bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ibrutinib for Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Meta-Analysis of Randomized Controlled Trials
Authors: Zhang Shijia , Sanchez Larysa , Liu Jieqi , Chang Victor , Goldberg Stuart L. 
Published: October 2019

Background: Ibrutinib, a Bruton's tyrosine kinase inhibitor, was approved by FDA for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This study aims to evaluate the efficacy and safety data from randomized controlled trials (RCT) of ibrutinib-based therapy in patients with CLL or SLL.
Methods: PubMed, ASH, and ASCO databases (2008-2016) were searched for randomized control trials of ibrutinib therapy (either single-agent or combination) for chronic lymphocytic leukemia or small lymphocytic lymphoma through June 30, 2016. Study endpoints included overall survival (OS), progression-free survival (PFS), and adverse events (AE). Pooled hazard ratios (HR) for survival outcomes and relative risks (RR) for dichotomous data with 95% confidence interval (CI) were calculated with a random effect model using MedCalc.
Results: Four randomized controlled trials (RESONATE-1, RESONATE-2, HELIOS, and CLL12) were identified, but CLL12 trial was excluded from this study since the efficacy data were not available at the time of this meta-analysis. Pooled data from the 3 RCTs (1238 patients) showed that ibrutinib-based therapy improved overall survival (HR 0.419; 95% CI 0.242-0.725, P = 0.002) and progression-free survival (HR 0.201; 95% CI 0.162-0.251, P < 0.001) compared to regimens without ibrutinib. Subgroup analysis showed that the PFS benefits were independent of sex (male: HR 0.188, 95% CI 0.143-0.249, P < 0.001; female: HR 0.225, 95% CI 0.154-0.331, P < 0.001), Rai stage (0-II: HR 0.154, 95% CI 0.109-0.217, P < 0.001; III-IV: HR 0.235, 95% CI 0.167-0.333, P < 0.001), bulky disease (<5 cm: HR 0.219, 95% CI 0.155-0.309, P < 0.001; ≥5 cm: HR 0.179, 95% CI 0.135-0.238, P < 0.001) or chromosome 11q deletion (positive: HR 0.099, 95% CI 0.060-0.163, P < 0.001; negative: HR 0.261, 95% CI 0.212-0.322, P < 0.001). Ibrutinib-based therapy significantly increased the risk of developing all-grade diarrhea (RR = 2.135, 95% CI = 1.437-3.174, p < 0.001), pyrexia (RR = 1.265, 95% CI = 1.011-1.583, p = 0.040), and arthralgia (RR = 1.863, 95% CI = 1.101-3.152, p = 0.020), but not anemia (RR = 0.955, 95% CI = 0.694-1.313, p = 0.777), neutropenia (RR = 1.048, 95% CI = 0.760-1.446, p = 0.774), fatigue (RR = 0.897, 95% CI = 0.746-1.078, p = 0.247), or nausea (RR = 0.951, 95% CI = 0.600-1.506, p = 0.829).
Conclusions: Ibrutinib-based therapy significantly improves OS and PFS (independent of sex, Rai stage, bulky disease or chromosome 11q deletion) in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, but increases the risks of all-grade adverse events including diarrhea, pyrexia, and arthralgia.

Disclosures
Chang: Johnson and Johnson: Other: Stock; Amgen: Other: Research; Boehringer Ingelheim: Other: Research. Goldberg:Neostem: Equity Ownership; Bristol Myers Squibb, Novartis: Speakers Bureau; COTA Inc: Employment; Pfizer: Honoraria; Novartis: Consultancy.
Preliminary Detection of Leukemia with Blood By a Novel Electrochemical Method
Authors: Wang Yujie , Chen Baoan , Ge Zheng 
Published: October 2019

Abstract
Information
A simple, novel and fast electrochemical method was applied for clinical diagnosis of leukemia. Blood samples of leukemia patients were identified by screen-printed electrodes with potassium ferricyanide (III) probes. Our study successfully developed and raised the possibility of utilizing the electrodes in the identification and diagnosis of leukemia.
Background
Accurate preliminary detection of leukemia is vital for timely and suitable chemotherapy and clinical outcomes of patients. Electrochemical methods have been widely used in cytobiology, including identification of leukemia cells. In the present study, we creatively applied the use of an electrochemical method to the analysis of human blood samples. The aim of this study was to identify leukemia, breast cancer, respiratory infection and healthy individuals by detecting the electrochemical characteristics of leukocytes in the peripheral blood of patients with a screen-printed electrode. This method might be effectively used in the preliminary screening of leukemia.
Methods
A total of 99 blood samples obtained from Zhongda hospital in China (May 2016 - July 2016) were divided into four groups: healthy individuals (n = 25), respiratory infection (n=23), leukemia (n = 29) and breast cancer (n = 22). We used probes to distinguish leukocytes of people's blood from different samples immediately due to the different electrochemical behaviors of leukocytes. A screen-printed electrode was used to measure differential pulse voltammetry by a potassium ferricyanide (III) probe combined with a simple bio-sensor system. Then, one-way analysis of variance (ANOVA) method was applied to analyze the scanning curves and peak potential and peak shifts were compared (ΔEp).
Results
The scanning curves demonstrated the specific electrochemical behaviors of the blank potassium ferricyanide solution and which mixed with different samples in different groups. Significant differences in mean peak potentials were observed over the four groups (P< = 0.001). 105.00±8.02mV, 111.84±9.53mV, 120.90±11.18mV, 132.84±11.53mV for Group healthy, Group respiratory infection, Group leukemia, and Group breast cancer, respectively. Meanwhile, there were 4.67±3.14mV, 10.91±5.81mV,20.42±8.50mV, 33.42±10.05mV in peak shifts for above four groups respectively.
Conclusions
Using the screen-printed electrode to identify cancer was a novel method with good sensitivity and specificity. It might be effective and had a potential utility in the preliminary screening of leukemia.

Disclosures
No relevant conflicts of interest to declare.
Global Increase in Replication Fork Speed during a p57KIP2-Regulated Erythroid Cell Fate Switch
Authors: Hwang Yung , Futran Melinda , Hidalgo Daniel , Ramalingam Iyer Divya , Rhind Nicholas , Socolovsky Merav 
Published: October 2019

Abstract
Cell cycle regulators are increasingly implicated in cell fate decisions such as the acquisition or loss of pluripotency and self-renewal potential. The cell cycle mechanisms that regulate these cell fate decisions are largely unknown. Here we studied an S phase- dependent cell fate switch in the erythroid fetal liver, in which murine early erythroid progenitors transition in vivo from a self-renewal state into a phase of active erythroid gene transcription and concurrent maturational cell divisions. In the fetal liver, this transition corresponds to the transition from subset S0 (CD71-low, Ter119-negative) to subset S1 (CD71-high, Ter119-negative). We found that the S0 to S1 transition takes place during an S phase that is abruptly shorter (decreasing from 7 hours to 4 hours). Further, self-renewing S0 cells uniquely express the cyclin-dependent kinase (CDK) inhibitor p57KIP2 during S phase. To investigate its potential role, we studied DNA replication in vitro and in vivo in p57KIP2 -deficient fetal liver progenitors, employing a variety of techniques, including DNA combing. We found that S0 erythroid progenitors are dependent on p57KIP2-mediated slowing of replication forks for self-renewal, either in vivo, or in dexamethasone-dependent expansion cultures in vitro. The switch from self-renewal in S0 to differentiation in wild-type S1 progenitors entails rapid downregulation of p57KIP2 with a consequent global increase in replication fork speed and an abruptly shorter S phase. In the absence of p57KIP2, replication fork processivity increases prematurely in self-renewing S0 cells, prior to the activation of the erythroid transcriptional program (Figure 1), resulting in replicative stress and cell death.
It is well established that differentiation leads to reprogramming of DNA replication, reflected by changes to origin usage and to the timing of replication of chromatin domains. Here we find that the replication program is fundamentally altered in additional key respects: the global processivity of replication forks, regulated by CDK activity, increases abruptly with the switch from self-renewal to differentiation, affecting DNA synthesis rates and S phase duration. Our results are also of interest since the regulation of replication kinetics was thought to be primarily via the regulation of origin firing efficiency, rather than via fork processivity. Here we found no difference in the former (there was no significant change in inter-origin distances, Figure 1). While the full significance of faster forks to the activation of the erythroid transcriptional program is yet to be understood, a recent report found that T cell help leads to faster forks and a shorter S phase in B cells (Gitlin et al., Science 349, 643-646 2015). Regulation of global fork speed may therefore be an intrinsic part of physiological developmental programs.

Disclosures
No relevant conflicts of interest to declare.
Pleckstrin-2 Plays an Essential Role in the Pathogenesis of JAK2V617F-Induced Myeloproliferative Neoplasms
Authors: Zhao Baobing , Mei Yang , Sumagin Ronen , Yang Jing , Thorsheim Chelsea , Zhao Liang , Stalker Timothy J. , Wen Jeremy Q. , Crispino John , Abrams Charles S. , Ji Peng 
Published: October 2019

Abstract
V617F driver mutation of JAK2 is the leading cause of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs). Studies on the pathogenesis of JAK2V617F positive MPNs have primarily focused on deregulation of JAK2 and STAT activities. It remains unclear exactly how JAK2-STAT downstream targets are involved in the development of the MPNs. We previously reported that pleckstrin-2 (Plek2) plays an important role in terminal erythropoiesis in vitro. Here we show that Plek2 is a downstream target of the JAK2-STAT5 pathway in erythroid, megakaryocytic, and granulocytic cells. Plek2 is significantly upregulated by JAK2V617F in both transduced primary mouse hematopoietic cells and in patients with JAK2V617F positive MPNs. Using a JAK2V617F knockin mouse model, we demonstrated that loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes including reticulocytosis, thrombocytosis, neutrophilia, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality of JAK2V617F knockin mice (Figure 1A). These phenotypes were also transplantable indicating the role of Plek2 in mediating the pathogenesis of JAK2V617F-induced MPNs is cell-intrinsic (Figure 1B). Our study identifies Plek2 as a novel effector of JAK2-STAT5 pathway and a key factor in the pathogenesis of JAK2V617F-induced MPNs.
Figure 1. Loss of Plek2 Rescues The Lethality of JAK2V617F Knockin Mice. (A) Kaplan-Meier survival analysis of indicated mice. Both males and females were included in each group. JAK2+/+Plek2+/+mice, n=34; JAK2+/+Plek2-/-mice, n=34;JAK2VF/+Plek2+/+ mice, n=36; JAK2VF/+Plek2-/- mice, n=36. (B) Kaplan-Meier survival analysis of the transplanted mice. JAK2+/+Plek2+/+mice, n=10; JAK2+/+Plek2-/-mice, n=10;JAK2VF/+Plek2+/+ mice, n=17; JAK2VF/+Plek2-/- mice, n=17. Figure 1. Loss of Plek2 Rescues The Lethality of JAK2V617F Knockin Mice. (A) Kaplan-Meier survival analysis of indicated mice. Both males and females were included in each group. JAK2+/+Plek2+/+mice, n=34; JAK2+/+Plek2-/-mice, n=34;JAK2VF/+Plek2+/+ mice, n=36; JAK2VF/+Plek2-/- mice, n=36. (B) Kaplan-Meier survival analysis of the transplanted mice. JAK2+/+Plek2+/+mice, n=10; JAK2+/+Plek2-/-mice, n=10;JAK2VF/+Plek2+/+ mice, n=17; JAK2VF/+Plek2-/- mice, n=17.

Disclosures
No relevant conflicts of interest to declare.
Defining Cellular States, Differentiation Trajectories, and Regulatory Networks Through Single Cell Profiling
Authors: Gottgens Bertie 
Published: October 2019

Abstract
Transcription factor proteins have long been recognized as key regulators of blood stem cell function. They are thought to act as components of wider regulatory networks, with combinatorial interactions responsible for directing blood stem cell fate choices. However, the complexity of these networks coupled with the infrequency of stem cells have presented formidable challenges for past research efforts aiming to define blood stem cell regulatory networks. Importantly, recent innovations in single cell genomics and computational network inference technologies offer new opportunities to better understand the regulatory network control of blood cell development. The Göttgens group uses a combination of experimental and computational approaches to study how transcription factor networks control the function of blood stem cells and how mutations that perturb such networks cause leukemia. This integrated approach has resulted in the discovery of new combinatorial interactions between key blood stem cell regulators, as well as experimentally validated computational models for blood stem cells. Current research focuses on single cell genomics of early blood development and the development of computer models to chart the transcriptional landscape of blood stem and progenitor cell differentiation.

Disclosures
No relevant conflicts of interest to declare.
The Mitochondrial Metabolic Checkpoint and Reversing Stem Cell Aging
Authors: Chen Danica 
Published: October 2019

Abstract
Cell cycle checkpoints are surveillance mechanisms in eukaryotic cells that monitor the condition of the cell, repair cellular damages, and allow the cell to progress through the various phases of the cell cycle when conditions become favorable. Recent advances in hematopoietic stem cell (HSC) biology highlight a mitochondrial metabolic checkpoint that is essential for HSCs to return to the quiescent state. As quiescent HSCs enter the cell cycle, mitochondrial biogenesis is induced, which is associated with increased mitochondrial protein folding stress and mitochondrial oxidative stress. Mitochondrial unfolded protein response and mitochondrial oxidative stress response are activated to alleviate stresses and allow HSCs to exit the cell cycle and return to quiescence. Other mitochondrial maintenance mechanisms include mitophagy and asymmetric segregation of aged mitochondria. Because loss of HSC quiescence results in the depletion of the HSC pool and compromised tissue regeneration, deciphering the molecular mechanisms that regulate the mitochondrial metabolic checkpoint in HSCs will increase our understanding of hematopoiesis and how it becomes dysregulated under pathological conditions and during aging. More broadly, this knowledge is instrumental for understanding the maintenance of cells that convert between quiescence and proliferation to support their physiological functions.

Disclosures
No relevant conflicts of interest to declare.
Regulation and Impact of Chromatin Decondensation in Mammalian Cells
Authors: Casellas Rafael 
Published: October 2019

Abstract
50 years ago Vincent Allfrey and colleagues discovered that lymphocyte activation promotes histone acetylation and gene expression. Recent studies clarified that G0 B cells proportionally amplify their transcriptome upon stimulation by a mechanism that involves Myc and TFIIH. We now show that B cell chromatin undergoes massive decondensation by the amplification of histone acetylation, methylation, and nucleosome remodeling. Super-resolution microscopy revealed that histone acetylation triggers rapid spreading of chromatin nanodomains from the periphery to the entire nucleus. Furthermore, nanodomains decompact into single nucleosome fibers by a process that requires Myc and ATP production. Using single molecule tracking, we show that chromatin decompaction increases the dynamics of transcription factor binding. Architecturally, B cell activation mediates a marked shift from long-range to short-range interactions and the formation of loops and contact domains that facilitate interaction between cognate regulatory elements. The data thus reveal the epigenetic and topological features that support transcriptome amplification, and help explain the primed nature of B cells.

Disclosures
No relevant conflicts of interest to declare.
Thrombocythemia and Pulmonary Intra-Alveolar Coagulum in a Young Woman
Authors: LEVINSON B. , JONES R. S. , WINTROBE M. M. , CARTWRIGHT G. E. 
Published: October 2019

Abstract
A description is given of the clinical course and findings at autopsy in a 19-year-old girl with a myeloproliferative syndrome characterized primarily by thrombocythemia. This was associated with an unusual pulmonary disorder in which the alveoli were filled by a non-cellular exudate comprised of carbohydrate, fat and protein which resembled in some respects pneumonia attributed to Pneumocystis carinii. The possible interrelationship of the thrombocythemia and the intra-alveolar coagulum is discussed.
A Comparative Study of Two Regimens of Combination Chemotherapy in Acute Leukemia
Authors: FREI EMIL , HOLLAND JAMES F. , SCHNEIDERMAN MARVIN A. , PINKEL DONALD , SELKIRK GEORGE , FREIREICH EMIL J. , SILVER RICHARD T. , GOLD G. LENNARD , REGELSON WILLIAM 
Published: October 2019

Abstract
A comparative clinical trial of two regimens of combination chemotherapy has been accomplished in acute leukemia by four separate medical and pediatric services. Sixty-five patients were allocated at random to one of two treatment programs. Daily administration of methotrexate with daily 6-mercaptopurine has been compared to methotrexate every third day in the same total dose with daily 6-mercaptopurine.
No difference in frequency of remission, extent of remission or toxicity was observed between the two groups. Among those patients who attained remission status, however, duration of remission (P = .05-.10) and of survival (P = <.05) was longer for the continuous group.
All remissions in children occurred in acute lymphocytic leukemia, whereas all remission in adults were observed in acute myelocytic leukemia. The duration of remissions was somewhat shorter for children with acute lymphocytic leukemia than for adults with acute myelocytic leukemia. The frequency of remission, either partial or complete, was higher in children, however (36 per cent), than in adults (19 per cent), although the confidence limits for each figure overlap.
The duration of acute leukemia in previously untreated patients did not influence response to therapy from the two antimetabolite regimens in this study. In patients who had had prior antimetabolite therapy, however, complete remissions were attained less often than in previously untreated patients.
The toxic manifestations encountered during the administration of these antimetabolites are described. Seventeen deaths occurred during this study, of which 8 occurred in the first 10 days, presumably from leukemia and not drug toxicity. Five patients died with hypoplastic marrows ascribed to drug toxicity.
The toxic manifestations were qualitatively and proportionately the same in patients who attained remission status, and in those patients who failed to remit, but who lived long enough to recognize the onset of remission if it were going to occur. No indication was obtained, therefore, that patients who attained remission were subjected to a greater toxic hazard, in order to achieve the therapeutic benefits observed, than those who did not remit.
The median survival of patients who achieved remission was longer (p <.05) than for patients who did not remit. Since the survival time of remitters from relapse to death was almost identical with the survival time of nonremitters from onset of treatment to death, this difference can be accounted for by the time spent in remission and getting to remission.
The median survival time from symptomatic onset for all children in this study was 12 months, and for adults, 7 months. The median in children is similar to that reported from other clinics. This is evidence that a comparative therapeutic trial in acute leukemia can be accomplished without recognizable compromise of patient welfare.
The Nature and Significance of Megaloblastic Blood Formation
Authors: REISNER EDWARD H. 
Published: October 2019

Abstract
Evidence is presented for a hypothesis that megaloblasts are red blood cell precursors with a prolonged resting phase between mitoses, allowing a longer time for dispersion of the chromatin throughout the nucleus. Anything that retards the rate of cell division can produce cells of similar appearance, but the conditions most conducive to megaloblastic blood formation are states in which vitamin B12 or folic acid are deficient. These two substances function in the synthesis of nucleoproteins as co-enzymes or their precursors concerned with the transfer of one-carbon units. In their absence the synthesis of the extra amounts of deoxyribonucleic acid essential for mitosis can go on but slowly, and the marrow becomes crowded with cells waiting to divide.
The principle source of the extra DNA is cytoplasmic RNA which appears to supply the ribonucleotide precursors of several deoxyribose containing compounds. Most important among these is deoxyuridylic acid which is methylated to form thymidylic acid. The failure of these reactions to occur in the absence of the essential co-enzymes leads to a persistence of RNA in the megaloblastic cytoplasm during the maturation phase, and this is probably responsible for their development into macrocytes.
This hypothesis accounts for the occasional presence of megaloblasts in conditions other than pernicious and related deficiency anemias and the occurrence of "macronormoblastic" or "megaloblastoid" marrows in intrauterine life and liver disease. The hypothesis also explains the rapid replacement of megaloblasts by normoblasts in the marrow following specific therapy.
Sickle Cell—Thalassemia Disease in Jamaica
Authors: MACIVER J. E. , WENT L. N. , CHUICKSHANK E. K. 
Published: October 2019

Abstract
Two cases of sickle cell—thalassemia disease are described in young women of mixed Chinese and African parentage. On hemoglobin electrophoresis, a complete suppression of hemoglobin A was found, giving a picture indistinguishable from that seen in sickle cell anemia. The findings in these two cases are contrasted with those in other examples of this disease which we have studied in Jamaica. The importance of these findings in relation to the diagnosis of sickle cell anemia is discussed.
A Circulating Inhibitor (Anti-AcG) Specific for the Labile Factor-V of the Blood-Clotting Mechanism
Authors: FERGUSON JOHN H. , JOHNSTON CHARLES L. , HOWELL DORIS A. 
Published: October 2019

Abstract
Study of the present hemorrhagic disorder establishes, without doubt, the presence of a powerful specific anti-AcG. The deprivation of AcG due to this inhibitor confirms the view that the labile factor plays a key role in the blood clotting system in at least two phases, namely, (1) during thromboplastin generation, and (2) later, during the conversion of prothrombin to thrombin. AcG is an essential component of many special clotting-test systems.
An Unusual Type of Hemoglobinopathy Resembling Sickle Cell-Thalassemia Disease in a Jamaican Family
Authors: WENT L. N. , MACIVER J. E. 
Published: October 2019

Abstract
Three generations of a Jamaican family of African extraction are described, in several members of which an abnormal gene is carried. This gene produces high levels of fetal hemoglobin unassociated with the usual stigmata of thalassemia. It is found in all three generations of the family associated with hemoglobin A only and is also found in at least two members of the family interacting with hemoglobin S. In the latter combination little or no disability results.
The mode of inheritance of this abnormal gene is discussed, and reasons are put forward for a possible protective effect of high fetal hemoglobin levels due to inhibition of sickling.
The findings in the cord blood of the youngest child, including an unusually high percentage of sickling, are discussed, together with follow-up studies to the age of 25 weeks.