bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factor VIII and Platelets Cooperatively Accelerate Proteolytic Cleavage of Von Willebrand Factor by ADAMTS13 Under Shear Stress
Authors: Skipwith Christopher G. , Cao Wenjing , Zheng X. Long 
Published: April 2020

Abstract
ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats-13) cleaves von Willebrand factor (vWF) at the Tyr1605-Met1606 bond of the central A2 domain. Inability to cleave vWF results in thrombotic thrombocytopenic purpura (TTP), which is characterized by profound thrombocytopenia and microangiopathic hemolytic anemia with various degrees of organ involvement. Previous studies have demonstrated that coagulation factor VIII (Cao et al, PNAS, 105:7416–21, 2008) or platelets (Shim et al, Blood, 111:651–7, 2008) can accelerate proteolytic cleavage of multimeric vWF in solution by ADAMTS13 under mechanic induced shear stresses. However, the concentrations of factor VIII or platelets required to achieve a detectable increase in the proteolytic cleavage product (350K) were beyond the physiological ranges. Therefore, the physiological significance of these findings remained to be determined. In this study, we assessed whether factor VIII and platelets, both of which bind vWF with high affinity, cooperatively affected the proteolytic cleavage of vWF by ADAMTS13 under high shear stress. All experiments were performed with a fixed concentration of vWF (150 nM) and ADAMTS13 (25 nM), and various concentrations of factor VIII and platelets in a buffer containing 20 mM HEPES, pH 7.5, 150 mM NaCl and 2 mM CaCl2. The reaction mixtures (total volume 20 μl in a 0.2 ml PCR tube) were subjected to vortexing at 2,500 rpm in MixMate (manufactured by Eppendorf), which generates laminar shear stress of approximately 30 dynes/cm2. We showed that in the absence of factor VIII, lyophilized platelets at the concentration of 1,000×109 per liter did not increase the proteolytic cleavage of plasma-derived vWF by ADAMTS13. An addition of factor VIII (1, 2, and 5 nM) to the reaction mixture markedly accelerated the rate enhancing effect of lyophilized platelets in a concentration-dependent manner. In the presence of physiological concentration of factor VIII (1–2 nM), the proteolytic cleavage product (350K) detected by Western blot under non-reducing conditions reached the maximal intensity at the platelet concentration of 100×109 per liter. B-domain deleted factor VIII (FVIII-SQ) showed the similar cooperativity with platelets accelerating proteolytic cleavage by ADAMTS13. However, a construct with the acidic region (a3) that binds vWF with high affinity removed (FVIII-2RKR) did not show any cooperativity with platelets in vWF proteolysis by ADAMTS13. We conclude that binding of factor VIII and platelets to vWF cooperatively accelerates the proteolytic cleavage of vWF by ADAMTS13 under high (arterial) shear stress. These findings provide novel insight into the regulation of ADAMTS13-mediated vWF proteolysis by a coagulation factor and platelets under physiological conditions. The data also suggest a potential role of factor VIII and platelets in the therapeutic regimen for TTP.
Array-CGH Identifies Both Common and Subtype-Specific Genomic Aberrations in Marginal Zone Lymphomas
Authors: Rinaldi Andrea , Rancoita Paola MV , Bhagat Govind , Novak Urban , Nandula Subhadra , Murty Vundavalli V. , Ponzoni Maurilio , Govi Silvia , Ferreri Andres JM , Baldini Luca , Gascoyne Randy , Soulier Jean , Thieblemont Catherine , Marasca Roberto , Franceschetti Silvia , Gaidano Gianluca , Canzonieri Vincenzo , Gattei Valter , Facchetti Fabio , Tucci Alessandra , Mollejo Manuela , Piris Miguel A. , Uccella Silvia , Tibiletti Maria Grazia , Dirnhofer Stephan , Forconi Francesco , Chigrinova Ekaterina , Doglioni Claudio , Dalla-Favera Riccardo , Zucca Emanuele , Kwee Ivo , Bertoni Francesco 
Published: April 2020

Abstract
Background and Aim. In the current WHO classification, marginal zone B-cell lymphomas (MZL) have been divided into three distinct subtypes (extranodal, EMZL; nodal, NMZL; splenic, SMZL) according to clinical, pathological and cytogenetic features, however the relationship between any of the different subtypes is still unclear. We thus performed a comprehensive analysis of genomic DNA copy number changes in a very large series of MZL cases with the aim of addressing this question.
Materials and Methods. DNA extracted from frozen samples of MZL was analyzed with Affymetrix Human Mapping 250K SNP arrays.
Results. Samples from 193 patients with MZL (23 NMZL, 63 EMZL, 84 SMZL and 23 not better specified MZL) from 15 Institutions were analyzed. Among EMZL, main primary sites were orbital adnexa in 28%, GI-tract in 16%, lung and salivary glands 5% each. Overall, MZL displayed more recurrent deletions than gains. Gains of 3q and 18 gains were common to all three MZL subtypes as were losses at 1p32.3-pter, 7p22.1-pter, 7q11.21–q11.23, 9q33.3-qter, 16p, 17p and 19. EMZL had significantly more gains at 3p14.2-pter, 6p and 7q31.3-qter and losses at 6q15, 6q23.3 and 14q11.2 than SMZL. Conversely, the latter had deletions of 7q31.32-qter and 14q23.3–q32.13 more frequently than EMZL. NMZL profiles showed the EMZL-specific 6q losses and the SMZL-related 7q losses at very low frequency while presented recurrent gains of chromosome 11, which was unique of NZML among the three subtypes. The 6q23.3 region contains the gene coding for TNFAIP3/A20, a negative regulator of the NFkB pathway. In SMZL a minimal deleted region was observed in 7q32.1. Regarding chromosome 3, gains targeted the whole chromosome in EMZL while, in SMZL and NMZL, the long arm was more commonly affected.
Conclusions. EMZL, NMLZ and SMLZL share genetic alterations, which differ from other B-cell lymphomas. However subtype-specific genetic lesions are observed. In particular, gains of 6p and losses of 6q23.3 (TNFAIP3) are specific for EMZL, and 7q31-qter for SMZL.
MicroRNA 15a and 16-1 Target Identification in Deletion 13 Multiple Myeloma
Authors: Henry Travis J. , Fonseca Rafael 
Published: April 2020

Abstract
Deletion 13 multiple myeloma (MM) is detected in nearly 50 % of patients diagnosed with MM and confers a shorter survival. A region of minimal deletion was identified for chromosome 13 using Agilent 500K aCGH arrays that included microRNAs 15a and 16- 1. MicroRNAs (miRs) are small RNAs that negatively regulate gene expression through degradation of mRNA transcripts or translational inhibition. In order to determine the contribution of deletion of miRs 15a and 16-1 to MM progression, miR precursors were transfected into KMS-11 and JJN3 adherent myeloma cell lines and total RNA hybridized to Affymetrix U133 Plus 2.0 gene expression arrays for the purpose of identification of mRNA target transcripts. Thirty nanomolar miR 15a and 16-1 precursors and a nonsilencing siRNA control were transfected into adherent KMS-11 and JJN3 myeloma cell lines. Cultures were harvested 16 hours after transfection to minimize the downregulation of transcripts that are not direct targets of miRs 15a and 16-1. Total RNA was extracted using the miRNeasy kit to allow retention of the miR fraction for RT-PCR confirmation of miR over-expression following transfection. Following transfection of miR precursors, expression of miRs 15a and 16-1 were increased 64 and 128-fold, respectively, compared to non-silencing control. Total RNA was hybridized to Affymetrix gene expression arrays using protocols supplied by the manufacturer. Transcripts down-regulated following miR transfection were compared to mathematical models for prediction of miR targets. Additionally, the 3′ UTRs of down-regulated transcripts were inspected for complementarity to miR 15a and 16-1 seed sequences. RT-PCR validation of identified targets was performed. Cross reference of down-regulated transcripts with the TargetSCAN and PictarVERT miR prediction algorithms resulted in a list of 9 genes that represented potential miR-15a/16-1 targets in MM. This list included: FGF2, BCL2, CCNE1, V-MYB, WEE1, E2F7, CDK6, CDC25A and CDC27. Following target identification, reporter constructs were used to confirm direct regulation of transcripts by miRs 15a and 16-1. Functional investigation of miR targets was performed using siRNA reduction of identified targets followed by MTT assay and cell cycle analysis.
Increased Signaling through p62 in the Marrow Microenvironment Increases Myeloma Cell Growth and Osteoclast Formation
Authors: Hiruma Yuko , Kurihara Noriyoshi , Jelinek Diane F. , Roodman David 
Published: April 2020

Abstract
Marrow stromal cells in the bone microenvironment of multiple myeloma (MM) patients play a critical role in promoting both tumor growth and bone destruction. Binding of MM cells to marrow stromal cells, through VCAM-1 on stromal cells and α4β1 integrin on MM cells, results in increased production of TNF-α, receptor activator of NF-KB ligand (RANKL) and IL-6 by marrow stromal cells. These factors in turn increase osteoclast (OCL) formation and the growth of MM cells. Adhesive interaction between MM cells and marrow stromal cells also decrease the sensitivity of MM cells to chemotherapeutic agents. Many of the downstream effects of these adhesive interactions are mediated through the NF-KB, p38 MAPK and JNK signaling pathways. The adapter protein sequestosome-1 (p62) sits at the crossroads of these signaling pathways and mediates the effects of cytokines and other factors that activate NF-KB, p38 MAPK and JNK. However, the role that increased signaling through p62 plays in MM tumor growth and bone destruction is unknown. It is our hypothesis that increased signaling through p62 in marrow stromal cells is necessary for their capacity to increase the growth of MM cells and OCL formation in MM, and thus p62 may be an attractive therapeutic target for MM. To test these hypotheses, we established long-term Dexter-type marrow cultures to isolate marrow stromal cells from MM patients and normals and measured signaling through p62 and PKCζ activation in MM marrow. We found significantly elevated levels of phosho-PKCζ, total PKCζ and VCAM-1 in MM stromal cells. The enhanced IL-6 production resulted from increased p38 MAPK activity and the increased VCAM-1 expression was NF-KB dependent. We then examined the effects of blocking p62 activity in primary patients and normal stromal cells with p62 siRNA (10μg). We confirmed that p62 expression was decreased by at least 90% in both these stromal cells by Western blot analysis. Stromal cells expressing p62siRNA or control siRNA were cultured with or without MM1.S cells for 3 days in separate experiments. Knocking-down p62 in MM derived marrow stromal cells significantly decreased the levels of PKCζ, VCAM-1 and IL-6 in marrow stromal cells and markedly decreased stromal cell support of MM cell growth and OCL formation. Similarly, marrow stromal cells from p62−/− mice produced much lower levels of IL-6, TNF-α, VCAM-1 and RANKL and minimally supported MM cell growth and OCL formation compared to normal cells. Thus, increased signaling through p62 in marrow stromal cells in patients with MM plays an important role in the increased tumor growth and OCL formation in MM, and support p62 as an attractive therapeutic target for MM.
REFRACTORY MEGALOBLASTIC ANEMIA
Authors: DAVIDSON L. S. P. , LOND  
Published: April 2020

Abstract
1. Fifty-nine cases of megaloblastic anemia refractory partially or completely to potent liver extracts given parenterally have been investigated in Edinburgh during the past six years. Thirty-four of these cases were associated with pregnancy, the puerperium or the sprue syndrome. No explanation of the cause of the megaloblastic anemia was discovered in the remaining 25 cases.
2. The etiology, clinical features and treatment of 25 cases of idiopathic refractory megaloblastic anemia are described. Attention is directed to the excellent therapeutic effects produced by proteolysed liver or folic acid.
3. The mechanisms involved in refractoriness to potent parenteral liver extracts are discussed.
4. In certain cases of refractory megaloblastic anemia it is suggested that an unknown hematinic principle, in addition to the liberating factor in purified parenteral liver extract and folic acid, is required for the complete restoration of normoblastic blood formation.
Targeted remodeling of breast cancer and immune cell homing niches by exosomal integrins
Authors: Myint Phyoe Kyawe , Park Eun Jeong , Gaowa Arong , Kawamoto Eiji , Shimaoka Motomu 
Published: April 2020

AbstractExosomes represent an important subset of extracellular vesicles involved in inter-cellular communications in health and diseases. Exosomes secreted from cancer and immune cells travel to the specific tissues containing homing niches. The exosomes reaching the niches dynamically modify the gene expression and molecular architectures of the homing niche micro-environments. Cell adhesion molecule integrins regulate the tissue-specific homing patterns of not only cancer and immune cells, but also of the exosomes secreted from those cells. The exosome-mediated remodeling of the homing niches would affect immune lymphocyte migration and host defense, as well as cancer metastasis, thereby representing a potential therapeutic target.
AcademH, a lineage of Academ DNA transposons encoding helicase found in animals and fungi
Authors: Kojima Kenji K. 
Published: April 2020

Abstract
Background
DNA transposons are ubiquitous components of eukaryotic genomes. Academ superfamily of DNA transposons is one of the least characterized DNA transposon superfamilies in eukaryotes. DNA transposons belonging to the Academ superfamily have been reported from various animals, one red algal species Chondrus crispus, and one fungal species Puccinia graminis. Six Academ families from P. graminis encode a helicase in addition to putative transposase, while some other families encode a single protein which contains a putative transposase and an XPG nuclease.

Results
Systematic searches on Repbase and BLAST searches against publicly available genome sequences revealed that several species of fungi and animals contain multiple Academ transposon families encoding a helicase. These AcademH families generate 9 or 10-bp target site duplications (TSDs) while Academ families lacking helicase generate 3 or 4-bp TSDs. Phylogenetic analysis clearly shows two lineages inside of Academ, designated here as AcademH and AcademX for encoding helicase or XPG nuclease, respectively. One sublineage of AcademH in animals encodes plant homeodomain (PHD) finger in its transposase, and its remnants are found in several fish genomes.

Conclusions
The AcademH lineage of TEs is widely distributed in animals and fungi, and originated early in the evolution of Academ DNA transposons. This analysis highlights the structural diversity in one less studied superfamily of eukaryotic DNA transposons.
Stair-climbing gait for a four-wheeled vehicle
Authors: Nakajima Shuro 
Published: April 2020

AbstractThis paper proposes a stair-climbing gait for a four-wheeled vehicle. The idea and methodology of climbing stairs are described, and the results of experiments are shown. Crawler-type vehicles and vehicles with special, complicated mechanisms are commonly used for climbing continuous steps (stairs). In contrast, in this paper, a four-wheeled vehicle with additional degrees of freedom, whose mechanism is not as complicated, is discussed. A gait algorithm based on a pace gait is proposed, and its performance is evaluated.
Lysine-Specific Demethylase 1 Affects the Progression of Papillary Thyroid Carcinoma via HIF1α and microRNA-146a
Authors: Long Miaoyun , Zhu Yue , Chen Zuhe , Lin Shaojian , Peng Xinzhi , Luo Dingyuan , Li Honghao , Tan Langping 
Published: April 2020

Abstract

Context
Lysine-specific demethylase 1 (LSD1) stabilizes hypoxia-inducible factor 1α (HIF1α) to advance tumor progression, while HIF1α functions as a transcription factor to increase the expression of microRNA-146a (miR-146a).

Objective
We aim to investigate whether LSD1 affects the development of papillary thyroid carcinoma (PTC) via HIF1α and miR-146a.

Design
In vitro assays were performed with Nthy-ori 3-1, BHP5-16, BCPAP, K1, and BHP2-7 cell lines. In vivo assays were conducted with established xenograft tumors in nude mice.

Setting
This study was conducted at our lab.

Patients and Materials
PTC tissues and corresponding adjacent normal tissues were obtained from 45 patients hospitalized in Sun Yat-Sen Memorial Hospital. Assays were conducted using Nthy-ori 3-1, BHP5-16, BCPAP, K1, and BHP2-7 cell lines, as well as 50 male BALB/c nude mice.

Intervention
Cells were transfected with sh-LSD1, sh-GABPA, oe-LSD1, oe-HIF1α, miR-146a mimic, and miR-146a inhibitor. In addition, K1 cells expressing lv-oe-LSD1, lv-miR-146a inhibitor, lv-oe-LSD1 or miR-146a inhibitor were injected into the right side of the mice. LSD1 gene and protein expression patterns were analyzed in 45 clinical PTC tissue samples.

Main Outcome Measure
Expression of LSD1, HIF1α, miR-146a, and GA-binding protein transcription factor alpha (GABPA), as well as their effects on PTC.

Results
LSD1 was highly expressed in clinical PTC tissues. LSD1 stabilized HIF1α and inhibited the degradation of its ubiquitin proteasome. HIF1α was enriched in the promoter region of miR-146a, an upregulated miRNA in PTC. HIF1α increased miR-146a expression to promote PTC progression in vitro, which was achieved by inhibiting GABPA, a target gene of miR-146a. LSD1 upregulated miR-146a to enhance the development and metastasis of PTC in nude mice.

Conclusion
Our results show that LSD1 functions as an oncogene in PTC by upregulating HIF1α and miR-146a, elucidating an understanding of undefined mechanisms associated with tumor progression in PTC.
Estradiol Valerate in COC Has More Favorable Inflammatory Profile Than Synthetic Ethinyl Estradiol: A Randomized Trial
Authors: Kangasniemi Marika H , Haverinen Annina , Luiro Kaisu , Hiltunen J Kalervo , Komsi Elina K , Arffman Riikka K , Heikinheimo Oskari , Tapanainen Juha S , Piltonen Terhi T 
Published: April 2020

Abstract

Context
Combined oral contraceptives (COCs) alter inflammatory status and lipid metabolism. Whether different estrogens have different effects is poorly understood.

Objective
We compared the effects of COCs containing ethinyl estradiol (EE) or estradiol valerate (EV) and dienogest (DNG) with those containing DNG only on inflammation and lipid metabolism.

Design
Randomized, controlled, open-label clinical trial.

Setting
Two-center study in Helsinki and Oulu University Hospitals.

Participants
Fifty-nine healthy, young, nonsmoking women with regular menstrual cycles. Age, body mass index, and waist-to-hip ratio were comparable in all study groups at the beginning. Fifty-six women completed the study (EV + DNG, n = 20; EE + DNG, n = 19; DNG only, n = 17).

Interventions
Nine-week continuous use of COCs containing either EV + DNG or EE + DNG, or DNG only as control.

Main Outcome Measures
Parameters of chronic inflammation (high-sensitivity C-reactive protein [hs-CRP], and pentraxin 3 [PTX-3]) and lipid profile (high-density lipoprotein [HDL], low-density lipoprotein [LDL], triglycerides, and total cholesterol).

Results
Serum hs-CRP increased after 9-week use of EE + DNG (mean change ± standard deviation 1.10 ± 2.11 mg/L) compared with EV + DNG (−0.06 ± 0.97 mg/L, P = 0.001) or DNG only (0.13 ± 0.68 mg/L, P = 0.021). Also, PTX-3 increased in the EE + DNG group compared with EV + DNG and DNG-only groups (P = 0.017 and P = 0.003, respectively). In the EE + DNG group, HDL and triglycerides increased compared with other groups (HDL: EE + DNG 0.20 ± 0.24 mmol/L vs EV + DNG 0.02 ± 0.20 mmol/L [P = 0.002] vs DNG 0.02 ± 0.18 mmol/L [P = 0.002]; triglycerides: EE + DNG 0.45 ± 0.21 mmol/L vs EV + DNG 0.18 ± 0.36 mmol/L [P = 0.003] vs DNG 0.06 ± 0.18 mmol/L [P &lt; 0.001]).

Conclusions
EV + DNG and DNG only had a neutral effect on inflammation and lipids, while EE + DNG increased both hs-CRP and PTX-3 levels as well as triglycerides and HDL.

Trial Registration
ClinicalTrials.gov NCT02352090
Familial Longevity is Associated with an Attenuated Thyroidal Response to Recombinant Human Thyroid Stimulating Hormone
Authors: Zutinic Ana , Pijl Hanno , Ballieux Bart E , Roelfsema Ferdinand , Westendorp Rudi G J , Blauw Gerard J , van Heemst Diana 
Published: April 2020

Abstract

Context
Longevity is associated with higher circulating levels of TSH in the absence of differences in circulating thyroid hormones (TH), as previously observed in F2 members of long-lived families (F2-LLS) and their partners (F2-Con). The mechanism underlying this observed difference remains unknown.

Objective
We hypothesized that the thyroid gland of members from long-lived families are less responsive to TSH stimulation, thereby requiring higher circulating TSH levels to maintain adequate TH levels.

Methods
We performed a case-control intervention study with a single intramuscular (gluteal) injection with 0.1 mg recombinant human TSH in a subgroup of 14 F2-LLS and 15 similarly aged F2-Con. They were followed for 4 days. No serious adverse events were reported. For analyses, we compared time trajectories of TSH and TH, and the ratio of TH to TSH using area under the curve (AUC) calculations.

Results
The AUC free T4/AUC TSH ratio was significantly lower in F2-LLS than in F2-Con (estimated mean [95% confidence interval] 1.6 [1.2-1.9] and 2.2 [1.9-2.6], respectively, P = 0.01). The AUC thyroglobulin/AUC TSH ratio was also lower in F2-LLS than in F2-Con (median [interquartile range] 2.1 [1.4-3.6] and 3.2 [2.7-7.4], respectively, P = 0.04). We observed the same trend with the AUC free T3/AUC TSH ratio, although the difference was not statistically significant (estimated mean [95% confidence interval] 0.6 [0.4-0.7] and 0.7 [0.6-0.8], respectively, P = 0.07).

Conclusions
The present findings show that members of long-living families have a lower thyroid responsivity to TSH compared with their partners.
Primary Aldosteronism in the Elderly
Authors: Mulatero Paolo , Burrello Jacopo , Williams Tracy Ann , Monticone Silvia 
Published: April 2020

Abstract

Context
The clinical spectrum and knowledge of the molecular mechanisms underlying primary aldosteronism (PA), the most frequent form of endocrine hypertension, has evolved over recent years. In accordance with the Endocrine Society guidelines and in light of the growing evidence showing adverse cardiovascular outcomes, it is expected that a progressively wider population of patients affected by hypertension will be screened for PA, including the elderly.

Evidence Acquisition
A systematic search of PubMed was undertaken for studies related to the renin-angiotensin-aldosterone system (RAAS), PA, and adrenal histopathology in the elderly population.

Evidence Synthesis
Several studies showed an age-dependent decrease in the activity of RAAS, together with a progressive decrease of the aldosterone response to sodium intake, particularly after the sixth decade of life. The positive correlation between age and serum aldosterone during liberal sodium intake over serum aldosterone during sodium restriction is paralleled by histological changes in adrenal aldosterone synthase (CYP11B2) expression patterns. Immunohistochemical studies showed a progressive loss of the continuous expression of CYP11B2 in the adrenal zona glomerulosa with aging and a concomitant increase of aldosterone-producing cell clusters, which might be responsible for relatively autonomous aldosterone production. Additionally, following PA confirmation and subtype diagnosis, older age is correlated with a lower benefit after adrenalectomy for unilateral PA.

Conclusions
Accumulating evidence suggests that RAAS physiology and regulation show age-related changes. Further studies may investigate to what extent these variations might affect the diagnostic workup of patients affected by PA.