bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ectopic Expression of Mer Receptor Tyrosine Kinase in Childhood T Cell Acute Lymphoblastic Leukemia.
Authors: Salzberg Dana B. , Keating Amy K. , Cao Jian-zhe , Sather Susan , Hill Kimberley , Anwar Adil , Graham Douglas K. 
Published: October 2019

Abstract
Tyrosine kinases play an important role in normal cellular growth and differentiation. Deregulation of tyrosine kinase activity can result in cellular transformation leading to the development of human cancer. The Mer receptor tyrosine kinase, initially cloned from a human B lymphoblastoid cell line, is expressed in a spectrum of hematopoetic, epithelial, and mesenchymal cell lines. Interestingly, while the RNA transcript of Mer is detected in numerous T and B lymphoblastic cell lines, Mer RNA is not found in normal human thymocytes, lymphocytes or in PMA/PHA stimulated lymphocytes. We have developed an anti-human Mer monoclonal antibody to further study the ectopic Mer expression in lymphoblasts. The antibody detects several forms of the Mer protein including a fully glycosylated 205 kD Mer protein in monocytes and a less glycosylated 170–180 kD Mer protein in acute lymphoblastic leukemia (ALL) cell lines. We analyzed lymphoblasts from 16 T cell ALL patients diagnosed between July 1995 and July 2004 at The Children’s Hospital, Denver for Mer protein surface expression. Of the T cell ALL patient samples, we found that 9/16 (56%) were positive for Mer protein surface expression. Although we were not able to statistically evaluate the clinical outcomes relative to Mer expression due to the study sample number, there was a statistically significant association between positive expression of Mer and lack of surface expression of CD3 (p = 0.035). We found that 7/9 (78%) of the Mer positive lymphoblasts lacked CD3 surface expression, while only 1/6 (17%) of the Mer negative samples lacked CD3 surface expression (see figure). Lymphoblasts that lack surface expression of CD3 represent an immature phenotype and have been associated with a decreased event free survival as compared with surface positive CD3 lymphoblasts. Further investigation of the ectopic expression of Mer in lymphoblasts may reveal the use of this novel Mer glycosylated protein as a prognostic marker and possibly a future therapeutic target in the treatment of childhood leukemia.
Figure Figure
Effect of hTERT Antisense on Cisplatin Sensitivity of Acute Lymphoblastic Leukemic Cells.
Authors: Li Wenyu , Zhang Yuan 
Published: October 2019

Abstract
AIM: To investigate the effect of human telomerase reverse transcriptase(hTERT) antisense phosphorothioate oligodeoxynucleotide(AS PS-ODN) on enhancing cisplatin sensitivity in acute lymphoblastic leukemic cells.
METHODS: The expression levels of hTERT protein were detected by immunofluorescence using fluoresce isothiocyanate(FITC) lable. Cell surviving fraction was determined using the trypan blue dye exclusion assay. Apoptosis was detected by morphological observation and flow cytomertric cell cycle analysis.
RESULTS: The expression of hTERT protein was inhibited after treated by hTERT AS PS-ODN. Treatment with cisplatin after 24h of exposure to AS PS-ODN had significantly reduced the number of viable ALL cells. However, there was no difference on ALL cells survival between sense oligodeoxynucleotide(S PS-ODN)/CDDP combination and CDDP treated cells alone. In morphological observation of apoptotic cells using Hoechst 33258 and PI double staining techniques, cells displayed classic apoptotic changes treated with CDDP or CDDP combined with hTERT AS PS-ODN or S PS-ODN at 48h. Apoptotic rates of cells added CDDP and AS PS-ODN were higher than that of cells added CDDP only(P<0.05). Apoptotic rates of cells added CDDP and S PS-ODN were similar with that of cells added CDDP only(P>0.05).
CONCLUSION: hTERT AS-ODN inhibited the expression of hTERT protein and increased the CDDP induced apoptosis in primer acute lymphoblastic leukemic cells.
Single Agent Gemtuzumab Ozogamycin (Mylotarg) Is Effective in Inducing Hematologic Remission in Elderly Patients with Normal Cytogenetics.
Authors: Agha Mounzer E. , Sarah Miller , Kirkland Howard , Crandall Theodore L. , Mucenski John W. 
Published: October 2019

Abstract
The treatment of elderly patients with acute myelogeneous leukemia is quite difficult primarily due to the treatment related morbidity and the poor response rate to induction chemotherapy. Elderly patients are often offered supportive care only. Mylotarg has been shown to be an active agent in patients with relapsed AML with a reported response rate of 31%. The role of Mylotarg in front-line therapy for AML remains to be determined.
Patients : Six patients with newly diagnosed acute myelogenous leukemia (non-M3) were treated with single agent Mylotarg. The mean age was 77 years (71–84). All patients had low white blood cell counts upon presentation with a mean WBC of 1550. Several patients had other co-morbid conditions upon diagnosis, primarily cardiac. The average ECOG performance status before treatment was 1-1.
Treatment Plan : The treatment consisted of Mylotarg 9 mg/m2 on days 1 and 14. The treatment was given either in the hospital or as an outpatient. All patients received full doses of therapy. No further consolidation therapy was given. The bone marrow was re-evaluated within 60 days of the second dose of Mylotarg.
Results : One patient died during induction of sepsis and is not evaluable. All patients developed neutropenic fevers and required hospitalizations. One patient developed clinical evidence of pulmonary fungal infection and was treated successfully with oral voriconazole. No other end organ toxicity was encountered.
Response : Four of 5 evaluable patients (80%) achieved complete remission as documented by bone marrow evaluation. All four patients became transfusion independent, although the platelet counts remained below 100x109. The remission duration is 5.5+ months with two patients remaining in remission more than 6 months following treatment. All four responders had normal bone marrow cytogenetics upon diagnosis. The patient who died of early sepsis had complex cytogenetics and the patient who did not respond also had abnormal cytogenetics. The treatment was well tolerated despite the neutropenic hospitalizations and all responders regained normal performance status.
Conclusion : These results are very encouraging despite the small patient sample and suggest that Mylotarg as a single agent may be an effective therapy for elderly patients with normal cytogenetics. This treatment is less toxic than standard induction chemotherapy that may be poorly tolerated in this patient population. We are currently investigating the role of further Mylotarg consolidation in maintaining the duration of remission in those patients responding to initial therapy.
CD123 Expression in Chronic Lymphocytic Leukaemia - Strong Correlation with ZAP70 and CD38 Expression.
Authors: Petrie James A. , Milne Tim , Ridler Colin , Cavenagh Jamie D. , Agrawal Samir G. 
Published: October 2019

Abstract
CD123 constitutes the alpha subchain of the human interleukin 3 receptor (IL-3R). Interleukin 3 binds to its receptor with high and low affinities, induces tyrosine phosphorylation and promotes the proliferation and differentiation of haematopoietic stem cells. CD123 expression has been associated with a poor prognosis in AML and has been shown to be a useful marker in hairy cell leukaemia (HCL). However, it has been little studied in CLL, with data in the literature suggesting few cases of positivity. Here we studied CD123 expression by flow cytometry on fresh peripheral blood in 134 unselected, consecutive cases of CLL. We utilised anti CD123 PE (BD Pharminogen) in a dual combination with anti CD19 FITC (Coulter Immunotech) to target B cells. The results were correlated with expression of CD38 and ZAP70, markers of poor prognosis in CLL. CD123 was expressed in = 20% (median 33, range 20–92%) of cells in 32/134 cases (24%). Typical of CLL, the intensity of surface CD123 expression was weak-moderate, unlike HCL cases, where the intensity is moderate-strong. CD38 positivity was seen in 20/32 CD123+ cases (63%). Of the remaining 102 cases where CD123 was negative, a CD38 count was available in 92 cases and 29/92 (32%) were positive. ZAP70 positivity was seen in 18/32 CD123+ cases (56%). ZAP70 data was available in 98/102 CD123− cases and positivity was seen in 26/98 (27%). These findings represent the first account of a significant percentage of CLL cases expressing CD123 positivity. Furthermore we have been able to show that CD123 positivity strongly correlates with two known markers of poor prognosis ZAP70 (p= 0.004) and CD38 (p=0.004) (Chi-Square with Yate’s correction). CD123 may therefore be of prognostic significance in CLL and should be further investigated.
Effect of Administration Styles of Arsenic Trioxide on the Intracellular Arsenic Concentration and the Efficiencies of Differentiation and Apoptosis.
Authors: Zhou Jin , Meng Ran , Yang Baofeng 
Published: October 2019

Abstract
Objective: Study on the effects of As2O3 on intracellular arsenic concentration, differentiation and apoptosis rates and sensitivities by different administration styles.
Methods: Evaluated the intracellular arsenic concentrations,the apoptosis rates, and the ratios of differentiation phenotypes on cell surface CD33 (−)/CD11b (+), when incubated cells with As2O3 in different culture media in vitro and treated leukaemia patients with As2O3 in different administration styles in vivo.
Results: When incubated cells in a constant arsenic concentration culture medium for 24 hours, the intracellular arsenic concentrations were (33.4±0.88) μg/L in NB4, (18.6±1.12) μg/L in K562, and (28.8±0.64) μg/L in APL; the apoptosis rates were NB4 56.6%, K562 27.6%, APL 52.2%; the ratios of differentiation phenotype CD33(−)/CD11b(+) were: NB4 (19.5±0.5)%, K562 (24.5±0.6)%, APL (18.5±0.6)%, whereas, when incubated cells above in a changing arsenic concentrations culture medium for 24hours, which initial arsenic level was 5μmol/L, the intracellular arsenic concentrations were: NB4(17.6±0.88) μg/L, K562(9.2±0.64)μg/L, APL(15.2±1.04)μg/L, the apoptosis rates were: NB4 23.2%, K562 11.0%, APL 21.0%; the ratios of differentiation phenotype CD33 (−)/CD11b (+) were: NB4 (51.5±0.4)%, K562 (57.5±0.8)%, APL (46.5±0.5)%. 24hours after one time continuous and slowing intravenous As2O3 infusion, the intracellular arsenic concentrations were APL (26.6±2.5) μg/L,AML-M2 (15.5±3.1) μg/L, CML (18.5±2.3) μg/L; the apoptosis rates were APL 28.5%, AML-M2 9.5%, CML 12.5%; the ratios of differentiation phenotype CD33 (−)/CD11b (+) were: APL (29.5±0.5)%, AML-M2 (28.5±0.6) %, CML (23.5±0.5)%. Whereas, when 24hours after treated with one time general speed intravenous As2O3, the intracellular arsenic concentrations were: APL(12.3±2.1) μg/L, AML-M2 (5.5±2.3) μg/L, CML (8.5±2.7) μg/L; the apoptosis rates were: APL 13.2%, AML-M2 3.9%, CML4.2%; the ratios of differentiation phenotype CD33 (−)/CD11b (+) were: APL (53.6±0.8) %, AML-M2 (48.5±0.9) %, CML (67.5±0.8) %.
Conclusions: The administration styles affect the intracellular arsenic concentrations, the differentiation rates and the ratios of apoptosis of leukaemia cells. Treated with the continuous and slowing intravenous As2O3 infusion can obtain a higher intracellular arsenic concentration, a higher efficiency of apoptosis and a lower differentiation ratio than that in general speed intravenous As2O3 infusion in clinical dosage. The continuous and slowing intravenous As2O3 infusion can promote apoptosis and inhibit from differentiation, so this As2O3 medication can relieve leukocytosis and elevate therapeutic effects.
Comparison of Pharmacokinetics and Pharmacodynamics of two different dosing regimens of Proleukin® (IL-2) in Combination with rituximab: The effect of NK cell expansion.
Authors: Milan Sandra , Hurst Deborah , Michelson Glenn , Samara Emil 
Published: October 2019

Abstract
Background: Published results from studies testing two different dosing regimens of IL-2 in combination with rituximab have shown that thrice-weekly dosing of IL-2 resulted in greater expression of NK cell as compared to a daily dosing (Gluck, et al. Clin Cancer Res 2004). Expanded NK cells are desired to drive effective rituximab induced ADCC. Here we report on the observed pharmacokinetic (PK) differences associated with the differences in pharmcodynamics (PD) observed with the two regimens.
Methods: Two different subcutaneous (SC) IL-2 dosing regimens in combination with rituximab (375 mg/m² weekly IV infusions weeks 1 through 4) were studied: daily IL-2 (6 MIU daily weeks 2–5) versus thrice-weekly IL-2 (14 MIU weeks 2–5) resulting in a total of 42 MIU weekly for each regimen. Serum samples for IL-2, rituximab, and soluble IL-2 receptor (sIL-2r) were analyzed using an ELISA assay. Anti-IL-2 and anti-rituximab antibodies (Ab) were also determined. IL-2 and rituximab serum concentration-time data were analyzed by model-independent methods using WinNolin.
Results: Daily dosing of IL-2 exhibited time-dependent pharmacokinetics characterized by lower concentrations of IL-2 upon repeat SC dosing. An increase in IL-2 clearance coincided with an increase in sIL-2r concentrations in the systemic circulation. By the fifth dose, sIL-2r concentrations reached steady state at approximately 2–3 times higher concentrations than the baseline value. In contrast, the thrice-weekly dosing of IL-2 demonstrates no time-dependent kinetics; there were no observed differences in IL-2 plasma concentrations after the first dose or after repeated dosing. Surprisingly, a similar increase in sIL-2r levels from baseline was observed after multiple thrice-weekly dosing of IL-2. The pharmacokinetics of rituximab was similar after daily or thrice-weekly regimens of IL-2 and were comparable to values reported in the literature. The incidences of Ab against IL-2 and rituximab were low (<7%).
Conclusion: Concomitant administration of IL-2 with rituximab is well tolerated, with no evidence of pharmacokinetic interaction. Thrice-weekly dosing regimen results in more sustained plasma IL-2 levels with repeated dosing than daily IL-2 dosing. Hence the sustained plasma levels and AUC associated with the thrice-weekly dosing potentially explains why this regimen results in greater NK cell expansion that does the daily dosing.
Mobilization of Ph-Negative Peripheral Blood Stem Cells (PBSCs) with rHu-G-CSF in Chronic Myeloid Leukemia (CML) Patients Achieving Complete Cytogenetic Response with Imatinib Mesilate (Glivec).
Authors: Pungolino Ester , Draisci Michela , Gargantini Livio , Farioli Renata , Rossi Valentina , Cozzi Paola , Alamos Sara Miqueleiz , Cafro Anna Maria , Morra Enrica 
Published: October 2019

Abstract
Imatinib Mesilate (Glivec) is able to induce a high rate of Complete Cytogenetic Response (CCyR) with low treatment-related toxicity. The long-term duration of this Ph-negative status is, however, still undefined. Therefore, some groups (Drummond et al, Br J Haematol123:479, 2003; Hui et al, Leukemia17:821,2003) decided to mobilize and to collect Ph-negative PBSCs in patients reaching CCyR with Glivec. In our experience we studied 12 Ph-negative, FISH-negative patients, median age 50 yrs (26–61). Three of them were also PCR-negative, being the minimal residual disease assessed using RT-PCR. All patients received Imatinib Mesilate at the daily dose of 400 mg. The median duration of treatment with Glivec was 25 months (range 11–35). Eight of 12 pts (67%) were pre-treated with α-interferon (α-IFN) for a median time of 9.5 months (range 3–54). The median duration of CML was 39 months (range: 21–152).
We discontinued Imatinib four days (range 3–5) before starting rHu-G-CSF as single agent (5–10 μg/Kg/day), which was maintained until WBC < 50x109/L. Failure of mobilization was defined as CD34+ circulating cells < 10/m L. The collection started after a median of 6 days (range 4 –10), when CD34+ cells were > 10/μ L. Eleven of 12 pts (92%) reached the threshold of 10/μ L and started harvesting. The single patient failing collection had been pretreated with IFN and was PCR negative at the time of mobilization. The remaining 11 reached the target of 2.5 x106 CD34+ cells/Kg with a median of two apheresis (range 1–3). The median harvest was 3.14 CD34+ x 106/Kg (range 2.56–4.55). Conventional cytogenetic analysis, RT-PCR and coltural tests were performed in all apheretic samples. All the 11 mobilized patients obtained a Ph-negative harvest, which was also PCR negative in 4/11 (36%).
In our experience adequate yields of PBSCs were collected with rHu-G-CSF alone in 11/12 patients achieving CCyR with Glivec, as well as in the majority of those previously treated with α-IFN (7/8).
Results of harvesting after rHu-G-CSF alone in 11 CML patients achieving CCyR after Imatinib Mesilate
Patient N. Apheresis CD34+ x 10^6/kg RT-PCR T.M 2 4.55 pos. O.I 2 3.34 neg. V.E. 1 3.33 neg. S.G. 3 3.07 neg. R.R. 1 4.45 pos. M.G. 3 2.56 pos. S.C. 1 3.2 pos. S.C. 2 2.6 pos. C.A. 1 3.75 pos. T.G. 2 3.14 neg. V.M. 2 2.65 pos.
Unlike CML Patients, Patients with Gastrointestinal Stromal Tumors (GIST) Treated with Imatinib Do Not Develop Hematopoietic Clonal Cytogenetic Abnormalities.
Authors: Abecasis Manuel M. , Lage Pedro , Salazar Maria , Freire Joao , Moreira Antonio , Jorge Margarida , Alaiz Helena 
Published: October 2019

Abstract
Imatinib has the ability to inhibit the dysregulated kinase activities of the BCR-ABL fusion protein in CML pts as well as the mutated KIT in GIST patients and has been successfully used to treat both diseases. Several cases of chromosomal abnormalities in Ph-negative metaphases have been reported in CML patients in chronic phase during treatment with imatinib. This is different from true clonal evolution in that the additional cytogenetic abnormalities occur in Ph-negative cells. Although this has also been rarely reported in patients receiving other therapies its frequency in patients on imatinib is relatively high (up to 17% patients) and it may occur when imatinib is given upfront or after other treatment modalities.The most common abnormalities are trisomy 8 and chromosome 7 defects, often associated with myelodysplasia. The time from the beginning of treatment until their appearance is variable, ranging from 3 months to more than a year, with the largest published series reporting a median of 6 months (Cancer2003; 98:1905). The pathogenesis and clinical significance of these findings is still unclear and an important question is whether these clones are induced or favored by the treatment itself, since imatinib is known to have several effects on important growth regulatory proteins involved in hematopoiesis. GIST patients without hematological disease and treated with imatinib offer a unique opportunity to address this question. From Aug 2001 to Aug 2003, 11 patients with GIST were treated with imatinib at our institution and 7 agreed to participate in the sutdy. Their median age was 54-y and they were on imatinib for a median of 18 months (4 to 18) at doses between 400 to 800mg daily. Complete karyotyping on metaphase spreads from peripheral blood and bone marrow aspirates were performed. PB and BM smears were examined for myelodysplastic features. A median of 19 (15 to 24) PB and 16 (13 to 22) BM metaphases were examined for each patient. No abnormal hematological clones were detected and 1 patient had a constitutional variant 46XY, (inv9)(p11;q12) on PB and BM cells. No dysplastic features were observed. These data, although based on a small number of patients suggest that in patients without hematological disease imatinib by itself does not induce hematopoietic clonal cytogenetic abnormalities.
Characterization of Oncogene Dysregulation in Multiple Myeloma by Combined FISH and DNA Microarray Analyses.
Authors: Neri Antonino , Fabris Sonia , Agnelli Luca , Mattioli Michela , Baldini Luca , Ronchetti Domenica , Morabito Fortunato , Verdelli Donata , Nobili Lucia , Intini Daniela , Callea Vincenzo , Stelitano Caterina , Lombardi Luigia 
Published: October 2019

Abstract
Chromosomal translocations involving the immunoglobulin heavy chain (IGH@) locus and variuos partner loci are frequently associated with multiple myeloma (MM). We investigated the expression profiles of FGFR3/MMSET, CCND1, CCND3, MAF and MAFB genes, respectively involved in t(4;14)(p16.3;q32), t(11;14)(q13;q32), t(6;14)(p21;q32), t(14;16)(q32;q23) and t(14;20)(q32;q12), in purified plasma cell populations from 39 MMs and six plasma cell leukemias (PCL) using DNA microarray analysis, and compared the results with the presence of translocations as assessed by dual-color FISH or RT-PCR. The t(4;14) was found in six MMs, t(11;14) in 9 MMs and 1 PCL, t(6;14) in one MM, t(14;16) in 2 MMs and 1 PCL, and t(14;20) in one PCL. The translocations were associated with the spiked expression of target genes in all cases. Furthermore, gene expression profiling allowed the identification of putative translocations dysregulating CCND1 (1 MM and 1 PCL) and MAFB (1 MM and 1 PCL) without any apparent involvement of immunoglobulin loci. Notably, all of the translocations were mutually exclusive. Markedly increased levels of MMSET expression were found in one MM showing associated FGFR3 and MMSET signals on an unidentified chromosome. Our data suggest the importance of using combined molecular cytogenetic and gene expression approaches to detect genetic aberrations in MM.
Renal Impairment and the Use of Bisphosphonates in Patients with Multiple Myeloma: Retrospective Analysis of 114 Patients with Respect to Age and Other Clinical Characteristics.
Authors: Mazj Sam , Lichtman Stuart M. 
Published: October 2019

Abstract
Backgound: The clinical course of multiple myeloma is often associated with significant bone related morbidity. This can be modified by the use of bisphosphonates. Studies have shown renal toxicity associated with different bisphosphonates especially following the exposure of zoledronic acid. Published literature suggests renal function deterioration occurs in 8.8–15.2% of patients at recommended dose of 4 mg infused intravenously over 15 minutes.
Methods: We retrospectively reviewed the records of all patients with multiple myeloma who received bisphosphonates during the period of January 2002-June 2004 at our institution. 114 patients were analyzed (male/female 63/51; age-median 69;mean 71;range 40–92). 61 (54%) were >70 years of age. They received a total of 1301 doses (mean 11.4) during this period. The type of bisphosphonate used was: zolendronate: 58; pamidronate: 23; pamidronate changed to zolendronate (both) : 33. Patients were categorized to the type and sequence of bisphosphonates [ pamidronate vs. zoledronate and pamidronate followed by zoledronate (both) ], age and sex. Renal dysfunction was defined as an increase in serum creatinine of >0.5 mg/dl over baseline.
Results: There were 19 patients (16.7%) who developed renal dysfunction. 15 of the 19 episodes (79%) occurred in the 70 years and older group. The table shows the distribution of patients, type of bisphosphonate and the distribution of patients with renal toxicity.
Conclusion: This analysis showed increase in renal dysfunction occurs in all ages with use of bisphosphonates. The elderly may be particularly susceptible to this toxicity. Although we have not analyzed the impact of associated comorbidities (including type of multiple myeloma) leading to renal insufficiency in this study, the elderly patients may need more close monitoring of renal function with the use of bisphosphonates.
Age and renal impairment with bisphosphonate use
Age Zolendronate Pamidronate Both Total Number in paranthesis indicates the renal impairment case 40–49 6 (0) 2 (0) 2 (0) 10 (0) 50–59 10 (0) 1 (0) 4 (0) 15 (0) 60–69 14 (2) 3 (0) 11 (1) 28(3) 70–79 19 (3) 9 (1) 14 (4) 42 (8) 80+ 9 (3) 8 (0) 2 (4) 19 (7) Total 58 (9) 23 (1) 33 (9) 114 (19)