bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erythroid Development in the Absence of Hemoglobin.
Authors: Liu Shan-Run , McConnell Sean C. , Huo Yongliang , Zhang Ting-Ting , Yang Rui , Ulrey Clayton L. , Ryan Thomas M. 
Published: October 2019

Abstract
The mammalian erythrocyte is a highly specialized blood cell that differentiates via an orderly series of committed progenitors in the bone marrow in a process termed erythropoiesis. Homeostasis of the erythron is carefully maintained by balancing the proliferation and destruction of early and late erythroid progenitors. In mature red blood cells over ninety-five percent of the protein is hemoglobin (Hb). What happens to committed erythroid cells in the absence of hemoglobin? To answer this question we have derived a novel line of embryonic stem (ES) cells from mouse embryos that have all eight adult alpha and beta globin genes knocked out. These “Null” Hb ES cells were injected into wild-type blastocysts to examine their in vivo potential to contribute to the tissues of developing chimeric mice. Examination of the peripheral blood and bone marrow of these chimeras by flow cytometry revealed that the “Null” Hb ES cells were able to produce normal levels of each type of white blood cell analyzed. However, “Null” erythrocytes were absent from the circulation and only early committed progenitors were found in the bone marrow. Very few “Null” erythroid cells matured beyond the proerythoblast to the basophilic erythroblast stage (Ter119low, CD71hi). To study this maturational block in more detail, an erythroid culture system was established by in vitro differentiation of the “Null” Hb ES cells. These pure erythroid progenitor (EP) cultures support and amplify the proerythroblast stage of development. Interestingly, EP cells could be derived from “Null” Hb ES cells demonstrating that Hb is not required for the development of proerythroblasts. “Null” derived EP cells express erythroid lineage markers (EKLF, GATA1, GypA, EpoR, Tal1), but express no adult globins or markers of other hematopoietic lineages (Mpl, GATA3, IL7R, PAX5, CEBPα, CD41b). Upon terminal differentiation most “Null” derived EP cells undergo apoptosis by 48 hours (7AAD−, Annexin V+) and are dead (7AAD+) by 72 hours. These “Null” Hb ES cells provide a novel experimental system to elucidate the role of hemoglobin during erythroid differentiation, maturation, and homeostasis.
The IPI Predicts Outcome in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Immunochemotherapy: A Report of the University of Iowa/Mayo Clinic SPORE
Authors: Habermann Thomas M. , Link B.K. , Maurer M.J. , Wooldridge J.E. , Geyer S.M. , Macon W.R. , Allmer C. , Ansell S.M. , Witzig T.E. , Weiner G.J. , Cerhan J.R. 
Published: October 2019

Abstract
The International Prognostic Factor Index (IPI) predicts survival in DLBCL in patients treated with chemotherapy. The Revised IPI (R-IPI) has been reported to be a simpler and more accurate predictor of outcome in patients treated with immunochemotherapy (rituximab and anthracycline-based chemotherapy). We evaluated the predictive value of the IPI and the R-IPI in an observational cohort of unselected patients treated with R-CHOP. Consecutive, newly diagnosed patients age 18 years and older with DLBCL were prospectively offered enrollment into our Lymphoma SPORE Registry. Pathology was centrally reviewed, and composite lymphomas and history of concurrent or prior cancers were excluded. All patients were actively followed for progression free progression (PFS) and overall survival (OS). Here we report on patients enrolled from 9/2002 – 6/2006. 229 patients with a median age of 62 years (range 20–93) were evaluated. 56% were >60 years of age, 16% had a performance score ≥2, 54% had an elevated LDH, 19% had >1 extranodal site, and 51% were stage III/IV. During follow-up, there were 63 progressions (28%) and 45 deaths (20%), and the median follow-up time for living patients was 34 months (range 6–61 months). As shown in the table and figure, the IPI and R-IPI were predictive for both PFS and OS (all p<0.001). The predictive ability of the IPI as measured by 3-year concordance index was stronger for the IPI (0.71) compared to the R-IPI (0.67) and the bootstrap 95% confidence interval for the difference (0.01, 0.08) indicates that this difference was statistically significant. While all factors in the IPI were statistically significant (p<0.05) predictors of OS individually, when included in a multivariate model, an elevated LDH (HR=1.5; p = 0.32) and >1 extranodal sites (HR=1.0; p = 0.96) were no longer significant; similar results were obtained for PFS. The IPI remains a strong predictor of PFS and OS in the immunochemotherapy era.
Figure Figure Group % Pats 3 Y PFS HR 95% CI 3 Y OS HR 95% CI Standard IPI Low (0,1) 41% 87% 1.0 ref 93% 1.0 ref Low-Int (2) 22% 62% 3.1 (1.4, 6.8) 74% 4.2 (1.6, 11.1) High-Int (3) 21% 60% 3.1 (1.4, 6.8) 77% 3.4 (1.2, 9.7) High (4,5) 15% 39% 7.2 (3.4, 15.2) 47% 10.2 (4.0, 26.5) R-IPI Very good (0) 11% 96% 1.0 ref 100% 1.0 ref Good (1,2) 53% 74% 6.2 (0.8, 46.0) 84% - - Poor (3–5) 36% 52% 13.5 (1.8, 98.9) 65% - -
R-HCVAD/R-MTX-ARAC Is an Effective Regimen for Untreated Diffuse Large B-Cell Lymphoma (DLBCL) with Aggressive Features in Patients Younger Than 60 Years
Authors: Fayad Luis , Pro Barbara , Hagemeister Fredrick , Cabanillas Fernando , Samaniego Felipe , McLaughlin Peter , Wang Michael , Neelapu Sattva , Kwak Larry , Romaguera Jorge , Rodriguez Maria A. 
Published: October 2019

Background: R-HCVAD (rituximab-cyclphosphamide, vincristine, dexamethasone, doxorubicin) alternating with R-MTX-ARAC (rituximab, methotrexate-cytarabine) is a chemoimmunotherapy regimen with activity in ALL, mantle cell, and Burkitt’s lymphomas. Histological differentiation between BL. atypical BL, and DLBCL with high-grade features can be difficult. We treated patients with DLBCL with high-grade histological features, and/or poor-risk IPI. Patients who received at least one dose of R-HCVAD were included in this cohort.
Methods: Twenty-seven consecutive patients younger than 60 years, with information collected prospectively in the NCCN database, treated between 7/2002 and 10/05 at M.D. Anderson Cancer Center, 17 (63%) male, 15 (55%) HI and High IPI, 17 (63%) ↑LDH, 14 (52%) with Stage III/IV, 2 (5%) with PS>1, 60% had a Ki-67 higher than 80%.
Results: ORR was of 100% with (95%) CR/CRu. With a median follow-up of 26 months, 2 patients failed: One died of disease, and another received a SCT when the patient was in PR. Four patients have died, three of disease, one of pulmonary embolism. The 3-year OS is 96% (95% CI 77%–100%); 3-year FFS is 86% (95% CI 64%–100%). The 3-year FFS for patients with L/LI risk (2-failures of 12 pts) was 69% and for patients with HI/H age-adjusted IPI (0 failures of 15 pts) 100%.
Conclusions: R-HCVAD/R-MTC-ARAC is a very active regimen for DLBCL. Toxicity was mostly hematological and infectious. We are currently doing a prospective randomized phase II study comparing this regimen to standard R-CHOP in poor risk younger patients.
The Addition of Rituximab to CHOP Chemotherapy Improves Response Rate, Failure-Free Survival and Overall Survival for Follicular Grade 3 Lymphoma Compared to CHOP Alone
Authors: Overman Michael J. , Feng Lei , Pro Barbara , McLaughlin Peter , Hess Mark , Samaniego Felipe , Younes Anas , Romaguera Jorge E. , Hagemeister Frederick B. , Kwak Larry , Cabanillas Fernando , Rodriguez Maria A. , Fayad Luis E. 
Published: October 2019

Abstract
Background: FL3 is a subcategory of follicular lymphomas that is challenging in that it behaves aggressively like large cell lymphomas. If treated with CHOP, however it has a clinical course of relapse and treatment failure similar to grade 1–2 follicular lymphoma. We looked at the outcome of FL3 patients treated with RCHOP, combining rituximab with CHOP. There are no large study reports of this regimen’s results in FL3 to our knowledge.
Patients and Methods: We retrospectively reviewed the records of 45 patients with follicular grade 3 lymphoma who were treated with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) at The University of Texas MD Anderson Cancer Center (UTMDACC). Response rate (RR), failure-free survival (FFS), and overall survival (OS) were estimated and a historical comparison to 111 CHOP only treated patients was made.
Results: The International Prognostic Index (IPI) distribution was: 47% Low, 36% Low-Intermediate, 13% High-intermediate, and 4% High-risk. The complete response rate was 96%. Forty-four out of 45 patients are still alive. Median follow-up is 3.5 years. The 3-year FFS rate according to IPI was 80% (95% CI: 64% to 100%) in low risk, 81% in low-intermediate (95% CI 64% to 100%), and was 50% (95% CI: 25% to 100%) in high-intermediate/high-risk patient group. The addition of rituximab to CHOP improved both 5-year FFS, 71% (95% CI: 58% to 87%) compared to 44% of CHOP alone (95% CI: 36% to 55%) with p-value of 0.019 and 5-year OS, 98% (95% CI: 93% to 100%) compared to 75% (95% CI: 67% to 84) with p-valule of 0.0034. The addition of rituximab to CHOP improve the FFS compared to CHOP alone when subgroups of IPI were analyzed and compared (p=.002)
Conclusion: The addition of rituximab to CHOP provided a high response rate and excellent early survival. Poor risk patients continue to demonstrate a high rate of failure despite the use of rituximab.
The Contact Activation Coagulation Pathway Is Involved in (Recurrent) Coronary Disease.
Authors: Dielis Arne W.J.H. , Govers-Riemslag Jose W.P. , Winkens Mark , Wijers-Holys Patricia , Hamulyak Karly , Spronk Henri M.H. , Waltenberger Johannes , Cate Hugo ten 
Published: October 2019

Abstract
The classic contact activation coagulation system emerges as a potentially important mechanism in arterial thrombosis. Recent studies not only indicate that coagulation factor (F) XII is associated with atherothrombotic coronary disease, but also that it contributes to clot formation via activation of downstream FXI. The time course of contact activation after an acute myocardial infarction (AMI), has not been studied. In addition, its relevance for arterial thrombosis has not been addressed in prospective studies. We measured the plasma concentrations of activated FXII (FXIIa), FXIa and Kallikrein in complex with their natural inhibitors in 135 consecutive patients with a documented first AMI (chest pain between 30 minutes and 24 hours accompanied by ST-segment elevation on ECG and/or elevated plasma levels of creatine kinase and troponin T). FXIIa-C1 inhibitor, kallikrein-C1 inhibitor, FXIa-C1 inhibitor and FXIa-antitrypsin complexes were measured in established homemade ELISAs (Govers-Riemslag et al. J Thromb Haemost2007; 5: 1896–1903). Mean FXIIa-C1 inhibitor complexes were highest on admission (0.081 U/mL) as compared to day 4 (0.065 U/ml), when most patients were still hospitalized and treated with low molecular weight heparin (LMWH) and dual platelet inhibition (aspirin and clopidogrel). At 90 and 180 days after admission mean FXIIa-C1 inhibitor values were 0.064 U/mL, (P<0.05 vs. admission) and 0.067 U/mL, respectively. Except for 1 patient, kallikrein-C1 inhibitor complexes were undetectable at all time points. Mean FXIa-complexes were highest on day 4, in both the FXIa-C1 inhibitor assay (0.64 U/mL) and the FXIa-antitrypsin assay (0.33 U/mL, P<0.01 vs. admission). Mean FXIa-C1 inhibitor complexes decreased to 0.46 and 0.44 U/mL after 90 and 180 days (both P<0.05 vs. day 4), while FXIa-antitrypsin complexes decreased to 0.29 U/mL after 90 and 180 days (both P<0.0001 vs. day 4). Surprisingly, patients with one or more recurrent events (n=15; combined endpoint of death, recurrent MI, stroke, angiographic or percutaneous intervention) during follow-up of 180 days had lower FXIa-C1 inhibitor complexes on admission than those without such events (mean values 0.24 U/mL versus 0.67 U/mL in patients without events; P<0.05). These results indicate that the contact activation coagulation system is activated in atherothrombotic coronary disease. The degree of activation (reflected in FXIa-C1 inhibitor complexes) is inversely related to outcome, which may prognostically indicate that patients with evidence of intrinsic hypercoagulability on admission respond better to subsequent treatment (dual platelet inhibitors plus LMWH) than patients with less pronounced coagulation activity.
Expression of Complement Regulatory Protein CD55 on Tumor Cells Has an Adverse Effect on the Outcome of Follicular Lymphoma Patients Treated with Immunochemotherapy
Authors: Sommarhem Antti , Leppä Sirpa , Karjalainen-Lindsberg Marja-Liisa , Meri Seppo 
Published: October 2019

Abstract
The addition of rituximab to chemotherapy has considerably improved the outcome of follicular lymphoma (FL) patients, but the lengths of remissions are still variable. Activation of the C system has been shown to be an important effector mechanism of rituximab. The aim of this study was to evaluate whether differences in the expression of CD20 and C regulatory molecules (C-REG) in lymphoma cells correlate to the clinical course of FL. We used oligonucleotide microarray analysis to study mRNA levels of CD20, CD46 (MCP), CD55 (DAF) and CD59 (protectin) in the FL tissue of 23 patients treated with R-CHOP. The median follow-up time was 55 months. The patients were divided into long-term (progression free survival (PFS) >35 mo) and short-term (PFS <21 mo) responders, and mRNA levels were compared between the groups. High CD55 expression was observed more often in FL patients who relapsed early resulting in a shorter progression free survival (p=0.027). Median PFS time for patients with a low CD55 level was significantly longer than for those with high CD55 expression (not reached vs. 20 mo, p=0.003). The results were validated prospectively by analyzing the protein levels of CD20 and C-REGs with flow cytometry. The results of a pilot study of 12 FL patients showed that relative expression of CD20 to CD55 in CD20 positive cell population was higher in patients in remission in comparison to ones who relapsed. According to Kaplan-Meier estimates, the patients with low CD20/CD55 and CD20/C-REGave (average C regulator expression) ratios relapsed more often than the other patients. The results suggest that the expression of C regulators, especially of CD55, affects the efficacy of immunochemotherapy, and that C regulatory molecules represent an effective escape mechanism of immunochemotherapy in FL.
The Role of Serial Testing for Heparin/PF4 Antibodies in Evolving HITT: A Unique Phenomenon of Delayed Seroconversion with Thrombosis.
Authors: Sabnani Indu , Cohen Marc , Baran David A. , Tsang Patricia , Arroyo Luis H. , Camacho Margarita , Zucker Mark J. 
Published: October 2019

Abstract
In the appropriate clinical setting, a negative ELISA test for Hep/PF4 antibodies (Ab) has traditionally been considered sufficient to rule out HIT/HITT. We describe a series of 20 cases of HIT/HITT in which the ELISA at the onset of thrombocytopenia was negative despite high (6/8) “4T’s” scores (Thrombocytopenia, Timing of thrombocytopenia in relation to heparin exposure, Thrombosis, and no oTher explanation of thrombocytopenia) but showed strong seroconversion subsequently. This suggests that the negative predictive value of the ELISA test may be too low to definitively exclude HITT. We retrospectively reviewed 494 consecutive Hep/PF4 ELISA assays (sensitivity >90%) performed on 395 patients (pts). Of the 292 pts who tested negative, 73 pts underwent repeat ELISA testing due to the development of a new thrombotic event or the persistence of strong clinical suspicion of HIT/HITT. Twenty of the 73 pts (27%) were observed to have initial negative Hep/PF4 titers (mean = 0.13) at the time of thrombocytopenia but a positive assay (mean = 1.5) on follow-up testing (figure 1 right panel). All 20 pts presented with high “4T’s” scores (6 of 8) at the time of the negative ELISA and had a history of recent heparin exposure. The M:F ratio was 11:9. Eleven pts had prior cardiopulmonary bypass while six had left ventricular assist devices. Fifteen pts (75%) had >50% drop in platelet count (figure 1 left panel). Mean platelet count at the time of negative ELISA was 71x109/l (vs. baseline mean platelet count of 171x109/l) (figure 2). Fourteen of 15 pts (for which data was available) had thrombotic events (9 arterial, 5 venous). Strong seroconversion was seen in all pts (mean = 8 days after initial test) and surprisingly, it accompanied platelet recovery in 15 of 20 pts (figure 1 left panel), with mean platelet count of 136x109/l at the time of the positive ELISA (figure 2). Argatroban was used as a direct thrombin inhibitor (DTI) in 16/20 pts. The prognosis was poor: 10 pts (50%) succumbed with multi-system organ failure.
Conclusion: We have described 20 cases of HIT/HITT with initial negative Hep/PF4 Ab titers at the time of thrombocytopenia, followed by delayed seroconversion. This observation suggests that in the proper clinical setting one isolated negative ELISA result cannot exclude evolving HIT/HITT. Follow-up testing may be informative even as the platelet count begins to recover. As HIT/HITT may have potentially fatal outcome, clinicians should maintain a high degree of suspicion despite a negative serology by ELISA, especially in pts with “4T’s” scores ≥ six. Empiric treatment with DTI’s may be warranted until two consecutive ELISA tests are negative.
Figure Figure Figure Figure
Absolute Lymphocyte Count Is Independent of the Anaplastic Lymphoma Kinase and Predicts Survival in Primary Anaplastic Large Cell Lymphoma.
Authors: Porrata Luis F. , Ristow Kay , Witzig Thomas E. , Haberman Thomas M. , Inwards David J. , Ansell Stephen M. , Micallef Ivana N. , Johnston Patrick B. , Colgan Joseph , White William L. , Markovic Svetomir N. 
Published: October 2019

Abstract
Peripheral blood absolute lymphocyte count (ALC) at diagnosis is a predictor of survival in B-cell lymphomas. The role of ALC at diagnosis on survival in T-cell lymphoma has not been studied. Thus, we studied the role of ALC at diagnosis on clinical outcome in adult patients with primary anaplastic large cell lymphoma (PALCL) that were diagnosed, treated, and followed at the Mayo Clinic, Rochester. Between 1985 and 2006, 50 patients with PALCL qualified for the study. ALC was identified to be a strong predictor for complete response (CR), area under the curve (AUC = 0.83, p < 0.002). The median follow-up was 31.8 months (range: 1–212.6 months). ALC, as a continuous variable was a predictor for overall survival (OS) (HR = 0.143; 95%CI = 0.042–0.416; p < 0.0001) and progression-free survival (PFS) (HR = 0.150; 95%CI = 0.047–0.415; p < 0.0001) .Superior OS and PFS (Figure 1) were observed with an ALC ≥ 1.0 x 109/L (N = 31) versus an ALC < 1.0 x 109/L (N=19) (median OS: not reached vs 7.5 months, OS rates at 5 years, 81% vs 36%, p < 0.0006, respectively; and median PFS: not reached vs 6.3 months; PFS rates at 5 years, 77% vs 37%, p < 0.0007, respectively). Multivariate analysis demonstrated ALC to be an independent prognostic indicator for OS (HR = 0.196; 95%CI = 0.125–0.693; p < 0.002) and PFS (HR = 0.191; 95%CI = 0.053–0.559; p < 0.0008) when compared to anaplastic lymphoma kinase, international prognostic index, and cutaneous versus systemic presentation.
Figure 1 Figure 1.
Generation of Regulatory Dendritic Cells by Administration of Donor Alloantigen in Mouse Transplantation Model.
Authors: Shirasugi Nozomu , Aramaki Osamu , Zhang Qi , Iwami Daiki , Ando Kiyoshi , Niimi Masanori 
Published: October 2019

Abstract
Backgrounds: Various lines of evidence indicate that regulatory cells control peripheral immune responses in self-tolerance and transplantation. Here we show that administration of donor alloantigen via the trachea generated not only CD4+ regulatory cells but also regulatory dendritic cells (DCs) and induced hyporesponsiveness to fully allogeneic grafts in mouse transplantation model.
Methods and Results: CBA mice (H-2k) received administration of C57BL/10 (B10: H-2b) splenocytes via the trachea (intratracheal delivery; ITD). Seven days later, the CBA mice underwent transplantation of B10 hearts. Untreated CBA recipients rejected B10 allografts acutely (median survival time [MST], 8 days). ITD of B10 splenocytes induced prolongation of B10 allograft survival in CBA recipients (MST, 67 days). To determine whether regulatory cells were generated by ITD treatment, adoptive transfer study was conducted. Seven days after CBA mice (primary recipients) were given B10 splenocytes by ITD, splenocytes from the primary recipients were adoptively transferred into naive secondary CBA recipients that underwent B10 cardiac grafting the same day. Secondary CBA recipients given not only whole but also CD4+ splenocytes from ITD-treated CBA mice (primary recipients) 7 days before had significantly prolonged survival of B10 allografts (MST, 78 and 68 days, respectively, compared to those in control secondary CBA recipients with adoptive transfer of naive whole or CD4+ splenocytes, MST, 11 and 13 days, respectively). Interestingly, adoptive transfer of CD11c+ cells from ITD-treated CBA mice also induced prolongation of B10 allograft survival in naïve secondary recipients (MST, 85 days, compared to that in control secondary recipients with adoptive transfer of naive CD11c+ cells, MST, 9 days). These CD11c+ cells produced interleukin (IL)-10 upon activation. Experiments using anti-IL-10 monoclonal antibody revealed that both induction and effector function of the regulatory cells required IL-10.
Conclusion: Our data indicate that ITD of donor alloantigen induced hyporesponsiveness to fully allogeneic grafts, and generated regulatory cells that contained both DCs and CD4+ cells in our model.
C57BL/10 allograft survival in secondary recipients (naive CBA recipients) with adoptive transfer Adoptively transferred cells Adoptively transferred from; Allograft survival (days) ITD: intratracheal delivery of C57BL/10 alloantigen Whole splenocytes (5x107) ITD-treated CBA mice 49, 63, 71, 85, 89, >100 naive CBA mice 8, 8, 9, 13, 14, 18 CD4+ splenocytes (2x107) ITD-treated CBA mice 60, 61, 68 ,69, >100 naive CBA mice 8, 11, 12, 14, 14, 24 CD11c+ cells (1x106) ITD-treated CBA mice 26, 54, 65, 85, 86, 91, >100 naive CBA mice 7, 7, 9, 13,14