Wells Philip , Rodger Marc A. 
Published: April 2020

Abstract
Introduction: Cancer patients with venous thromboembolism (VTE) are at high risk of treatment failures (i.e. recurrent VTE while on therapeutic anticoagulants). Management of these treatment failures is controversial/poorly studied. Whereas some clinicians recommend inferior vena cava (IVC) filter insertion, others do not. We sought to assess the efficacy and safety of escalating the dose of low-molecular weight heparin (LMWH) in the management of treatment failure recurrent VTE in cancer patients.
Methods: Retrospective cohort study of outpatients with cancer and treatment failure recurrent VTE seen at the Ottawa Hospital Thrombosis Unit from January 2007 to June 2008. Patients were followed for three months following the treatment failure event.
Results: Thirty cancer patients had recurrent VTE despite ongoing anticoagulation. The mean age was 60.7 years. Twenty two patients (73.3%) were on LMWH treatment at the time of the recurrent event. Of these 22 patients, 4 (18.2%) were on full (100%) therapeutic doses, 15 (68.2%) on 75% of therapeutic doses and 3 (13.6%) on prophylactic doses of LMWH. All 4 patients on full therapeutic dose were treated by increasing the weight-adjusted dose of LMWH by 20% for 6 weeks. Patients on 75% of therapeutic doses were treated by increasing the weight-adjusted LMWH by 25% for 6 weeks (4/15 patients) or 3 months (11/15 patients). All three patients on prophylactic doses were treated with one month of full therapeutic doses of LMWH followed by 75% thereafter. No patients had an IVC filter inserted or a major bleeding episode. One patient had a minor bleeding episode (4.5%; 95% CI: 1.1–21.9%), 2 patients died (9.1%; 95% CI: 2.8–28.0) (no VTE-related death) and one patient (4.5%; 95% CI: 1.1–21.9%) had a second treatment failure event during the three-month follow-up period while on full therapeutic doses of LMWH.
Eight patients (26.7%) were on vitamin-K antagonist at the time of the recurrent VTE due to treatment failure. Five (62.5) patients had a therapeutic INR on the day of the recurrent VTE. All patients were treated with LMWH at full doses for a month followed by 75% thereafter. One patient (12.5%; 95%CI 2.8–48.3) had a minor bleeding episode during follow-up.
Conclusion: Escalading the dose of LMWH following a recurrent VTE due to treatment failure seems to be a safe and effective method to prevent further recurrence in cancer patients. Our data challenges the concept of using IVC filters in this setting.