bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endogenous Arteriolar Fibrinolysis Requires Urokinase Plasminogen Activator and Leukocyte Urokinase Plasminogen Activator Receptor-1.
Authors: Bai Xufang , Gross Peter L. 
Published: October 2019

Abstract
Background: In venous thrombi, urokinase associated with leukocytes activates plasminogen to initiate endogenous fibrinolysis. Leukocytes also interact with arteriolar thrombi.
Objectives: We hypothesized that urokinase plasminogen activator (uPA) activity would also be delivered to arteriolar thrombi by leukocytes.
Methods: Using established techniques of high-speed intravital fluorescence microscopy to observe the cremaster muscle of mice, we measured platelet and fibrin accumulation in thrombi generated by a laser injury to arterioles. The accumulation of platelets in a thrombus is quantitated by measuring the fluorescence from anti-CD41 antibody tagged with a fluorescent secondary antibody and the presence of fibrin is detected using a fluorescence-tagged anti-fibrin antibody (T2G1).
Results: In C57BL/6 wild type mice, fibrin increased to a maximum at about three minutes after thrombus formation and then decreased, such that by eight minutes after thrombus formation fibrin is present at 34% of its maximal value. When wild type mice are pretreated with epsilon-aminocaproic acid (16 mg/kg IV), the decrease in thrombus fibrin content was less (to 54% of maximal 8 minutes after thrombus formation), implying that the fibrin loss is at least partially the result of plasmin activity. Thrombus fibrin accumulation in tissue-plasminogen activator deficient mice (Plat) was greater, peaking at 229% the amount found in wild type mice, but the amount of fibrin present at eight minutes after thrombus formation was not dissimilar from wild type mice (45% ± 5% v. 34% ± 3%, P=0.09). In uPA-deficient mice (Plau) and uPA-receptor-1-deficient mice (Plaur), the amount of maximal thrombus fibrin was 189% and 273% that of fibrin content in wild type mice. Also, although thrombus fibrin did decrease over time in Plau and Plaur mice, it decreased to only 51% and 48% of maximal (each were P < 0.005 v. wild type) at eight minutes after thrombus formation. When wild type leukocytes, isolated from blood by differential centrifugation and sucrose density gradient, were transfused into Plaur mice, thrombus fibrin loss was restored to wild type levels (38% of maximal at 8 minutes after thrombus formation, P=0.36 vs. wild type, P=0.016 vs. Plaur), implying that transfused wild type leukocytes, which express uPA-receptor-1, can rescue fibrinolysis in uPA-receptor-1-deficient mice.
Conclusions: These results confirm that endogenous fibrinolytic activity in vivo occurs soon after arteriolar thrombus formation. The plasminogen activators that are required for this fibrinolysis to occur are uPA, and the uPA-receptor-1 on leukocytes. These findings are compatible with the hypothesis that leukocytes can deliver plasminogen activator activity to arteriolar thrombi to initiate endogenous fibrinolysis.
Impact of Regulatory T Cells on Antigen Specific T Cell Response Using Recombinant Chimeric T Cell Receptors In Vivo.
Authors: Kofler David M. , Chmielewski Markus , Koehler Heike , Riet Tobias , Schmidt Patrick , Rappl Gunter , Hombach Andreas , Hallek Michael , Wendtner Clemens M. , Abken Hinrich 
Published: October 2019

Abstract
Recombinant T cell receptors with defined specificity against tumor cells are a promising experimental approach in the elimination of residual leukemia and lymphoma cells. It is so far unresolved whether regulatory T cells with suppressor activities impair the efficiency of cytolytic T cells grafted with a recombinant immunoreceptor. The frequency of regulatory T cells is highly increased in tumor patients and their suppressive function seems to play a role in the fail of an autologous T cell response against the malignant cells.
In this study we analyzed the antigen-triggered, specific activation of receptor grafted T cells in the presence or absence of regulatory CD4+CD25high T cells. CD3+ T cells were grafted with CEA-specific immunoreceptors containing the CD3-zeta signaling domain for T cell activation. Co-cultivation of receptor grafted effector T cells together with regulatory T cells repressed proliferation of the effector cells and decreased IL-2 secretion. Secretion of IFN-gamma and IL-10 was not impaired. Interestingly, the cytotoxicity of grafted effector T cells towards CEA-expressing tumor cells was not impaired by regulatory T cells in vitro.
To evaluate the relevance in vivo, we used a Crl:CD1 Nu/Nu mouse model to assess growth of CEA+ tumor cells in the presence of receptor grafted effector T cells and of regulatory T cells. Mice inoculated with tumor cells together with CD3+ effector T cells without immunoreceptor and regulatory T cells developed earlier tumors with faster growth kinetics compared to mice that were inoculated with tumor cells, CD3+ T cells and CD4+CD25- control T cells. Using effector T cells that were equipped with a recombinant CEA-specific CD3-zeta immunoreceptor, 2 of 5 mice developed a tumor in the presence of regulatory T cells while none of the mice developed a tumor in the absence of regulatory T cells.
Taken together, regulatory T cells obviously impair an antigen-specific, anti-tumor T cell attack in vivo. This seems to be due to repression of proliferation of the effector T cells and not to diminished cytotoxicity. These findings have major impact on the design of clinical studies involving adoptively transferred effector T cells.
A Review of the Economic Burden of Pleural and Pericardial Effusions in Cancer Patients.
Authors: Liou Sarah Y. , Stephens Jennifer M. , Tran Kimbach T. , Botteman Marc F. 
Published: October 2019

Abstract
OBJECTIVES: Pleural and pericardial effusions can lead to severe outcomes. Cancer accounts for an estimated 40% of all pleural effusions. About half of the effusions diagnosed in cancer patients are malignant, while the rest are nonmalignant and may occur as complications of the cancer treatments themselves. Pleural and pericardial effusions are associated with increased morbidity and mortality as well as high healthcare costs. The objective of this study was to review the economic burden of pleural and pericardial effusions in cancer patients.
METHODS: A systematic search of the English-language medical literature published between 1990 and 2006 was conducted. Additional publications and conference proceedings were retrieved from the article bibliographies and included in the review. Articles selected include prospective or retrospective studies specifically designed to examine burden of illness, direct medical costs, indirect costs, or cost drivers associated with pleural or pericardial effusions in cancer patients. All original costs were reported, with adjusted figures (to 2006 US dollars) presented in parentheses using the medical care component of the consumer price index from the US Bureau of Labor Statistics.
RESULTS: Of 15 studies identified, 11 met selection criteria and were reviewed in detail. Seven references reported data on costs associated with pleural or pericardial effusions in cancer patients. The cost per episode of pleural effusion ranged from $3,391 (2006 US $4,387) for outpatient treatment with pleural catheter to $20,996 ($37,341) for talc pleurodesis. The most common treatment for malignant pleural effusion is chest tube insertion and drainage with instillation of a sclerosing agent. Key cost drivers for significant pleural effusions included operating room costs, surgeon fees, and drugs such as sclerosing agents. Resources used for management of low grade pleural effusions include chest x-rays, physician outpatient visits, diuretics, and corticosteroids. For the treatment of pericardial effusion, the costs of performing pericardiocentesis and a pericardial window procedure were estimated to be $4,446 and $14,641 (2006 US$), respectively. Cost components for pericardial effusions, depending on treatment modality selected, included echocardiogram (3–10%), intensive care unit (17–56%), sclerosant (1–4%), surgeon fees (28–29%), anesthesia fees (20%), and operating room costs (31%).
CONCLUSIONS: Pleural and pericardial effusions lead to significant direct medical costs, contributing to the total cost of care among patients treated for cancer. These costs should be included in the economic evaluation of therapies that increase the risk of pleural and pericardial effusions. Given the scarcity of published analyses in this area, additional research is warranted to better understand the burden of pleural and pericardial effusions.
Blood Management Strategies Effect on Hemoglobin Levels in Hospitalized Patients.
Authors: Ford Patricia A. , Keck Gina R. , Ricci Angela F. 
Published: October 2019

Abstract
Phlebotomy for diagnostic testing is a notable source of blood loss, causing hospitalized patients to lose significant volumes of blood in a short period of time. Previous studies have documented correlations in phlebotomy blood loss, decline in hemoglobin and possible contributions to transfusion volume. One study reported average blood drawn for phlebotomy to be 12.4 mL/day for patients in medical wards, 33.5 mL/day in ICU patients, and 73.9 mL/day in patients with an arterial line (Smoller et al. NEJM.1986; 314: 1233–1235). Another study concluded that an average hemoglobin decrease of .79 g/dL was due to a similar volume of phlebotomy blood loss (Thavendiranthan et al. J Gen Intern Med2005; 20:520–524). Patients treated at the Center for Bloodless Medicine and Surgery (CBMS) at Pennsylvania Hospital decline blood products. Thus, to minimize iatrogenic blood loss, strategies were implemented including the use of pediatric tubes, reduced phlebotomy and the avoidance of central line wastage. In this study we attempt to analyze the adherence to and effectiveness of these strategies in preventing hemoglobin decline. We conducted a retrospective chart review of 46 out of 341 hospitalizations in the CBMS between October 2005 and July 2006, excluding ICU patients and those with blood loss such as surgical patients, patients with gastrointestinal bleeding, and dialysis patients. Erthropoietin (EPO) therapy was not given before or during the days evaluated. The analyzed population had a mean age of 58.7, an initial hemoglobin of 12.3 g/dL and a hospitalization period of 5.1 days. The absolute change between initial and final hemoglobin was on average .71 g/dL. Taking into account fluctuations during their stay, the average change from highest documented hemoglobin to lowest was 1.2 g/dL. In 30.4 percent of this population EPO therapy was subsequently initiated during their hospitalization. Therapy began at an average hemoglobin of 10.8 g/dL and was presumably the result of phlebotomy induced anemia. An average of 2.8 laboratory tests were ordered per day; 57 percent were chemistry panels or complete blood counts. These two tests were ordered almost daily. Thus, even at a CBMS where pediatric tubes are utilized and strict staff protocols are prescribed, the average iatrogenic blood loss is not appreciably different from a non-bloodless center without these regulations. Pediatric tubes can be costly and labor intensive and may not be the most important determinant of iatrogenic blood loss. Therefore, hospitals should work more diligently to eliminate daily and unnecessary phlebotomies by retraining house staff to keep patient blood loss at a minimum.
Evaluation of Once Weekly Subcutaneous Idraparinux Versus Standard Therapy with Heparin and Vitamin K Antagonists in the Treatment of Deep-Vein Thrombosis or Pulmonary Embolism - The Van Gogh Investigators.
Authors: Buller Harry R. ,   on Behalf of the Van Gogh Investigators
Published: October 2019

Abstract
Background
Venous thromboembolism is treated with heparins, followed by a vitamin K antagonist. It would be desirable to replace this complex approach with one simple anticoagulant regimen.
Methods
We conducted two randomized, open-label trials involving 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism to compare efficacy and safety of idraparinux alone versus standard therapy, and document non-inferiority for efficacy. Patients received either idraparinux (2.5 mg once-weekly, subcutaneously), or low-molecular-weight heparin/unfractionated heparin with adjusted-dose vitamin K antagonists, for three or six months. The primary efficacy outcome was the three-month incidence of symptomatic recurrent venous thromboembolism (nonfatal or fatal).
Results
In the deep-vein thrombosis study the incidence of recurrence at day 92 was 2.9 percent with idraparinux and 3.0 percent in controls (odds ratio 0.98, 95 percent confidence interval 0.63 to 1.50), satisfying the pre-specified non-inferiority requirement. The six-month hazard ratio was 1.01. The incidence of clinically relevant bleeding at day 92 was 4.5 percent and 7.0 percent , respectively (P<0.01). By six months bleeding rates were similar. In the pulmonary embolism study the incidence of recurrence at day 92 was 3.4 percent with idraparinux and 1.6 percent in controls (odds ratio 2.14, 95 percent confidence interval 1.21 to 3.78), excluding non-inferiority.
Conclusion
In patients with deep-vein thrombosis, once-weekly subcutaneous idraparinux for three or six months had similar efficacy and safety as heparins and vitamin K antagonists, while, in pulmonary embolism, this regimen was less efficacious than standard anticoagulant therapy which had an unexpectedly low recurrence rate.
Anti-Leukemic Potency of Stapled BH3 Helices Correlates with Their Capacity for Bifunctional Activation of Apoptotic Pathways.
Authors: Walensky Loren D. , Pitter Kenneth , Morash Joel G. , Verdine Gregory L. , Korsmeyer Stanley J. 
Published: October 2019

Abstract
Selective targeting of apoptosis in vivo is a promising pharmacologic strategy for subverting cancer. BCL-2 family protein interactions constitute a critical control point for the regulation of apoptosis. Whereas multidomain anti-apoptotic proteins such as BCL-2 guard against cell death, multidomain pro-apoptotic proteins such as BAX constitute a gateway to cell death through mitochondrial damage. The BH3-only proteins function as death sentinels situated throughout the cell, poised to transmit signals of cell injury to multidomain members. BH3-only proteins deliver death signals via their alpha-helical BH3 domains, which are either neutralized by anti-apoptotic proteins or delivered, directly or indirectly, to the mitochondrial executioners BAX and BAK. By inserting hydrocarbon “staples” into native BH3 peptide sequences, we have generated a chemical toolbox of stabilized alpha-helices of BCL-2 domains (SAHBs) to dissect apoptotic pathways and develop prototype therapeutics. We previously demonstrated that a stapled peptide corresponding to the BID BH3 domain is a helical, protease-resistant, and cell-permeable compound that binds to anti-apoptotic targets with high affinity and exhibits anti-leukemic activity in vitro and in vivo. Using our expanded panel of compounds, we find that a stapled BAD BH3 likewise displays high affinity binding to select anti-apoptotic targets; however, BID SAHB is uniformly more potent than BAD SAHB in inducing apoptosis of a panel of leukemia cell lines. To explore the molecular mechanism underlying the differential potencies of BID and BAD SAHBs, we evaluated a model in which select BH3-only proteins directly engage pro-apoptotic multidomain proteins to trigger mitochondrial apoptosis. We detect and measure, for the first time, direct binding between select SAHBs, such as BID, and BAX. The observed interaction between BID SAHB and BAX triggered functional activation of BAX in vitro, resulting in mitochondrial cytochrome c release and FITC-dextran release from liposomes. The specificity of the BID SAHB-BAX interaction and its biochemical consequences is highlighted by abrogation of BID SAHB activity by point mutation and by competitive binding to anti-apoptotic BCL-XL. We confirmed the physiologic relevance of our observed in vitro interaction between BID SAHB and BAX by their co-immunoprecipitation from BID SAHB-treated leukemia cells. In contrast, BAD SAHB does not bind or activate multidomain pro-apoptotic BAX. These data provide an initial mechanistic explanation for the relative potency of BID SAHB in activating leukemia cell apoptosis. Thus, bifunctional SAHBs that directly engage both pro- and anti-apoptotic multidomain proteins may be more robust pro-apoptotic therapeutics, compared to compounds that selectively target anti-apoptotic proteins.
Evaluating the Performance of a Previously Reported Risk Score To Predict Venous Thromboembolism: A VERITY Registry Study.
Authors: O’Shaughnessy Denise , Rose Peter , Pressley Fran , Scriven Nicholas , Farren Tim , Nokes Tim , Arya Roopen 
Published: October 2019

Abstract
Accurate prediction of venous thromboembolic (VTE) risk remains a clinical challenge, and no prospectively validated risk scoring systems have been described. Recently, a computer-based alert to highlight hospitalised patients at risk of VTE that employed a simple risk score based on eight principal VTE risk factors was shown to improve patient outcome (N Engl J Med2005;352:969–977). The objective of this study was to assess the performance of this risk score in identifying those at risk of VTE.
The study cohort consisted of all patients who were enrolled in ‘VERITY’ up to 30th November, 2004. VERITY is a UK, prospective VTE treatment registry that enrolls patients presenting to hospital with suspected VTE (www.verityonline.co.uk). The vast majority of patients enrolled have no history of hospitalization and therefore patients will not have been risk assessed or have been given thromboprophylaxis, so essentially reflecting an untreated population.
The risk score was applied to the patient database and a score calculated for each patient for whom all 8 risk factors were known. Risk was scored as previously described: score=3 for cancer, prior VTE, hypercoagulability; score=2 for major surgery; score=1 for age>70 years, BMI>29, bed rest not related to surgery, use of hormone-replacement therapy or oral contraceptives. An increased risk was defined as a cumulative risk score of at least 4.
Of 27,179 patients presenting with suspected VTE, 6,124 had a positive diagnosis of deep vein thrombosis, pulmonary embolism, or both; in 15,980 cases the diagnosis was not confirmed. All 8 risk factors were known for 5,692 cases (1880 with confirmed VTE [31%] and 3812 VTE-negative cases [24%]). An increasing risk score was associated with an approximately linear rise in the proportion of patients with confirmed VTE; more than 50% of patients with a risk score ≥4 were diagnosed with VTE, rising to more than 71% in those with a score >7 (see figure).
Although this patient cohort is not identical to the population the risk score was developed for, these data suggest the value of this weighted risk score in identifying those at risk of VTE. Further refinement of this score, perhaps using more sophisticated modeling to increase the accuracy of the score to predict thromboembolic events, would be highly valuable for routine integration of VTE assessment into clinical practice.
Final diagnosis of VTE and weighted risk score (n=5,692) Final diagnosis of VTE and weighted risk score (n=5,692)
Osteoclasts but Not Macrophages or Dendritic Cells Support Long-Term Plasma Cell Survival.
Authors: Geffroy-Luseau Alexandrine , Jego Gaetan , Bataille Regis , Pellat-Deceunynck Catherine 
Published: October 2019

Abstract
Long-lived plasma cells (PCs) located within the bone marrow are the source of protective antibody for extended periods of time. Recent studies pointed out that PC survival depends on the ability of PCs to find a suitable niche. Bone marrow environment of PCs is constituted by cells of either mesenchymal (stromal cells and osteoblasts) or hematopoietic origin (macrophages, dendritic cells, osteoclasts (OCs)). In this work, we evaluated the ability of these five types of cells to support the long-term survival of human PCs in vitro.
Stromal cells were derived from normal bone marrow mononuclear cells and osteoblasts were SAOS2 cells (malignant osteoblastic cells). Macrophages, dendritic cells and OCs were derived from adherent circulating mononuclear cells with M-CSF, IL4 and GM-CSF or RANKL and M-CSF, respectively. Morphology, phenotype and functional features were used to characterize each cell type. On the other hand, plasmablasts (PBs) were generated from tonsil CD27+ B cells activated by CD40L expressing fibroblasts and then induced to differentiate by removal of fibroblasts in the continuous presence of IL2 and IL10. PBs were purified (by CD20 depletion) and cocultured with the five types of cells previously described.
To assess PC differentiation and survival in cocultures, we monitored the frequency of PCs by flow cytometry using an anti-CD38 and anti-CD138 double staining, along with Ig accumulation. Among cells of either mesenchymal (stromal cells and osteoblasts) or hematopoietic origin (macrophages, dendritic cells, OCs), only OCs allowed PBs to survive and differentiate into PCs that remained alive more than 14 days. Indeed, after a 5-day coculture with OCs, 100 000 PCs were alive (400 000 PBs were seeded at day 0) as compared to less than 10 000 PCs in the other culture conditions. Moreover, the total frequency of PCs after 14 days in culture with OCs was approximately 5% of the original input at day 0. PCs fully maintained their antibody secretory capacity since the level of secreted antibodies increased. Cellular interactions were required since PBs cultured with either OC conditioned medium or with OCs in transwell did not survive nor differentiate. Identification of membrane and soluble molecules supporting PC survival is now under investigation.
Our data indicate that the interaction with OCs is not limited to malignant PCs i.e., myeloma cells, and pointed out that OC is an essential partner of normal PC.