bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV-1 Protease Inhibitor Ritonavir Potentiates the Effect of 1,25-Dihydroxyvitamin D3 to Induce Growth Arrest and Differentiation of Human Myeloid Leukemia Cells Via Inhibition of CYP24.
Authors: Ikezoe Takayuki , Yang Yang , Bandobashi Kentaro , Sekiguchi Nobuo , Sakai Shuichi , Koeffler H. Phillip , Taguchi Hirokuni 
Published: April 2020

Abstract
Ritonavir (RTV) is a potent inhibitor of cytochrome p450 (CYPs) enzymes. This study explores the effects of RTV on CYP24 which converts 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] to its inactive form 1,24,25,(OH)3. Real-time RT-PCR showed that exposure of HL-60 cells to 1,25(OH)2D3 (10−7 M, 1h) induced expression of CYP24 by 80-fold, and pre-incubation of these cells with RTV (2X10−5 M, 3h) decreased 1,25(OH)2D3-stumulated expression of CYP24 transcripts by 30 %, resulting in increased levels of 1,25(OH)2D3 in culture media (50.7 vs 82.4 nmol/L). Importantly, pre-incubation of HL-60 cells with RTV (2X10−5 M, 3h) and then exposure to 1,25(OH)2D3 (10−7 M, 24 h) also increased intracellular levels of 1,25(OH)2D3 (1.20 vs 2.46 nmol/L) and potentiated the ability of 1,25(OH)2D3 to induce growth arrest of HL-60 cells. Clonogenic assay showed that either RTV (5X10−6 M) or 1,25(OH)2D3 (10−8 M) alone inhibited colonal growth of HL-60 cells by either a mean 30 ± 12 (±SD) % and 40 ± 12 %, respectively; when both were combined, colony formation was inhibited by a mean 80 ± 13 % (p&lt;0.01). Measurement of CD14 expression, NBT reduction, and non-specific esterase staining showed that RTV augmented the prodifferentiative effects of 1,25(OH)2D3 in HL-60 cell. For example, 1,25(OH)2D3 (10−8 M, 2 days) induced approximately 48 % of HL-60 cells to become CD14 antigen positive. RTV (2X10−5 M, 48h) alone did not stimulate expression of CD14 antigen; when 1,25(OH)2D3 was combined with RTV, approximately 65 % of cells expressed CD14. Furthermore, androgen-independent DU145 human prostate cancer cells, that are resistant to growth inhibition by 1,25(OH)2D3, expressed 80-fold higher levels of CYP24 transcripts compared to HL-60 cells, and intracellular levels of 1,25(OH)2D3 were not detectable (&lt;0.3 nmol/L) after exposure of these cells to 1,25(OH)2D3 (10−7 M, 24 h). Of note, pre-incubation of these cells with RTV (2X10−5 M, 3h) and then exposure to 1,25(OH)2D3 (10−7 M, 24 h) increased intracellular levels of 1,25(OH)2D3 to 0.94 nmol/L and sensitized DU145 cells to growth inhibition mediated by 1,25(OH)2D3 as measured by MTT assay. Taken together, inhibition of CYP24 might open a new paradigm for therapy using vitamin D compounds.
Leukemia Proto-Oncoprotein MLL Forms a SET1 like Complex with Menin to Regulate Hox Gene Expression.
Authors: Yokoyama Akihiko , Wang Zhong , Wysocka Joanna , Sanyal Mrinmoy , Aufiero Deborah J. , Kitabayashi Issay , Herr Winship , Cleary Michael L. 
Published: April 2020

Abstract
MLL (Mixed Lineage Leukemia) is a proto-oncogene that is mutated in a variety of human leukemias. Oncogenic MLL fusion genes created by chromosomal translocations cause acute myeloid or lymphoid leukemias often in infants. MLL, a homolog of Drosophila trithorax, displays intrinsic histone methyltransferase activity and functions genetically to maintain embryonic Hox gene expression. But its regulatory mechanism is poorly understood. Our previous studies showed that MLL undergoes a variety of post-translational modifications to assume its mature form. Most uniquely, MLL is proteolytically processed after translation into two major polypeptides, MLL-N and MLL-C, which possess opposite transcriptional properties and associate with each other through their intra-molecular interaction domains. In order to understand the function of MLL and its regulatory mechanism, we performed the biochemical purification of MLL. MLL-C was found to associate with a cohort of proteins shared with the yeast and human SET1 histone methyltransferase complexes, including ASH2L (highly conserved protein of unknown function whose Drosophila homolog genetically interacts with trithorax), WDR5 and RBBP5 (two WD repeat proteins implicated in histone binding) to form an MLL-C histone methyltransferase (HMT) sub-complex centered on its SET domain. Two other members of the novel MLL complex identified here are Host Cell Factor 1 (HCF-1), a transcriptional coregulator, and the related HCF-2, both of which specifically interact with a conserved binding motif in the MLL-N (p300) subunit of MLL and provide a potential mechanism for regulating its antagonistic transcriptional properties. Menin, a product of the MEN1 tumor suppressor gene, is also a component of the 1 MDa MLL complex. Abrogation of menin expression phenocopies loss of MLL, and reveals a critical role for menin in the maintenance of Hox gene expression. Oncogenic mutant forms of MLL retain an ability to interact with menin, but not other identified complex components. These studies link the menin tumor suppressor protein with the MLL histone methyltransferase machinery, with implications for Hox gene expression in development and leukemia pathogenesis.
Dysregulation of Actin Polymerization in Hematopoietic Cells Transformed by Bcr-Abl.
Authors: Dai Zonghan , Li Yingzhu , Clough Nancy , McNiece Ian 
Published: April 2020

Abstract
Actin polymerization is a fundamental cellular process that controls cytoskeletal functions such as adhesion, migration, and homing. This dynamic cellular process is spatiotemporally regulated in normal cells but its dysregulation is often observed in tumor cells and is believed to contribute to tumor metastasis. Hematopoietic cells isolated from Bcr-Abl positive leukemia patients exhibit multiple abnormalities in cytoskeletal function. The mechanism associated with these abnormalities is not completely understood. Previously, we showed that the expression of Bcr-Abl in hematopoietic cells induces tyrosine phosphorylation of Ableson interactor (Abi) 1 and ubiquitin dependent degradation of Abi 2. The dysregulation of Abi 1 and Abi 2 requires the SH3 domain and C-terminal proline-rich sequences of Bcr-Abl. Deletion of these sequences in Bcr-Abl not only abrogates Abi-1 tyrosine phosphorylation and Abi-2 degradation but also impairs leukemogenic activity of Bcr-Abl. Notably, the mutant Bcr-Abl with deletion of these sequences failed to induce splenomegaly in a bone marrow transplant mouse model. Because Abi proteins have been shown to function as a key regulator of actin polymerization, we examined the F-actin organization in Ba/F3 cells transformed by wild type Bcr-Abl (p185wt) and a mutant Bcr-Abl defective in signaling to Abi (p185ΔSH3ΔC). Actin polymerization is increased in Ba/F3 cells transformed by either p185wt or p185ΔSH3ΔC, as compared to control Ba/F3 cells. However, the pattern of F-actin organization in these cells appears different. The expression of p185wt induces a localized abnormal F-actin structure which is not observed in control Ba/F3 cells and the Ba/F3 cells transformed by p185ΔSH3ΔC. We have characterized this abnormal F-actin structure and show that it co-localizes with Bcr-Abl. Investigation is now underway to determine whether the Abi/WAVE pathway is involved in Bcr-Abl-induced abnormal F-actin structure. These studies may provide insight into the mechanism by which Bcr-Abl induces cytoskeletal abnormalities in CML cells.
Venous Thromboembolism (VTE) Risk Factors among Nursing Home Residents: A Population-Based Case-Control Study.
Authors: Petterson Tanya M. , Leibson Cynthia L. , Heit John A. , Bailey Kent R. , Melton L. Joseph 
Published: April 2020

Abstract
Confinement to a nursing home (NH) is an independent risk factor for VTE and accounts for 13% of all VTE occurring in the community, but the question of which NH residents are at risk is largely unanswered.
Objective: To determine VTE risk factors among NH residents.
Methods: Using the Minnesota State Case Mix Review Program Public Research Files, we performed a case-control study of all Olmsted County, MN NH patients with an ICD-9 code-identified diagnosis of VTE from 1988–1994. From the same source, we identified one age-, sex-matched control and used conditional logistic regression to estimate odds ratios for an association of VTE with 46 characteristics assessed in the Minnesota Case Mix data.
Results: Univariate associations between characteristics and odds of VTE are described below. Significantly increased odds were observed for residents assessed following hospitalization (a nearly 4-fold increase, p=0.002, Table) and residents considered incapable of self-preservation (i.e., unable to cope with potentially harmful situations) (&gt; 2.0 fold increase, p=0.03). Non-significant 2–3 fold increased odds were observed for limitations in certain specific Activities of Daily Living (ADL) (including walking and dressing) and for limitations in more than 3 ADLs. Similar increased odds were observed for residents using a wheelchair, taking more than 3 oral medications, enrolled in professional activity programs, and needing behavior management.
Conclusions: Need for assistance (especially problems with immobility), lack of self preservation, and recent hospitalization may identify a subset of NH residents that are at especially high VTE risk and who may warrant consideration of prophylaxis.
Univariate VTE Risk Factors for Nursing Home Residents
Characteristic Odds Ratio 95% CI P-value Oral medications &gt; 3 3.00 0.97-9.30 0.06 Activities of Daily Living High/Medium (4-8) vs. low (0-3) 2.20 0.76-6.33 0.14 Help dressing 2.75 0.88-8.64 0.08 Help walking 3.00 0.61-14.86 0.18 Wheelchair use 2.50 0.97-6.44 0.58 Needs behavior management 3.00 0.62-14.86 0.18 Help toileting 2.00 0.68-5.85 0.20 Lack of self-preservation 2.33 1.07-5.10 0.03 Transfer from hospital 3.86 1.68-8.86 0.0015 Anti-depressant drugs 0.50 0.19-1.33 0.16 Professional activity program 2.25 0.69-7.3 0.18
Endothelial Cells Derived from Human Vessel Walls Contain a Complete Hierarchy of Endothelial Progenitor Cells.
Authors: Ingram David A. , Mead Laura E. , Woodard Wayne , Fenoglio Amy , Murphy Brian , Harvey Celeste , Moore Daniel B. , Yoder Mervin C. 
Published: April 2020

Abstract
Endothelial progenitor cells (EPCs) can be isolated from adult peripheral and umbilical cord blood. EPCs are thought to originate from bone marrow, circulate in peripheral blood, and migrate to sites of angiogenesis. However, the number of circulating EPCs in peripheral blood is remarkably low, and recent genetic studies show that the contribution of bone marrow derived EPCs to newly formed vascular networks is minimal. Further, while endothelial cells (ECs) derived from vessel walls are widely considered to be differentiated mature ECs, these cells retain extensive proliferative potential and can be passaged for at least 40 population doubling in vitro. Based on these observations, we tested whether EPCs potentially reside in vessel walls utilizing a newly developed single cell deposition assay (Blood, 2004). Analogous to a paradigm established in the hematopoietic cell system, we can utilize this assay to reproducibly identify the following EPCs: (1) high proliferative potential - endothelial colony forming cells (HPP-ECFC), which form macroscopic colonies that form secondary and tertiary colonies upon replating, (2) low proliferative potential - endothelial colony forming cells (LPP-ECFC), which form colonies greater than 50 cells, but do not form secondary colonies upon replating, (3) endothelial cell clusters (EC-clusters) that contain less than 50 cells, and (4) mature terminally differentiated endothelial cells (EC), which do not divide. Utilizing this assay, we compared the clonogenic potential of 1000 single adult human dermal microvascular endothelial cells (HMVECds), human umbilical vein endothelial cells (HUVECs), human umbilical artery endothelial cells (HUAECs), human coronary artery endothelial cells (HCAECs), and human aortic endothelial cells (HAECs) to the potential of adult peripheral and umbilical cord blood derived EPCs. We conducted four independent experiments. Remarkably, we demonstrate that a complete hierarchy of EPCs can be identified in EC populations derived from every vessel wall tested (Table I and n=4). Further, we show that ECs derived from each vessel wall cell population tested contain more proliferative EPCs (LPP-ECFCs and HPP-ECFCs) compared to EPCs derived from adult peripheral blood.
Percent of 1,000 Single Cells Plated
Mature EC EC-Cluster LPP-ECFC HPP-ECFC HUVEC 42±6 18±2 29±9 11±5 HAEC 37±3 23±8 21±4 20±6 HMVECd 65±9 21±6 12±4 2±0.6 HCAEC 46±2 18±2 20±2 16±2 HUAEC 41±1 10±1 27±4 21±2 Adult EPC 81±9 9±1 12±8 0.2±0.2 Cord EPC 50±20 7±2 20±10 23±9
Thus, this study provides evidence that a diversity of EPCs exists in human vessels and provides a new conceptual framework for determining both the origin and function of EPCs in maintaining vessel integrity and contributing to new sites of angiogenesis.
Hyperhomocysteinemic Mice Have Increased Susceptibility to Carotid Artery Thrombosis.
Authors: Wilson Katina M. , Dayal Sanjana , Bottiglieri Teodoro , Lentz Steven R. 
Published: April 2020

Abstract
Hyperhomocysteinemia is a risk factor for cardiovascular disease, stroke, and venous thrombosis. In animal models, hyperhomocysteinemia produces endothelial dysfunction due to decreased bioavailability of endothelium-derived nitric oxide (NO). Because NO has antithrombotic properties, we tested the hypothesis that hyperhomocysteinemia accelerates photochemically-induced carotid artery thrombosis induced in mice. Mice heterozygous for a targeted disruption of the cystathionine β-synthase (Cbs) gene (Cbs+/−) and wild type littermates (Cbs+/+) were fed either a control diet or a high methionine/low folate (HM/LF) diet for 8 months. Plasma total homocysteine was elevated by the HM/LF diet compared with the control diet in both Cbs+/+ (11.6±1.2 vs. 3.7±0.5 μmol/L; p&lt;0.05) and Cbs+/− mice (26.4±3.8 vs. 6.2±0.6 μmol/L; p&lt;0.001). The time to stable occlusion after photochemical injury (rose bengal and green laser) of the carotid artery was 50% shorter in mice fed the HM/HF diet (17.5±2.3 and 18.2±4.0 minutes for Cbs+/+ and Cbs+/− mice, respectively) compared with mice fed the control diet (44.0±9.1 and 31.4±4.7 minutes for Cbs+/+ and Cbs+/− mice, respectively; p&lt;0.001). Using the oxidative dye, dihydroethidium (DHE), increased production of superoxide was detected in Cbs+/+ and Cbs+/− mice fed the HF/HM diet compared with the control diet. To determine whether lack of endothelium-derived NO may accelerate carotid artery thrombosis, mice deficient in endothelial nitric oxide synthase (Nos3−/ −) were also studied. Time to occlusion did not differ between Nos3−/ − mice and wild type mice (55.0±10.2 vs. 42.1±7.1 minutes, p=0.31). We conclude that hyperhomcysteinemia increases susceptibility to experimental thrombosis through a mechanism that is independent of endothelium-derived NO, but may involve oxidative stress.
Cerebral Vascular Dysfunction in Methionine Synthase-Deficient Mice.
Authors: Dayal Sanjana , Devlin Angela M. , McCaw Ryan B. , Liu Mei-lan , Arning Erland , Bottiglieri Teodoro , Shane Barry , Faraci Frank M. , Lentz Steven R. 
Published: April 2020

Abstract
Methionine synthase (MS) is a key enzyme involved in remethylation of homocysteine to methionine. We tested the hypothesis that deficiency of MS influences endothelial function. Mice heterozygous for disruption of the Ms gene (Ms+/−), and wild type littermates (Ms+/+), were fed either a control diet or a low folate (LF) diet. Plasma total homocysteine was similar in Ms+/+ and Ms+/− mice fed the control diet (4.5±0.3 and 5.3±0.4 μmol/L, respectively), and was mildly elevated in Ms+/+ or Ms+/− mice fed the LF diet (7.5±0.7 and 9.6±1.2 μmol/L, respectively; p&lt;0.001 vs. control diet). Dilatation of cerebral arterioles (~30 μm diameter) to the endothelium-dependent dilator, acetylcholine (10 μM), was blunted in Ms+/− mice compared with Ms+/+ mice fed the control diet (21±4 vs. 32±4%; p&lt;0.05). Both Ms+/+ and Ms+/− mice exhibited impaired dilatation of cerebral arterioles to acetylcholine when they were fed the LF diet (12±2 and 17±3%, respectively; p&lt;0.01 vs. Ms+/+ mice fed the control diet). Dilatation of cerebral arterioles in response to the endothelium-independent dilator, nitroprusside, was similar in all groups of mice. Relaxation of aortic rings to acetylcholine was not influenced by Ms genotype or diet. Elevated levels of superoxide and hydrogen peroxide were detected by dihydroethidium (DHE) and dichlorodihydrofluorescein (DCF), respectively, in cerebral arterioles of Ms+/− mice fed the control diet and in both Ms+/+ and Ms+/− mice fed the LF diet. These findings demonstrate that defective homocysteine remethylation caused by deficiency of either MS or folate produces endothelial dysfunction and increased oxidative stress in the cerebral microcirculation of mice. Interestingly, impairment of cerebral vascular function was independent of plasma tHcy concentration.
Modulation of Tissue Factor-Factor VIIa Coagulant and Signaling Functions by Membrane Cholesterol and Caveolae.
Authors: Awasthi Vineet , Rao L. Vijaya Mohan , Pendurthi Usha 
Published: April 2020

Abstract
Cholesterol in the membrane not only regulates flexibility and mechanical stability of the membrane but also plays a critical role in differentiating and maintaining cell surface microdomains of differing lipid composition, particularly sphingolipid rafts. Cholesterol- and sphingolipid-rich rafts in association with a structural protein, caveolin, form caveolae, flask-shaped invaginations in the plasma membrane. Lipid rafts and caveolae are shown to regulate various cellular functions, including receptor function, endocytosis, intracellular trafficking of receptors and signaling pathways. In the present study, we investigated the role of membrane cholesterol and caveolae in modulating coagulant and signaling functions of tissue factor (TF)-factor VIIa (VIIa) complexes on tumor cells. Breast carcinoma cells, MDA-MB-231, were treated with ß-methyl cyclodextrin (CD), which depletes membrane cholesterol and thereby disrupts caveolae, or with filipin, which disrupts caveolae without depleting the membrane cholesterol. TF-VIIa coagulant function was measured in factor X activation assay and the signaling function was evaluated in IP3 hydrolysis and IL-8 gene induction. As expected, CD (10 mM) treatment of tumor cells depleted cellular cholesterol level by more than 70% whereas filipin (5 μg/ml) treatment did not reduce the cellular cholesterol level. Both the treatments had no effect on the cell viability as measured in trypan blue exclusion method and MTT assay. CD treatment, in a dose-pendent manner (1 to 10 mM CD), impaired both TF-VIIa coagulant function and the signaling function (both IP3 hydrolysis and IL-8 gene expression). In contrast, varying effects were observed with filipin treatment. Filipin treatment (5 μg/ml) increased TF-VIIa coagulant function, reduced the TF-VIIa-induced IP3 hydrolysis and no effect on TF-VIIa-induced IL-8 gene expression. Detergent (Triton X-100) extraction of cells followed by fractionation on sucrose gradient centrifugation showed that TF was distributed both in lipid rafts and soluble fractions. CD and filipin treatments slightly reduced TF association with lipid rafts. Overall these data suggest that the membrane cholesterol modulates TF-VIIa proteolytic function and hence the TF-VIIa protease-induced signaling. In contrast, disruption of caveolae uncouples selective signaling pathways activated by TF-VIIa without impairing TF-VIIa protease activity.
Phase II Study of SGN-30 (Anti-CD30 Monoclonal Antibody) in Patients with Refractory or Recurrent Hodgkin’s Disease.
Authors: Leonard John P. , Rosenblatt Joseph D. , Bartlett Nancy L. , Gopal Ajay , Younes Anas , Fisher David , Foss Francine , Forero Andres , Bernstein Steven , Cheson Bruce , Carabasi Matthew H. , Bociek R. Gregory , Hart Bruce , McDonald Michael 
Published: April 2020

Abstract
SGN-30 is a chimeric monoclonal antibody which recognizes the CD30 antigen found on tumor cells from patients with Hodgkin’s disease (HD) and anaplastic large cell lymphoma (ALCL). Preclinical studies with this agent have demonstrated anti-lymphoma effects in both in vitro cell line assays and in vivo murine model systems. The results of a multi-dose phase I study showed minimal toxicity associated with doses from 2 to 12 mg/kg administered as six weekly IV infusions over 120 minutes each. Of the 21 patients with Hodgkin’s Disease accrued to the phase I study, four patients had stable disease (SD). A phase II multi-dose study is currently underway to further evaluate the safety, antitumor activity and pharmacokinetics of six weekly IV infusions of 6 mg/kg of SGN-30 in patients with relapsed or refractory HD or systemic ALCL (sALCL). Fifteen subjects (6M, 9F) with HD have been enrolled, with baseline data as follows: median age 34 (range 20–65), median number of prior therapies 3 (range 1–5), and 11 patients (73%) have disease which progressed after prior high-dose chemotherapy and stem cell transplant. Multiple doses of SGN-30 have been well tolerated in all subjects. Drug-related adverse events have been typically mild and consistent with monoclonal antibody administration. The most common drug-related adverse event has been fatigue. No grade 3/4 events have occurred. Twelve patients are currently evaluable for response, with 6 having had stabilization of their disease. Assessment of duration of disease stabilization and response is continuing. While the acceptable safety profile and frequency of stable disease following therapy in this heavily pretreated patient population are encouraging, a 12 mg/kg/dose regimen is now being tested in subsequent subjects to further explore the dose-response relationship of SGN-30 in Hodgkin’s Disease. Further evaluation of this novel immunotherapy in additional HD patients is ongoing.