bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systems Biology Analysis of Human Primary T Cells Identifies SAP145 as Rate Limiting for the G1→S Phase Transition.
Authors: Orr Stephen J. , Wang Rong , Lea Nicholas C. , Chronis Constantinos , Ramani Arun K. , Mufti Ghulam J. , Marcotte Edward M. , Thomas N. Shaun B. 
Published: October 2019

Abstract
We identified a G0→G1 commitment point in primary human T cells that controls entry into the cell cycle from quiescence. We demonstrated proof of principle that cellular pathways regulating cell cycle progression and effector functions that normally coincide during CD3/CD28 stimulation can be uncoupled experimentally. We have now used systems biology approaches to identify nuclear protein networks in primary human T cells that are regulated during the transition from quiescence into the cell cycle (G0→G1→S-phase). First we sequenced proteins that became bound to chromatin & nuclear matrix in G1 but were not bound in G0 and vice versa by mass spectrometry. Bioinformatic analysis identified 76 proteins specifically bound in G0 not G1 and 254 bound in G1 not G0. 179 of the 254 proteins bound in G1 not G0 (i.e. dynamic protein changes) were mapped to the 55,000 human protein interaction dataset. These are involved in numerous cellular functions, including epigenetics, transcription, RNA splicing & transport, and others. Cell cycle regulated chromatin/matrix binding of a subset was verified by western blotting (2/2 bound in G0 not G1 and 22/23 bound in G1 not G0). One of the proteins induced and bound in G1 was SAP145 (SF3B2). This is a component of the ubiquitous SF3b RNA splicing complex, involved in both major (U2-type) and minor (U12-type) spliceosomes. Since SAP145 is induced during G1 we investigated whether there was a role for SAP145 in regulating cell cycle progression. T cells depleted of SAP145 by siRNA enter G1 from G0 but progress poorly through S phase and die, probably by apoptosis. The same occurs if another component of the SF3B complex, SAP49 (SF3B4) is depleted with siRNA, indicating that the effect is due to depleting the complex rather than the individual SF3B protein. Proteins that are induced during G1 by CD3/CD28 stimulation e.g. cyclin D3, Cdc6 and cdc2 are produced normally when SAP145 is depleted, suggesting that their pre-mRNAs are spliced normally. In contrast, the expression of p107 and cyclin A2 are reduced markedly when SAP145 is depleted. Therefore, a systems biology approach to analysing cell cycle transitions identifies the splicing protein, SAP145 as rate-limiting for the G1 →S phase cell cycle transition but not for the transition from G0→G1.
High Expression of MDR1 and BCRP1 in Leukemic Stem Cells Correlates with Reversible Drug Resistance Ex Vivo and Predicts Failure of Remission Induction Chemotherapy in Patients with Acute Myeloid Leukemia.
Authors: Ho Maria M. , Hogge Donna E. , Ling Victor 
Published: October 2019

Abstract
Although overexpression of members of the ATP-Binding-Cassette (ABC) transporter superfamily has been implicated in chemotherapy failure in acute myeloid leukemia (AML) in some studies, results have been conflicting. Previously we found no consistent difference in pre-treatment ABC transporter expression when comparing total blasts of 18 patients achieving complete remission (CR) and 13 patients who were refractory to induction chemotherapy (NR). However, among the CD34+CD38− AML cells (enriched for candidate “leukemic stem cells” which engraft in immunodeficient mice), as assessed by quantitative RT-PCR, elevated expression of MDR1 and/or BCRP1, two ABC transporters associated with drug resistance, was found in 8/10 NR patients as compared to 0/7 CR patients. No difference between CR and NR samples was observed in the more differentiated CD34+CD38+ or CD34− AML cells while none of the subpopulations showed a significant difference in MRP1 expression between CR and NR patient samples. To determine if this difference in gene expression was associated with altered functional activity of MDR1/BCRP1, the relative sensitivity of subpopulations of AML cells to induction of apoptosis following ex vivo treatment with daunorubicin with or without ABC inhibitors (PSC-833 and Verapamil) was assessed. All subpopulations of AML cells isolated from 2 CR patients showed similar drug sensitivity profiles (IC50 <0.04 μg/ml). In contrast, CD34+CD38− cells from 6 NR patients were more resistant to daunorubicin-induced apoptosis (p<0.05 for comparison of IC50s between CR and NR samples). ABC transporter inhibition in CD34+CD38− cells did not change daunorubicin sensitivity in CR samples, but increased drug sensitivity in a dose-dependent manner in NR samples, particularly in the CD34+CD38− fraction. This suggests a role for ABC transporters in sustaining a population of chemotherapy resistant leukemic stem cells which may allow survival of the malignant clone in patients following induction therapy. If the value of measuring MDR1/BCRP1 expression among these cells in predicting chemotherapy outcome is confirmed in a larger patient population, it may be possible to use such analysis to modify therapy for individual AML patients to overcome drug resistance.
Expression of ROR1 in Chronic Lymphocytic Leukemia Cells Enhances Cells Survival by Wnt5a Signaling.
Authors: Chen Liguang , Tang Li , Fukuda Tetsu , Kipps Thomas J. 
Published: October 2019

Abstract
ROR1 is a type I membrane-receptor tyrosine kinase with intracellular tyrosine kinase domains and extracellular Frizzled-like cysteine-rich domains (CRDs) and kringle domains, which are common to receptors of members of the Wnt-family. We found that ROR1 might serve as an orphan receptor for Wnt5a, which can activate NF-κB via a non-canonical Wnt-signaling pathway. In prior studies we found that CLL cells expressed ROR1 and high-levels of Wnt3, Wnt5b, Wnt6, Wnt10a, Wnt14, and Wnt16, but not Wnt5a, which is found expressed on dendritic cells and other stromal cells that can support leukemia-cell survival in vitro, and presumably in vivo. As such, we examined whether cells could support the survival of CLL cells in a Wnt5a-dependent manner. For this we cultured CLL cells alone or together with Chinese Hamster Ovary (CHO) cells or CHO transduced to express Wnt5a (CHO-Wnt5a) and monitored the viability of CLL cells over time. We found that the viability of CLL cells co-cultured with CHO cells or CHO-Wnt5a cells was greater than that of CLL cells cultured alone. However the viability of CLL cells co-cultured for two days with CHO-Wnt5a cells (71% ± 18% S.D) was significantly greater than that of CLL cells co-cultured with CHO cells (45% ± 17% S.D) (N=10, P<0.01). The capacity of CHO-Wnt5a to enhance the viability of CLL cells relative to that of CHO cells could be neutralized by anti-ROR1 antisera generated in patients who received autologous CLL cells transduced to express the CD40-ligand (CD154), but not by normal human serum or pre-treatment human serum. CHO cells transduced to express ROR1, but not CHO cells transduced with a control vector, could absorb the capacity of the anti-ROR1 antisera to bind ROR1 and removed its capacity to neutralize the capacity of CHO-Wnt5a cells to provide for a protecive advantage over CHO cells for CLL cell survival in vitro. These studies provide the first evidence that the survival of CLL cells can be enhanced by cells expressing Wnt5a, let alone Wnt factors in general, and might account in part for the enhanced survival of CLL cells in tissue microenvironments containing cells that express Wnt5a. Conceivably, the anti-ROR1 antibodies induced by autologous CLL cells transduced to express CD154, or the administration of antibodies or antagonists that can inhibit Wnt5a-ROR1 signaling, could have therapeutic activity in patients with CLL.
Hospital Readmission within 30 Days: A New Benchmark for Quality Care among Children with Sickle Cell Disease.
Authors: Frei-Jones Melissa J. , DeBaun Michael R. 
Published: October 2019

Abstract
The National Association of Children’s Hospitals and Related Institutions (NACHRI) has established benchmarks for measuring quality of care in children that are hospitalized. Readmission within 30 days of discharge is the benchmark chosen to assess the quality of care for patients with Sickle Cell Disease (SCD). Limited data exist to determine risk factors for re-admission and whether such risk factors are modifiable. We performed a retrospective case-control study to identify risk factors for hospital readmission in children with SCD. All hospital admissions of patients with SCD for one year were reviewed. Cases were defined as children with SCD who were readmitted within 30 days of their first admission during the 12 month study period. Controls were defined as children with SCD who were not readmitted within 30 days of their first admission. A total of 30 cases and 70 controls were identified. The average time between admissions was 10.7 days with 50% readmitted within 8 days and 77% readmitted within 21 days. No difference in demographic data was found between cases and controls. The most common admission and readmission diagnosis was pain, 78% and 70%, respectively. The greatest risk factor for readmission was no follow-up appointment within 30 days after discharge in the SCD clinic (OR 7.7, 95% CI 2.4–24.4). The second highest risk factor was severity of disease, defined as patients with ≥ 3 hospitalizations in the previous 12 months versus patients with ≤ 2 hospitalizations in the previous 12 months (OR 7.3, 95% CI 2.8–18.9). A diagnosis of asthma was also a risk factor for readmission (OR 2.9, 95% CI 1.2–7.3). Patients who initially required supplemental oxygen to maintain their oxygen saturation in the normal range and were subsequently on room air for ≤ 24 hours at discharge were also more likely to be readmitted (OR 3.3, 95% CI 1.1–9.7). Steroid administration was not a risk factor for readmission (OR 1.2, 95% CT 0.5–3.2). Potential modifiable risk factors exist to decrease the rate of readmission. Specifically, strategies targeted at the modification of disease severity, aggressive management of asthma, and outpatient follow-up after hospitalization may decrease the 30 day readmission rate.
Zanolimumab (HuMax-CD4™), a Fully Human Monoclonal Antibody: Efficacy and Safety in Patients with Relapsed or Treatment-Refractory Non-Cutaneous CD4+ T-Cell Lymphoma.
Authors: d’Amore Francesco , Radford John , Jerkeman Mats , Relander Thomas , Tilly Herve , Osterborg Anders , Morschhauser Franck , Gramatzki Martin , Dreyling Martin , Bang Bo , Baadsgaard Ole , Hagberg Hans 
Published: October 2019

Abstract
Combination chemotherapy has been the basis of treatment for peripheral T-cell lymphoma (PTCL) for many years, but relapses are frequent, often rapid and usually associated with a poor outcome. New treatment strategies are therefore required. Zanolimumab is a fully human monoclonal cytotoxic IgG1κ antibody, targeting the CD4 molecule on T-cells. The present open-labeled exploratory clinical trial investigated the efficacy and safety of Zanolimumab in 21 patients with biopsy-proven, treatment-refractory or relapsed CD4+ PTCL of non-cutaneous type. Zanolimumab was administered by i.v. infusion at a dose of 980 mg once weekly for 12 weeks. Patients (11 male, 10 female, median age 69 years) were enrolled with the following diagnoses: enteropathy-associated T-cell lymphoma (n=1), anaplastic large T-cell lymphoma (ALTL, n=4, 3 ALKneg subtype, 1 unknown), angioimmunoblastic T-cell lymphoma (n=9) and PTCL-unspecified (n=7). Patients had received a median of 1 previous treatment (range, 1–5) and 3 had undergone high dose chemotherapy with autologous stem cell rescue. The primary endpoint was objective tumor response. Responses were based on CT scan and clinical examination and classified according to the Cheson criteria. Objective tumor response was obtained in 5 out of 21 patients (23.8%; 95% CI: [8.2; 47.2]). Three patients (1 Anaplastic Large T-cell lymphoma and 2 angioimmunoblastic T-cell lymphoma) obtained a partial response of 43 and 51 days duration, respectively, one had not relapsed after 182 days, no further data available. Two patients (PTCL-unspecified and angioimmunoblastic T-cell lymphoma) obtained a complete response (unconfirmed) of 46 days duration and in the latter no relapse after 252 days was observed. 27 serious AEs were reported of which 6 were assessed as related to Zanolimumab treatment. Four infusion related AEs, one transient thrombocytopenia, one febrile neutropenia in a patient that was neutropenic at trial entry. All patients with serious AEs had complete recovery. Two non-serious grade 3 infusion related AEs were reported and one joint pain. In conclusion, zanolimumab was found to be active and well tolerated in heavily pretreated patients with aggressive PTCL. Zanolimumab in combination with CHOP is now being investigated in the setting of previously untreated patients with nodal T-cell lymphoma.
Preliminary Pharmacokinetic (PK) Analysis of Eastern Cooperative Oncology Group Protocol E4402: Rituximab Extended Schedule or Re-Treatment Trial (RESORT).
Authors: Kahl Brad S. , Williams Michael E. , Hong Fangxin , Gascoyne Randy , Horning Sandra J. 
Published: October 2019

Abstract
Background: E4402 is a randomized phase III study comparing two different rituximab dosing strategies for patients (pt) with low tumor burden, indolent histology non-Hodgkin’s lymphoma. Eligible pt receive rituximab weekly x 4 and responders are randomized to receive either re-treatment at progression or a scheduled dose every 3 months (mo). Each strategy is continued until the development of rituximab resistance with a primary endpoint of time to rituximab failure. Administration of a single rituximab dose every 3 mo was based on PK data derived from the Pivotal trial (ref) that suggested 25 mcg/mL may be an important threshold to maintain response, and a PK study (ref Gordon) that suggested this level could be maintained with a single dose administered every 3 mo.
Methods: Rituximab levels were measured within 30 minutes of completion of the 4th infusion and at 12 weeks (time of response assessment). Pt randomized to re-treatment have trough levels measured at 6 mo, at 1st relapse, and at the first restaging after re-treatment. Pt randomized to scheduled rituximab have trough levels measured at 6 and 12 mo and upon progression. Presented here is an analysis of serum rituximab levels in 159 and 161 follicular lymphoma pt with available data of week 4 and week 12, respectively.
Results: The median level after the 4th infusion is 316 mcg/mL (range 56.4–754.0 mcg/mL). The median level at 12 weeks is 26.9 mcg/mL (range 0.0 -87.7). Fifty-three percent of the patients had levels ≥ 25 mcg/mL at 12 weeks. The median week 4 levels are somewhat lower than the Pivotal trial and a comparison of mean levels indicates a statistically significant difference, (312.9 mcg/mL vs. 450 mcg/mL, p-value < 0.0001). However the week 12 levels are similar (table). No correlation between week 4 and week 12 levels was observed in the 132 follicular lymphoma pt with paired data.
Time N Median (mcg/mL) STD Min (mcg/mL) Max (mcg/mL) E4402 week 4 159 316.0 108.6 56.4 754.0 Pivotal week 4 141 460.7 187.0 115.4 996.6 E4402 week 12 161 26.9 19.6 0.0 87.7 Pivotal week 12 104 20.2 20.8 0.0 96.8
Conclusions: Despite the fact that the E4402 pt are untreated and have a low tumor burden, the week 4 serum drug levels are somewhat lower and the week 12 levels are very similar to the Pivotal trial. The week 4 level is not predictive of the week 12 level. These data suggest that serum levels in nearly half of patients receiving a single rituximab dose every 12 weeks will be below a 25 mcg/mL threshold. Future analysis will correlate week 4 and week 12 levels with initial response to rituximab. Later PK time points will be correlated to the time to rituximab resistance.
R-ESHAP as Salvage Therapy for Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Spanish GEL-TAMO Multicenter Study.
Authors: Martin Alejandro , Conde Eulogio , Arnan Montserrat , Canales Miguel A. , Deben Guillermo , Andreu Rafael , Salar Antonio , Garcia-Sanchez Pedro , Nistal Sara , Requena Maria J. , Donato Eva M. , Gonzalez Jose A. , Leon Angel , Ruiz Concepcion , Grande Carlos , Arranz Reyes , Duran Soledad , Ortegon Sergio , Rodriguez Juan N. , Sandoval Virgilio , Andreu Maria A. , Bernal Teresa , Hernandez Miguel T. , Gonzalez-Barca Eva , Caballero Maria D. 
Published: October 2019

Abstract
The addition of Rituximab to CHOP-like chemotherapy (CT) regimens has improved survival in diffuse large B-cell lymphoma (DLBCL). For this reason, Rituximab is also extensively used in combination with salvage CT regimens, although the information published on this setting is scarce. In the present study, we have analysed a large series of patients (pt) treated with R-ESHAP. 151 pt with relapsed or refractory DLBCL received R-ESHAP (Rituximab, etoposide, cytarabine, cisplatinum and methylprednisolone) as salvage therapy between May 2000 and March 2007. Median age was 54 years (19–70). 22% of pt were refractory to front-line therapy, 19% were partial responders, and 56% had relapsed disease. 56% of pt had received Rituximab in addition to CT as first-line treatment. 15 pt had been treated with autologous stem-cell transplantation (ASCT) prior to R-ESHAP. Patients received a median of 3 cycles of R-ESHAP (1–6). Overall response (OR) rate was 72%, with 69 pt (46%) achieving complete response (CR) and 40 (26%) partial response (PR). Factors with significant influence on CR rates in multivariate analysis were: absence of bulky disease (RR: 3.1), PR to first-line treatment (RR: 3.9) or relapsed disease (RR: 5.8), low-risk IPI (RR: 6.6), and administration of ≥3 cycles (RR: 5). Patients who had received Rituximab prior to R-ESHAP had lower CR (39 vs 54%) and OR (66 vs 80%) rates than patients who had not received it, but the difference did not reach statistical significance. In total, 94 out of 151 pt underwent transplantation after the salvage therapy (91 autologous, and 3 allogeneic). With a median follow-up of 22 months (3–73), the 4-year freedom from treatmet failure (FFTF) and overall survival (OS) were 49% and 48%, respectively. Patients who received Rituximab prior to R-ESHAP had a significantly worse FFTF (26 vs 67% at 4 years) and OS (30 vs 63% at 4 years) as compared with patiens who did not receive it. On multivariate analysis, factors significantly associated with a poor OS were: prior exposure to Rituximab (RR: 2.8), high-risk IPI (RR: 5.2), thrombocytopenia <100x109/l at the time of R-ESHAP (RR: 9.5); and achievement of PR (RR: 6.4) or progressive disease (RR: 17) after R-ESHAP. Our results show the efficacy of R-ESHAP prior to ASCT for refractory or relapsed DLBCL. Although prior exposure to Rituximab was associated with a worse outcome, still a significant number of patients responded to the regimen. Future studies are needed in order to determine which patients will benefit from Rituximab re-treatment.
Outcome of Limited-Stage Peripheral T-Cell Lymphoma: Results from the Nebraska Lymphoma Study Group.
Authors: Bierman Philip , Vose Julie M. , Bociek R. Gregory , Loberiza Fausto , Bast Martin , Weisenburger Dennis D. , Armitage James Olen 
Published: October 2019

Abstract
The outcome of treatment for the majority of patients with peripheral T-cell lymphoma who have advanced-stage disease is worse than similar patients with diffuse large B-cell lymphoma. Patients with limited-stage diffuse large B-cell lymphoma have a good prognosis and are often treated differently than patients with advanced-stage disease. There is little information on results of treatment for patients with limited-stage peripheral T-cell lymphoma. We have performed a retrospective review of patients with limited-stage peripheral T-cell lymphoma who were identified in the database of the Nebraska Lymphoma Study Group. Patients with masses ≥10 cm. and those with B symptoms were excluded. We identified 36 patients with non bulky stage I-A (n=21, 58%) or II-A (n=15, 42%) disease who were diagnosed between and April, 1984 and February, 2006. The median age was 59 (range 18–87) years. There were 20 (56%) males. Histology was classified according to the World Health Organization (WHO) classification. Three patients (8%) had angioimmunoblastic T-cell lymphoma, 25 (69%) had peripheral T-cell lymphoma, unspecified, and 8 (22%) had anaplastic large cell lymphoma. Thirty patients (83%) were treated with anthracycline- or mitoxantrone-based therapy, 5 (14%) were treated with radiation, alone, and 1 (3%) received other chemotherapy. Seventeen patients (47%) were treated with combined chemotherapy and radiation. The median follow-up of surviving patients is 108 (range 12–235) months. The progression-free survival and overall survival are displayed in the figure, below. The actuarial 5-year and 10-year progression-free survival rates are 77% and 63%, respectively. The corresponding values for overall survival are 71% and 56%, respectively. Univariate analysis did not demonstrate significant differences in the risk of treatment failure or death when the influence of histology, stage (I vs. II), and type of treatment (chemotherapy vs. chemotherapy + radiation; <3 cycles of chemotherapy vs. ≥3 cycles) were analyzed, although the numbers in each group were relatively small. Similarly, the outcome was not influenced by age, gender, performance status, LDH level, bulk, or the presence of extranodal disease. These results demonstrate that long-term progression-free survival can be observed for patients with limited-stage peripheral T-cell lymphoma. These results are better than the results of treatment for higher stages of peripheral T-cell lymphoma. Currently available therapy for limited-stage peripheral T-cell lymphoma can achieve results that are close to the results of treatment for limited-stage diffuse large B-cell lymphoma.
Figure Figure