bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kpm/Lats2 of the Hippo Pathway Is Linked to Chemo-Sensitivity of Leukemic Cells.
Authors: Kawahara Masahiro , Hori Toshiyuki , Chonabayashi Kazuhisa , Oka Tsutomu , Sudol Marius , Uchiyama Takashi 
Published: April 2020

Abstract
The Hippo pathway is now recognized as a major signaling network for development and organ size control in mammals as well as in Drosophila melanogaster. We previously identified human kpm/Lats2, the key serine/threonine kinase in the Hippo pathway, and reported that its overexpression induced cell cycle arrest and apoptosis. Down-regulation of kpm/Lats2 expression has been described in various malignancies. It is of particular importance in hematology that low expression of kpm/Lats2 has been reported to be associated with poor prognosis in acute lymphoblastic leukemia. In the present study, we first measured the expression level of kpm/Lats2 mRNA in various hematological malignancies and found that it was markedly decreased in adult T cell leukemia (ATL) and NK cell leukemia/lymphoma, both of which are known to be highly resistant to conventional chemotherapy. In order to investigate the relationship between down-regulation of kpm/Lats2 expression and chemo-resistance, we made kpm/Lats2-knockdown sublines from KG-1a, an AML-derived cell line, and ED-40515+, an ATL-derived cell line, by using shRNA-expression retrovirus vector targeting kpm/Lats2. Silencing of kpm/Lats2 expression in both leukemic cell lines did not change the rate of cell growth but rendered them resistant to DNA damage-inducing agents such as DOX and ETP. Expression of p21 and PUMA was strongly induced by these agents in control cells, despite defective p53, but was only slightly induced in kpm/Lats2-knockdown cells. DNA damage-induced nuclear accumulation of p73, a member of p53 family, was clearly observed in control cells but hardly detected in kpm/Lats2-knockdown cells. ChIP assay showed that p73 was recruited to the puma gene promoter in control cells but not in kpm/Lats2-knockdown cells after DNA damage stress. The analyses with transient co-expression of Kpm/Lats2, YAP2, and p73 showed that Kpm/Lats2 contributed to the stability of YAP2 and p73, which was dependent on the kinase function of Kpm/Lats2 and YAP2 phosphorylation at serine 127. These results strongly suggest that Kpm/Lats2 is involved in the fate of p73 and the induction of p73-target genes that underlie chemo-sensitivity of leukemic cells.
Latexin: A Potential Tumor Suppressor.
Authors: Liang Ying , Van Zant Gary 
Published: April 2020

Abstract
We recently found that latexin is a negative regulator of the size of the hematopoietic stem cell population in mice. It acts by increasing apoptosis and decreasing cell proliferation. This 29 kD protein bears a strong structural resemblance to tazarotene-induced gene 1 (TIG1), a tumor suppressor down-regulated in a variety of cancers. The structural similarity and close genetic linkage led us to hypothesize that latexin also may have tumor suppressor properties. We found that latexin was down-regulated in a variety of human leukemias and lymphomas as determined by a survey of malignant cell lines and by analysis of CD34+ cells isolated from the blood and marrow of patients diagnosed with these malignancies and presenting with very high white cell counts. Bisulfite sequencing revealed that methylation of CpG dinucleotides in the latexin promoter at least partially accounted for latexin down-regulation. 5-aza-deoxycytidine treatment reinitiated or significantly increased latexin expression in K562, Molt4, CRF-CEM, Jurkat, U937, HL60, KG-1, and Sup B15 cell lines. To test the hypothesis that ectopic latexin expression in tumor cells would inhibit their growth, we developed a retrovirus-based expression vector with which we infected the murine lymphoma cell lines, WEHI231 and A20, neither of which contained significant latexin levels by Western blot. A vector containing GFP, but not latexin, was used to infect control cells. In triplicate experiments, the growth of both cell lines in vitro was inhibited an average 48% by infection with the latexin vector. Western blots revealed that latexin was durably expressed throughout the 2-week culture period at 2- to 4-fold the level expressed in normal T and B cells. As we found in our normal stem cell studies, latexin caused growth inhibition of lymphoma cells by significantly increasing apoptosis by 6-fold, and by suppressing cell proliferation by 2-fold. To test whether tumor inhibition extended to lymphomas in vivo, we injected either control or latexin vector-infected A20 cells subcutaneously in the flanks of BALB/c mice. Three weeks following adoptive transfer of identical numbers of cells, in duplicate experiments the latexin-expressing cells developed tumors only half the volume of those caused by the control cells. These results are consistent with a tumor suppressor role for latexin and suggest that latexin, or molecular mimics thereof, may have clinical efficacy in the treatment of malignancies.
VIDAS D-Dimer in Combination with Clinical Pre-Test Probability to Rule out Pulmonary Embolism. A Systematic Review of the Management Outcome Studies.
Authors: Carrier Marc , Righini Marc , Djurabi Reza Karami , Huisman Menno , Perrier Arnaud , Wells Philip , Wuillemin Walter , Le Gal Gregoire 
Published: April 2020

Abstract
Background: Clinical outcome studies have shown that it is safe to withhold anticoagulant therapy in patients with suspected pulmonary embolism (PE) who have a negative D-dimer result and a low pre-test probability (PTP) either using a PTP model or clinical gestalt.
Purpose: To assess the safety of the combination of a non-high PTP using the Wells or Geneva models with a negative VIDAS© D-dimer result to exclude PE.
Data Source: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews.
Study Selection: Seven studies (6 prospective management studies and 1 randomized controlled trial) reporting failure rates at three months were included in the analysis. Non-high PTP was defined has “unlikely” or “low/intermediate” PTP using either, the Wells’ score, the Geneva, Revised Geneva Score, or gestalt estimation.
Data extraction: Two reviewers independently extracted data onto standardized forms.
Data Synthesis: A total of 5,622 patients with non-high PTP were assessed using the VIDAS© D-dimer. PE was ruled out by a negative VIDAS© D-dimer test in 40% (95% confidence intervals (CI) 38.7 to 41.2%) of patients. The three-month thromboembolic risk in patients left untreated was 0.14% (95% CI 0.05 to 0.4%).
Table 1. Accuracy Indices
Total non-high PTP and negative VIDAS© D-Dimer Wells’ “unlikely” PTP and negative VIDAS© D-dimer Geneva* “low/intermediate” and negative VIDAS© D-dimer Number of patients 5,622 2,017 3,208 Sensitivity (%, 95% CI) 99.7 (99.0– 99.9) 98.7 (96.2– 99.6) 100.0 (99.4–100) Specificity (%, 95% CI) 47.4 (46.0– 48.9) 57.3 (55.0– 59.6) 40.8 (38.9– 42.7) NPV (%, 95% CI) 99.9 (99.6– 100) 99.7 (99.1– 99.9) 100.0 (99.6– 100)
Conclusion: The combination of a non-high PTP with a negative VIDAS© D-dimer result, effectively and safely exclude PE in an important proportion of outpatients with suspected PE.
The Relationship Between D-Dimer Level, Venous Valvular Reflux and Development of the Post-Thrombotic Syndrome after Deep Venous Thrombosis.
Authors: Latella Jennifer , Desmarais Sylvie , Kahn Susan ,   Veto Investigators
Published: April 2020

Abstract
Background: The pathophysiology of the post-thrombotic syndrome (PTS) is postulated to involve persistent venous thrombosis and valvular reflux. We prospectively studied if d-dimer levels or valvular reflux were associated with subsequent development of the PTS after objectively confirmed deep venous thrombosis (DVT).
Methods: Consecutive patients with objectively diagnosed acute symptomatic DVT were recruited at 8 hospital centres in Quebec and Ontario, Canada. Patients attended study visits at Baseline, 1, 4, 8, 12, and 24 months. Blood was taken to measure d-dimer (VIDAS d-dimer; cut off &lt;500 ug/L) at the 4 month visit. A standardized ultrasound assessment for popliteal venous valvular reflux was performed at the 12 month visit. Standardized assessments for PTS (using Villalta scale) were performed at each follow-up visit. Subjects were classified as having developed PTS if the ipsilateral Villalta score was &gt;5 on at least 2 visits starting at the 4 month visit or later or was &gt;5 at the final follow-up visit. Statistical analyses assessed associations between d-dimer level, ipsilateral reflux and PTS.
Results: 387 patients were recruited and followed. Mean age was 56 years and 51% were male. PTS developed in 45% of patients. Mean d-dimer was significantly higher in patients who developed PTS compared with those who did not (712.0 vs. 444.0 ug/L; p= 0.02). In logistic regression analyses adjusted for age and warfarin use at the time of d-dimer determination, d-dimer levels significantly predicted PTS (p=0.03). Ipsilateral venous valvular reflux was more frequent in patients with moderate/severe PTS than in patients with no PTS or mild PTS (65% vs. 40% vs. 43%, respectively; p=0.013). Finally, mean d-dimer was higher in patients who developed recurrent VTE during follow-up (n=31) than in those who did not (1126.8 vs. 514.9 ug/L; p=0.05), and d-dimer was an independent predictor of recurrent VTE (p=0.04) after adjustment for other known predictors of recurrence.
Conclusion: D-dimer levels measured 4 months after DVT are associated with subsequent development of PTS and are predictive of VTE recurrence. Venous valvular reflux was associated with moderate/severe PTS. Further studies are required to assess whether d-dimer or valvular reflux may be useful in determining which patients are most at risk of developing PTS or severe PTS and who may thus benefit from preventive strategies.
R93W Mutation in Orai1 Causes Impaired Calcium Influx in Platelets.
Authors: Bergmeier Wolfgang , Oh-hora Masatsugu , McCarl Christie-Ann , Roden R. Claire , Bray Paul F. , Feske Stefan 
Published: April 2020

Abstract
The intracellular Ca2+ concentration of non-excitable cells is regulated by calcium store release and store-operated calcium entry (SOCE). In platelets, STIM1 was recently identified as the main calcium sensor expressed in the endoplasmatic reticulum. To evaluate the role of the SOC channel moiety, Orai1, in platelet SOCE, we generated mice expressing a mutated, inactive form of Orai1 in blood cells only (Orai1R93W). Platelets expressing Orai1R93W were characterized by markedly reduced SOCE and impaired agonist-induced increases in [Ca2+]i. Orai1R93W platelets showed reduced integrin activation and impaired degranulation when stimulated with low agonist concentrations under static conditions. This defect, however, did not significantly affect the ability of Orai1R93W platelets to aggregate or to adhere to collagen under arterial flow conditions ex vivo. In contrast, these adherent Orai1R93W platelets were defective in surface phosphatidylserine exposure, suggesting that Orai1 is crucial for the platelets pro-coagulant response rather than for other Ca2+-dependent cellular responses.
Determinants for Iron Overload-Related Disease in Siblings of Probands with Clinically Detected HFE Hereditary Hemochromatosis: The Hemochromatosis Family Study.
Authors: Jacobs Esther M.G. , Hendriks Jan C.M. , Kreeftenberg Herman G. , de Vries Richard A. , Marx Joannes J.M. , van Deursen Cees Th. B. M. , Stalenhoef Anton F.H. , Verbeek Andre L.M. , Swinkels Dorine W. 
Published: April 2020

Abstract
The clinical expression of HFE-associated hereditary hemochromatosis (HH) gen is highly variable and may be influenced by nongenetic factors and coinherited genetic modifiers, complicating early screening options to prevent iron-overload related disease. The aim of this study was to verify the existence of HH-related disease in C282Y homozygous siblings of C282Y homozygous probands with clinically detected HFE-related HH and to identify factors predictive for the iron-related disease within these siblings. To this end, C282Y homozygous (n=110, males n=53) and non-homozygous siblings (n=318, males n=145) of 224 probands were compared for levels of serum iron parameters, and self-reported environmental and lifestyle factors and previously diagnosed HH-related diseases. Compared to non-homozygous C282Y siblings, C282Y homozygous siblings more often mentioned to have been diagnosed with arthropathy (Odds Ratio [OR] 2.76, 95% Confidential Interval [CI] 1.71–4.46) and liver disease (OR 2.90, 95%CI 1.27– 6.62). Using multivariate logistic regression modelling, genotype (OR 2.29, 95%CI 1.04– 5.02), age (OR 1.07, 95% CI 1.04–1.09) and gender (OR 1.71, 95%CI 1.04–2.80) were found predictive for the development of iron-associated organ disease. With genotype in the model, there was neither an additive predictive value of the serum iron parameters, nor of body mass index (BMI) or alcohol intake. However, when the predictive value of the iron parameters was analyzed in siblings above 55 yrs, the input of the serum ferritin levels was also significant, with a less prominent influence of gender. In conclusion, our results show that the prevalence of hemochromatosis-attributed morbid conditions is increased in the C282Y homozygous siblings compared to their non-homozygous counterparts. Results furthermore suggest that age and gender, but not BMI and alcohol intake, add to the identification of C282Y homozygous siblings most at risk to develop hemochromatosis-associated disease. These findings will be instrumental in the definition of a high-risk group for iron overload-related disease among siblings of clinically detected C282Y homozygous probands and may contribute to the cost-effectiveness of family screening.
CD36 Mediated Reactive Oxygen Species Formation Contributes to Thrombosis.
Authors: Li Wei , Febbraio Maria , Silverstein Roy L. 
Published: April 2020

Abstract
We previously showed that mice in which the CD36 gene was deleted had significantly prolonged time to form an occlusive thrombus in response to FeCl3-induced vascular injury than wild type (WT) mice. In other studies we and others have shown that CD36 promotes reactive oxygen species (ROS) formation in murine models of cerebral and cardiac ischemia. In this study, we examined the formation and roles of ROS in FeCl3-induced carotid artery injury and thrombosis using CD36 null and WT mice. Hydroethidine, a fluorescent superoxide indicator, was injected via the jugular vein and then carotid artery injury was induced in the contralateral artery by direct topical application of FeCl3 at concentrations of 7.5% or 12.5%. Fluorescence images were monitored with intravital microscopy. FeCl3 dose dependently induced significant accumulation of ROS in the vessel wall; however, the degree was significantly less in CD36 null mice than in WT mice exposed to the lower dose of FeCl3. Direct injection of Edavarone (1 mg/Kg body weight), a free radical scavenger, significantly elongated the time to thrombosis in WT mice. Thrombosis time was also increased in the CD36 null mice, but not to the same extent as WT. We also found fewer endothelial cell-derived microparticles (CD105 positive) in plasma of CD36 null mice 3 minutes after injury with the low dose of FeCl3. Immunoblots of lysates prepared from carotid arteries with thrombi or from untreated normal carotid arteries showed that levels of peroxiredoxin 2 (Prx 2), an antioxidant enzyme known to detoxify ROS, were lower in the thrombi formed from CD36 null mice, but higher in the normal vessel wall, suggesting that an anti-oxidative system may exist in the vessel wall of CD36 null mice. We conclude that CD36 plays a role in ROS formation during thrombosis and may also sensitize the vessel to injury induced by FeCl3. High Prx 2 expression in the vessel wall in CD36 null mice may contribute to the anti-oxidative effect observed in these mice.
Select γ-Secretase Inhibitors Induce Apoptosis in Pre-B ALL Cells and Disrupt the Balance Between Constitutive Notch Signaling and Repression.
Authors: Wilson Bridget S. , Meng Xiangbing , Mazel Tomas , Willman Cheryl L. , Atlas Susan , Harvey Richard , Chen I-Ming , Hunger Stephen P. , Oliver Janet M , Winter Stuart S. 
Published: April 2020

Abstract
Several γ secretase inhibitors (GSIs) were tested for the ability to induce apoptosis in precursor B acute lymphoblastic leukemia (pre-B ALL) cells. Of five GSI’s tested, treatment with two compounds resulted in effective killing of both pre-B lymphoblasts and cells from multiple pre-B ALL lines. Since Notch receptors represent an important group of γ secretase targets, we evaluated expression and activation status of Notch receptors in CD19+ lymphoblasts from pediatric pre-B ALL patients, as well as cultured pre-B ALL cells. We found that, unlike T-ALL where activating mutations are common, pre-B ALL cells appear to drive constitutive Notch signaling through autocrine signals. Blasts from 11 patients expressed 3 Notch receptors and multiple Notch counter-ligands. Expression of Notch pathway genes was also confirmed by microarray analysis of genes expressed in 207 children with high risk B precursor ALL. GSI treatment of pre-B ALL cells led to dephosphorylation of AKT and Foxo3, Bim expression and caspase activation. GSI treatment also blocked cleavage of Notch 1 and 2 to their active forms and inhibited expression of Notch targets, Hey2 and Myc. In contrast, increased expression of Hes1 and Hey1 was correlated with GSI-induced loss of the co-repressor, SMRT. GSI treatment appears to induce precursor B cell death by disrupting the balance between constitutive Notch signaling and repression.
Toxicities in Adults with Acute Lymphoblastic Leukemia (ALL) Treated with Regimens Using Pegasparaginase.
Authors: Rytting Michael , Earl Marc , Douer Dan , Muriera Brenda , Advani Anjali , Bleyer Archie 
Published: April 2020

Abstract
Background: The current therapeutic strategy of applying pediatric-based regimens for acute lymphoblastic leukemia (ALL) to adults with ALL exposes these patients to multiple doses of asparaginase (ASP). Exposure to long-acting or pegylated ASP is particularly prominent due to dosing convenience, since pegylated ASP can be administered intravenously and requires fewer doses than shorter-acting forms. Previously, adult patients were much less likely to be treated with ASP-containing regimens due to reports from the 1970s of increased toxicity from ASP in adults compared with children. We report on the toxicities encountered in 3 protocols that include multiple doses of pegylated ASP as part of therapy for ALL in adult patients.
Methods: Thus far, the 3 protocols have enrolled 92 patients between the ages of 14 and 71 years. The pegylated ASP dose ranges from 2000–2500 IU/m2. Approximately 330 doses of pegylated ASP have been given.
Results: Grade 3–4 hepatic toxicity is the most prominent; grade 3–4 transaminase elevation occurred in 47 (51%) patients, and grade 3–4 hyperbilirubinemia was seen in 22 (24%) patients (Table). Hyperglycemia was grade 3–4 toxicity in 30 (33%) patients. Grade 3–4 allergic reactions to pegylated ASP occurred in 5 (5%) patients. Twelve (13%) patients developed thromboses. Of note, 3 (3%) patients have had leukoencephalopathy on magnetic resonance imaging scans with reversible stroke-like symptoms. The majority of hepatic toxicities resolve spontaneously, allowing patients to continue chemotherapy. All of the patients with stroke-like symptoms have fully recovered.
Conclusions: Considerable hepatotoxicity and hyperglycemia occur in adult ALL patients treated with polychemotherapy that includes long-acting ASP. Other toxicities occur with a frequency similar to that seen in pediatric patients treated with a long-acting ASP. This toxicity profile warrants close monitoring and continued data collection from clinical trials that use pegylated ASP in adults with ALL.
USC Cleveland Clinic M.D. Anderson Total *No. of patients with grade 3–4 toxicities. Median age (years) 33 46 20 33 Age range (years) 18–57 20–71 14–34 14–71 No. doses/patients 127/39 56/25 147/28 330/92 Toxicity* Elevated liver enzymes 23 7 17 47 Hyperbilirubinemia 7 6 9 22 Hyperglycemia 12 5 13 30 Clinical pancreatitis 5 N/A 3 8 Fatigue 3 1 7 11 Thrombosis 3 (SVC only) 2 7 12 Hypofibrinogenemia N/A 8 N/A 8 Elevated PT / INR N/A 1 N/A 1 Bleeding 0 N/A 0 0 Nausea / vomiting 1 4 2 7 Allergy / hypersensitivity 0 2 3 5 Neuropathy 1 1 N/A 2 CNS stroke-like syndrome 0 0 3 3
Platelets in Storage: Altered S-Nitrosothiol Metabolism and Decreased Responsiveness May Be Related.
Authors: Kanter Julie , McLaughlin Dk , Dimitry J , Rogers S. , Kell Pj , Frazier WA , Doctor A. 
Published: April 2020

Abstract
Under normal physiologic conditions, platelets circulate in an inactivated state and require only minimal stimulation ensuring their immediate availability for hemostasis. Previous research has shown that during platelet pheresis and storage, platelets undergo early activation resulting in expression of the surface activation marker CD62, release of α granule contents, and a decrease in inducible activation. In addition to regulating vascular tone, nitric oxide (NO) groups in plasma may provide tonic inhibition to circulating platelets thereby preventing the inappropriate adhesion and aggregation seen in stored platelets. S-Nitrosothiols (RSNOs) may serve as a reservoir for nitric oxide (NO) in the normal circulation. We hypothesize that platelets are prematurely activated during the process of apheresis in part due to the lack of RSNOs in the microenvironment during collection and storage. Furthermore, RSNO metabolism by stored platelets is changed by the process of apheresis itself. To test this hypothesis, we monitored the activation status of platelets using CD62 flow cytometry and quantified intracellular NO content and uptake using the fluorescence probe diaminodifluorofluorescein diacetate (DAF-FM DA). Both measurements were made on freshly isolated platelets (Fl-Plts) and on apheresis platelets (A-Plts). In addition, we employed these techniques to evaluate the responsiveness of Fl-Plts and A-Plts to agonists [thrombin receptor activating peptide (TRAP), ADP, and collagen] and to NO-donating molecules after varying storage times. In preliminary studies we have found that Fl-Plts bind RSNOs and demonstrate steroselectivity in their degree of uptake. Fl-Plts incubated with L-RSNOs produce over 2-fold the fluorescence compared to Fl-Plts incubated with D-RSNOs. A-Plts lose this stereoselectivity in RSNO uptake following the collection and storage process. We have also found that A-Plts have up to a 10-fold increase in uptake of nitric oxide from RSNOs compared to Fl-Plts. This significant increase and loss of stereoselectivity in RSNO uptake in A-Plts correlates with the loss of inducible activation over storage time. These data suggest RSNO metabolism in platelets is fundamentally altered during apheresis, collection, and storage and provides a novel target with therapeutic potential for further investigation into the loss of platelet function during storage.