bluuebunny/crossref_metadata_2025_split huggingface dataset:
Honokiol Overcomes Conventional Drug Resistance in Human Multiple Myeloma.
Authors: Ishitsuka Kenji , Hideshima Teru , Hamasaki Makoto , Noopur Raje , Shaji Kumar , Hideshima Hiromasa , Shiraishi Norihiko , Richardson Paul , Munshi Nikhil C. , Chauhan Dharminder , Arbiser Jack , Anderson Kenneth C. 
Published: October 2019

Abstract
Honokiol is an active component isolated and purified from Magnolia, a plant used in traditional Chinese medicine. It is an anti-oxidant, and inhibits both xanthine oxidase and angiogenesis. In this study, we first examined the direct toxicity of honokiol against human multiple myeloma (MM) cell lines in vitro. Honokiol significantly inhibited growth of MM cell lines (RPMI8226, U266 and MM.1S) via induction of G1 growth arrest, followed by apoptosis, with IC50 values at 48h of 5 to 10 μg/ml. Moreover, honokiol similarly inhibited growth of doxorubicin (Dox)-resistant (RPMI-Dox40), melphalan resistant (RPMI-LR5), and dexamethasone (Dex)-resistant (MM.1R) cell lines. Furthermore, flow cytometric analysis demonstrated that honokiol (6–10 μg/ml, 48h) induced death of CD38+CD138+ tumor cells isolated from 5 patients with relapsed refractory MM. In contrast, no toxicity was observed in normal peripheral blood mononuclear cells or long term-cultured bone marrow stromal cells (BMSCs) treated with honokiol (≤20 mg/ml). Neither culture of MM cells with BMSCs nor interleukin-6 (IL-6) and insulin like growth factor-1 (IGF-1) protected against honokiol-induced cytotoxicity in MM.1S cells. We next delineated the mechanism of honokiol-triggered cytotoxicity. Honokiol triggered increased expression of Bax and Bad; down regulated Mcl-1 protein expression, followed by caspase-8/9/3 cleavage. Importantly, the pan-caspase inhibitor z-VAD-fmk only partially inhibited honokiol-induced apoptosis in MM.1S cells. Furthermore, honokiol induced apoptosis even in SU-DHL4 cells, which express low level of caspase-8 and -3 and are resistant to both conventional (doxorubicin, melphalan, dexamethason) and novel (bortezomib, revimid) drugs. These results suggest that honokiol may induce apoptosis via both caspase-dependent and -independent pathways. Finally, honokiol inhibited IL-6-induced phosphorylation of ERK1/2, STAT3, and Akt, known to mediate growth, survival, and drug resistance, respectively. Taken together, our results suggest that providing the rationale for clinical evaluation of honokiol to improve patient outcome in MM.
Genetic Polymorphisms Associated with Clinical Outcome in the Intergroup Trial S9321, Comparing High Dose Therapy with Standard Dose Therapy for Myelomaon, on Behalf of ECOG, SWOG, CALGB, and the Bank on a Cure.
Authors: Santana-Davila Rafael , Crowley John , Durie Brian , Barlogie Bart , Greipp Philip , Van Ness Brian 
Published: October 2019

Abstract
Genetic variations in patient populations likely contribute to disease progression and therapeutic outcomes. We have begun a systematic approach to examine the association of genetic variations (ie. functional, single nucleotide polymorhisms, SNPs) involved in myeloma growth promotion, metabolic events, drug responses, and DNA repair on clinical outcome in the intergroup trial S9321. This trial tested a single high dose regimen with autologous stem cell support against a conventional dose regimen, with further randomization of responders to maintenance with interferon or not, in newly diagnosed patients with multiple myeloma. ECOG, CALGB and SWOG enrolled 899 patients with newly diagnosed MM to receive VAD induction x 4 cycles followed by randomization to PBSC-supported high dose therapy (HDT) versus standard dose therapy (SDT) of VBMCP, using CTX 4.5 g/m2 + G-CSF for PBSC mobilization in all patients. Responders to VBMCP or HDT were randomized to IFN or no maintenance. Specimens were distributed through ECOG for biologic correlative studies, including candidate SNP analysis. SNP assays have been developed using the Sequenom Mass-extend platform for functional SNPs in IL-6, IL-1, IL-RA, IL-10, TNF, Lta, TGFb, MDR1, MPO, CYP3A4, GST (M, P, T), ERCC2 and XRCC1, and are being evaluated on 803 DNA samples prepared from patients enrolled in S9321. Preliminary findings (n=135) demonstrate functional genetic variants of IL-10 (position -1082), IL-1 (position +3953), TGFb (postion -509), and TNFa (position -308) are showing trends associated with differences in progression free survival; and variants in IL-6 (position -174) are associated with response. Median survival of the IL-10 variants was 31 months for A/A low producer alleles versus 19 months for the G/G high producer alleles (p=.5). For TNFa, 2 cases with the high producer A/A alleles died within a year, while the median survival for the lower producer G/G alleles was 2 years (p=.04). For patients with the high producer C/C/ allele of IL-1 (n=67), median survival was 2 years, versus 5 patients with the T/T low producer alleles that had a median survival greater than 5 years (preliminary p=.29). While these preliminary results are now only suggestive of trends in genetic polymorphisms associated with clinical outcome, completion of the full SNP panel on the entire sample base should provide a extensive association study, and analysis of potential differences in therapy arms of the trial. The full panel and association studies will be presented.ααββααα
Prognostic Diversity of Cytogenetic Lesions in Myelofibrosis with Myeloid Metaplasia: A Prospective Study of 88 Patients.
Authors: Dingli David , Arora Brijesh , Sirhan Shireen , Gordon Dewald W. , Ayalew Tefferi 
Published: October 2019

Abstract
Background : Thirty to 50% of patients with myelofibrosis with myeloid metaplasia display detectable bone marrow cytogenetic abnormalities at diagnosis with some(Demory et al. Blood1988;72:855, Dupriez et al. Blood1996;88:1013, Reilly et al. BJH1997;98:96) but not other studies (Cervantes et al. BJH1998;102:684, Okamura et al. Int J Hematol2001;73:194) suggesting a detrimental effect on survival.
Methods : The current prospective study was conducted as a follow-up of the observations from an antecedent retrospective study that identified sole abnormalities of either 13q- or 20q- as ‘favorable’ to survival (Tefferi et al. BJH2001;113:763). All clinical and laboratory measurements, including bone marrow examination and karyotype analysis, were performed concurrently in consecutive cases of histologically confirmed MMM regardless of either duration of disease or presence of active therapy. Survival, leukemic transformation rate, and clinical progression were determined from the time of cytogenetic analysis.
Results : Karyotypic analysis was successfully performed in a total of 88 patients (median age 61 years; 31 females) and the results were normal in 49 (56%) and abnormal in the remaining 39 patients with 9 (10%) displaying ‘favorable’, and 30 (34%) ‘other’ clonal abnormalities. At the time of study entry, 57 patients were not recieving any form of therapy, 18 were newly diagnosed, and the Dupriez prognostic score distributions were ‘0’ in 33 patients, ‘1’ in 35 and ‘2’ in 20 (Dupriez et al. Blood1996;88:1013). All patients were followed for a minimum of 3 years and a median of 42 months. The 3 cytogenetic categories were similar in age and gender distribution. Survival in the favorable cytogenetic group was similar to that of the normal group and significantly better than the group with other cytogenetic abnormalities (p=0.02).
Figure Figure
Similarly, no patient (0%) in the ‘favorable’ group transformed into acute leukemia while 6 of 30 (20%) in the ‘other’ and 5 of 49 (10%) in the normal groups did (p=0.21). In a Cox regression analysis, cytogenetic lesions other than the ‘favorable’ kind, hemoglobin below 10 g/dL, leukocytosis, hypercatabolic symptoms, increased blood blast %, blood CD 34 count above 100 x 106/L were individually associated with shortened survival. In a multivariate analysis, only hemoglobin level and leukocyte count retained their significance.
Conclusion : Single chromosomal abnormalities of either 13q- or 20q- should be considered as ‘favorable’ cytogenetic lesions in MMM while other abnormalities are associated with an adverse prognosis. The current observation explains the discrepancy in the literature regarding the prognostic relevance of cytogenetic findings in MMM and warrants additional studies to determine the value of incorporating the specific information in prognostic scoring systems.
A Potential New Application of Mobilization/Leukapheresis for Enrichment of Peripheral Blood in Circulating Non-Hematopoietic CXCR4+CD45− Tissue-Committed Stem Cells (TCSC) for Organ/Tissue Regeneration.
Authors: Kucia Magda , Reca Ryan , Wysoczynski Marcin , Gozdzik Jolanta , Ratajczak Janina , Janowska-Wieczorek Anna , Ratajczak Mariusz Z. 
Published: October 2019

Abstract
During mobilization hematopoietic stem cells (HSC) egress from the bone marrow (BM) into peripheral blood (PB) where they temporarily circulate and can be collected by leukapheresis. However, recently we demonstrated that BM, in addition to HSC, contains heterogeneous populations of CXCR4+ tissue-committed stem cells (TCSC) and we contend that the contribution of these cells to organ/tissue regeneration after transplantation of BM cells has been misinterpreted as evidence for “plasticity” or “trans-dedifferentiation” of HSC (Leukemia2004:18;29–40). To determine whether TCSC could also be mobilized into PB we i) evaluated the presence of these cells in the PB of G-CSF-mobilized patients (n=11), ii) attempted to increase mobilization of the TCSC in a murine model by combining G-CSF with T140 (a CXCR4 antagonist) or SB290157 (the C3a complement fragment receptor antagonist which we have found to desensitize the responsiveness of HSC to SDF-1), and iii) tested the hypothesis that TCSC could also be mobilized into PB during stress related to tissue/organ injury, e.g., heart infarct, stroke, partial body irradiation. The presence of mobilized/circulating TCSC in PB was evaluated by i) real-time RT-PCR, ii) immunohistochemical staining for TCSC markers and iii) demonstrating the potential of mobilized TCSC to grow neurospheres or to form myotubes in vitro. We present evidence for the first time that i) G-CSF efficiently enhances the release into PB not only of HSC but also of TCSC expressing markers for early skeletal muscle, myocardium, neural tissue, pancreas and liver, ii) a combination of G-CSF with T140 or SB290157 is 25–30 times more effective in selectively mobilizing TCSC compared to G-CSF alone, and iii) TCSC are also mobilized to PB during stress related to heart infarct, stroke or partial body irradiation. Furthermore, we observed that TCSC, like HSC, express CXCR4 and Sca-1 but do not radioprotect lethally irradiated mice and, unlike HSC, are CD45-negative. Based on these findings we postulate that mobilization/leukapheresis procedures may find a new application for obtaining TCSC for use in tissue/organ regeneration. We are currently testing this hypothesis in murine models.
Pilot Study of Reduced-Intensity Conditioning Followed by Allogeneic Stem Cell Transplantation in Patients with Myelofibrosis.
Authors: Kroeger Nicolaus , Zabelina Tatjana , Schieder Heike , Panse Jens , Ayuk Francis , Fehse Natalja , Fehse Boris , Waschke Olga , Kvasnicka Hans M. , Thiele Jurgen , Zander Axel 
Published: October 2019

Abstract
We evaluated in a prospective pilot- study the effect of reduced intensity conditioning with busulfan (10 mg/kg), fludarabine (150 mg/m²) and anti-thymocyte globulin followed by allogeneic stem cell transplantation from related and unrelated donors in 14 patients with myelofibrosis. Study objectives were engraftment, chimerism, treatment- related mortality (TRM) and response. The median age of the patients was 51 (range, 32 – 63) years. According the Lille score there were low risk (n=4), intermediare risk (n= 7) and high risk (n=3) The median time until leukocyte (> 1.0 x 109/l) and platelet (> 20 x 109/l) engraftment was 16 (range, 11 – 26) days and 26 (range, 9 – 139) days, respectively. No graft failure occurred. Complete donor chimerism on day 100 was seen in 13 patients (93%). Acute graft-versus host disease (GvHD) grade II-IV occurred in 50% and grade III/IV 29 % of the patients. The incidence of chronic GvHD was 54 %. Two patients died due to treatment complications, resulting in a TRM at one year of 15% (95% CI: 0–35%). Hematological response after allogeneic transplantation was seen in all patients and complete histopathological remission was observed in 90%of patients. After a median follow-up of 13 (range, 3 – 48) months, the 3-years estimated overall and disease-free survival is 85 % (95 % CI: 65–100 %).
Prognostic Factors in Primary Chronic Myelofibrosis in Patients Aged Less Than 70 Years: A Report on 207 Patients with the Description of a Scoring System and Its Validation on 100 Other Patients.
Authors: Tanimoto Tetsuya E. , Shimoda Kazuya , Yamaguchi Takuhiro , Okamura Takashi , Mizoguchi Hideaki , Omine Mitsuhiro , Niho Yoshiyuki , Harada Mine 
Published: October 2019

Abstract
Primary chronic myelofibrosis (PCMF) is a rare myeloproliferative disorder among young individuals. Conventional therapies are often ineffective and only palliative. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) using myeloablative or reduced-intensity conditioning offers the only possible curative treatment. However, the course of PCMF is highly variable from only a few months to more than a decade. To identify PCMF patients for allo-HSCT candidates, we analyzed a Japanese cohort aged less than 70 years and established a new prognostic system based on simple clinical parameters. In a training series, we used 207 patients with complete data, whose diagnoses were made over a period of 10 years (1988 to 1997) (Okamura T et al. Int J Hematol 2001). Patients who received allo-HSCT were not included. Using the Cox proportional hazard regression model, four initial variables were independently associated with shorter survival: Male sex (hazard ratio [HR], 2.26; 95% confidence interval [C.I.], 1.35–3.46), Hemoglobin < 10 g/dL (HR, 3.01; 95% C.I., 1.83–4.93), the presence of constitutional symptoms (fever, sweats and weight loss) (HR, 2.33; 95% C.I., 1.33–4.06), and circulating blasts ≥ 1% (HR, 1.53; 95% C.I., 1.00–2.33). Based on the above criteria, two groups were identified; a low-risk goup with up to one adverse prognostic factor and a high-risk group with two or more adverse prognostic factors. With the median follow-up time of 83 months, the median survival was 292 months in the low-risk group, and 66 months in the high-risk group, respectively (P <.0001, Figure). An external data set of 100 patients who diagnosed after 1999 was used for validation. The 4 prognostic systems separated the validation series in groups with significantly different survival rates despite the median follow-up time of 12 months. A simple prognostic model using the combination of sex, Hb level, constitutional symptoms and circulating blasts was developed and validated. This model might help to select patients with PCMF for treatment and to evaluate therapeutic results including allo-HSCT.
Figure Figure
Increased Granulocyte CD11b and Monocyte Tissues Factor Expression in Patients with Essential Thrombocythemia and Thrombosis.
Authors: Arellano-Rodrigo Eduardo , Alvarez-Larran Alberto , Cervantes Francisco , Reverter Juan-Carlos , Villamor Neus , Montserrat Emili 
Published: October 2019

Abstract
The mechanisms accounting for the increased risk of thrombosis in patients with essential thrombocythemia (ET) are not well known. Recently, a possible role for the granulocytes in the development of thrombosis in ET has been suggested. To analyze the possible relationship between granulocyte activation and a history of thrombosis in ET, granulocyte activation was studied in 53 ET patients (26 with a previous history of thrombosis and 27 without) and 26 healthy controls. Neutrophil and monocyte CD11b expression, monocyte tissue factor (mTF) expression, and platelet-neutrophil (PNC) and platelet-monocyte (PMC) complexes were studied using whole blood cytometry and the results were expressed as percentages and in MESF (molecules of equivalent soluble fluorochrome) units. Granulocyte CD11b and mTF expression were measured at baseline and after activation with lipopolysaccharide (LPS). The results are as follows: 1) ET patients had significantly higher baseline percentages of circulating PNC and PMC as well as neutrophil CD11b MESF expression than the controls (p=0.0001); 2) monocyte CD11b expression was higher in patients with ET and thrombosis (mean 151241 MESF) than in those without (127191 MESF) and in the controls (65717 MESF) (p= 0.0001); 3) mTF baseline surface expression was increased in ET patients as compared with the controls (15635 vs 9385 MESF, p= 0.0001); 4) following LPS activation, patients with ET and previous thrombosis had significantly higher mean percentage of mTF expression than those without thrombosis and the controls (48%, 36% and 25%, respectively) (p= 0.0001). No differences were noted when the results were analysed according to the treatment that the patients were receiving at the time of study. In conclusion, patients with ET and a history of thrombosis show a marked increase in granulocyte activation, especially in monocyte activation, and therefore such alteration might play a role in the pathogenesis in these patients.
Sub-Cellular Localization Determines the Delicate Balance between the Anti and Proapoptotic Activity of Livin.
Authors: Ben-Yehuda Dina , Nachmias Boaz , Ashhab Yaqoub , Lazar Itay , Perlman Rebeca 
Published: October 2019

Abstract
Inhibitor of Apoptosis proteins (IAP) comprise a family of intracellular proteins that play an essential role in the regulation of apoptosis. IAP family members are defined by one or more repeats of a highly conserved anti-apoptotic domain termed the baculovirus IAP repeat (BIR), located at the amino-terminus. In addition, some IAPs contain a conserved domain termed RING finger at the carboxy-terminus. In a previous study, we identified an IAP family member termed Livin, which contains a single BIR domain and a carobxy-terminal RING finger motif. Livin inhibits apoptosis induced by a variety of stimuli. We further demonstrated that following apoptotic stimuli, Livin is cleaved by effector caspases 3 and 7, to produce a truncated form with paradoxical proapoptotic activity. In our current study, we reveal that while the full-length Livin shows a cytoplasmic distribution, the truncated form is readily detected in the nucleus. Using mutation analysis, we identified two domains outside the BIR sequence that are strongly engaged in determining the subcellular localization as well as the proapoptotic activity of Livin. These two domains are the N-terminus post-cleavage exposed area and the C-terminus RING domain. Remarkably, a single substitution of the first exposed amino acid Glycine, is sufficient to significantly diminish nuclear localization as well as the proapoptotic activity, thus linking the nuclear accumulation of the cleavage fragment with the proapoptotic activity. We demonstrate that the cytoplasmic localization of Livin is mediated through the RING domain, as a mutation that disables Livin from forming the zinc finger results in both a cytoplasmic and nuclear localization. Moreover, RING-mutated Livin subunit also loses its proapoptotic activity. Thus we suggest a model in which the exposed N-terminal region counteracts the cytoplasmic localization signal of the RING domain, promoting nuclear localization of the truncated form. The change in sub-cellular localization allows the RING domain to mediate the proapoptotic effect. To the best of our knowledge, this is the first example of such a regulatory mechanism in IAP family members.
Enforced BCL6 Expression Inhibits B Cell Development in Vivo.
Authors: Robbiani Davide F. , Colon Kaity , Naik Kruti , Nickerson Helen , Affer Maurizio , Chesi Marta , Bergsagel Peter Leif 
Published: October 2019

Abstract
The B-Cell Lymphoma 6 (BCL6) gene encodes for a zinc finger motifs containing transcriptional repressor that is frequently dysregulated by chromosomal translocations in germinal center lymphomas. A putative protooncogene, its transforming ability in vivo was reported in I-mu-HA-BCL6 knock-in mice by Cattoretti et al last year. We also tested this assumption in transgenic mice expressing BCL6 in B cells under the control of kappa light chain regulatory elements. We replaced the murine C-kappa locus with the 16kb human BCL6 genomic locus in a construct containing the murine kappa light chain regulatory elements (Vk, EiK, 3′RR).
While control transgenics were readily obtained (5/32 founders), only 3/68 founders were positive for the BCL6 transgene, of which only one (bearing a single copy of the transgene) was able to transmit the transgene to its progeny, thus suggesting embryonal toxicity of exogenous BCL6.
In the bone marrow, flow cytometry revealed a nearly complete block of B cell development at the pro-B to pre-B transition. This was also the stage at which we first detected expression of EGFP in control reporter mice that were generated in parallel. Spleens of transgenic mice weighed about 50% of control spleens and less than 5% of splenocytes were CD19+ B cells. These were IgM high, IgD intermediate, corresponding to an immature B cell phenotype. Lymph nodes were smaller and B cells barely detected. Peyers’ patches were not visible.
Combined, our analysis of 6–8 weeks old VkHABCL6 transgenic mice reveals that enforced expression of BCL6 early in development results in a profound block of B lymphocyte differentiation. How transgenic BCL6 modulates this effect at the transcriptional level remains to be investigated. To test the oncogenic potential of BCL6 in B cells, it will be interesting to precisely turn on this gene in the germinal center.