bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of hTR Antisense Oligodeoxynucleotides on Telomerase Acitvity and Ciplatin -Sensitivity of Primary Acute Leukemia Cells.
Authors: Xiao Yang 
Published: October 2019

Abstract
BACKGROUND: Between the three key components part of human telomerase, human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) have significant correlation with telomerase activity. The previous study has identified that the telomerase activity of K562 and HL-60 cells was special suppresssed significantly by phosphorothoate antisense oligodeoxynucleotide (ASODN) complementary to the initiator codon of hTR. This study was designed to evalutae the effection of hTR ASODN on telomerase activity and apoptosis of primary acute leukemic cells. To research whether hTR ASODN could enhance apoptosis rates of primary leukemic cells to cisplatin.
METHODS: Primary leukemic cells were treated with phosphorothoate ASODN complementary to the initiator codon of hTR in vivo. The changing of telomerase activity was assayed by telomeric repeat amplification protocol(TRAP) and polymerase chain reaction enzyme-linked immunoassay(PCR-ELISA). The survival rates of cells was measured by trypan blue exclusion. Apoptosis was assayed by morphological observation (Giemsa and PI), DNA gel electrophoresis and flow cytometry analysis technology.
RESULTS: Primary acute leukemic cells expressed high level of telomerase activity which decreased as the cells treated by hTR ASODN. The telomerase activity was suppresssed significantly by 10umol/L ASODN and the effecttion was most significantly at 72h; Apoptotic bodies of primary leukemic cells were observed easily by fluorescence micrscope when cisplatin was added 48h after ASODN treatment for 24h; Agarose gel electrophoresis of genomic DNA from primary leukemic cells treated with ASODN and cisplatin combination for 72h showed typical DNA ladder; neither did DNA from primary leukemic cells treated with sense oligodeoxynucleotide (SODN) plus cisplatin nor cisplatin alone. In addition, apoptosis rates of primary leukemic cells treated with ASODN for 24h and then with cisplatin for 72h were 41.36±9.28%. There were statistically significant difference in the percentage of apoptotic cells between hTR ASODN plus cisplatin and SODN plus cisplatin (14.51±4.78%) or cisplatin alone group (12.61±2.56)% (P<0.01).
CONCLUSIONS: ASODN complementary to the region of hTR could significantly inhibit the telomerase activity of primary acute leukemic cells, and increased the cisplatin-induced apoptosis and enhanced cisplatin-sensitivity in vivo, indicating telomerase may be a new target of treatment to leukemia.
HHT-Induced Cell Apoptosis Is Associated with Reduction of Survivin mRNA Expression.
Authors: Cai Zhen , Bao Hanying 
Published: October 2019

Abstract
The inhibitor of apoptosis (IAP) gene family, which was discovered less than a decade ago, encodes a group of structurally related proteins that, in addition to their ability to suppress apoptotic cell death, are involved in an increasing number of seemingly unrelated cellular functions. The IAP families have evolved as highly conserved regulators of cell death. Homoharringtonine(HHT) is a plant alkaloid with antileukemia activity which is currently tested for treatment of acute and chronic leukemia. Our previous study suggested that HHT could induced apoptosis of MUTZ-1 in vitro, but little is know about the possible molecular mechanisms of HHT induced cell apoptosis. The study on the mechanisms of HHT in regulation of apoptosis will give us insight into further understanding of the role HHT. The data generated from this study will also provide theoretical ground for making use of HHT in clinical treatment. In this study, five cell lines including MUTZ-1, K562, Jurkat, RMPI and HL60 were used in the experiments to detect the effects of HHT on the induction of apoptosis and to study the possible mechanisms of HHT in regulation of apoptosis of the cells. Cell apoptosis were observed by flow cytometry (FCM). Cell apoptotic morphology was observed by transmission electron microscope. Semi-quantitative RT-PCR was used to evaluate the mRNA expression of survivin, XIAP, Bcl-2 and Bax in these cells. Our results demonstrated that HHT was capable of inducing apoptosis in all the five cell lines, with an increasing apoptotic rate in the order of K562, MUTZ-1/RMPI, and Jurkat/HL60, at a HHT concentration of 0.1 μg/ml for 12 hours (p<0.05). Survivin mRNA was not detected without HHT treatment but was detected in all the five cell lines after induction with HHT. Interestingly, the level of survivin mRNA expression was detected in the same but reversed order as with apoptotic rate: cell lines showed lowest apoptotic rate had highest survivin mRNA level, indicating a negative correlation between the two (p=0.003). The expression of Bcl-2 and Bax mRNA showed no significant correlation to HHT-induced apoptotic rate. There was no significant difference in XIAP expression in the 5 cell lines. We conclude that HHT might act via reduction of survivin expression and the level of survivin mRNA may serve as a predictor for chemotherapy sensitivity to HHT.
Study on the Resistant Mechanisms of K562 Cells Induced by STI571.
Authors: Liu Xiaoli , Zhang Song , Du Qingfeng , Fan Wei , Li Rong 
Published: October 2019

Abstract
STI571 is a highly effective drug for the therapy of CML, but there is still drug resistance, especially in blast crisis. To study the possible mechanisms of resistance to STI571, we established the BCR/ABL+ cell line with resistance to STI571 (K562-R) in vitro by culturing a wild-type K562 cells (K562-W) in gradually increased concentrations of STI571 over a period of months. Trypan blue staining, MTT assay and Hoechst 33342 staining confirmed that K562-R can live steadily at 0.5umol/L STI571. Furthermore MDR-1 expression assay, sequence analysis, fluorescence in situ hybridization(FISH) and cDNA array were used to study the potential mechanisms of acquired resistance. The MDR-1 expression percentages of K562-W and K562-R with FASC analysis were 2.68% and 1.39% respectively. No point mutant in the BCR/ABL ATP-binding site was detected and the copies of BCR/ABL fusion gene were found increased in K562-R by FISH analysis. By a expression profile of cDNA microarray, 327 genes’ expression were found down-regulating including one of homo sapiens protein tyrosine phosphatase genes(PTPRF) and 335 genes up-regulating including homo sapiens hematopoietic cell-specific Lyn substrate 1 gene(HCLS1). Our studies proved the possible mechanism of K562-R resistance involved amplification of BCR/ABL fusion gene and increase of phosphorylation activity in this cell line.
MDR Proteins Expression in AIDS-Related Non-Hodgkin’s Lymphoma.
Authors: de Faria Giselle Pinto , de Souza Barreto Luciana , Romano Sérgio , Faria Paulo Antônio , Ferreira Carlos José , Dobbin Jane , Klumb Claudete Esteves , Maia Raquel Ciuvalschi 
Published: October 2019

Abstract
Multidrug resistance (MDR) to chemotherapeutic drugs is a major obstacle in the treatment of patients with cancer. One of the best characterized resistance mechanisms of resistance in tumors cells is the MDR mediated by P-glycoprotein (Pgp) and multidrug resistant related protein (MRP). MDR expression in non-Hodgkin lymphoma (NHL) range widely being dependent on factors as the different antibodies, detection methods used, and clinical status (untreated patients or after failure of chemotherapy). AIDS-related NHL is associated with high rate of relapse and short overall median survivals. Previous study demonstrated that MDR positive AIDS-related LNH patients had a lower complete remission compared with MDR negative patients. In this study we analysed expression of Pgp and MRP by immunohistochemistry (IHC) in 62 high grade B-cell types NHL in an attempt to determine if MDR expression is dependent on previous anti-HIV therapy, a group of drugs well-known substrates for MDR expression. IHC detection of Pgp and MRP was performed using monoclonal antibodies according avidin-biotin method. Expression of Pgp was observed in 30 of 62 (48.4%) cases of AIDS-related NHL. MRP expression was examined in 27 specimens being 7 cases considered positives (25.9%). Co-expression of Pgp and MRP was detected in 5 out of 27 (18.5%) samples, whose patients had not previous NHL diagnosis. Anti-HIV therapy was used in 31/62 patients prior NHL diagnosis. Sixteen out of 30 patients that exhibited positive Pgp cells had not received anti-HIV therapy before NHL. Our study shows that expression of Pgp did not correlate to previous anti-HIV therapy and can be also observed in newly diagnosed AIDS-related NHL. The biological linkages between NHL and MDR phenotype are not fully understood. However, our results showed an intrinsic resistance in these patients indicating that the MDR modulation during chemotherapy could be a new approach for treatment in AIDS-related NHL.
Little Evidence of the Protective Role of MTHFR Genetic Polymorfism in Acute Leukaemia and Down Syndrome in Brazil.
Authors: Zanrosso Crisiane W. , Emerenciano Mariana , Ramos Flavio , Figueiredo Alexandre , Magalhaes Isis Q. , Leite Edinalva , Cavalcanti Vanessa , Muniz Maria TC , Pombo-de-Oliveira Maria S. 
Published: October 2019

Abstract
Immunomolecular and genetic markers are great tools to understand the pathway of leukemogenesis. Because of acute leukemias (ALs) commonly arise as result of DNA damage and/or DNA translocations, the polymorphism of 5,10-methylenetetrahydrofolate reductase gene (MTHFR) have been associated to reduced enzyme activity and altered distribution of cellular folate metabolites. We have determined the prevalence of MTHFR mutations C677T and A1298C in 227 children with AL from different regions of Brazil and 279 region-matched subjects as the control group. PCR-RFLP method was applied using HinfI and MboII restriction digestion to determine the MTHFR 677 and 1298 respectively. Odds ratio (OR) and 95% confidence intervals (95%CI) were used as statistics standard methods. There were 202 acute lymphoblastic leukemias (ALL) and 65 acute myeloid leukemias (AML) from three different regions of Brazil. The frequencies of the 677CC, 677CT and 677TT genotype were 57%, 33%, 10% in the ALL cases; and 51%, 40%, 9% in the controls, respectively. Whereas the frequencies of MTHFR 1298AA, 1298AC and 1298CC were 52%, 40%, 8% in the ALL cases and 61%, 32%, 7% in the controls, respectively. Also, we analyzed separately a group of Down syndrome (DS) cases that include (i) DS with AL and, (ii) DS without AL. The frequencies of the 677CC, 677CT and 677TT genotype were 2,16%, 2,37%, 0% in the DS with AL cases, and 4,31%, 3,02%, 0,22% in the DS without AL, respectively. Whereas the frequencies of MTHFR 1298AA, 1298AC, 1298CC were 2,94%, 1,05%, 0,84% in the DS with AL and 4,83%, 2,10%, 0,63% in the DS without AL, respectively. There were no differences of MTHFR C677T frequencies in both groups in overall analysis.
However, the frequency of MTHFR 677 and MTHFR 1298 genotypes differ between cases and controls in different regions of Brazil (p<0.04). The overall analysis indicates that MTHFR C677T and A1298C may confer a protective effect against childhood acute leukemia only in distinct group of cases.
Region OD IC (95%) p South 0.41 0.045–3.59 0.69 Southeast 0.78 0.265–2.33 0.84 Northeast 1,02 0.385–2.65 0.69
Elevation of Normal B Cells in Children with ALL Can Predict Relapse.
Authors: Kapelushnik Joseph , Levi Itai , Yermoau Tikva , Moser Asher , Haj-Yhia Atamma , Shubinski Geora 
Published: October 2019

Abstract
Flow cytomerty analysis of bone marrow (BM) is performed routinely in children with acute leukemia in different phases of chemotherapy. The aim of flow cytometric monitoring is to measure the amount of residual blasts and to evaluate the efficacy of chemotherapy. Multiparametric flow cytometry may be also used to evaluate normal hematopoisis in BM of patients with acute leukemia in different phases of chemotherapy. The aim of this study was to study normal lymphopoiesis in patients with relapsed disease. Twenty-two pediatric patients with ALL were enrolled in the protocol of study. Patients were treated in accordance with BFM-98 protocol. Eighteen children were in complete remission during follow-up period, while 4 children relapsed. Three of the relapsed children had B-lineage ALL, and one had T-cell ALL. Using multiparamertic flow cytometry we measured normal pro-B cells (CD19+CD34+), immature B (CD19+CD10+CD20+ and CD19+CD10−CD20+) and mature B (CD19+CD10−CD20+) cells in BM of relapsed patients in different phases of chemotherapy. Amounts or different subsets of B cells were compared with reference values determined in patients with relapse-free disease. Reference values were expressed as mean ± confidence interval for each subset of B cells and for each phase of chemotherapy. Elevation of immature normal B-cells was determined in all 4 patients who relapsed.Three during chemotherapy. Increased amount of mature B cells was determined 3 mo before the diagnosis of relapse in the patient who relapsed after the end of chemotherapy.This event was not observed in patient who did not relapse We conclude that elevation of normal immature B cells in BM of patient with ALL can be a predictive marker for eventual relapse.
Sensitivity of Childhood Acute Lymphoblastic Leukemia (ALL) to Idarubicin Is Significantly Higher Than to Daunorubicin Treatment Based on Ex Vivo Apoptosis Induction.
Authors: Prokop Aram , Bagci Banu , Lingfeld Guenaelle , Badiali Lucia , Garbrecht Karin , Mietzsch Ulrike , Wieder Thomas , Daniel Peter T. , Henze Günter 
Published: October 2019

Abstract
Anthracyclines, especially daunorubicin, play a very important role in the treatment of acute lymphoblastic leukemia (ALL) and the relapsed ALL in childhood.
In the present study, primary lymphoblasts isolated from 65 children with de novo ALL (median: 5.8 years; range: 1.9 – 16.9 years) and relapsed ALL (median: 12.7 years; range: 1.3 – 17.9 years) were treated with daunorubicin (10 mmol/l) or idarubicin (2 mmol/l) in vitro. We could show that both anthracylines induce apoptosis, as evidenced by measurement of genomic DNA fragmentation. Interestingly, daunorubicin only induced modest apoptosis, whereas idarubicin displayed a significantly stronger apoptosis inducing effect. Furthermore the treatment of daunorubicin-resistant lymphoblasts with idarubicin resulted in good response in most of the resistant cell populations.
Out of the 65 patients analysed in this study 23 were female (13 de novo ALL, 10 relapsed ALL) and 42 were male (29 de novo ALL, 13 relapsed ALL). Primary lymphoblasts were obtained by bone marrow aspiration and separated by centrifugation over Ficoll. Within these cell populations following immunologic subgroups were found: 35 c-ALL, 10 pre-B-ALL, 7 pro-B-ALL, 10 T-ALL and 3 pre-T-ALL.
Daunorubicin induced apoptosis in 33 out of 65 lymphoblast populations (response rate 50.8 %). Nevertheless, a far higher response rate was observed for idarubicin with 59/65 (90,8 %) (p < 0.008), if response is defined as apoptosis induction higher than 1 %. Daunorubicin-resistance was found in 32/65 (49,2 %), resistance to both was observed in 6/65 (9,2 %). Treatment of daunorubicin-resistant lymphoblasts with idarubicin resulted in significant apoptosis induction in 26 out of 32 cell populations (81,3 %).
We clearly demonstrated here that the in vitro treatment of lymphoblasts from children with de novo or relapsed ALL with idarubicin induces significantly higher response rates than daunorubicin treatment. The ex vivo sensitivity of daunorubicin-resistant lymphoblasts of childhood ALL to idarubicin treatment reflects the better potency of idarubicin to induce apoptosis and to overcome daunorubicin resistance. These data prompted us to study the clinical relevance of idarubicin in ongoing clinical trials to improve existing therapeutic regiments. First clinical data point to a good tolerability of idarubicin in the treatment of relapsed ALL in childhood.
Assessment of the Frequency of Additional Malignancies in Patients with Splenic Marginal Zone Lymphoma (SMZL).
Authors: Iannitto Emilio , De Cantis Stefano , Minardi Viviana , Callea Vincenzo , Calvaruso Giuseppina , Mulè Antonino , Ammatuna Emanuele , Stelitano Caterina , Tripodo Claudio , Ambrosetti Achille , Pizzolo Giovanni , Florena Ada , Franco Vito , Florena Ada 
Published: October 2019

Abstract
Splenic marginal zone lymphoma (SMZL) is an indolent neoplasm, mostly occurring in the elderly, with a median survival time exceeding 10 years. The incidence of secondary cancer and late complications related to therapy have not been investigated. To assess the frequency of additional neoplasms in a series of consecutive SMZL patients and to estimate the corresponding risk of second cancers compared with that of the general population. we investigated the incidence of additional cancers in 129 patients diagnosed with SMZL in three italian hematological centers.
With a median follow-up time of 33.2 months, twelve additional invasive cancers were recorded (9.3%). The 3 and 5-year cumulative incidence rates of second malignancy were 5.7% and 19.4%, respectively. Five more patients (3.8%) had a diagnosis of malignant epithelial tumor prior to that of SMZL.
The incidence of second malignancies was slightly, but significantly, higher than the expected incidence rate. The Observed-to-Expected ratio (O/E) was 12/5.92=2.03, 95% confidence interval (CI) 1.05 to 3.56; p <0.05. Of the twelve second malignancies observed, four were urologic neoplasms ( O/E=4/1,08=3.70 (95% CI:1.01 to 9.48; p <0.05), four were lung cancers (O/E=4/0.44365=9.16; 95% CI: 1.41 to 13.25; p <0.05) and the other four diagnosis were of hepatic carcinoma (1), endometrial cancer (1), breast cancer (1), and colo-rectal cancer (1). Our findings evidence an increased frequency of additional neoplasms in patients with SMZL and suggest that this figure is significantly different than that expected in the general population. The incidence of cases with urinary tract and lung malignancies in our series is higher than expected. Although confirmatory data are needed, in our opinion SMZL patients are at risk of secondary maligancies and should be carefully investigated at diagnosis and monitored during the follow-up.
SDX-105 (Treanda™) Enhances the Tumor Growth Inhibitory Effect of Rituximab in Daudi Lymphoma Xenografts.
Authors: Kanekal Sarath , Crain Brian , Elliott Gary 
Published: October 2019

Abstract
SDX-105 (Treanda™, Bendamustine HCl), a structurally and mechanistically unique multifunctional anticancer drug, has been demonstrated to be more potent than other 2-chloroethylamine alkylators in a variety of cell lines resistant to traditional alkylating agents. We previously reported that SDX-105 inhibits growth of SUDHL-1 and Daudi human lymphoma tumor xenografts in SCID mice in a dose-dependent manner (AACR PROC 45: Abs #4575). The current studies examine whether SDX-105 in combination with rituximab confers better efficacy. Daudi cells (1.0 X 107 cells/mouse) were inoculated s.c. in the flanks of SCID mice. After the tumors reached approximately 100 mm3, SDX-105 (10 mg/kg/d i.p., d 0–4), rituximab (75 mg/kg/d i.v., d 0, 2, 4) or both (same respective doses and treatment days) were administered; a second cycle of treatment was subsequently initiated on day 28. Tumor growth and body weight were monitored for 60 days. On day 20, mean tumor volumes were 2118, 847, 511 and 221 mm3 for the control, rituximab, SDX-105 and the combination group, respectively. Tumors in treated groups were significantly smaller than tumors in the control group, and the tumors in the combination group were significantly smaller than tumors in the rituximab group (p <0.02). In the combination group, the antitumor effect was sustained up to day 60 and there was one ‘cure’ (non palpable). There was no body weight loss in the control or rituximab group; 10% body weight loss was observed in SDX-105 and the combination groups. These results corroborate our previous in vivo single agent data in this model and provide further support for the use of SDX-105 with rituximab in clinical trials.
Bronchial-Associated Lymphoid Tissue (BALT) Lymphoma: A Multicenter Retrospective Analysis.
Authors: Laszlo Daniele , Steffanoni Sara , Andreola Giovanna , Balzano Rosaria , Pruneri Giancarlo , Spaggiari Lorenzo , Crosta Cristiano , Zucca Emanuele , Martinelli Giovanni 
Published: October 2019

Abstract
Surgery has been the treatment of choice in patients affected by BALT NHL; however, radical surgery is not always possible and does not avoid the risk of relapse. Systemic treatment is recommended for symptomatic patients who relapse after surgery or cannot undergo such procedure; nevertheless, there is no standard systemic chemotherapy which could be recommended for such indolent disease. Here we report clinical data of 16 patients (9 men and 7 female) with biopsy-proven low grade BALT lymphoma followed at EIO and IOSI from 1992 to 2004. Median age was 62 years (range 50–77); 8 patients presented symptomatic disease at diagnosis. Thoracotomy was necessary to obtain histological material in eight patients, while in the other 8 no-invasive procedures were performed. Thirteen patients were considered in stage IE and 3 in stage IV (bone marrow involvement in 2 patients, gastric in 1), according to Ann Arbor. Five patients received upfront aggressive surgery: 1 underwent wedge resection and 4 lobectomy. Surgery was the definitive treatment for 3 patients. With a median follow-up of 17 months (range 9–31), all these patients are still alive with no evidence of disease. Twelve patients received systemic treatment: two because of non-radical surgery and ten because of advanced stage, symptomatic disease or psychosocial reasons. The majority of them (7 patients) received alkylating containing regimen (Chlorambucil ± PDN), alone or in combination with Rituximab (Mabthera) (2 patients). Three additional patients, refusing CT, received Rituximab alone in a standard schedule. Hematological and non-hematological toxicity was in general mild: transient G3 neutropenia occurred in only one patient. No patient discontinued treatment because of treatment-related toxicity and no toxic death was recorded. All patients responded to systemic therapy with five patients achieving CR. Four of them are still alive and free of disease after 24, 65, 27, 42 months respectively. One patients still in CR died for reasons different from lymphoma after 54 months. With a median follow-up of 60 months (range 31 – 63), only four patients developed progressive disease or relapse after 67, 5, 63, 18 months respectively (median TTP=40 months). Our experience suggests that systemic treatment, when appropriate, is able to achieve an high response rate in this relative uncommon disease. Considering the clinical results and the low degree of toxicity observed, alkylating containing regimen (Chlorambucil ± PDN) alone or in combination with monoclonal antibody could be considered as first line treatment for patients with BALT lymphoma.