bluuebunny/crossref_metadata_2025_split huggingface dataset:
PML Controls PTEN Localization and Function in APL through a Novel Deubiquitination Pathway
Authors: Carracedo Arkaitz , Song MIn-Sup , Salmena Leonardo , Egia Ainara , Lo-Coco Francesco , Teruya-Feldstein Julie , Pandolfi Pier Paolo 
Published: October 2019

Abstract
PML was discovered as a gene frequently involved in the t(15:17) translocation of acute promyelocytic leukemia (APL). Since then, consequences of PML-loss of function in APL and other solid tumors have been extensively studied. Numerous pathways influenced by this tumor suppressor, including the PI3K pathway, have been identified but their importance for the pathogenesis APL is still unclear. We have now discovered that PTEN, the main tumor suppressor opposing PI3K signaling, is aberrantly delocalized to the cytoplasm in APL, but not in AML. Moreover, we show that drugs such as arsenic trioxide and retinoic acid, currently used for the treatment of APL and known to target the oncogenic PML-RARalpha fusion protein, rescue the nuclear localization of PTEN. This discovery has critical biological implications since nuclear localization of PTEN is central to its tumor suppressive activity. Utilizing an APL cell line, genetically engineered cells and transgenic mice, we have delineated the mechanism by which PML sustains nuclear PTEN. PML opposes the activity of a novel PTEN-deubiquitinating enzyme, HAUSP, towards PTEN through a framework involving the adaptor protein DAXX (death domain-associated protein). We demonstrate that PML-RARalpha translocation results in overactive HAUSP and as a consequence, nuclear-excluded PTEN. In support of this notion, we show that HAUSP is overexpressed in human cancer, (e.g. in prostate cancer) which is in turn associated with a nuclear exclusion phenotype of PTEN. Overall our results describe a novel role for PML in the maintenance of PTEN function that is perturbed by oncogenic cues in human leukemia and solid tumors. Significantly, our findings open new avenues for the design of targeted therapies focused on potentiating the activity of the PML-PTEN tumor suppressive network.
Differing Clot Distribution in Black Compared to White Patients Presenting with Acute Lower Extremity Deep Venous Thrombosis
Authors: Buckner Tyler W , Puvvada Soham , Amin Chirag , Key Nigel S. 
Published: October 2019

Abstract
Venous thromboembolism (VTE) is a major cause of morbidity and mortality in the United States. There is growing evidence that VTE incidence and mortality rates differ among ethnic/racial groups. Specifically, it has been demonstrated previously that blacks with VTE have a higher proportional rate of pulmonary embolism (PE), as well as a higher case fatality rate from PE compared to whites (Arch Int Med2003;163(15):1843–8). We therefore compared the location of DVT (proximal vs. distal) in blacks and whites at the time of diagnosis. The null hypothesis was that there is no difference in the location of DVT between white and black patients at the time of diagnosis. We reviewed all lower extremity Doppler ultrasound studies that were positive for acute DVT at our Institution over a 3-year period to create a retrospective case series of 941 patients. Subjects were further classified by self-reported race (black or white), disposition at diagnosis (inpatient or outpatient), and clot location (proximal or distal). Distal DVT was defined as thrombus in one or more deep veins distal to -- but not including -- the popliteal vein. Results were analyzed using Stata version 10. We found that the rate of any proximal (proximal or both proximal and distal) DVT compared with distal only was significantly higher in black patients (OR = 1.4; 95%CI: 1.03, 1.8; P = 0.032), both for 637 inpatients (OR = 1.3; (0.94, 1.9); P = 0.11) and for 304 outpatients (OR = 2.0; (1.01, 3.8); P = 0.048). These differences persisted after controlling for sex and age. We conclude that blacks with acute lower extremity DVT are more likely to present with proximal DVT than whites. These results confirm earlier suggestions that the proportion of proximal lower extremity DVT is higher in blacks, which might account in part for the higher rate of PE (Arch Int Med2004;164(12):1348–9). We are further examining the possible causes of this disparity. Possibilities include genetic factors (such as factor V Leiden which is associated with more distal DVT presentation and is rare in blacks), co-morbid conditions (such as diabetes which is more prevalent in blacks), and access to healthcare and diagnostic services, which may lead to more delayed evaluation. Efforts will also be made to determine rates of idiopathic and provoked DVT in these sub-groups.
Risk of Venous Thromboembolism with Thalidomide in Cancer Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Gray Keriann N , Chu David , Wu Shenhong , Lin Richard Z. 
Published: October 2019

Abstract
Background: Thalidomide, an oral angiogenesis inhibitor with immunomodulatory activity, is effective in the treatment of multiple myeloma, and also undergoing evaluation for other malignancies. The use of thalidomide is associated with significant side effects, including venous thromboembolism (VTE). Currently the overall risk of VTE with thalidomide is not well-defined.
Objective: We conducted a systematic review and meta-analysis of published randomized controlled trials (RCT) to determine the risk of VTE with thalidomide in cancer patients, and assess whether it is affected by anti-thrombosis prophylaxis.
Methods: We searched databases including PUBMED, the Web of Science (January, 1966–July, 2008), and abstracts presented at recent American Society of Clinical Oncology and American Society of Hematology conferences to identify relevant studies. Eligible studies included prospective RCT in which a standard anti-cancer therapy or placebo was employed with or without thalidomide with available data on VTE for analysis. The summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated using a random- or fixed-effects model based on the heterogeneity of the included studies.
Results: From 17 RCTs, a total of 3977 patients with multiple myeloma and a variety of solid tumors (prostate, breast, renal cell, melanoma, ovarian) were included for analysis. The overall incidence of VTE was 11.7% (95% CI: 8.1–16.5%). Patients treated with thalidomide had a significantly increased risk of VTE with a RR of 2.4 (95% CI: 1.9–3.0, p<0.001) when compared to controls. The risk was significantly decreased with prophylaxis from a RR of 3.5 (95%CI: 2.5–4.9, p<0.001) in the absence of prophylaxis to 1.9 (95%CI: 1.4–2.5, p<0.001) in the presence of prophylaxis. The risk of VTE may vary with tumor types; in patients with multiple myeloma, the incidence and RR were 15.7% (95%CI: 10.9–22.1) and 3.1 (95%CI: 2.1–4.5, p<0.001) respectively; while for patients with solid tumors, the incidence and RR were 5.3% (95% CI 2.1–12.8) and 3.5 (95% CI: 1.1–10.6, p=0.028) respectively.
Conclusion: Thalidomide therapy is associated with a significantly increased risk of VTE in cancer patients. The risk varies with anti-thrombosis prophylaxis and tumor type. It is strongly recommended to have surveillance for VTE in all patients receiving thalidomide, and prophylaxis to reduce the risk in patients with multiple myeloma.
Total Tissue Factor Pathway Inhibitor and Incident Venous Thrombosis: The Longitudinal Investigation of Thromboembolism Etiology
Authors: Zakai Neil A , Lutsey Pamela , Folsom Aaron R , Heckbert Susan , Cushman Mary 
Published: October 2019

Abstract
Introduction: Tissue Factor Pathway Inhibitor (TFPI) inhibits tissue factor, a potent coagulation initiator. Limited evidence suggests that low TFPI levels are associated with increased risk of venous thromboembolism (VT).
Methods: VT was ascertained in the Longitudinal Investigation of Thromboembolism Etiology, which combines data from the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Total TFPI was measured in a nested case-control sample. With 12 years of follow-up, 534 cases of new VTE were age-, sex-, and race-frequency matched with 1091 controls. The odds ratio for VT was determined for quartiles of TFPI, and for the bottom 5% versus the top 95% in logistic regression models adjusting for demographics (age, race, gender, study), coagulation factors (Factors VII, VIII, IX, XI, D-dimer), and other VT risk factors. To evaluate for greater than additive interactions we calculated the percent relative excess risk of interaction between TFPI and other VT risk factors.
Results: Mean TFPI in ng/mL (standard deviation) in cases and controls was 36.4 (12.8) and 35.0 (11.1), respectively. Increasing quartiles of TFPI were associated with male gender and increasing age, body mass index, factors VII, VIII, IX, XI, and D-dimer (all p<0.05). TFPI quartiles were not related to ethnicity, factor V Leiden, or the prothrombin gene polymorphism. Compared with those in the upper 95%, those in the bottom 5% of TFPI (32 cases, 56 controls) had an age-, sex-, race-, and cohort-adjusted odds ratio of 1.35 (0.86, 2.12) for VT. Adjusting for factors VII, VIII, IX, XI, and D-dimer increased the odds ratio to 1.93 (1.05, 3.53). Further addition of BMI to the coagulation factor adjusted model slightly attenuated the odds ratio to 1.70 (0.98, 2.93). There were no associations of TFPI in quartiles or as a continuous variable with VT. TFPI in the bottom fifth percentile did not demonstrate greater than additive interaction with factor V Leiden or with higher BMI.
Conclusions: Associations of high TFPI levels with VT were masked by concurrent higher procoagulant levels. After adjusting for procoagulant factors and D-dimer, TFPI ≤ 5% was associated with a 1.9-fold increased odds of VT. These data suggest high total TFPI may be a response to procoagulant states.
Iron Sufficient to Cause Hepatic Fibrosis and Ascites Does Not Cause Cardiac Arrhythmias in the Gerbil
Authors: Kaiser Lana , Davis John , Patterson Jon , Johnson Abby , Bohart George , Schwartz Kenneth A. 
Published: October 2019

Abstract
Chronic iron overload associated with hereditary hemochromatosis or repeated red cell transfusions is known to cause cardiac failure. Cardiac arrhythmias have been incidentally noted in patients with iron overload, but often times dismissed as being caused by other co-morbid conditions. Studies with iron-loaded gerbils suggest a role for iron in the development of cardiac arrhythmias, however these studies utilized short duration recordings of anesthetized gerbils. Furthermore, we were unable to reproduce these loading protocols without significant morbidity and mortality. Our goal was to characterize iron-induced arrhythmias in the chronically instrumented, untethered, telemetered gerbil. Monitored gerbils were divided into 2 groups: iron-loaded (n=23) and control (n=8). Iron loaded gerbils received iron dextran intraperitoneally at a dose of 1.7 (n=4), 3.0 (n=5) or 6.2 (n=14) g/kg; control gerbils received dextran. Gerbils were weighed and given a physical exam weekly. Electrocardiograms were recorded for 10 seconds every 30 minutes for approximately 6 months (DSI Ponehma) and reviewed daily. Quantitative analysis was completed on 6 iron loaded (6.2g/kg) and 3 control gerbils. Heart rate and intervals were calculated and arrhythmias were characterized and counted. Cardiac and hepatic histology and tissue iron concentration were assessed.
All gerbils showed evidence of frequent sinus arrhythmia (more than one episode per hour). However, except for two control gerbils that showed frequent unifocal PVCs, no significant arrhythmias were noted in daily review. There was no difference in heart rate, P duration, PR interval, QRS duration or QT interval between groups. Neither total number of arrhythmias nor arrhythmias per minute were different between groups. One iron-loaded gerbil had a single episode (11 beats) of supraventricular tachycardia. Two iron-loaded gerbils had PVCs, one had only a single beat and the other had 9 unifocal PVCs over the duration of the study. Iron-loaded gerbils rarely showed other arrhythmias One control gerbil had 260 unifocal PVCs over the duration of the study. Other arrhythmias were noted rarely.
Body weight and heart weight was not different between groups, while liver weight increased with increasing iron dose. Cardiac and hepatic iron were significantly increased in iron loaded gerbils when compared to control. Liver weight increased as iron dose increased. Seven of 14 gerbils loaded to 6.2 g/kg developed ascites as assessed both by physical examination and necropsy.
We conclude that an iron load sufficient to cause clinical liver disease does not, in the absence of co-morbid conditions, cause cardiac arrhythmias in the gerbil model of iron overload. This suggests that iron alone is insufficient to cause cardiac arrhythmias.
The GM-CSF Receptor Utilises Members of the Canonical Wnt-Signaling Pathway during Macrophage Differentiation
Authors: Brown Anna , Salerno Diana , Wilkinson Christopher , Perugini Michelle , Kok Chung , Goodall Greg , Solomon Patricia , Gonda Thomas , D’Andrea Richard 
Published: October 2019

Abstract
Over the past several years we have used a factor-dependent murine bi-potential cell line, FDB1, in combination with activated mutants of the GM-CSF receptor common beta subunit (hβc) to dissect receptor pathways and gene expression changes that can contribute to myeloid cell growth and differentiation. Of particular interest are the mechanisms by which signalling from the GM-CSF receptor can promote simultaneous granulocyte and macrophage differentiation. In this context we have characterised differentiation of FDB1 cells in response to an activated hβc mutant (FIΔ). For this mutant, which confers growth factor-independent granulocyte-macrophage differentiation in the FDB1 cell line, the presence of a single intracellular tyrosine residue (Y577) is a requirement for granulocyte differentiation. In the absence of this tyrosine residue FDB1 cells expressing FIΔ undergo uni-lineage macrophage differentiation (Brown et al., 2004). Comparative transcriptional profiling of these FDB1 populations has allowed us to identify gene expression changes associated with receptor-induced granulocyte or macrophage differentiation. An examination of the genes selectively associated with macrophage differentiation revealed a potential role for the transcription factor TCF4/TCF7L2, which is a central mediator of the canonical Wnt signalling pathway through its role as the DNA binding co-factor for β-catenin. Over-expression of TCF4 in FDB1 cells could initiate growth arrest and differentiation, under growth-promoting conditions. In FDB1 cells expressing the FIΔ mutant forced TCF4 expression resulted in an increase in the proportion of cells differentiating to macrophages. Further examination of signalling in the FDB1 FIΔ populations demonstrated that stabilisation of β-catenin is associated with the switch to macrophage differentiation. GM-CSF signalling in FDB1 cells also induces transient β-catenin stabilisation during bi-lineage GM differentiation. In FDB1 cells stabilisation of β-catenin and myeloid differentiation is also induced using the GSK3β inhibitor BIO (6-bromoindirubin-3′-oxime). The results using this unique model of receptor-induced GM differentiation are consistent with a role for the β-catenin pathway in regulating the macrophage lineage.
In Vitro Myelo-Lymphoid Colony Formation by Mouse Hematopoietic Stem Cells
Authors: Ooehara Jun , Takano Hina , Takayanagi Shin-ichiro , Nakauchi Hiromitsu , Ema Hideo 
Published: October 2019

Abstract
Hematopoietic stem cells (HSCs) clonally differentiate into all myeloid, B-lymphoid, and T-lymphoid lineages. Mouse HSCs are known to form in vitro colonies comprised of morphologically identifiable myeloid cells such as neutrophils, macrophages, erythroblasts, and megakaryocytes. Whether HSCs are able to differentiate along B-and T-lymphoid lineages in such colonies remains obscure. The co-culture systems with stromal cells such as S17, OP9, OP9/Delta cells have been shown to support B- and T-cell development. These systems have been used to identify subclasses of progenitors with lymphoid potentials. However, neither B cells nor T cells have been successfully generated from HSCs in vitro. This is most likely due to the lack of culture conditions which support HSCs to differentiate into a certain stage of lymphoid progenitors. In this study, we attempted to use serum-free single-cell culture to identify cytokines which fill the developmental gap between HSCs and lymphoid progenitors. Here we show that myelo-lymphoid colonies are formed by HSCs in the presence of thrombopoietin (TPO), interleukin (IL)-11, or IL-12 together with stem cell factor (SCF). CD34-negative/low, c-Kit-positive, Sca-1-positive, lineage marker-negative (CD34-KSL) bone marrow cells were individually cultured with a combination of cytokines for 7 days. All cells in each colony were transplanted into each from a group of lethally irradiated mice, along with compromised bone marrow cells. The recipient mice were periodically analyzed after transplantation to detect transient myeloid and lymphoid reconstitution. All myeloid, B-, and T-lymphoid progenitor activities were detected in single colonies formed in the presence of SCF+TPO, SCF+IL-11, SCF+IL-12. Only myeloid progenitor activity was predominantly detected in single colonies formed in the presence of SCF+IL-3, consistent with previous observations in blast colony assays. All these combinations of cytokines support self-renewal in HSCs to varying degrees. We conclude that TPO, IL-11, and IL-12 directly act on HSCs and support them to differentiate into progenitors with lymphoid differentiation potential. Early differentiation pathways in HSCs are likely to be used in common by myeloid and lymphoid lineages and be supported in common by multiple cytokines.
CSF-1 Promoter-Driven IL-34 Expression Can Rescue Phenotypes of CSF-1-Deficient Mice
Authors: Wei Suwen , Lin Haishan , Stanley E. Richard 
Published: October 2019

Abstract
Colony Stimulating Factor-1 (CSF-1) is the primary regulator of the survival, proliferation and differentiation of mononuclear phagocytes. All of the effects of CSF-1 are mediated by the high affinity CSF-1 receptor (CSF-1R), a protein tyrosine kinase encoded by the c-fms proto-oncogene. Previous studies have shown that the phenotype of CSF-1 receptor-deficient (Csf1r−/−) mice is more severe than the phenotype of CSF-1-deficient (Csf1op/op) mice. Csf1r−/− mice have a more severe osteopetrosis, fewer osteoclasts, lower survival and fewer tissue macrophages and these differences are more pronounced on single strain backgrounds. This led us to speculate that there may be another ligand for the CSF-1R (Dai et al., Blood99:111–120, 2002; Dai et al., J. Bone Min. Res.19:1441–1451, 2004). This was recently confirmed by the discovery of the novel cytokine Interleukin 34 (IL-34), which specifically binds to the CSF-1R (Lin et al., Science320:807-11, 2008). Like the secreted glycoprotein isoform of CSF-1 (sgpCSF-1), with which it shares no sequence similarity, IL-34 is a dimeric glycoprotein. Like CSF-1, it is broadly expressed in embryonic and adult tissues and it stimulates macrophage colony formation. We hypothesized that there is an incomplete overlap in the expression pattern of IL-34 and CSF-1 in the various cell types in which they are expressed and/or that expression of IL-34 and CSF-1 are differently regulated during mouse development. In transgenes, the CSF-1 promoter and first intron drives normal tissue specific and developmental expression of CSF-1 and such transgenes expressing sgpCSF-1 on the Csf1 op/op background partially rescue defects associated with CSF-1 deficiency (Nandi et al., Blood107:786–795, 2006). Thus one test of this hypothesis is to determine whether expression of IL-34 under the control of the same driver rescues those aspects of the CSF-1-deficient phenotype rescued by sgpCSF-1. We therefore generated the transgenic lines in which the expression of mouse IL-34 is under the control of CSF-1 promoter and first intron. One of these transgenic mouse lines rescued the Csf1op/op deficiences, like similarly-driven sgpCSF-1. These studies indicate that IL-34 can function like sgpCSF-1 in vivo when expressed in a CSF-1-dependent manner.
Effect of Iron Chelators on Cardiac Iron Assessed by MR T2* in Thalassemia Major
Authors: Galanello Renzo , Piga Antonio , Lai Maria- Eliana , Forni Gianluca , Danjou Fabrice , Longo Filomena , Agus Annalisa , Origa Raffaella 
Published: October 2019

Abstract
Introduction: Cardiac iron overload secondary to red blood cell transfusion is a common complication of thalassemia major despite the wide use of chelation therapy and cardiac disease still account for up to 70% of deaths in these patients. Furthermore, myocardial siderosis can be accurately assessed by cardiovascular magnetic resonance (CMR) using T2* sequence. Available chelators seem to have unique profiles of organ iron removal. We report a retrospective analysis of the effect of three available chelators on cardiac iron in patients with thalassemia major.
Methods: Fifty-two patients on subcutaneous desferrioxamine (DFO), 28 on deferiprone (DFP) and 28 on deferasirox (DFX) are included in the study. DFO was administered at a mean dosage of 36 ± 8 mg/kg/d for 10 to 14 hours per day for 21 ± 13 months, DFP at 86 ± 10 mg/kg/d for 23 ± 12 months and DFX at 27 ± 6mg/kg/d for 15 ± 5 months. T2* was measured according to Westwood et al (2005). Entry criteria included in each patient a value of T2* lower than 20 ms at baseline or at final assessment. Left ventricular ejection fraction (LVEF) was measured by echocardiography.
Results: At baseline, the 3 treatment groups did not show any significant difference in age blood consumption and cardiac T2* (DFO group: 13.4 ± 4.5 ms, DFP 13.9 ± 3.7 and DFX 12.8 ± 3.7; p=0.573).. At the last evaluation mean cardiac T2* was slightly increased in patients on DFO (13.9 ± 8.6 ms, p=0.8) and in those on DFX (13.8 ± 4.4 ms, p=0.04), while was substantially increased in patients on DFP (21.7 ± 9.2 ms, p=0.001). To correct for the different duration of treatment we calculated the percentage monthly cardiac T2* changes that were significantly higher in patients on DFP (1,84 ± 1.94), as compared to patients on DFO (0.2 3 ± 2.15) or DFX (0.45 ± 1.49) (p<0.001). No differences were detected between mean LVEF at baseline and at last assessment in all 3 groups.
Conclusions: In this retrospective study monotherapy with deferiprone was significantly more effective than desferrioxamine and deferasirox in alleviating myocardial siderosis in patients with beta-thalassemia major. Further studies are needed to understand if the cardiac T2* changes are influenced by the chelator dosages.