bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primitive Hematopoietic Cells Resist HIV-1 Infection Via P21Waf1/Cip1/Sdi1.
Authors: Zhang Jie Lin , Crumpacker Clyde S. , Scadden David T. 
Published: October 2019

Abstract
Hematopoietic stem cells are resistant to HIV-1 infection. We have identified a novel mechanism by which the cyclin-dependent kinase inhibitor, p21Waf1/Cip1/Sdi1 (p21), known for its regulation of stem cell pool size (1,2), restricts HIV-1 infection of primitive hematopoietic cells in a non-cell cycle dependent manner. Knocking down p21 by siRNA increased HIV-1 infection and induction of p21 expression by phorbol ester (TPA) blocked HIV-1 replication. P21 did not affect the overall levels of cDNA synthesis, but significantly blocked viral integration and resulted in marked increase in 2-LTR circles, a surrogate marker of abortive integration. Consistent with these observations, p21 coimmunoprecipitated with viral integrase and both were detected in the preintegration complex (PIC). Furthermore, silencing p27Kip1 and p18INK4C, cyclin dependent kinase inhibitors related to p21 that affect cell cycle, revealed no impact on viral DNA integration. A closely related dual-tropic lentivirus with a distinct integrase, SIVmac-251 and the other cell-intrinsic inhibitors of HIV-1, Trim5a, PML, Murr1, and IFN-a were unaffected by p21. These results indicate a new function for p21, participating in prevention of HIV integration into the cellular genome. Therefore p21 is an endogenous cellular component in stem cells that provides a unique molecular barrier to HIV-1 infection and may explain the basis for these cells being an uninfected ‘sanctuary’ in HIV disease.
Prognostic Value of Seric Immunoglobulins in CLL: Analysis of 331 Patients with a Median Follow-Up Time of 7.5 Years.
Authors: Garidi Réda , Guilhaume Marie-Noëlle , Vaida Ioana , Brevet Marie , Mazière Jean-Claude , Desablens Bernard 
Published: October 2019

Abstract
Prognostic value of seric immunoglobulins in CLL has been rarely studied. So we look at all our CLL and we find 331 pts with an initial dosage of IgG, IgA and IgM without M component at diagnosis or during the first year of survey. Ages at diagnosis range from 38 to 93 yrs and median age is 66 yrs. Sex ratio M/F is 1.55 and staging according to Binet’s system notes 264 stages A (188 stages A0), 43 stages B and 24 stages C. IgG levels range from 0.9 to 22.2 g per l with a mean value of 9.38±3.18 g. In logistic regression, IgG level is linked with sex, age, number of lymphoid area according to Binet’s system, blood lymphocytosis and hemoglobin levels used as continuous values. IgA range from 0.1 to 7.8 g (mean value=1.66±1.03 g) and is linked with the same parameters and platelet level too. At least, IgM range from 0 to 3.4 g (mean value=0.78±0.63 g) and is linked with age, number of lymphoid area, blood lymphocytosis and platelet levels. Immunoglobulins levels are also linked with LDH, β2-microglobulin, sCD23 and sCD25 values.
Looking at “corrected” survival after exclusion of not CLL-related deaths including those due to a solid tumor because this complication is independent of initial prognostic factors of CLL, we find that the best cut-off values are 7 g for IgG and 2 g for IgA. For IgG, median survival time is 14.6 yrs for the 268 pts with initial IgG ≥ 7 g versus 6.5 yrs for the 63 other pts (p=0.00004). For IgA, the best cut-off value is 2 g: median survival time is >13.3 yrs for the 100 pts with IgA ≥ 2 g versus 10 yrs for the 231 other pts (p=0.04). These 2 cut-off values are independent and so we can build a prognostic system: 98 pts with IgG ≥ 7 g and IgA ≥ 2 g - 172 pts with IgG < 7 g or IgA < 2 g - 61 pts with low IgG and IgA levels. Median “corrected” survival times of these 3 groups are statistically different: > 13.3, 10.6 and 6.8 yrs (p=0.0009) and when we look at global survival, rates are more different: >13.3, 8.6 and 5.7 yrs (p=0.00009). Same data are noted among stage A patients only and among stage A0 too. So when we opposite this system and with Binet’s and Rai’s classifications, only Rai’s system is ruled out by Cox model looking at “corrected” or global survival. Curiously, this new system has no impact of initiation on treatment among stage A pts while it is linked to evolution to stage C (p=0.05). Finally, we find no correlation with occurrence of an M component or an immunological complication, and also with occurrence of a zoster infection or a Richter syndrome while it is a trend for occurrence of a second neoplasia (p=0.06).
Fludarabine Monophosphate as First Line Therapy for Chronic Lymphocytic Leukemia (CLL) - 11 Years Clinical Experience.
Authors: Novoa J.E. , Rojo A.L. , Beñaran B. , Draper R. , Calvo H. , Iriondo N. , Diaz L. , Rivero M. , Cabrera A. , Pebet M. , Brignoni S. , Luongo A. , De Bellis R. 
Published: October 2019

Abstract
Background: fludarabine (F) has become the standard first line therapy for chronic lymphocytic leukemia (CLL) in younger patients. Treatment of early stage patients with chlorambucil without risk stratification has not been shown to prolong survival. In recent years effective and potentially curative approaches such as nucleosides analogues, stem cell transplantation or monoclonal antibodies have been developed. The attraction of monoclonal antibodies is based on selective targeting of tumor - relevant surface markers and a distinct mechanism of action (antibody-dependent cellular cytotoxicity).
Aims: to assess the efficacy, safety and quality of life of F in previously untreated B-cell CLL patients in a group of medical institutions in Uruguay during 11 years (1995–2006).
Methods: 168 patients between the period 1995 – 2006 were evaluated.120 of them received F intravenous formulation (1995–2006) and 48 the oral one (2002–2006). Age: 48 – 85 years old, media 67 years old. Gender: male 90, female 78. Inclusion criteria for B-cell CLL was Binet stages B, C and A progressive (Ap), 18 to 85 years old, non multiorganic failure, performance status 0 – 2 (WHO), written informed consent. First condition was non previous treatment. Staging: Binet A 12/168, B 116/168 & C 40/168. Treatment: as first line therapy all the patients received (minimum): 6 cycles of i.v. Fludarabine (Fludara®, Schering) 25 mg/m2/daily (5 days) e/30 days or Oral Fludarabine, 40 mg/m2/daily (5 days), 6 cycles.
Results: on this B-cell CLL cohort the overall response rate (ORR) was 78% (CR+PR), 80% of them have immunophenotypic response. Safety: on the 1100 cycles in 168 patients, the toxicity was: 1 AIHA, 2 pancytopenia, 3 plaquetopenia. Grade 3–4 infection rate was 1,3%. No alopecia was observed in any patient. Kaposi sarcoma (0,7%). Mortality rate: 1,7% (3/168 patients). Other adverse factors to overall survival were, age over 65 (p=0,0001) and hepatic impairment (p=0,0001). Toxicity: (WHO>2): granulocytopenia 28%, thrombocytopenia 8%, infection 2%. Although fludarabine-treated patients experienced more significant myelosuppression, no difference in the treatment group was demonstrated. Causes of death: Richter 12%, sepsis 5%, associated disease 34%, second malignancy 17% and others 30%. Comparing oral with intravenous formulation in overall survival the results were: CLL 34% vs 36% (p= NS).
Conclusions: fludarabine monofosfate (Fludara®) looks like an effective and safe treatment for B-cell CLL. The oral and intravenous formulations have a similar response rate in elderly and young patients. The challenge remains to integrate new information to apply novel therapies in a disease-specific and risk-adapted maner. A longer follow up and a larger trial, might be needed to confirm these results.
Metabolism, Disposition and Pharmacokinetics of PR-171, a Novel Inhibitor of the 20S Proteasome.
Authors: Yang Jinfu , Fonseca Fabiana , Ho Mark , Kirk Christopher J. , Sehl Louis S. , Lewis Evan R. 
Published: October 2019

Abstract
Clinical studies using the boronic acid-based proteasome inhibitor bortezomib have validated the proteasome as a therapeutic intervention point for the treatment of multiple myeloma and non-Hodgkin’s Lymphoma. PR-171 is a novel peptide epoxyketone inhibitor of the 20S proteasome that is currently in phase I clinical trials. Herein, the metabolism, disposition and pharmacokinetics of PR-171 are described. Incubation of 3H-PR-171, labeled in the phenylalanine ring, with freshly prepared rat, monkey and human hepatocyte preparations showed similar metabolite profiles with six predominant radiolabeled metabolites observed in all three species; no metabolites unique to human hepatocytes were detected. The diol of PR-171, formed via epoxide ring hydrolysis, was the most abundant observed metabolite in hepatocyte preparations of each of the three species. Single dose IV bolus PK studies using unlabeled PR-171 in Sprague Dawley rats (2 to 9 mg/kg) and cynomolgus monkeys (1 to 4 mg/kg) showed approximately dose linear PR-171 exposure for both species as measured by plasma AUCs. In both species, PR-171 plasma clearance values (554 and 227 mL/min/kg in rat and monkey, respectively) exceeded hepatic blood flow implying that extrahepatic clearance mechanism(s) must be involved. While the in vitro hepatocyte results suggest that hepatic clearance mechanism(s) are also likely to be involved, in vivo hepatic clearance cannot be conclusively inferred from available data. As predicted by the in vitro hepatocyte results, PR-171 diol was detected at abundant levels in plasma from both rat and monkey. Human pharmacokinetics are similar to those of rat and monkey. Mass balance and tissue distribution were also investigated in rats using 3H-PR-171. Radioactivity was widely distributed following a single IV bolus dosing and reached maximum concentrations at times ranging from 0.5 to 24 hours in different tissues. At 168 hours post-dose, more than 44% of the administrated radioactivity remained in tissues. Excretion via urine and feces accounted for 14% and 18%, respectively, of administered radiation. The distribution of radioactivity may not be indicative of the true distribution of PR-171 as much of the radioactivity may reflect metabolic incorporation of the radiolabel and/or 3H exchange with water.
Effectiveness of GVHD and GVL of Donor-Derived NK Cell of MHC Haplotype-Mismatched BMT in Mice.
Authors: Wang Chunyan , Tan Huo , Kunyuan Guo 
Published: October 2019

Abstract
Objective: To study Effectiveness of GVHD and GVL of donor-derived NK cell of MHC haplotype-mismatched BMT in mice.
Methods: CB6F1 H-2b/d mice model of EL9611 (H-2d) erythroleukemia was developed by injection of EL9611 (H-2d) cells in tail vein, CB6F1 H-2b/d mice as the recipient, and C57BL/6H-2b mice as the donor. 70 CB6F1 H-2b/d mice were randomly separated into 7 groups (10 mice per group). Control groups (4 groups): the first group was the one without treatment, the second one was simple-irradiation group, the third one was the Ara-c-treated group which Ara-c were injected into mice at 50mg/(kg·one)×6d followed by infusion of EL9611(H-2d) 5 days, the fourth one was haplotype-mismatched GVHD-control group which bone marrow cells and spleen cells of C57BL/6H-2b mice were injected into the mice after 4 hours irradiation. Experimental groups(2 groups): Irradiated 9Gy, mice were injected C57BL/6H-2b NK cells(1×106) and then BM cells after 4 hours in the first experimental group. After irradiation of 9Gy, mice were injected C57BL/6H-2b NK cells(1×106) and then BM cells and spleen cells after 4 hours secondly. The effect was assessed by blood routine test, survival time, body weight, and histopathology in the recipients.
Results: [circ1]Life span: the survival time was (10.10±0.88) days, (9.80±0.92)days, (22.70±3.23) days and (20.10±1.73) days in the first, second, third and fifth control groups respectively, (30.10±15.95) days in the fourth control group in which the survival time of 2 mice was more than 30 days. The survival time was (39.10±18.11) days and (49.30±17.24) days in the first and second experimental groups respectively. The survival time in 4 mice of the first experimental group was more than 30 days and 7 mice of the second experimental group. The survival time of the first of experimental group was much longer than that in the first, second, third and fifth control groups (P<0.01). The survival time of the second experimental group was much longer than that in other groups (P<0.05). [circ2]Histopathology change: It was observed that the liver and spleen were enlarged and destroyed in the mice died from leukemia by leukemia cells. [circ3]It was noted that chimerism of Y chromosome appeared in mice of experimental groups of long survival time.
Conclusion: The findings provide that donor-derived NK cell has the ability of antileukemia and can reduce GVHD in C57BL/6H-2b→CB6F1 H-2b/d of erythroleukemia mice (EL9611, H-2d).
Allogeneic SCT with Matched Related and Unrelated Donors for Patients (pts) with Refractory Anemia (RA): Improved Survival after Introduction of Reduced Intensity Conditioning (RIC) Regimens.
Authors: de Witte T.M. , Brand Ronald , van Biezen Anja , Mufti Ghulam , Ruutu Tapani , Finke Jurgen , von dem Borne Peter , Vitek Antonin , Delforge Michel , Alessandrino Paolo E. , Harhalakis Nicholas , Russell Nigel H. , Carreras Enric , Verdonck Leo F. , Niederwieser Dietger W. 
Published: October 2019

Abstract
Early alloSCT of pts with MDS before transformation usually results in a 50% EFS, but the nonrelapse mortality (NRM) has precluded a general application of alloSCT for patients with RA. Introduction of RIC has allowed the application of alloSCT to more advanced ages. This study evaluated the impact of recipient age, transplant year, interval between diagnosis and SCT (Dx-SCT), cytogenetic characteristics, T-cell depletion (TCD), type of donor, and the intensity of the conditioning regimen on the outcome of alloSCT. The study population consisted of 374 pts, 244 of whom have received a transplant from an HLA-id. sibling. None of the pts had progressed to advanced stages of MDS. 83 Pts received TCD grafts and 102 pts received SCT after RIC. 58 Pts were <20 yrs, 52 between 20–30, 66 between 30–40, 95 from 40–50 and 103 pts >50 yrs. 86 Pts received SCT before 1996, 125 in 1997–2001, and 163 pts more recently. 184 Pts have been transplanted with a Dx-SCT of <12 months, and 190 >12 months. Cytogenetic data were available for 197 pts, 85 of whom had cytogenetic abnormalities. The overall 5-year survival was 50% (SE: 3%). Relapse occurred in 44% pts resulting in a 5-year relapse risk of 21% (SE: 3%). NRM was the cause of failure in 120 pts resulting in a 5-year NRM of 41% (SE: 3%). The survival after SCT with matched related and unrelated donors was 54% and 48% resp. Young age was associated with better survival in the univariate model (p=0.04). An association exists between various factors such as between age and regimen type, transplantation year, or donor type. Therefore the outcome of the multivariable analyses was based on Cox models with age, transplant year, type of donor, Dx-SCT, stem cell source, and regimen type as main factors. Variables with a significant impact on survival were transplant year with an improved survival in more recently performed SCT (HR=0.95/year; p=0.05), TCD (HR=1.5; p=0.03) and Dx-SCT >12 months (HR=1.4; p=0.05) while higher age (HR=1.1/10 years; p=0.08) and RIC (HR=1.0; p=1.0) did not influence outcome significantly. The HR of RIC for relapse-free survival was 1.2; p=0.5. The fully adjusted estimate for relapse after RIC was HR=4.1 (p=0.002). The NRM was lower after RIC: HR 0.7 (P=0.22), but this difference was not significant. The donor type and the source of stem cells did not influence significantly any of the outcome variables. This data show that alloSCT results in excellent outcome nowadays, even at older age and using matched unrelated donors. The relatively high relapse rate observed after RIC warrants prospective studies.
Marrow Stromal Cell (MSC) Growth from Long Term Cryopreserved Bone Marrow.
Authors: Lane Thomas A. , Garls Davina , Mackintosh Ellen , Cramer Steven C. 
Published: October 2019

Abstract
Autologous MSC are under active investigation for a variety of potential clinical indications in regenerative medicine and gene therapy. The potential to derive autologous MSC from long-term cryopreserved bone marrow has not been fully elucidated. We report here the growth characteristics of MSC from bone marrow that was cryopreserved for more than 10 years.
Methods: We identified 3 deceased patients whose cryopreserved autologous bone marrow that was originally intended for autologous transplant, was to be discarded after fulfilling all accepted criteria for discard. The pts were age 46, 47, and 60 at the time of harvest, one had high risk and 2 had metastatic breast cancer (both to bone) and all had had multiple chemotherapy regimens prior to harvest. The marrow was cryopreserved between 1994–1995 in 10% DMSO using a controlled-rate freezer and stored in the vapor phase of liquid nitrogen until June, 2006 (11–12 years). The marrow was thawed in a 37 C waterbath, diluted with an equal volume of PBS, washed × 3 in PBS, resuspended in culture medium with 20% fetal bovine serum and plated at 5 × 10E6 mononuclear cells (mnc)/cm2 in 2 – 4 T175 flasks. Culture medium was changed in 48 hours and the plates were observed during subsequent culture medium changes every 3–4 days.
Results: At 2 – 4 days only scattered round cells were observed, but all samples grew scattered spindle-shaped cells were between days 4 – 12. Six of 8 primary cultures became > 70% confluent between days 11 and 21; 2 remained at < 40% confluence until replated (then achieving > 70% confluence at day 31). First passage cultures (n=12) became > 70% confluent in 4 – 10 days (median = 7) and 2nd passage cultures were > 70% confluent in 7 – 10 days (median = 9). Second or 3rd passage cultures yielded 2.1 – 4.2 × 10E6 MSC/T175 (n= 14; median 3.15) and were 89 – 96 % viable. Flow cytometry (n = 3) confirmed that 3rd passage cells stained positive for CD105 and CD73 and negative for CD14 and CD45. Additional characterization of the differentiation potential of these presumptive MSC are in progress.
Conclusion: These studies indicate that cells typical for MSC can be readily grown from marrow that has been cryopreserved for > 10 years and suggest that even long-term stored bone marrow may serve as a source of cells for regenerative medicine.
Hematopoietic Stem Cell Transplantation (HSCT) Using Plasma Depleted Umbilical Cord Blood (UCB) That Were Not Red Cell Depleted.
Authors: Chow Robert , Tan Patrick , Jaing Tang-Her , Rosenthal Joseph , Nademanee Auayporn , Karanes Chatchada , Graham Michael , Eames Gretchen , Chan Lee Lee , Wang Brian , Chow Tiffany , Wu Tina , Tan Ah Moy , Tan Poh-Lin , Lin Hai-Peng , Gjertson David , Petz Lawrence 
Published: October 2019

Abstract
UCB is an attractive source for HSCT; however, limiting cell dose has hampered its widespread use. The red cell depletion (RCD) techniques that are widely used incur significant nucleated cell loss after processing; therefore, to minimize cell loss and still reduce volume during processing, a technique was devised to deplete plasma (PD) but not red blood cells. A large racially diverse inventory of over 25,000 PD UCB is available on stem cell registries. Of the 265 PD UCB transplanted into 240 patients up to May 2006, an updated retrospective audited analysis of all 205 patients with engraftment and/or survival data was performed. The characteristics for the patients were: median age 8.8 yo, range 0.3–59, 76 ≥16 yo (32%); median weight 29 kg, range 5–137, 84 ≥50kg (35%); male 59%; median # HLA ABDR matches 4.0; median pre-freeze TNC dose 5.31 × 107/kg (n=229); transplant center reported median post-thaw TNC dose 4.92 × 107/kg (n=112); median pre-freeze CD34 dose 1.7 × 105/kg; malignant indications 71%; transplants outside U.S. 39%; double transplant 23%; and non-myeloablative 15%. For all engrafted patients, the median time to engraftment for ANC 500 (n=192), platelet 20K (n=174) and 50K (n=169) were 22.0 days (range 7–64), 49.5 days (range 12–181), and 63.5 days (range 21–374) respectively. Kaplan-Meier estimates of engraftment of ANC500, platelet 20K and 50K engraftment were 88±3%, 82±4% and 76±4% respectively. The incidence of grade III–IV acute GVHD and extensive chronic GVHD were 13% and 14% respectively. One-year relapse rate was 23±4% for all patients (n=190), and TRM was 29±3% (n=203) at 1 year. With a median follow-up of 178 days (range 4–1402 days) for the surviving patients, the Kaplan-Meier estimates of 1-year OS (n=203) and DFS (n=190) are 59±4% and 54±4% respectively for all patients. These results demonstrate that HSCT using PD UCB can be performed safely and effectively.
Quantitative Monitoring of Lineage-Specific Chimerism after Dual Hematopoietic Stem Cell Transplantation (Umbilical Cord Blood with Co-Infusion of Third Party Donor CD34+ Cells).
Authors: Sanchez-Hernandez Noemi , Manzano Cintia , Barroso Diana , Iglesias Gustavo , Balsalobre Pascual , Serrano David , Carrion Rafael , Gomez-Pineda Alfonso , Diez-Martin Jose L. , Buño Ismael 
Published: October 2019

Abstract
Background: Allogeneic umbilical cord blood (UCB) stem cell transplantation (SCT) shows some advantages (HLA matching requirements or availability) respect to SCT using other sources of matched unrelated donor (MUD) stem cells. However, it is correlated with slower engraftment, increasing risk of infections and early mortality. It has been recently shown that co-infusion of third party donor (TPD) CD34+ cells (dual SCT) is useful to speed up engraftment.
Objective: To evaluate the usefulness of lineage-specific chimerism quantification in the management of this transplant setting.
Patients and methods: 8 dual SCT (Tables 1, 2) in 7 patients (1 CML-BC, 2 AML-M2, 1 AML-M4, 1 ALL-Ph+, 1 biphen. ALL, 1 NHL). Chimerism was analyzed by STR-PCR (AmpFlSTR SGM Plus, Applied Biosystems; sensitivity 1%) and quantitative real-time PCR (qrt-PCR) of null alleles and insertion/deletion polymorphisms (Light Cycler, Roche; sensitivity 0,01%). Peripheral blood (PB) and leukocyte lineages (T cells, CD3+, and myeloid cells, CD15+), isolated by positive selection using automated immunomagnetic technology (AutoMACS, Miltenyi Biotec), were analyzed weekly. Bone marrow (BM) was analyzed at days +30, +100, +180 and +365).
Results: 7/8 cases showed initially a high proportion of TPD cells in PB which were progressively replaced by UCB cells. UCB complete chimerism (UCB-CC, absence of recipient or TPD cells even in qrt-PCR assays) was acquired in a median of 22.5 days (range 18–39). In one patient, fully HLA-mismatched with the TPD, no TPD cells were observed after dual SCT. 4/8 cases showed recipient cells in PB after dual SCT during a median period of 12 days (range 4–18 days). In 3/8 cases, recipient cells were found after CC had been acquired, which allowed early diagnosis of 1 graft rejection and 2 relapses. T cells (CD3+) are mainly of UCB origin early after dual SCT and reach UCB-CC a median of 7 days (range 0–21) before PB. However, myeloid cells (CD15+) derive primarily from the TPD and reach CC together with PB. TPD cellularity favoured early engraftment (before UCB-CC took place) in 4 cases. In this context, only one important infectious complication (hepatosplenic tuberculosis) was observed, which resolved with the appropriate treatment.
Conclusions: Lineage-specific chimerism quantification allowed a close monitoring of the dynamics of engraftment of cells of both donors which is of key importance in this SCT setting. Moreover, lineage-specific chimerism analysis was useful to diagnose one graft rejection and two relapses (the patient with NHL showed a ganglionar relapse in CC).
Table 1. Transplantation characteristics. Table 2. Transplantation results. Median (range).