bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unraveling the Danger Signal Necessary for the Immune Response to Therapeutic Factor VIII.
Authors: Skupsky Jonathan , Zhang Ai-Hong , Scott David W. 
Published: April 2020

Abstract
It is well established that mice which do not produce endogenous factor VIII (fVIII−/−) can manifest a robust immune response to exogenous fVIII treatments. They form B-cell and T-cell responses even when they encounter fVIII through traditionally tolerogenic routes (e.g., intravenous or intraperitoneal). In the fVIII−/− mouse, repeated administration of recombinant human fVIII has emerged as a useful model for studying the physiologic response in hemophilic patients iatrogenically immunized to therapeutic factor VIII treatments. While environmental factors likely offer some co-stimulatory signals, nonetheless, the ability to respond effectively in the absence of extrinsic adjuvant begs the questions of what is the “danger signal” required for immune responsiveness to fVIII? We have previously shown that when factor VIII is heat inactivated (56°, 30′), it completely losses function and much of its immunogenicity (Skupsky and Scott, Blood110: 2685 Abstract, 2007). Heated fVIII lacks several of its B-cell epitopes (we did not find a subsequent response to neo-epitopes), but retains its T-cell epitopes. We concluded that fVIII’s immunogenicity is inherently tied to its function. To explore this topic further, we have immunized hemophilic mice with rfVIII and compared the response to mice treated with both rfVIII and Hirudin. Hirudin is the reactive agent found in medicinal leech saliva and its anti-coagulant activity is based on its ability to inhibit thrombin. We found that T cell responses to rfVIII in mice protected with Hirudin are significantly reduced (p&lt;0.05) and the anti-fVIII antibody concentration has decreased by 25%. As a control, we injected a third group of mice i.v. with an equivalent amount of another foreign protein, ovalbumin (OVA) in PBS. As expected, the mice did not respond to this historically tolerogenic treatment. Interestingly, when mice were injected simultaneously with rfVIII and OVA, they did form a humoral response to both the fVIII (200 μg/ml) and the OVA (30μg/ml). This suggests that fVIII may have adjuvant properties remaining to be discovered. Overall, these data suggest that the activation of thrombin provides co-stimulatory signals necessary for the immune response. Activated thrombin does this directly or indirectly through the activation of other blood components, including platelets.
Screening Tool for Bleeding Disorders in Women with Menorrhagia: Evaluation in a Prospective US Multi-Site Cohort.
Authors: Philipp Claire S. , Faiz Ambarina , Byams Vanessa , Miller Connie H. , Heit John A. , Kouides Peter A. , Kulkarni Roshni , Lukes Andrea , Stein Sidney F. 
Published: April 2020

Abstract
Menorrhagia is a common clinical problem among reproductive age women and annually 5% of reproductive age women seek medical attention, usually with gynecologists and other primary care physicians, for this symptom. Since underlying bleeding disorders are common in women presenting with menorrhagia, and referral for comprehensive hemostatic testing of substantial numbers of women with otherwise unexplained menorrhagia is problematic from the public health and cost perspective, a short, easy-to-administer screening tool comprised of 8 questions for identifying women with menorrhagia for hemostatic evaluation was previously developed (Am J Ob Gyn2008;198:e1–163e8). In the present study, the validity of the screening tool was evaluated in a multi-site, prospectively recruited cohort of women with menorrhagia. 232 women with menorrhagia age 18 and older with a pictorial blood assessment chart (PBAC) score &gt; 100 were recruited from 5 US centers as potential subjects for a prospective cross-over study for evaluation of intranasal DDAVP versus tranexamic acid. All subjects underwent comprehensive laboratory testing for bleeding disorders, including VWF, platelet aggregation/ATP release, and factor assays. Study participants were administered a questionnaire which included the 8 screening tool questions in 4 categories, including history of duration and severity of menorrhagia, anemia treatment, excessive bleeding with hemostatic challenges, and family diagnosis of bleeding disorder. A screening tool was considered positive if there was a positive response for any of the questions in the four categories. Sensitivity of the screening tool with 95% confidence interval was calculated for bleeding disorders and also separately for low VWF (ristocetin cofactor &lt; 50%), and platelet function defects.217 women with menorrhagia including 78% white and 16% black women with complete data were evaluated. In this population, a positive screening tool had a sensitivity of 89% (95% CI, 83–93) for bleeding disorders, 89% for platelet function defects (95% CI, 82–94), and 73% for low VWF (95% CI, 39–94). The sensitivity for bleeding disorders was 87% (95% CI, 79–92) among white women and 94% (95% CI, 79–99) among black women. Adding a PBAC score &gt; 185 increased the sensitivity of the screening tool for bleeding disorders to 95% (95% CI, 90–98). Using a multi-site US population of adult women with menorrhagia, this study confirms the benefit of a short screening tool to assist primary care physicians in the selection of women with menorrhagia to refer for comprehensive hemostatic testing and evaluation. population of adult women with menorrhagia, this study confirms the benefit of a short screening tool to assist primary care physicians in the selection of women with menorrhagia to refer for comprehensive hemostatic testing and evaluation.
CD300f Triggering Modifies Myeloid Cell Function
Authors: Hart Derek , Modra Courtney , Clark Georgina 
Published: April 2020

Abstract
CD300f, a member of the CD300 family of immunoregulatory molecules, is capable of signalling through association with both SHP-1 phosphatase and the p85α subunit of phosphoinositide 3-kinase. On normal cells, CD300f is expressed on monocytes and dendritic cells in the blood and bone marrow. CD300f is expressed on myeloid derived cell lines and Acute Myeloid Leukaemias (AMLs) and is an acknowledged candidate for antibody targeting of AML (Modra CJ et al. Blood2006;108:225B-225B and Zhao X et al Blood2007;110:531a–532a). We have generated a monoclonal antibody, MMRI- 23, specific for the extracellular domain of CD300f. MMRI-23 immunoprecipitates a 57kd protein from the myeloid derived cell lines HEL, THP-1 and U937 and this protein binds to a polyclonal antibody to CD300f (LMIR3) in Western blot analysis. Binding of MMRI-23 to myeloid cells was blocked by the CD300f recombinant proteins or the polyclonal CD300f antibody. The MMRI-23 mAb was used as a surrogate ligand to study the functional consequences of crosslinking CD300f on normal monocytes and myeloid derived cell lines. Purified peripheral blood monocytes were cultured for 18 hours in the presence of immobilised MMRI-23 or control mAb. MMRI-23 binding was not altered by activation of peripheral blood monocytes but crosslinking monocytes with MMRI- 23 induced downregulation of CD14 and CD33. There was significant inhibition of IL-6 but not IL-1β, IL-8 or TNFα secretion. Crosslinking monocytes or the U937 cell line with MMRI-23 increased specific chemotaxis towards CXCL12 (SDF-1). This increased migration index following MMRI-23 crosslinking was reversed in the presence of wortmannin indicating that MMRI-23 induces signalling through phosphoinositide 3-kinase. The effect of crosslinking did not enhance CXCR4 upregulation but did induce localization of CD300f and CXCR4 to the lipid rafts in myeloid cell line, U937. Thus CD300f plays a significant role in the regulation of monocyte migration to CXCR4. As CD300f is upregulated on around 70% of AMLs, this regulation of homing has major implications for the treatment of AML.
Ficolin-1 Is Present in a Highly Mobilizable Subset of Human Neutrophil Granules and Associates with the Cell Surface after Stimulation with fMLP.
Authors: Roervig Sara , Honore Christian , Larsson Lars-Inge , Ohlsson Sophie , Pedersen Corinna cavan , Jacobsen Lars Christian , Cowland Jack B. , Garred Peter , Borregaard Niels 
Published: April 2020

Abstract
Ficolins are soluble pattern recognition molecules that bind carbohydrate structures on the surface of microorganisms. Three ficolins have been identified in man: ficolin-1, ficolin-2, and ficolin-3. Ficolin-1 is derived from the FCN1 gene on chromosome 9 and is synthesized in monocytes and type II alveolar epithelial cells. Ficolin-1 has been shown to be present in secretory granules of human neutrophils, but which subset of the neutrophils secretory granules harbors ficolin-1 is not known. In order to determine the exact subcellular localization of ficolin-1 in neutrophils, recombinant ficolin-1 was expressed in Chinese hamster ovary cells and used for generation of polyclonal antibodies. This allowed detection of ficolin-1 in subcellular fractions of human neutrophils by ELISA and western blotting, and by immunohistochemistry. Real time PCR examination of normal human bone marrow showed FCN1 gene expression largely in myelocytes, metamyelocytes, and band cells with a profile quite similar to that of gelatinase. In accordance with this, immunohistochemistry and subcellular fractionation demonstrated that ficolin-1 is primarily localized in gelatinase granules, but also in highly exocytosable gelatinase poor granules, not previously described.
Ficolin-1 is released from neutrophil granules by stimulation with fMLP or PMA, and a significant part becomes associated with the surface membrane of the cells and can be detected by flow cytometry. Our studies show that neutrophils are a major source of ficolin-1, which can be readily released to the surroundings by stimulation.
Figure. Left: Distribution profile of ficolin-1 in unstimulated (control) neutrophils and neutrophils stimulated with fMLP or PMA. Right: Distribution profile of ficolin-1 and granule marker proteins in subcellular fractions of unstimulated human neutrophils. Figure. Left: Distribution profile of ficolin-1 in unstimulated (control) neutrophils and neutrophils stimulated with fMLP or PMA. Right: Distribution profile of ficolin-1 and granule marker proteins in subcellular fractions of unstimulated human neutrophils.
The Role of Endothelial PECAM-1 Polymorphism (S536N) as Heterophilic Counter Receptor for Neutrophil Specific CD177 in Transendothelial Cell Migration.
Authors: Bayat Behnaz , Andrei-Selmer Cornelia , Werth Silke , Newman Peter , Santoso Sentot 
Published: April 2020

Abstract
The human neutrophil-specific adhesion antigen CD177 (NB1, HNA-2a or PRV-1) becomes upregulated on the cell surface in a number of inflammatory settings, and human alloantibodies specific for CD177 have been implicated in the development of transfusion related acute lung injury (TRALI). Recent studies have shown that CD177 functions as an important counter-receptor for the endothelial cell-cell junctional protein PECAM-1 (CD31) – a heterophilic adhesive interaction that appears to be mediated by Ig domain 6 of PECAM-1 and a still-to-be-identified site on CD177. Interestingly, a common single nucleotide polymorphism (SNP) exists within the PECAM-1 gene that produces an S536N amino acid substitution within Ig domain 6 that is proximal to the CD177 binding site. Whether this polymorphism influences PECAM-1/CD177 interactions and subsequent neutrophil transendothelial cell migration, however, is not known. To investigate the potential for the S536N PECAM-1 SNP to affect functionally important interactions between PECAM-1 and CD177, recombinant CD177 and PECAM-1 S536 or N536 allelic isoforms were produced in CHO mammalian cells, purified by affinity chromatography, and subjected to surface plasmon resonance analysis. We found that the S536 isoform of PECAM-1 bound with much higher affinity to CD177 than did its N536 counterpart (Ka for PECAM-1S536/CD177 = 5×10−7 versus a Ka for PECAM-1N536/CD177=1×10−7). To analyze the possible functional impact of the S536N polymorphism on neutrophil transendothelial migration, fMLP-stimulated neutrophils were allowed to transmigrate across human umbilical vein endothelial cell (HUVEC) monolayers that had been genotyped to be either PECAM-1 homozygous SS, heterozygous NS, or homozygous NN. We found that neutrophils migrated significantly faster across HUVECs expressing the PECAM-1S536, rather than the PECAM-1N536, allelic isoform. In addition, western blot analysis using a phospho-specific antibody revealed that cytoplasmic PECAM-1 ITIM tyrosines became phosphorylated to a greater extent in PECAM-1S536- versus PECAM-1N536-expressing HUVECs that had been incubated with either soluble recombinant CD177 or an anti-PECAM-1 mAb specific for Ig domain 6. Taken together, these data demonstrate that
heterophilic interactions between neutrophil CD177 and endothelial cell PECAM-1 play an important role in neutrophil transendothelial migration, and the naturally-occurring S536N polymorphism within Ig domain 6 likely affects ligand binding-induced downstream PECAM-1 signaling.
Allele-specific, PECAM-1-mediated effects on neutrophil transendothelial migration and inflammatory events such as TRALI may represent an important area for future investigation.
Supplemental Use of Inferior Vena Cava Filters: A Review of An Institutional Experience.
Authors: Singh Parminder , Lerner Robert G. , Chugh Tarun , Lai Hoang , Aronov Wilbert S 
Published: April 2020

Abstract
Introduction: Increasing use of inferior vena cava (IVC) filters in recent years as a preventative measure against pulmonary embolism (PE) has raised concern for usage outside of accepted guidelines. Based on the American College of Chest Physicians 2004 guidelines for the initial treatment of deep vein thrombosis (DVT) and PE, and the Eastern Association for the Surgery of Trauma 2002 guidelines for prophylaxis of PE, placement of an IVC filter is indicated in patients who either have, or are at high risk for thromboembolism, but have a contraindication for anticoagulation, a complication of anticoagulant treatment, or recurrent thromboembolism despite adequate anticoagulation. The purpose of our study is to identify patients who meet the guidelines for IVC filter placement and to compare clinical outcomes with those who did not meet the guidelines.
Methods: Charts of 558 patients who received IVC filter placement were reviewed from Jan 1, 2004 to Dec 31, 2007. Patients were divided into two groups called within-guidelines or supplemental. The within-guidelines group included patients that met the criteria described above. The supplemental indication group included patients who did not have a contraindication or failure of anticoagulation. Patient characteristics and clinical outcomes between the two groups were compared and analyzed.
Results: The within-guidelines group had 362 patients and the supplemental group had 196 patients. While there were more males in the within-guidelines group, age, race, length of stay, and in-hospital mortality were comparable between the two groups. Clinical follow-up in patients with a supplemental indication showed 1 (0.5%) case of post-filter PE, 2 (1%) cases of IVC thrombosis, 7 (3.6%) cases of DVT. Patients who were in the within-guidelines indication group had 4 (1.1%) cases of post-filter PE, 13 (3.6%) cases of IVC thrombosis, and 34 (9.4%) cases of DVT. All patients who developed post-filter PE had a prior DVT at the time of filter placement, and the risk of developing post-filter IVC thrombosis and PE is higher in patients with prior thromboembolic disease. Conversely, patients who did not have a VTE event before filter placement were at a significantly lower risk of developing IVC thrombosis and PE.
Conclusion: Anticoagulation should be initiated at the earliest possible time in patients treated with an IVC filter to prevent subsequent venous thromboembolic disease. Our data does not support the use of IVC filter in patients who can tolerate anticoagulation and have no prior venous thromboembolic event due to the low risk of developing pulmonary embolism
Comprehensive Geriatric Assessment (CGA) in Elderly Patients with Hematological Neoplasia: CGA and Not Age Predicts Mortality - Results from in-GHO®-Registry
Authors: Wedding Ulrich , Honecker Friedemann , Rettig Klaus , Huschens Susanne , Bokemeyer Carsten 
Published: April 2020

Abstract
Background: The internet based registry of IN-GHOα prospectively collects data of elderly cancer patients (pts) 370 yrs. We report data from 450 pts with hematological neoplasia (HE) out of 1580 cancer patients registered currently. To gain more insight into feasibility of treatment in elderly patients, results of a comprehensive geriatric assessment (CGA), physicians’ and pts’ judgement of fitness, and outcome measures were studied.
Methods: Besides demographic data, activities of daily living (ADL), instrumental activities of daily living (IADL), Karnofsky-Performance-Statuts (KPS), co-morbidity (Charlson score), medication (number of drugs not related the HE treatment), mobility (Timed-Up&Go-Test), cognition (MMSE), and depression (SCID screening) results were collected. Age, results of CGA, physicians’ rating (fit vs. compromised vs. frail) and pts’ self rated fitness (lickert scale for 1= very fit to 6 very unfit) for treatment were analysed for their association with death. Follow up assessment was scheduled 8–12 weeks and 5–7 months after inclusion.
Results: 450 patients, mean age 77.7 years (SD 5.7; range 69–97), 43.3%male, were included. Main diagnoses were aggressive lymphoma n = 135 (30%), chronic lymphocytic leukemia n = 66 (14.7), multiple myeloma n = 54, acute myeloid leukemia n = 27 (6.0%), and others. Physicians rating of patientś fitness for treatment: fit 54.4%, compromised 39.1%, frail 5.5%. Patients rating of patientś fitness for treatment: 1 = 19.6%, 2 = 31.8%, 3 = 25.1%, 4 = 13.6%, 5 = 3.8%, 6 = 1.1%. During follow up (median 178 days), 98 pts (21.8%) patients died: mean age (77.5 vs. 78.5; p=0.219), mean BMI (25.6 vs. 25.3; p=0.228), mean Charlson-score (2.0 vs. 2.3; p=0.28) and mean number of drugs (4.0 vs. 4.2; p=0.14) were not associated with death. However significantly associated with death during follow up were mean ADL score (94.0 vs. 87.4; p=0.047), mean IADL score (7.1 vs. 6.3; p&lt;0.001), mean KPS score (83 vs. 74; p=0.001), mean MMSE score (26 vs. 24; p=0.03), categorical Timed-Up&Go-Test (&lt; 10 sec 18% vs. &gt; 20 sec 38%; p&lt;0.001), categorical SCID screening (no depression 18% vs. depression 31%; p&lt;0.001), physicianś rating of fitness (fit 18.8%, compromised 21.6%, frail 52.0%; p=0.001) and patientś rating of fitness (lickert scale 2.3 vs. 3.4; p&lt;0.001).
Conclusion: Patients characteristics as assessed by CGA and not age are associated with death in elderly patients with hematological malignancies. Results of CGA should be validated in treatment algorithm for this population.
Adipocytes Secrete Factors That Cause Leukemia Drug Resistance.
Authors: Behan James W , Yun Jason P , Proektor Marina P , Ehsanipour Ehsan A , Butturini Anna , Heisterkamp Nora , Mittelman Steven D 
Published: April 2020

Abstract
We have previously shown that obesity is an independent predictor of leukemia relapse in children. We have also shown that obese mice transplanted with syngeneic leukemia cells have poorer survival after chemotherapy, even when they are dosed proportional to body weight. Since interactions between leukemia cells and cells of the bone marrow niche are considered important for chemotherapy resistance and relapse, and adipocytes can comprise ~50% of the bone marrow niche, we developed in vivo and in vitro models to investigate the role of adipocytes in the leukemia microenvironment.
Obese C57Bl/6J mice were transplanted with GFP+ murine preB cell ALL (“8093”) cells and then treated with vincristine (0.5 mg/kg/week × 3 weeks). At the time of relapse, we found that GFP+ leukemia cells persisted in the fat pads of the mice. We then developed an in vitro co-culture system in which human or murine leukemia cells were cultured together with adipocytes (differentiated 3T3-L1s). Undifferentiated 3T3-L1 cells, which are fibroblastic in nature, were used as a control. In this model, adipocytes severely diminished the anti-leukemic effect of all chemotherapeutics tested against murine 8093 cells, including vincristine, dexamethasone, nilotinib, daunorubicin, and L-asparaginase. Adipocytes also protected murine T-cell ALL and human SD-1, RCH-ACV, and BV173 cells from vincristine and daunorubicin. Adipocyte protection of leukemia cells occurred independent of cell contact.
Further experiments demonstrated that media conditioned by adipocytes was able to protect 8093 cells from a 3-day exposure to 25 nM dexamethasone (viable cells were at 40±12% of their plated value in regular media, 66±17% in fibroblast-conditioned media, and 109±24% in adipocyte-conditioned media, p&lt;0.05). Surprisingly, adipocyte-conditioned media did not protect leukemia cells from daunorubicin. However, media conditioned by the presence of both adipocytes and leukemia cells simultaneously conferred a high degree of resistance to the leukemia cells (n=3, p&lt;0.05 compared to all other media types).
In summary, adipose tissue is a reservoir for relapsed leukemia cells in vivo. Adipocytes engender protection from multiple chemotherapies in murine and human leukemia cell lines. Adipocytes secrete factor(s) that confer dexamethasone and daunorubicin resistance to leukemia cells, though for the latter drug it appears that a two-way communication between leukemia and adipocytes may be necessary for this protection.
Figure Figure