bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Expression Level of Noxa in Peripheral Versus Lymph Node Chronic Lymphocytic Leukemia Cells Is Correlated with Survival Capacity.
Authors: Hallaert Delfine Y.H. , Smit Laura A. , Spijker Rene , de Goeij Bart , Jaspers Annelieke , Kater Arnon P. , van Oers Marinus H. , van Noesel Carel J.M. , Eldering Eric 
Published: October 2019

Abstract
Background: The gradual accumulation of chronic lymphocytic leukemia (B-CLL) cells is presumed to derive from proliferation centers in lymph nodes and bone marrow. To what extent these cells possess the purported anti-apoptotic phenotype of peripheral B-CLL cells is unknown. Recently, we have described that in B-CLL samples from peripheral blood, aberrant apoptosis gene expression was not limited to protective changes but also included increased levels of pro-apoptotic BH3-only member Noxa. The functional consequence of this finding is not known, nor whether this aberrant apoptosis gene profile is also present in CLL proliferation centers.
Aim: To perform a functional comparison of apoptosis gene profiles from peripheral blood (PB) B-CLL versus lymph node (LN) proliferation centers.
Methods: Immunofluorescence microscopy, RT-Multiplex-Ligation-dependent Probe Amplification (RT-MLPA), Western Blot, Transduction, RNA interference.
Results: PB samples (>90% CD5/CD19/CD23+ B-CLL cells) from 16 B-CLL patients and LN samples from 9 B-CLL patients were included in this study. LN samples contained over 90% CD5/CD19/CD23+ lymphocytes with Ki67+ cells either scattered throughout the LN or in follicle-like structures. RNA samples were subjected to the RT-MLPA procedure which monitors expression of 34 apoptosis genes. Apart from expected differences in survivin and Bcl-xL, the most prominent distinction with PB B-CLL cells was the generally low levels of Noxa in LN samples.
Figure 1: Profiling of apoptosis genes in peripheral blood and lymph node samples of B-CLL patients Figure 1:. Profiling of apoptosis genes in peripheral blood and lymph node samples of B-CLL patients
A reduction in Noxa RNA and protein levels could also be obtained by in vitro stimulation of PB B-CLL with CD40. Direct manipulation of Noxa protein levels was achieved by proteasome inhibition in B-CLL cells and via RNAi in model cell lines. In all these instances the viability of the cells was inversely correlated with Noxa levels.
Conclusions: These data indicate that spontaneous apoptosis of PB B-CLL cells in vitro is linked with high Noxa levels. We propose that suppression of Noxa in the LN contributes to the persistence of B-CLL, and that therapeutic targeting of Noxa might be beneficial.
Myeloma Cell Proliferation Is Inhibitied by the Activation of Adenosine Monophosphate Activated Protein Kinase (AMPK).
Authors: Baumann Philipp , Mandl-Weber Sonja , Emmerich Bertold , Straka Christian , Franke Daniel , Schmidmaier Ralf 
Published: October 2019

Abstract
In multiple myeloma (MM), a network of cytokines in the bone marrow microenvironment promotes myeloma cell proliferation. Consequent inhibition of intracellular signalling in the myeloma cells seems to be a promising strategy to encounter disease progression.
The multiple myeloma cell lines U266, OPM-2, RPMI-8226 and NCI-H929 were incubated with the AMPK activators AICAr and D942. Basal and cytokine stimulated proliferation rates of myeloma cells were measured by the WST-1 assay. Alterations of the cell cycle were determined by flow cytometry after staining with propidium iodide. Intracellular signalling was shown by western blotting.
The AMPK activators 5-aminoimidazole-4-carboxamide (AICAr) and D942 induced inhibition of proliferation in multiple myeloma cell lines. AICAr also induced a S-phase cell cycle arrest in all four tested cell lines and led to phosphorylation and herewith activation of AMPK. Furthermore, the inhibition of a nucleoside transporter by nitrobenzyl-thio-9-β-D-ribofuranosylpurine (NBTI), inhibition of the adenosine kinase by iodotubericidine and inhibition of AMPK by AMPKI Compound C reversed AICAr effects, indicating that the cellular effects of AICAr were mediated by AMPK. Activation of AMPK inhibited basal extracellular-signal regulated kinase (ERK), mTOR and P70S6 kinase (P70S6K) signalling and blocked cytokine induced increase of proliferation, which again was due to inhibition of ERK and P70S6K signalling. Troglitazone, a representative of a group of anti-diabetic drugs, similarly inhibited myeloma cell proliferation, activated AMPK and decreased ERK and P70S6K signalling.
We demonstrate for the first time that myeloma cell proliferation is controlled by AMPK activity. Consequently, targeting this pathway by inhibitors like glitazones provides a novel strategy in myeloma therapy.
In Vivo Phycocyanin Treatment of S180 Bearing-Mice: Increase in Immunic Function and Inhibition of Tumor Growth.
Authors: Pan Ling , Hao Wei , Zhang Xuejun , Niu Zhiyun , Wang Fuxu , Dong Zuoren 
Published: October 2019

Abstract
Objectives: To explore the effect of Phycocyanin (PC), with or without Cyclophosphamide(CY), on the growth inhibition of S180 cells and on the immunity improvement of S180-burdened mice. And to explore the anti-tumor mechanism of Phycocyanin.
Methods: Each 0.2ml of S180 cells, a sarcoma cell line cells, at the concentration of 2×107 cells/ml, were inoculated into the right axilla of each test mouse. These mice were randomizely divided into 4 groups: PC-treated group (including 50−, 75− and 100mg/kg·d- subgroups); CY-treated group (20mg/kg·d); PC plus CY-treated group and normal saline(NS)-treated group which served as control group. 24 hours after the inoculation, PC or CY or PC plus CY or NS, at a final volume of 0.2ml, were injected to the abdominal cavity of each mouse in different group, and consecutively for 7 days. These mice were killed after the seventh treatment, then the peripheral blood, the whole tumor and the spleen were collected from each mouse. Each mouse’s tumor weight was measured and blood routine exam was done. The serum level of IL-2, IFN-γ and TNF-α in each mouse was measured with ELISA method and the result was shown as pg/ml. Spleen cells from each mouse were collected and cultured respectively with ConA for 36 hours, and splenic T lymphocyte proliferation was measured.
Results: PC inhibited the growth of S180 cells at all three tested dosages, 50mg/kg·d, 75mg/kg·d and 100mg/kg·d, and the inhibition rates were 41.41%, 37.37% and 36.36%, respectively. PC-treatment increased WBC counts in PB of tumor-bearing mice. The results also showed that PC-treatment and tumor-bearing situation increased the spleen weight and enhanced the splenic T lymphocyte proliferation induced by ConA. PC-treatment did not reduce the body weight of tumor-bearing mice. Among these three dosage, 50mg/kg·d was shown to have the best effect in the above mentioned parameters, as well as in the increase of IL-2, IFN-γ and TNF-α secretion. PC at dosages of 75mg/kg·d and 100mg/kg·d just increased the serum level of IFN-γ and TNF-α, without the increase of IL-2. Compared with PC-treatment, CY-treatment diminished serum level of IL-2, IFN-γ and TNF-α. PC (75mg/kg·d) combined with CY-treatment increased the tumor inhibition rate to 92.93%.
Conclusions: 1, PC-treatment inhibited the growth of S180 cells. PC plus CY treatment showed more potential effect of growth inhibition. 2, PC enhanced markedly the immune function of S180-bearing mice in terms of increasing the spleen weight and the serum level of IFN-γ and TNF-α, and enhancing T lymphocyte proliferation induced by ConA. Those might account for the anti-tumor mechanism of PC. 3, PC-treatment antagonized the decrease in WBC count induced by CY-treatment. No obvious side effect of PC was found in the present study. Therefore, PC alone or combine with other chemotherapy drugs may offer a new approach in the treatment of hematological malignancies.
Pre-Emptive Treatment with Cidofovir for Cytomegalovirus Antigenemia in Autologous Bone Marrow Recipient and CLL Patients on Therapy with Alemtuzumab.
Authors: Iannitto Emilio , Minardi Viviana , Mulè Antonino , Scalone Renato , Calvaruso Giuseppina , Crescimanno Alessandra , Biundo Concetta Lo , Liardo Eliana , Abbadessa Vincenzo , Musso Maurizio , Arista Serenella 
Published: October 2019

Abstract
Cytomegalovirus (CMV) is an important cause of morbidity and mortality in patients who have undergone severe immunosuppressive therapy. Ganciclovir continues to be the first choice for pre-emptive therapy, but it needs multiple intravenous daily administration for three weeks and may cause myelosuppression. Cidofovir is a non myelotoxic nucleotide analogue effective against CMV; its favourable pharmacokinetic profile allows a once-a-week dosing. We reviewed a database on 110 consecutive Autologous Stem Cell Transplant (ASCT) and that of 15 Chronic Lymphocytic Leukemia (CLL) patients treated with alemtuzumab. All patients were virologically monitored by quantification of pp65 antigenemia in peripheral blood. Cytomegalovirus infections were identified respectively, in 13 of 110 (12%) ASCT group and in 10 of 15 (66%) CLL group. Nine out 23 CMV reactivation showed manifestation of the infection. All patients were treated on outpatient basis.
Patients with a positive pp65 assay were treated with cidofovir 5 mg/kg once-a-week for two weeks followed by one or two doses every two weeks. Twenty-three patients (13 autologus, 10 alemtuzumab) had 23 episodes of CMV-pp65 detection treated with cidofovir. The first positive antigenemia occurred after a median of 36 days from starting treatment (range 5–20) and the median antigenemia level at first appearance was 2 (range 1– 89).
The treatment produced regression of symptoms in all cases and clearance of the virus in 21 (11 post-transplant 84%; 10 post alemtuzumab 100%), stained by CMV antigenemia. Median duration of therapy was 21 days (range 14–30 days) and the time to the first undetectable antigenemia was seven days (range7–28). We did not observe any further CMV reactivations, also in six of the ten patients who restarted treatment with alemtuzumab after the end of pre-emptive therapy. We did not observe any of the side effects potentially related to cidofovir administration: notably, none of the patients experienced renal toxicity, proteinuria, nausea or vomiting, ophthalmological or neurological toxicity. In our experience, pre-emptive therapy of CMV infection with cidofovir is safe and effective. In our opinion it could be considered an interesting alternative to ganciclovir for pre emptive therapy, particularly advantageous for treatment of CLL and ASCT ambulatory patients at low risk of developing CMV disease.
Does Hypergammaglobulinemia Predispose to Secondary Solid Tumors in Patients with Chronic Lymphocytic Leukemia?.
Authors: Patel Vijay , Singh Jaswinder , Malani Ashok , Skikne Barry , Haung Chao , Vanveldhuizen Peter , Kambhampati Suman 
Published: October 2019

Abstract
Background:Occurrence of second hematological malignancies in patients with chronic lymphocytic leukemia (CLL) is well known but development of secondary solid tumors has not been well documented. Isolated case reports indicate, CLL patients may have a predisposition to develop solid tumors. There is not enough literature available to support this hypothesis. We here intend to study the incidence of secondary solid tumors in CLL patients with regard to their treatment and immunoglobulin levels.
Methods: We reviewed the medical records of 323 CLL patients over the last 20 years at Veteran Affairs Medical Center, Kansas City. Broadly the patients were divided into two groups; the group who received chemotherapy for CLL(74/323) versus the group who did not receive treatment (249/323) and their median immunoglobulin levels were also documented. Patients who developed secondary hematological malignancies were excluded from this study.
Results: The overall incidence of solid tumors was found to be 14.8% (48/323). In the chemotherapy treated CLL, the incidence of solid tumors was 18%(14/74) as compared to 13.6% (34/249) in the non-therapeutic group(P value 0.12). The most common malignancies noted were gastro-intestinal malignancies, genitor-urinary tumors and skin cancers including melanomas. Interestingly CLL patients who developed secondary solid tumors had a higher median IgG levels (1010 g/L) when compared to those who did not develop secondary tumors (738 g/L, P value <0.003)
Conclusion: Our study shows that there is a higher overall incidence of secondary solid tumors in patients with CLL when compared with incidence in the general population. There is no significant increase in the incidence of therapy related solid tumors in CLL patients. Upward drift in immunoglobulin levels should raise a suspicion for diagnosis of secondary solid tumors in patients with CLL. More studies are warranted to confirm this finding.
Reduced-Intensity Cord Blood Transplantation in Adult Patients for the Recurrence after Allogeneic Transplantation.
Authors: Seo Sachiko , Uchida Naoyuki , Yamamoto Hisashi , Matsuno Naofumi , Matsuhashi Yoshiko , Takagi Shinsuke , Kato Daisuke , Masuoka Kazuhiro , Wake Atsushi , Miyakoshi Shigesaburo , Taniguchi Shuichi 
Published: October 2019

Abstract
Backgrounds: For more than 10 years, umbilical cord blood has become an alternative stem cell source for the patients with hematological malignancies requiring allogeneic stem cell transplantation. Cord blood transplantation (CBT) can be performed more quickly than other stem cell transplantation, since cord blood units are preserved in the deep freeze and 1–3 HLA mismatched donors are acceptable. Considering these advantage, we examined the feasibility of cord blood transplantation using reduced-intensity regimens (RI-CBT) for adult relapsed patients after allogeneic tranplantation.
Patients/methods: We reviewed medical records of 26 patients who received RI-CBT at Toranomon Hospital between November 2003 and June 2006. Median age of the patients was 36 years (range, 20–66). Underlying diseases were acute leukemia (n=17), myelodysplastic syndrome (n=4) and lymphoma (n=5). The stem cell source of the first transplantation were bone marrow from sibling donor (n=2), bone marrow from unrelated (n=5) donor, peripheral blood stem cell from sibling donor (n=5) and unrelated cord blood (n=14). Conditioning regimens comprised fludarabine 125–180 mg/m2 in several combination with melphalan 80–140 mg/m2, Busulfan 8–16mg/kg and total body irradiation (TBI) (4–8 Gy). Graft-versus-host disease (GVHD) prophylaxis was cyclosporine (n=5) or tacrolimus (n=21). Median number of total nucleated cells and CD34+ cells was 2.56×106 cells/kg (1.91–5.94), and 0.86×105 cells/kg (0.57–1.77) respectively. HLA disparities were 5/6 (n=2), 4/6 (n=22), and 3/6 (n=2).
Results: Median observation period was 58 days (range, 32–380). Overall survival for 1 year was 15% and 16 patients were died of disease progression (n=5) and infection (n=11). The infection in 4 patients was considered to be caused by regimen related toxicity (RRT). No grade IV toxicities (NCI-CTC Ver.3.0) were observed. The duration between two transplantations was longer in surviving patients compared to dead patients (98 days (range, 39–2108) and 262 days (range, 95–901), respectively), although significant difference was not detected. The stage of the disease in the second transplantation, conditioning regimens and HLA disparities did not influence to the outcome.
Discussion: We demonstrated that RI-CBT could be an available and feasible treatment for the relapsed patients after stem cell transplantation. Moreover, the RRT is acceptable even in the patients with an advanced disease.
Myeloma Treatment Plan: Up-Front Dose-Dense Chemotherapy, Two Semi-High-Dose Autologous Transplants and a Non-Myeloablative Reduced Intensity Allogeneic Transplant.
Authors: Van Hoef Marlies E.H.M. 
Published: October 2019

Introduction: Our non-myeloablative transplants for early stage disease program started in 2000 for breast cancer and recommends treatment by combined modalities consisting of intensive or dose dense induction, an autologous transplant strategy and a non-myeloablative reduced intensity conditioning transplant (Blood2001; 98 (suppl 1): 5241, 5242). In myeloma aggressive treatment from diagnosis has rarely been practised. Steroids with other low-dosed agents have been the standard for years and resulted in substantial mortality. The reason has been that the majority of patients are over 60 years at diagnosis of the disease (80% of women, 75% of males); myeloma start to reveal themselves around 40 years.
Methods: Several databases were searched to provide insight in the matter.
Results: A medline search on dose dense and myeloma showed no articles. Standard treatment in myeloma (melphalan and prednison or VAD) induce 6-10% (complete) responses; the newer agents thalidomide or bortezomib in combination with other agents induce 12 to 16% (complete) response, but the agents are quiet toxic.
Standard CHOP in myeloma has been reported to induce 60 to 65% partial response with very low toxicity (Nippon Ronen Igakkai Zasshi1991;28(4):504–508). CHOP-14 is well tolerated in older lymphoma patients and should be evaluated in myeloma. Two intermediate high-dose autologous transplants without prior therapy induced 25% near complete response (Blood2004;104:3052–7). No treatment related mortality was reported.
Non-myeloablative reduced intensity conditioning transplants after high-dose autologous transplants converted 18% complete remission to 70% complete remission and induced long-term disease free survival (Blood2002;100:755); this therapy was though associated with 11% risk on treatment related mortality, mainly attributable to graft versus host diseases. Disease free survival was high at give follow-up. GVHD is well manageable with available agents.
In over 75% the disease was lethal prior to the non-myeloablative transplant era.
Conclusion: Conventional therapy in myeloma has been characterized by few low-dose regimens; myeloma have for years been undertreated. To improve disease outcome a systematic treatment approach from initial diagnosis for any of the stages I to III disease is required and herein discussed.
Reduced Intensity Stem Cell Transplant (RIST) as Salvage Treatment for Relapse Following Myeloablative Allogeneic Transplantation in Adult Acute Myeloid Leukemia.
Authors: Sica R. Alejandro , Tuscano Joseph M. , Law Lisa Y. , Richman Carol M. 
Published: October 2019

Abstract
Relapse of acute myeloid leukemia (AML) following myeloablative allogeneic stem cell transplantation portends a dismal prognosis. Therapy aimed at enhancing graft-versus-leukemia (GVL) effect, e.g., by donor leukocyte infusion, has limited success in AML, and a second ablative transplant is associated with prohibitive mortality in adults. From April 2001 to March 2006, nine patients, ranging in age from 21 to 57, with high risk myeloid malignancy (7 AML and 2 advanced myelodysplasia) and overt bone marrow relapse less than one year after ablative busulfan/cyclophosphamide conditioning have been treated with a cytoreductive regimen of fludarabine (30 mg/m2/day) and cytarabine (2g/m2/day) for 5 days (-7 through -3) and G-CSF administration (5 ug/kg daily starting day -8) with or without idarubicin (8 mg/m2 days -7, -5, and -3) (8 cases) or fludarabine 30 mg/m2 for 3 days and 200 cGy total body irradiation (1 case). G-CSF mobilized peripheral blood stem cells from their original HLA-matched donor (8 siblings, 1 unrelated) were infused. Graft versus host disease (GVHD) prophylaxis was mycophenolate mofetil for 30 days and cyclosporine with a rapid taper. The mean onset of relapse after the initial ablative transplant was day 172 (range 106–271). Fludarabine-based therapy was well tolerated with no treatment related mortality. Full donor chimerism was established by day 72 (range 26–113) in 6 patients (67%). Five patients died: 2 from relapse without GVHD at day +30 and +301 after RIST (one patient with complex and one with Ph+ cytogenetic abnormalities), 3 from relapse with evidence of GVHD. Four patients survive: one has relapsed at 91 days after RIST and is receiving alternate therapy, while three patients (30%) survive in complete remission at 100+, 635+ and 1795+ days after salvage RIST. In 5 cases (56%), the duration of complete remission after RIST was longer than after the initial ablative transplant. We conclude that fludarabine-based RIST is a safe and effective salvage therapy offering a chance for increased survival with low morbidity in patients relapsing after ablative transplant. In addition, RIST therapy has resulted in long-term disease free survival in over 20% of cases in this study.
The Relationship between CRP, Citrulline and Bacteremia among Patients Undergoing Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma.
Authors: Herbers Alexandra H.E. , Donnelly J. Peter , de Pauw Ben E. , Blijlevens Nicole N.A. 
Published: October 2019

Abstract
Background:
Infection remains a leading cause of morbidity and mortality in hematopoetic stem cell transplant (HSCT) recipients. The objective of the present study was to identify the relationship between C-reactive protein (CRP), serum citrulline as an indicator of gut mucosal barrier injury, and bacteremia in patients undergoing autologous peripheral blood (PB)HSCT for multiple myeloma.
Methods:
29 consecutive patients given high dose melphalan as conditioning therapy for a PBHSCT according to a national protocol from May 2004 to May 2005 were included in the analysis. Blood cultures were obtained at least twice weekly during three weeks of hospital admission; bacteremia was defined by any positive blood culture. SPSS for Windows version 12 was used to perform statistical calculations. CRP values were transformed to log10 whereas the actual citrulline values were used.
Results:
The mean age of the patients was 55 (range 33–65) years and the mean length of hospital stay was 23 (17–34) days. Blood cultures of 19 patients yielded bacterial growth. For the overall study population a specific pattern of citrulline levels that was not correlated with the occurrence of bacteremia was observed. At baseline the levels (mean ± SD) amounted to 25.4 ± 6.2 micromol/L, after 1 week 14.1 ± 4.7 micromol/L, after 2 weeks 7.1 ± 3.5 micromol/L and after 3 weeks 9.3 ± 5.2 micromol/L. The corresponding CRP levels showed a high SD pointing at a patient-specific level. The respective values (mean ± SD) were: 5 ± 3 mg/L at baseline, 8 ± 10 mg/L lst week, 95 ± 86 mg/L 2nd week and 47 ± 83 mg/L 3rd week. A strong correlation (p<0.01) was found between positive blood cultures and low citrulline (7.6 ± 3.8 micromol/L); for CRP such a relation was not established.
Conclusion: The occurrence of bacteremia coincides with low serum citrulline levels, but not with CRP levels. Extending our observation might be of help to establish a lower limit of citrulline levels that is indicative of an imminent bacteremia.