Статті в журналах: "S-NO-HSA"

1

Tsiountsioura, Melina, Gerhard Cvirn, Axel Schlagenhauf, Harald Haidl, Kathrin Zischmeier, Nicole Janschitz, Martin Koestenberger, et al. "The Antiplatelet Action of S-Nitroso Human Serum Albumin in Whole Blood." Biomedicines 10, no. 3 (March 11, 2022): 649. http://dx.doi.org/10.3390/biomedicines10030649.

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Nitric oxide donors (NO-donors) have been shown to have therapeutic potential (e.g., ischemia/reperfusion injury). However, due to their release rate/antiplatelet properties, they may cause bleeding in patients. We therefore studied the antiplatelet effects of the two different NO-donors, i.e., S-NO-Human Serum Albumin (S-NO-HSA) and Diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate) in whole blood (WB) samples. WB samples were spiked with S-NO-HSA or DEA-NONOate (100 µmol/L or 200 µmol/L), and the NO release rate (nitrite/nitrate levels via HPLC) and antiplatelet efficacy (impedance aggregometry, platelet function analyzer, Cone-and-platelet analyzer, thrombelastometry) were assessed. S-NO-HSA had a significantly lower NO release compared to equimolar concentrations of DEA-NONOate. Virtually no antiplatelet action of S-NO-HSA was observed in WB samples, whereas DEA-NONOate significantly attenuated platelet function in WB. Impedance aggregometry measurements revealed that Amplitudes (slope: −0.04022 ± 0.01045 ohm/µmol/L, p = 0.008) and Lag times (slope: 0.6389 ± 0.2075 s/µmol/L, p = 0.0051) were dose-dependently decreased and prolonged by DEA-NONOate. Closure times (Cone-and-platelet analyzer) were dose-dependently prolonged (slope: 0.3738 ± 0.1403 s/µmol/L, p = 0.0174 with collagen/ADP coating; slope: −0.5340 ± 0.1473 s/µmol/L, p = 0.0019 with collagen/epinephrine coating) by DEA-NONOate. These results in WB further support the pharmacological potential of S-NO-HSA as an NO-donor due to its ability to presumably prevent bleeding events even at high concentrations up to 200 µmol/L.

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Jakubovics, Nicholas S., Steven W. Kerrigan, Angela H. Nobbs, Nicklas Strömberg, Craig J. van Dolleweerd, Dermot M. Cox, Charles G. Kelly, and Howard F. Jenkinson. "Functions of Cell Surface-Anchored Antigen I/II Family and Hsa Polypeptides in Interactions of Streptococcus gordonii with Host Receptors." Infection and Immunity 73, no. 10 (October 2005): 6629–38. http://dx.doi.org/10.1128/iai.73.10.6629-6638.2005.

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ABSTRACT Streptococcus gordonii colonizes multiple sites within the human oral cavity. This colonization depends upon the initial interactions of streptococcal adhesins with host receptors. The adhesins that bind salivary agglutinin glycoprotein (gp340) and human cell surface receptors include the antigen I/II (AgI/II) family polypeptides SspA and SspB and a sialic acid-binding surface protein designated Hsa or GspB. In this study we determined the relative functions of the AgI/II polypeptides and Hsa in interactions of S. gordonii DL1 (Challis) with host receptors. For an isogenic mutant with the sspA and sspB genes deleted the levels of adhesion to surface-immobilized gp340 were reduced 40%, while deletion of the hsa gene alone resulted in >80% inhibition of bacterial cell adhesion to gp340. Adhesion of S. gordonii DL1 cells to gp340 was sialidase sensitive, verifying that Hsa has a major role in mediating sialic acid-specific adhesion to gp340. Conversely, aggregation of S. gordonii cells by fluid-phase gp340 was not affected by deletion of hsa but was eliminated by deletion of the sspA and sspB genes. Deletion of the AgI/II polypeptide genes had no measurable effect on hsa mRNA levels or Hsa surface protein expression, and deletion of hsa did not affect AgI/II polypeptide expression. Further analysis of mutant phenotypes showed that the Hsa and AgI/II proteins mediated adhesion of S. gordonii DL1 to human HEp-2 epithelial cells. Hsa was also a principal streptococcal cell surface component promoting adhesion of human platelets to immobilized streptococci, but Hsa and AgI/II polypeptides acted in concert in mediating streptococcal cell-platelet aggregation. The results suggest that Hsa directs primary adhesion events for S. gordonii DL1 (Challis) with immobilized gp340, epithelial cells, and platelets. AgI/II polypeptides direct gp340-mediated aggregation, facilitate multimodal interactions necessary for platelet aggregation, and modulate S. gordonii-host engagements into biologically productive phenomena.

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Nakajima, G., K. Uchida, K. Hayashi, Y. Xi, K. Takasaki, and J. Ju. "Non-coding microRNA hsa-let-7g as a novel chemoresponse biomarker for S-1 in colon cancer." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13513. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13513.

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13513 Background: MicroRNAs (miRNAs) are small non-cording RNAs (∼ 22 nucleotide) that regulate gene expression by suppressing their target mRNAs at post-transcriptional level. Previous studies from our group have identified a number of dis-regulated miRNAs due to the loss of p53 tumor suppressor in cancer cell lines. As part of the efforts to further investigate the in vivo biological significance of these miRNAs, the expression of both hsa-let-7g and hsa-miR-200c were investigated using formalin-fixed paraffin embedded (FFPE) colon cancer specimens to evaluate the potential correlation with chemosensitivity and tumorigenesis. Methods: Forty-six patients with recurrent or residual colon cancer lesion assessable were treated with 5-FU based antimetabolite S-1. This includes twenty-one pair of tumor and normal samples. Total RNAs were isolated from these samples FFPE specimens (contains either > 90% normal or > 90% tumor tissue). cDNAs were synthesized using primers specific for hsa-let-7g, hsa-miR-200c and internal control 5S. The expression levels of each particular miRNAs were quantified using real time qRT-PCR analysis. The expression level of each miRNAs was quantified by measuring the difference of threshold cycle (CT) of candidate miRNAs and internal control 5S (Δ-CT). Results: The expression level of hsa-let-7g was significantly higher in tumor tissues compare to normal tissues (p=0.0026; Wilcoxon test). In the forty-six tumor tissues, the expression level of hsa-let-7g in disease response group (patients group of complete response, partial response and no change after chemotherapy) was significantly lower than the disease progression group (p=0.03; Mann-Whitney test). The expression of hsa-miR-200c was significantly over-expressed in tumor tissues compare to normal tissues (p=0.0001; Wilcoxon test). Although hsa-let-7g is strongly associated with patient’s response to S-1 treatment, it is not a prognostic factor for predicting survival. Conclusion: hsa-let-7g and hsa-miR-200c may be associated with tumorigenesis in colon cancer. In addition, hsa-let-7g may be a significant indicator for chemoresponse to S-1 based chemotherapy. No significant financial relationships to disclose.

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Rogóż, Wojciech, Jadwiga Pożycka, Aleksandra Owczarzy, Karolina Kulig, and Małgorzata Maciążek-Jurczyk. "Comparison of Losartan and Furosemide Interaction with HSA and Their Influence on HSA Antioxidant Potential." Pharmaceuticals 15, no. 5 (April 19, 2022): 499. http://dx.doi.org/10.3390/ph15050499.

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Serum albumin (HSA) is the most important protein in human body. Due to the antioxidant activity, HSA influences homeostasis maintenance and transport of drugs as well as other substances. It is noteworthy that ligands, such as popular drugs, modulate the antioxidant activity of HSA. The aim of this study was to analyze the influence of losartan (LOS) and furosemide (FUR) on HSA antioxidant properties as well as the interaction between these drugs and protein using calorimetric and spectroscopic methods. LOS and FUR showed the high affinity for human serum albumin, and the binding reactions between them were spontaneous and exothermic. LOS and FUR, separately and together in the system, have no significant impact on the secondary HSA structure; however they have significant impact on the tertiary HSA structure. LOS and FUR mixed with HSA have the ability to scavenge free radicals, and the ligand(s)–HSA interactions were synergistic.

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Neumayer, C., A. Fügl, J. Nanobashvili, S. Hallström, H. Gasser, M. Prager, V. Brovkovych, P. Polterauer, T. Malinski, and I. Huk. "S-NITROSO HUMAN SERUM ALBUMIN (S-NO-HSA) REDUCES ISCHEMIA/REPERFUSION INJURY OF SKELETAL MUSCLE - HISTOMORPHOMETRIC ASPECTS." Shock 12, Supplement (November 1999): 58–59. http://dx.doi.org/10.1097/00024382-199911001-00182.

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Kerrigan, Steven W., Nick S. Jakubouvics, Gerardene Meade, Howard F. Jenkinson та Dermot M. Cox. "A Novel GPIbα Binding Protein on Streptococcus Gordonii Induces Platelet Rolling at Low Shear." Blood 104, № 11 (16 листопада 2004): 3663. http://dx.doi.org/10.1182/blood.v104.11.3663.3663.

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Abstract Infective endocarditis is associated with considerable morbidity and mortality and oral Streptococci are the priniciple causative organism. Platelet adhesion and subsequent aggregation play a critical role in the pathogenesis and dissemination of the infective process. The mechanism by which S. gordonii interacts with and subsequently leads to platelet activation is currently unknown. Previously we described the ability of Streptococcus sanguis to induce platelet aggregation via the platelet vonWillebrand factor receptor, GPIbα, however identification of the bacterial protein involved was not established. Here we describe the novel interaction between a Streptococcal protein that triggers aggregation via platelet GPIbα, in a unique fashion. Wildtype S. sanguis (133–79) and S. gordonii (DL1) support platelet adhesion and induce αIIbβ3 dependent platelet aggregation. Pre-incubation of platelets with an anti-GPIbα antibody inhibited the adhesion (61±6%, p<0.001) and abolished platelet aggregation (0% of control, p<0.001) induced by S. gordonii. These results suggest that GPIbα is a key receptor for recognition of platelets by streptococci. Passing a mutanolysin cell wall extract of S. sanguis through a GPIb affinity column identified a highly glycosylated protein, Hsa, also present on S. gordonii. S. gordonii DL-1 deficient in the Hsa gene, was generated by allelic exchange with an antibiotic resistance cassette. Platelet adhesion to S. gordonii ΔHsa was reduced by 41±5%, (p<0.001), however aggregation was unaffected (49±7% vs 55±5% wt). To confirm that Hsa was binding to platelet GPIbα we immobilised soluble GPIbα (glycocalicin, 0.2μg/ml) on a 96 well plate. Wildtype S. gordonii bound to immobilised glycocalicin, however, the Hsa mutant adhered significantly less (9±3% of wildtype, p<0.001). Furthermore, wildtype S. gordonii induced αIIbβ3 dependent platelet aggregation in washed platelets in the absence of vWf, suggesting a direct interaction between Hsa and GPIbα. We further investigated the interaction between GPIbα and Hsa under shear. Experiments were recorded in real time for a period of 8 minutes. Upon commencement of shear (50s-1), platelets interacted with S. gordonii DL-1 with a rolling fashion followed by firm adhesion. This adhesion was completely inhibited by addition of an anti-GPIbα antibody. When platelets were sheared over immobilized S. gordonii ΔHsa no interaction was observed. In addition, S. gordonii DL-1 failed to interact with platelets at the higher shear rate of 500s-1. Collectively, these results identify a unique interaction between S. gordonii Hsa and platelet GPIbα. This interaction occurs at static and low shear but not at high shear, which is in direct contrast to the interaction between vwf and GPIbα. Furthermore, we propose that the platelet interaction with S. gordonii appears to be a 2 step process. Firstly, platelets roll across the S. gordonii via a GPIbα - Hsa interaction. Following this a second more stable interaction firmly immobilizes the platelet, thereby facilitating the intravascular colonization of a septic plaque.

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Mahata, Shibendu, Suman Kumar Saha, Rajib Kar, Durbadal Mandal, and Nilotpal Banerjee. "A Heuristic Approach to Design Discrete Fractional Order Integrators without Using s-to-z Transform." Solid State Phenomena 261 (August 2017): 386–93. http://dx.doi.org/10.4028/www.scientific.net/ssp.261.386.

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In this paper, a heuristic optimization technique called Harmony Search Algorithm (HSA) is efficiently employed to design Infinite Impulse Response (IIR) Discrete Fractional Order Integrators (DFOIs). Unlike the methods reported in the literature, no discretization (s-to-z transform) operator is necessary to obtain the DFOIs by using the proposed approach. To investigate the design efficiency, the HSA-based DFOIs have been evaluated against the designs based on Real coded Genetic Algorithm (RGA), Particle Swarm Optimization (PSO), and Differential Evolution (DE) using different frequency response error metrics. The reliability in the performance of the proposed DFOIs are extensively investigated by conducting various statistical tests. Comparison of fitness convergence demonstrates that HSA achieves the near global optimal solution in the least number of iterations. Thus, HSA exhibits superior computational efficiency in solving this multimodal optimization problem. The proposed DFOIs also outperform the reported designs.

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Bahlis, Nizar J., Carolyn J. Owen, Paola Neri, Adnan Mansoor, Kathy J. Gratton, Peter Duggan, Pietro Ravani, and Douglas A. Stewart. "A miRNA Risk Score for the Prediction of Response to Rituximab-CHOP Therapy and Survival of Patients with Diffuse Large B-Cell Lymphoma." Blood 116, no. 21 (November 19, 2010): 324. http://dx.doi.org/10.1182/blood.v116.21.324.324.

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Abstract Abstract 324 Background: Diffuse large B-cell lymphoma (DLBCL) may be curable with current immuno-chemotherapy, however nearly 30% of patients fail to benefit from this therapeutic approach. Gene expression profiling studies identified lymphocyte as well as stroma-based mRNA signatures that are predictive of response to R-CHOP; however the need for optimally cryopreserved samples has limited their clinical applicability. MicroRNAs (miRNA) are highly preserved non-coding RNAs that act post-transcriptionally to regulate gene expression by binding to the 3′UTR of mRNAs. To date multiple studies have reported selective miRNAs expression at different lymphocyte differentiation stages, distinct expression in mRNA-defined DLBCL subgroups and have correlated the expression of “selected” miRNAs with disease outcomes. Herein, we have conducted a comprehensive profiling of miRNA expression in R-CHOP treated DLBCL patients and established a miRNA-based risk score that is predictive of response to therapy. Methods and results: We have postulated that a miRNA signature in DLBCL is predictive of survival post R-CHOP chemotherapy. To test this hypothesis, we analyzed the miRNA and mRNA signatures of R-CHOP sensitive “S” and resistant “R” DLBCLs (n=20). miRNAs were hybridized to the miRNA Affymetrix gene-chip (847 hsa-miRNA probes) and raw miRNA expression values were log2 transformed and normalized (miRNA-QC tool, Affymetrix). Comparison of normalized miRNAs expression in “S” versus “R” patients (Anova testing) identified 59 differentially expressed miRNAs (Fold change < -1.5 or > 1.5 with a p value and FDR <0.05). In order to establish a risk score based on the expression of these 59 miRNAs, column-dendrogram branches were then sorted left to right based on each patient's difference between the average log2-scale expression of the 37 up-regulated and the 12 down-regulated miRNAs: this difference is interpreted as an up-/down-regulated mean ratio (ie, geometric mean) on the log2 scale [Log2 Geometric mean ratio [GMR] up-/down-regulated miRNA = Log2 [(2^ΣupregulatedümiRNA/ni)/(2^ΣdownregulatedümiRNA/nii)] where ni and nii represent the number of up-regulated and down-regulated miRNAs. This univariate summary (ie, GMR) of the 59-miRNA expression profiles for each patient enabled accurate prediction of all S versus R patients. Patients with log2 GMR > 0 had a 6-years PFS rate of 100%, while all patients with log2 GMR < 0 relapsed (HR=0.293 [95% CI 0.132–0.647]). Cox regression was then used to model relapse free survival times from treatment as a function of miRNA expression. Separate regression models were also built looking at fit measures, proportionality assumption, and discrimination ability (Harrell C statistics) and only miRNA with a discrimination ability (Harrell C) of > 85% (n=12 miRNA) were used to calculate the log2 GMR of up-/down-regulated miRNAs. A simplified model based on 12 miRNAs (Sensitive vs Resistant: upregulated: hsa-let-7i; hsa-miR-130a; hsa-miR-199a-3p; hsa-199b-3p; hsa-miR-223; hsa-miR22; hsa-miR-24; hsa-miR-26b; hsa-miR-27a; hsa-miR-331-5p; downregulated: hsa-miR-1288) accurately predicted sensitivity or resistance to R-CHOP. With this 12 miRNAs model, only 1 patient in each group (S and R) was misclassified (Fig 1). In addition we have validated the differential expression of these miRNA by short-stem loop RT-PCR and found a strong correlation between the gene-chip and qRT-PCR results (correlation coefficient 0.717). mRNA profiling (U133A Plus2 array chip) was also performed on the whole lymph node sections; 176 genes were identified as differentially expressed between S and R patients with many of these genes belonging to the “stroma-1 and -2” DLBCL signature. Using the TargetScan miRNA target mRNA prediction tool, combinatory analysis of miRNA and mRNA expression profiles of DLBCL patients identified positive and negative correlations (P <0.05) between differentially expressed miRNA and mRNAs. Lastly in a multivariate Cox regression analysis that included the IPI and the 12 miRNA based GMR risk score, both variables were independent predictors of survival post R-CHOP therapy. Conclusion: We believe that this log2 GMR score based on the 12 identified miRNA provides a robust method of predicting sensitivity to R-CHOP in DLBCL patients and it is currently being tested in a larger independent validation cohort. Disclosures: No relevant conflicts of interest to declare.

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Rungatscher, A., S. Hallström, D. Linardi, H. Suzuki, B. Podesser, H. Gasser, A. Mazzucco, and G. Faggian. "595 Cardioprotective Effects of S-Nitroso Human Serum Albumin (S-NO-HSA) during Cardioplegic Arrest and Cold Storage in a Working Heart Heterotopic Transplant Model." Journal of Heart and Lung Transplantation 30, no. 4 (April 2011): S199—S200. http://dx.doi.org/10.1016/j.healun.2011.01.607.

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Lodi, Tiziana, Barbara Neglia, and Claudia Donnini. "Secretion of Human Serum Albumin by Kluyveromyces lactis Overexpressing KlPDI1 and KlERO1." Applied and Environmental Microbiology 71, no. 8 (August 2005): 4359–63. http://dx.doi.org/10.1128/aem.71.8.4359-4363.2005.

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ABSTRACT The control of protein conformation during translocation through the endoplasmic reticulum is often a bottleneck for heterologous protein production. The core pathway of the oxidative folding machinery includes two conserved proteins: Pdi1p and Ero1p. We increased the dosage of the genes encoding these proteins in the yeast Kluyveromyces lactis and evaluated the secretion of heterologous proteins. KlERO1, an orthologue of Saccharomyces cerevisiae ERO1, was cloned by functional complementation of the ts phenotype of an Scero1 mutant. The expression of KlERO1 was induced by treatment of the cells with dithiothreitol and by overexpression of human serum albumin (HSA), a disulfide bond-rich protein. Duplication of either PDI1 or ERO1 led to a similar increase in HSA yield. Duplication of both genes accelerated the secretion of HSA and improved cell growth rate and yield. Increasing the dosage of KlERO1 did not affect the production of human interleukin 1β, a protein that has no disulfide bridges. The results confirm that the ERO1 genes of S. cerevisiae and K. lactis are functionally similar even though portions of their coding sequence are quite different and the phenotypes of mutants overexpressing the genes differ. The marked effects of KlERO1 copy number on the expression of heterologous proteins with a high number of disulfide bridges suggests that control of KlERO1 and KlPDI1 is important for the production of high levels of heterologous proteins of this type.

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Agarwal, Rupesh, Barbara A. Bensing, Dehui Mi, Paige N. Vinson, Jerome Baudry, Tina M. Iverson, and Jeremy C. Smith. "Structure based virtual screening identifies small molecule effectors for the sialoglycan binding protein Hsa." Biochemical Journal 477, no. 19 (October 5, 2020): 3695–707. http://dx.doi.org/10.1042/bcj20200332.

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Infective endocarditis (IE) is a cardiovascular disease often caused by bacteria of the viridans group of streptococci, which includes Streptococcus gordonii and Streptococcus sanguinis. Previous research has found that serine-rich repeat (SRR) proteins on the S. gordonii bacterial surface play a critical role in pathogenesis by facilitating bacterial attachment to sialylated glycans displayed on human platelets. Despite their important role in disease progression, there are currently no anti-adhesive drugs available on the market. Here, we performed structure-based virtual screening using an ensemble docking approach followed by consensus scoring to identify novel small molecule effectors against the sialoglycan binding domain of the SRR adhesin protein Hsa from the S. gordonii strain DL1. The screening successfully predicted nine compounds which were able to displace the native ligand (sialyl-T antigen) in an in vitro assay and bind competitively to Hsa. Furthermore, hierarchical clustering based on the MACCS fingerprints showed that eight of these small molecules do not share a common scaffold with the native ligand. This study indicates that SRR family of adhesin proteins can be inhibited by diverse small molecules and thus prevent the interaction of the protein with the sialoglycans. This opens new avenues for discovering potential drugs against IE.

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Lhiaubet-Vallet, Virginie. "Photosensitization by chiral drugs: Looking for stereodifferentiating photoprocesses in the presence of biomolecules." Pure and Applied Chemistry 77, no. 6 (January 1, 2005): 995–1000. http://dx.doi.org/10.1351/pac200577060995.

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Photoreactivity of chiral carprofen (CP) and ofloxacin in the presence of two biomolecules, namely, DNA and human serum albumin (HSA), has been reported. Analysis of the photosensitization of 2'-deoxyguanosine and thymidine (Thd) by high-performance liquid chromatograpy has shown that racemic ofloxacin and levofloxacin [its (S)-stereoisomer] acts by a mixed type I/type II mechanism, while CP does not lead to significant degradation of the nucleosides. Studies on DNA relaxation have revealed formation of single-strand breaks and specific alterations of DNA bases. Ofloxacin and levofloxacin photoinduce direct single-strand breaks and formation of purine and pyrimidine oxidative photoproducts; no Thd dimer has been detected. CP produces only photosensitized single-strand breaks. Moreover, DNA photosensitization has shown a weak enantiodifferentiation in favor of levofloxacin and (S)-CP. In the case of HSA, a remarkable stereodifferentiation has been found in the interaction between the excited triplet state of CP and protein. Time-resolved laser flash photolysis measurements revealed the presence of two components with different lifetimes that have been assigned to complexation of CP to the two binding sites of albumin. Moreover, photobinding of the drug to protein and formation of the dehalogenated photoproduct of CP proceed via stereodifferentiating photoprocesses.

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Hajouj, Hanin, Ali Khattib, Dana Atrahimovich, Sanaa Musa, and Soliman Khatib. "S-Nitrosylation of Paraxonase 1 (PON1) Elevates Its Hydrolytic and Antioxidant Activities." Biomolecules 12, no. 3 (March 7, 2022): 414. http://dx.doi.org/10.3390/biom12030414.

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Covalent binding between nitric oxide (NO) and a protein’s free thiol group (SH) is termed protein S-nitrosylation. Protein S-nitrosylation is involved in cellular regulation mechanisms that underlie a wide range of critical functions, such as apoptosis, alteration of enzyme activities, and transcription-factor stability. Impaired protein S-nitrosylation is associated with a growing list of pathophysiological conditions, such as cardiovascular disease, multiple sclerosis, pulmonary hypertension, and sickle cell disease. The enzyme paraoxonase 1 (PON1) binds to high-density lipoprotein to provide many of its antiatherogenic properties. The enzyme has a strong antioxidant capacity, which protects fats, lipids, and lipoproteins from oxidation, in addition to breaking down oxidized fats. We investigated the effect of S-S transnitrosylation on PON1 activities. Incubation of recombinant PON1 (rePON1) with nitrosylated human serum albumin (HSA-NO) resulted in S-nitrosylation of about 70% of the rePON1, as measured by Q-TOF LC/MS. S-nitrosylation significantly increased rePON1 hydrolytic activities. It also increased rePON1’s ability to inhibit low-density lipoprotein oxidation induced by Cu2+. Finally, it increased the enzyme’s penetration into macrophage cells by 31%. Our findings suggest that S-nitrosylation of rePON1 improves its biological functions which may positively affect atherosclerosis disease progression.

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Jimenez, Camilo, Bennett B. Chin, Richard A. Noto, Richard B. Noto, Joseph S. Dillon, Lilja Solnes, Vincent A. DiPippo, Nancy Stambler, and Daniel A. Pryma. "Biochemical Tumor Marker Status and Its Role in Treatment Response in Patients Who Received High-Specific-Activity I-131 MIBG in Advanced Pheochromocytoma and Paraganglioma (PPGL): Results From a Pivotal Phase 2 Clinical Trial." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A164—A165. http://dx.doi.org/10.1210/jendso/bvab048.333.

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Abstract Background: High-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131 MIBG; AZEDRA®) has been approved for the treatment of adult and pediatric patients (pts) 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. We have previously presented data showing improved biomarker responses in pts treated with HSA I-131 MIBG. Here we report the impact of biomarker status on the study primary endpoint and objective tumor response. Methods: Pts with iobenguane-avid PPGL who were ineligible for surgery, failed prior therapy or not candidates for chemotherapy, and on a stable antihypertensive medication regimen were treated. Pts received up to two therapeutic doses, each at ~18.5 GBq (or 296 MBq/kg for pts ≤62.5 kg), administered ~90 days apart. Biomarkers were analyzed at baseline and over a 12-month efficacy period. Confirmed biochemical responses (at least ≥ 50% decrease in abnormal tumor marker value for all hypersecreted biomarkers) required subsequent responses to be identical to or better compared with the previous assessment. The primary endpoint was clinical benefit, defined as the proportion of pts with at least 50% reduction of all antihypertensive medication(s) for ≥6 months beginning during the efficacy period. The secondary endpoint, confirmed objective tumor response by RECIST, was also evaluated. Results: 68 pts received at least one therapeutic dose of HSA I-131 MIBG. For all pts with hypersecretory tumors (with a baseline biochemical marker level of ≥1.5× ULN) (n=60), a comparison of biomarker response with antihypertensive therapy yielded a correlation coefficient of 0.35 (P = 0.006; Fisher exact P = 0.012). For pts with norepinephrine only-hypersecreting tumors (n=31), a correlation coefficient of 0.47 (P = 0.008; Fisher exact P = 0.015) was observed. The overall biomarker response also correlated with objective tumor response (n=55) yielding a correlation coefficient of 0.36 (P = 0.007; Fisher exact P = 0.012) for all pts with hypersecreted biomarkers. Pts who were not biochemical hypersecretors for any biomarker (n=6) had only one responder for the primary endpoint and no objective tumor responses. Conclusions: The biomarker data from this study establish a moderate but statistically significant correlation between biomarker response following treatment with HSA I-131 MIBG and objective tumor response and durable reduction of antihypertensive therapy. This correlation was improved with norepinephrine only-hypersecreting tumors in pts with unresectable, locally advanced or metastatic PPGL.

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Petersen, Helen J., Ciara Keane, Howard F. Jenkinson, M. Margaret Vickerman, Amy Jesionowski, Janet C. Waterhouse, Dermot Cox, and Steven W. Kerrigan. "Human Platelets Recognize a Novel Surface Protein, PadA, on Streptococcus gordonii through a Unique Interaction Involving Fibrinogen Receptor GPIIbIIIa." Infection and Immunity 78, no. 1 (November 2, 2009): 413–22. http://dx.doi.org/10.1128/iai.00664-09.

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ABSTRACT The concept of an infectious agent playing a role in cardiovascular disease is slowly gaining attention. Among several pathogens identified, the oral bacterium Streptococcus gordonii has been implicated as a plausible agent. Platelet adhesion and subsequent aggregation are critical events in the pathogenesis and dissemination of the infective process. Here we describe the identification and characterization of a novel cell wall-anchored surface protein, PadA (397 kDa), of S. gordonii DL1 that binds to the platelet fibrinogen receptor GPIIbIIIa. Wild-type S. gordonii cells induced platelet aggregation and supported platelet adhesion in a GPIIbIIIa-dependent manner. Deletion of the padA gene had no effect on platelet aggregation by S. gordonii but significantly reduced (>75%) platelet adhesion to S. gordonii. Purified N-terminal PadA recombinant polypeptide adhered to platelets. The padA mutant was unaffected in production of other platelet-interactive surface proteins (Hsa, SspA, and SspB), and levels of adherence of the mutant to fetuin or platelet receptor GPIb were unaffected. Wild-type S. gordonii, but not the padA mutant, bound to Chinese hamster ovary cells stably transfected with GPIIbIIIa, and this interaction was ablated by addition of GPIIbIIIa inhibitor Abciximab. These results highlight the growing complexity of interactions between S. gordonii and platelets and demonstrate a new mechanism by which the bacterium could contribute to unwanted thrombosis.

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Bennette, Caroline Savage, Wei-Jhih Wang, Scott David Ramsey, and Jean A. McDougall. "Trends in the geographic distribution of cancer clinical trials in the US: 2008-2015." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 6515. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6515.

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6515 Background: Access to and patient enrollment in cancer clinical trials is likely strongly impacted by where trial enrollment sites are located. Our objective was to evaluate temporal trends in the geographic location of cancer clinical trials launched in the US. Methods: We obtained the recruiting location(s) of all public- and privately-funded phase II/ III cancer clinical trials launched in the US between 2008 and 2015 from the ClinicalTrials.gov database. We linked the recruiting location(s) of each trial to the relevant hospital service area (HSA), which are defined by ZIP codes as local health care markets for hospital care (n = 3436). We estimated the number of cancer clinical trial sites in each HSA each year between 2008 and 2015. We also calculated a statistical measure of inequality, the Gini coefficient. The Gini coefficient would be 0 if all hospital service areas launched the same number of cancer clinical trials, and would be 1 if all cancer clinical trials were launched in only a single hospital service area. Results: 62% of HSAs (n = 2133) did not launch a single cancer clinical trial between 2008 and 2015. There was a small and non-statistically significant decline in the overall number of cancer clinical trial sites in the United States between 2008 and 2015 (-1.6% per year [95% CI: -4.0, 0.9]). During this same period of time, however, inequality in the geographic distribution of cancer clinical trial sites considerably deepened. For example, in 2008-09, no trials were launched in 68% of HSAs while 19% of trial sites were in only 1% of HSAs. Trials launched in 2014-15 were even more concentrated: no new trials were launched in 74% of HSAs while 25% of trial sites were in the top 1% of HSAs. The Gini coefficient increased significantly from 0.683 (95% CI: 0.666, 0.700) for trials launched in 2008-09 to 0.726 (95% CI: 0.706, 0.746) for those launched in 2014-15. Conclusions: Our findings indicate increased inequality in the geographic distribution of cancer clinical trials launched in the United States since 2008. The underlying causes and consequences of such increasing concentration warrant further analysis given the importance in ensuring equitable geographic access to cancer clinical trials in the US.

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Olszowska, Anna, Jacek Waniewski, Andrzej Werynski, Björn Anderstam, Bengt Lindholm, and Zofia Wankowicz. "Peritoneal Transport in Peritoneal Dialysis Patients Using Glucose-Based and Amino Acid-Based Solutions." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 27, no. 5 (September 2007): 544–53. http://dx.doi.org/10.1177/089686080702700514.

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Objective To evaluate peritoneal transport of fluid and solutes in continuous ambulatory peritoneal dialysis (CAPD) patients using amino acid (AA)-based versus glucose-based dialysis solutions. Methods Using iodine-labeled human serum albumin (125I-HSA) as intraperitoneal volume marker, peritoneal transport was investigated in a group of 20 clinically stable patients (11 females and 9 men, age 53 ± 15 years) on CAPD for 15 – 101 months. Two paired 4-hour dwells, one with 1.36% glucose and one with 1.1% AA dialysis solution, were performed in each patient. Intraperitoneal dialysate volume, fluid absorption rate, and diffusive mass transport coefficients (KBD) and sieving coefficients (S) for glucose, creatinine, urea, potassium, and total protein were estimated for each dwell study. Dwell studies with AA solution were used to estimate KBD values for individual AAs. Results Intraperitoneal dialysate volume was higher for AA solution in comparison with glucose solution due to the higher osmolality of the AA solution. No statistically significant difference was found for KBD or S for creatinine, urea, potassium, or total protein in the dwell studies with either solution, whereas KBD for glucose was higher with AA than with glucose solution. Mean values of KBD of AA were similar but with high standard deviation, reflecting inter-individual variations in peritoneal transport rate. Conclusion Our results indicate that the AA peritoneal transport rate is strongly dependent on transport characteristics of the individual peritoneal membrane.

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Ganesan, Saravanan, Hamenth Kumar Palani, Vairavan Lakshmanan, Nithya Balasundaram, Ansu Abu Alex, Sachin David, Biju George, et al. "Osteoblast Differentiation of Stromal Cells Induced By Leukemic Cells." Blood 128, no. 22 (December 2, 2016): 5062. http://dx.doi.org/10.1182/blood.v128.22.5062.5062.

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Abstract There are numerous reports on bone marrow micro-environment mediated drug resistance (EM-DR) in cancer. We had previously reported, that there was significant EM-DR to ATO in APL. We had also shown that the effect of cross talk between leukemic cells and stromal cells leads to increased activation of NF-kB pathway in the leukemic cells. There are very limited data available on the effect of leukemic cell interaction on the stromal cells. We undertook a study to evaluate the changes induced by leukemic cells (NB4 cell line) on the HS-5 stromal cell line. After 2 days of co-culture with NB4 cells, the RNA from HS-5 stromal cells were subjected to gene expression profiling and small RNA sequencing. In a gene expression profiling, we observed an enrichment of Wnt signaling and BMP signaling pathway. When we subjected the array to functional analysis, a significant enrichment of osteoblast differentiation genes was observed in the stromal cells co-cultured with leukemic cells in comparison to HS-5 cells alone. A stringent miRNA analysis using DESeq (miRNAs whose FDR corrected p values < 0.05 are considered significant) revealed 21 miRNA were differentially regulated in the HS-5 cells co-cultured with leukemic cells in comparison to HS-5 cells alone. Consistent with the gene expression profile, we observed that most of the miRNA differentially regulated were involved in the regulation of osteoblast differentiation (such as hsa-miR-33b-5p, hsa-miR-210-3p and hsa-miR-222-5p). As previously reported (PNAS 2013;110 (23):9469) we also observed upon co-culture with leukemic cells a down-regulation of NF-kB pathway in HS-5 cells. This was demonstrated by documenting decreased translocation of p65 subunit in the nuclear compartment of HS-5 cells on day 2 and day 7 of co-culture. This was further validated by documenting downregulation of NF-kB pathway genes by real time PCR on day 2. Along with this we also observed an increased translocation of B-catenin in the nuclear compartment of HS-5 cells on day 2 and day 7 of co-culture. This observation was validated by a real time PCR assay where an upregulation of its target gene was seen (Fig 1a). We observed that there is an increased expression of osteoblast differentiation transcription factor (RUNX2) in HS-5 cells upon co-culture on day 2 by real time PCR and western blot (Fig 1a, 1b). We also observed an increase in alkaline phosphatase activity in HS-5 cells upon co-culture with NB4 cells at different time points detected by BCIP-NBT staining. Further validation of differentiation of HS-5 cells into osteoblast was done using alizarin red S stain on day 7. Similar differentiation effects were seen in HS-5 cells when it is co-cultured with other malignant cells (U937, U266 and Jurkat) where an increased expression of RUNX2 on day 2 of co-culture was observed, suggesting that this effect is common with different subtypes of leukemia. We did not observe any effect of PBMNC / normal cord blood CD34+cells on HS-5 cells in inducing osteoblast differentiation (no expression of RUNX2; Fig 1b). This study demonstrates a possible role of leukemic cells in establishing leukemic niche in the bone marrow by inducing osteoblast differentiation of stromal cells. The role of this leukemic cell induced osteoblast differentiation of stroma in drug resistance against various chemotherapeutic agents needs further evaluation. Disclosures No relevant conflicts of interest to declare.

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Vanhie, A., D. O, D. Peterse, A. Beckers, A. Cuéllar, A. Fassbender, C. Meuleman, P. Mestdagh, and T. D’Hooghe. "Plasma miRNAs as biomarkers for endometriosis." Human Reproduction 34, no. 9 (August 14, 2019): 1650–60. http://dx.doi.org/10.1093/humrep/dez116.

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Abstract STUDY QUESTION Can plasma miRNAs be used for the non-invasive diagnosis of endometriosis in infertile women? SUMMARY ANSWER miRNA-based diagnostic models for endometriosis failed the test of independent validation. WHAT IS KNOWN ALREADY Circulating miRNAs have been described to be differentially expressed in patients with endometriosis compared with women without endometriosis, suggesting that they could be used for the non-invasive diagnosis of endometriosis. However, these studies have shown limited consistency or conflicting results, and no miRNA-based diagnostic test has been validated in an independent patient cohort. STUDY DESIGN, SIZE, DURATION We performed genome-wide miRNA expression profiling by small RNA sequencing to identify a set of plasma miRNAs with discriminative potential between patients with and without endometriosis. Expression of this set of miRNAs was confirmed by RT-qPCR. Diagnostic models were built using multivariate logistic regression with stepwise feature selection. In a final step, the models were tested for validation in an independent patient cohort. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Plasma of all patients was available in the biobank of the Leuven Endometriosis Centre of Excellence. Biomarker discovery and model development were performed in a discovery cohort of 120 patients (controls = 38, endometriosis = 82), and models were tested for validation in an independent cohort of 90 patients (controls = 30, endometriosis = 60). RNA was extracted with the miRNeasy Plasma Kit. Genome-wide miRNA expression analysis was done by small RNA sequencing using the NEBNext small RNA library prep kit and the NextSeq 500 System. cDNA synthesis and qPCR were performed using the Qiagen miScript technology. MAIN RESULTS AND THE ROLE OF CHANCE We identified a set of 42 miRNAs with discriminative power between patients with and without endometriosis based on genome-wide miRNA expression profiling. Expression of 41 miRNAs was confirmed by RT-qPCR, and 3 diagnostic models were built. Only the model for minimal–mild endometriosis (Model 2: hsa-miR-125b-5p, hsa-miR-28-5p and hsa-miR-29a-3p) had diagnostic power above chance performance in the independent validation (AUC = 60%) with an acceptable sensitivity (78%) but poor specificity (37%). LIMITATIONS, REASONS FOR CAUTION The diagnostic models were built and tested for validation in two patient cohorts from a single tertiary endometriosis centre. Further validation tests in large cohorts with patients from multiple endometriosis centres are needed. WIDER IMPLICATION OF THE FINDINGS Our study supports a possible biological link between certain miRNAs and endometriosis, but the potential of these miRNAs as clinically useful biomarkers is questionable in women with infertility. Large studies in well-described patient cohorts, with rigorous methodology for miRNA expression analysis, sufficient statistical power and an independent validation step, are necessary to answer the question of whether miRNAs can be used as diagnostics markers for endometriosis. STUDY FUNDING/COMPETING INTEREST(S) The project was funded by a grant from the Research Foundation - Flanders (FWO). A.V., D.F.O. and D.P. are PhD fellows from the FWO. T.D. is vice president and Head of Global Medical Affairs Fertility, Research and Development, Merck KGaA, Darmstadt, Germany. He is also a professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium and an adjunct professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. Neither his corporate role nor his academic roles represent a conflict of interest with respect to the work done by him for this study. The other co-authors have no conflict of interest. Trial registration number Not applicable.

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Ishima, Yu, Ulrich Kragh-Hansen, Toru Maruyama, and Masaki Otagiri. "Poly-S-Nitrosated Albumin as a Safe and Effective Multifunctional Antitumor Agent: Characterization, Biochemistry and Possible Future Therapeutic Applications." BioMed Research International 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/353892.

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Nitric oxide (NO) is a ubiquitous molecule involved in multiple cellular functions. Inappropriate production of NO may lead to disease states. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. TheS-nitrosothiol fraction in plasma is largely composed of endogenousS-nitrosated human serum albumin (Mono-SNO-HSA), and that is why we are testing whether this albumin form can be therapeutically useful. Recently, we developed SNO-HSA analogs such as SNO-HSA with many conjugated SNO groups (Poly-SNO-HSA) which were prepared using chemical modification. Unexpectedly, we found striking inverse effects between Poly-SNO-HSA and Mono-SNO-HSA. Despite the fact that Mono-SNO-HSA inhibits apoptosis, Poly-SNO-HSA possesses very strong proapoptotic effects against tumor cells. Furthermore, Poly-SNO-HSA can reduce or perhaps completely eliminate the multidrug resistance often developed by cancer cells. In this review, we forward the possibility that Poly-SNO-HSA can be used as a safe and effective multifunctional antitumor agent.

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Lobjakas, Wiljar, Jaak Nerut, Heili Kasuk, Anu Adamson, Thomas Thomberg, Jaan Aruväli, Peeter Valk, et al. "Investigation of Oxygen Reduction on Platinum Nanoparticles Deposited Onto Peat-Derived Carbon Carrier." ECS Meeting Abstracts MA2022-01, no. 35 (July 7, 2022): 1498. http://dx.doi.org/10.1149/ma2022-01351498mtgabs.

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Carbon supported platinum catalysts for proton exchange membrane fuel cell (PEMFC) applications have been studied intensively in the scientific community.1,2 The catalytic activity of the catalyst depends on the characteristics of the carbon support material3 and on the Pt depositing method4,5. The aim of the study was to investigate the oxygen reduction reaction (ORR) on Pt nanoparticles deposited on peat-derived carbon. The Pt nanoparticles were deposited on the carbon support material by three different methods using NaBH4 (NBH), ethylene glycol (EG) and isopropyl alcohol (IA) as a reducing agent. The studied materials were characterized using N2 sorption, X-ray diffraction (XRD) and thermogravimetric analysis (TGA). Structure of the platinum nanocatalyst on carbon support was also studied using scanning electron microscopy with energy-dispersive X-ray analysis (SEM-EDX). For electrochemical characterization, the electrochemically active surface area (ECA) of the materials were measured in a three-electrode system (0,1 M HClO4) and in a completed PEMFC. The ORR kinetics of the materials were studied by the rotating disk electrode (RDE) method as well as in a PEMFC configuration. As a result, it was found that the higher the ECA of the material, the higher the catalytic activity. The catalytic activity of the synthesized materials increases in order: IA < NBH < EG. ECA of the materials increases in the same order. Also, the special surface area of the materials increases in the same order. The catalytic activities of the synthesized materials were compared to a commercial catalyst material, 60% Pt on HSA Ketjenblack. References O. Z. Sharaf and M. F. Orhan, Renew. sust. energ. rev., 32, 810–853 (2014). Y. Wang, K. S. Chen, J. Mishler, S. C. Cho, and X. C. Adroher, Appl. Energ., 88, 981–1007 (2011). S. Sharma and B. G. Pollet, J. Power Sources, 208, 96–119 (2012). S. Sepp et al., Electrochim. Acta, 203, 221–229 (2016). P. Valk et al., J. Electrochem. Soc., 165, F315–F323 (2018). Acknowledgements The author thanks the European Union Regional Development Fund for the financial support of the project TK141 “Innovative materials and high-tech equipment for energy recovery systems” (2014-2020.4.01.15-0011); the Estonian Research Agency project (personal research support group grant project No. PRG676) and the Estonian Energy Technology Program: SLOKT10209T “. Nanomaterials – research and applications (NAMUR)” project 3.2.0304.12-0397. The author also thanks the private limited company AuVe Tech.

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Fichelson, S., I. Vigon, I. Dusanter, M. Charon, T. Velu, C. Baillou, S. Gisselbrecht, and F. M. Lemoine. "In vitro transformation of murine pro-B and pre-B cells by v-mpl, a truncated form of a cytokine receptor." Journal of Immunology 154, no. 4 (February 15, 1995): 1577–86. http://dx.doi.org/10.4049/jimmunol.154.4.1577.

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Abstract v-mpl is a constitutively activated, truncated form of a cytokine receptor that has been transduced in a murine retrovirus, the myeloproliferative leukemia virus (MPLV). Expression of this oncogene results in the factor-independent proliferation of myeloid, erythroid, megakaryocytic, and mast precursor cells, which retain the ability to differentiate. However, no lymphoid disease was ever reported. To determine whether MPLV could infect and transform very early B cells and their precursors (BCPs), lymphoid long-term bone marrow cultures were infected with a helper-free MPLV. Within 3 wk after infection, highly proliferating BCPs could be isolated. These cells were able to clone spontaneously in semi-solid cultures, grown in the absence of feeder cell layer or exogenous growth factor and rapidly produced tumors after s.c. injection into synegic irradiated mice. In addition, MPLV transformation of pre-B cells led to the induction of an autocrine activity. Immunophenotypic and molecular analysis indicated that MPLV transformed early pro-B, pro-B, and pre-B cells, according to the expression of HSA, CD43, B220, Thy1, s-IgM and BP1 Ags, and to the rearrangements of Ig genes. Interestingly, MPLV-transformed BCPs expressed Mac1 Ag without acquiring further characteristics of macrophagic differentiation. Although the v-mpl cytoplasmic domain is devoid of tyrosine kinase consensus sequence, MPLV-transformed pre-B cells contained a major approximately 105-kDa tyrosine-phosphorylated protein that was not detected in uninfected cells or in cells transformed by the Abelson viral oncogene (v-abl). These results demonstrate that, like v-abl, the truncated cytokine receptor v-mpl is able to transform BCPs in vitro and suggest that the oncogenic transformation of BCPs by either v-mpl or v-abl use different pathways.

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Dantham, Subrahamanyam, Achal Srivastava, Sheffali Gulati, and Moganty Rajeswari. "Differentially Regulated Cell-Free MicroRNAs in the Plasma of Friedreich's Ataxia Patients and Their Association with Disease Pathology." Neuropediatrics 49, no. 01 (November 27, 2017): 035–43. http://dx.doi.org/10.1055/s-0037-1607279.

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AbstractFriedreich's ataxia (FRDA) is a multisystem disease affecting the predominately nervous system, followed by muscle, heart, and pancreas. Current research focused on therapeutic interventions aimed at molecular amelioration, but there are no reliable noninvasive signatures available to understand disease pathogenesis. The present study investigates the alterations of plasma cell-free microRNAs (miRNAs) in FRDA patients and attempts to find the significance in relevance with the pathogenesis. Total RNA from the plasma of patients and healthy controls were subjected to miRNA microarray analysis using Agilent Technologies microarray platform. Differentially regulated miRNAs were validated by SYBR-green real-time polymerase chain reaction (Thermo Fisher Scientific). The study identified 20 deregulated miRNAs (false discovery rate < 0.01, fold change ≥ 2.0 ≤) in comparison with healthy controls; out of which 17 miRNAs were upregulated, and 3 miRNAs were downregulated. Target and pathway analysis of these miRNAs have shown association with neurodegenerative and other clinical features in FRDA. Further validation (n = 21) identified a set of significant (p < 0.05) deregulated miRNAs; hsa-miR-15a-5p, hsa-miR-26a-5p, hsa-miR-29a-3p, hsa-miR-223–3p, hsa-24–3p, and hsa-miR-21–5p in comparison with healthy controls. These miRNAs were reported to influence various pathological features associated with FRDA. The present study is expected to aid in the understanding of disease pathogenesis.

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Gounari, Maria, Stavroula Ntoufa, Charles C. Chu, Athanasios Tsaftaris, Nicholas Chiorazzi, Kostas Stamatopoulos, and Paolo Ghia. "Promiscuous Antigen Reactivity May Underlie Clinical Aggressiveness and Increased Risk for Richter's Syndrome in Chronic Lymphocytic Leukemia with Stereotyped IGHV4-39/IGKV1(D)-39 B Cell Receptors." Blood 120, no. 21 (November 16, 2012): 561. http://dx.doi.org/10.1182/blood.v120.21.561.561.

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Abstract Abstract 561 Mounting evidence suggests that the molecular classification of CLL into subsets with stereotyped B cell receptors (BcRs) is functionally and clinically relevant. In fact, cases of the same subset can share not only BcR sequence motifs but also biological and clinical features as well. This suggests that the functional antigen reactivity profile of the BcR can be critical in determining the clinical features and outcome even independently of IGHV gene mutational status, at least for selected subsets. A distinctive CLL stereotyped subset, known as subset #8, is defined by the expression of unmutated, IgG-switched IGHV4-39/IGKV1(D)-39 BcRs. Subset #8 patients experience aggressive clinical courses and exhibit the highest risk for Richter′s transformation (RT) among all CLL. In order to obtain biological insight into the underlying reasons for this behavior, we profiled the antigen reactivity of subset #8 vs. other stereotyped subsets, in particular: (1) subset #1: unmutated IGHV1/5/7-IGKV1(D)-39 IgM BcRs, the largest unmutated CLL subset, with bad prognosis; (2) Subset #2: mostly borderline-mutated IGHV3-21/IGLV3-21 IgM BcRs, with bad prognosis; (3) subset #4: mutated IGHV4-34/IGKV2-30 IgG BcRs, the largest mutated CLL subset, with indolent disease. Twenty-five monoclonal antibodies (mAbs) from CLL cells were prepared as recombinant human IgG1: 11 subset #1, 6 subset #2, 3 subset #4, and 5 subset #8. The CLL mAbs were used as primary antibodies in ELISA assays against antigens which are representatives of the major classes of established antigenic targets for CLL, namely molecular structures on microbial pathogens, autoantigens and neo-epitopes created by chemical modifications during apoptosis. In particular, we tested the reactivity against lipopolysaccharides (LPS) from E. coli 055:B5, dsDNA, native BSA, malondialdehyde (MDA)-BSA, 4-hydroxynonenal (HNE)-BSA and Advanced Oxidation Protein Products (AOPP)-HSA. Subset #8 CLL mAbs exhibited broad polyreactivity as they bound to all antigens tested, showing in particular strong reactivity to BSA and MDA-BSA, E. coli LPS and dsDNA, but also against the other oxidation markers tested (HNE-BSA and AOPP-HSA), albeit to a lesser extent. This high binding was in clear contrast with the mAbs from all other stereotyped subsets. Indeed, subset #1 mAbs exhibited only medium to low reactivity against MDA-BSA and dsDNA and very low reactivity against E.coli LPS; subset #2 mAbs did not react against any of the tested antigens; and, subset #4 showed low-level reactivity only against MDA-BSA and E. coli LPS. A propos these findings, we previously demonstrated that subset #8 mAbs exhibited the strongest binding also to myosin-exposed apoptotic cells as compared to all CLL mAbs, both unmutated and mutated, including subset #1 and #2 mAbs. In addition, through in vitro functional studies of immune signaling in CLL, we observed an unrestricted and intense response of subset #8 CLL cells to ligands for Toll-like receptors (TLR) 1/2, 2/6, 7 and 9, thus differing significantly from other subsets that respond to ligands for selected TLRs only. Alltogether, these findings help to draw a scenario that may explain the particular aggressiveness of subset#8 and its increased propensity to transform. An unlimited capacity to respond to multiple immune/inflammatory stimuli present in the microenvironment may elicit unabated stimulation thoughout the natural history of these patients, leading to progressive selection of the more aggressive clonal variants. Finally, our work further indicates that immunogenetic information can be used for the rational categorization of CLL, with implications for both research and management of CLL. Disclosures: No relevant conflicts of interest to declare.

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von Grothusen, Carolina, Caroline Frisendahl, Vijayachitra Modhukur, Parameswaran Grace Lalitkumar, Maire Peters, Omid R. Faridani, Andres Salumets, Nageswara Rao Boggavarapu, and Kristina Gemzell-Danielsson. "Uterine fluid microRNAs are dysregulated in women with recurrent implantation failure." Human Reproduction 37, no. 4 (February 11, 2022): 734–46. http://dx.doi.org/10.1093/humrep/deac019.

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Abstract STUDY QUESTION Is the composition of microRNAs (miRNAs) in uterine fluid (UF) of women with recurrent implantation failure (RIF) different from that of healthy fertile women? SUMMARY ANSWER The composition of miRNAs in UF of women with RIF is different from that of healthy fertile women and the dysregulated miRNAs are associated with impaired endometrial receptivity and embryo implantation. WHAT IS KNOWN ALREADY It has previously been demonstrated that the miRNAs secreted from endometrial cells into the UF contribute to the achievement of endometrial receptivity. Endometrial miRNAs are dysregulated in women with RIF. STUDY DESIGN, SIZE, DURATION In this descriptive laboratory case–control study, miRNA abundancy was compared between UF collected during implantation phase from healthy fertile women (n = 17) and women with RIF (n = 34), which was defined as three failed IVF cycles with high-quality embryos. PARTICIPANTS/MATERIALS, SETTING, METHODS Recruitment of study subjects and sampling of UF were performed at two university clinics in Stockholm, Sweden and Tartu, Estonia. The study participants monitored their menstrual cycles using an LH test kit. The UF samples were collected on Day LH + 7–9 by flushing with saline. Samples were processed for small RNA sequencing and mapped for miRNAs. The differential abundance of miRNAs in UF was compared between the two groups using differential expression analysis (DESeq2). Further downstream analyses, including miRNA target gene prediction (miRTarBase), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis (g:Profiler) and external validation using relevant published data, were performed on the dysregulated miRNAs. Two miRNAs were technically validated with quantitative real-time PCR (RT-PCR). MAIN RESULTS AND THE ROLE OF CHANCE After processing of the sequencing data, there were 15 samples in the healthy fertile group and 33 samples in the RIF group. We found 61 differentially abundant UF miRNAs (34 upregulated and 27 downregulated) in RIF compared to healthy women with a false discovery rate of <0.05 and a fold change (FC) of ≤−2 or ≥2. When analyzed with published literature, we found that several of the differentially abundant miRNAs are expressed in endometrial epithelial cells and have been reported in endometrial extracellular vesicles and in association with endometrial receptivity and RIF. Their predicted target genes were further expressed both in the trophectodermal cells of blastocyst-stage embryos and endometrial mid-secretory epithelial cells, as assessed by publicly available single-cell transcriptome-sequencing studies. Pathway analysis further revealed that 25 pathways, having key roles in endometrial receptivity and implantation, were significantly enriched. Hsa-miR-486-5p (FC −20.32; P-value = 0.004) and hsa-miR-92b-3p (FC −9.72; P-value = 0.004) were successfully technically validated with RT-PCR. LARGE SCALE DATA The data are available in Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/ with GEO accession number: GSE173289. LIMITATIONS, REASONS FOR CAUTION This is a descriptive study with a limited number of study participants. Moreover, the identified differentially abundant miRNAs should be validated in a larger study cohort, and the predicted miRNA target genes and enriched pathways in RIF need to be confirmed and further explored in vitro. WIDER IMPLICATIONS OF THE FINDINGS RIF is a major challenge in the current IVF setting with no diagnostic markers nor effective treatment options at hand. For the first time, total miRNAs have been extensively mapped in receptive phase UF of both healthy women with proven fertility and women diagnosed with RIF. Our observations shed further light on the molecular mechanisms behind RIF, with possible implications in future biomarker and clinical treatment studies. STUDY FUNDING/COMPETING INTEREST(S) This work was financially supported by the Swedish Research Council (2017-00932), a joint grant from Region Stockholm and Karolinska Institutet (ALF Medicine 2020, FoUI-954072), Estonian Research Council (PRG1076), Horizon 2020 innovation (ERIN, EU952516) and European Commission and Enterprise Estonia (EU48695). The authors have no competing interests to declare for the current study.

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Krowiorz, Kathrin, Razan Jammal, Stephan Emmrich, Arefeh Rouhi, Michael Heuser, Lars Bullinger, Konstanze Döhner, et al. "The Mir-193 Family Antagonizes Stem Cell Pathways and Is a Potent Tumor Suppressor in Childhood and Adult Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 1244. http://dx.doi.org/10.1182/blood.v126.23.1244.1244.

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Abstract MicroRNAs (miRNAs) are essential for maintenance and differentiation of normal hematopoietic cells and their dysregulation is strongly implicated in leukemias. In order to identify tumor suppressor miRNAs in the context of hematological malignancies, we performed two complementary miRNA expression screenings in normal hematopoiesis as well as in childhood and adult acute myeloid leukemias (AML). We reasoned that tumor suppressor miRNAs are upregulated in mature myeloid cells, as compared to normal hematopoietic stem and progenitor cells (HSPCs), and downregulated in AML. Based on this screening strategy, we identified the miR-193 family members as potent suppressors of HSPC activity and AML growth. During normal hematopoiesis mmu-miR-193a-3p is exclusively expressed in mature myeloid cells and absent in normal HSPCs. Accordingly, in a cohort of 165 pediatric AML patients hsa-miR-193b-3p was broadly repressed throughout the cytogenetically characterized subgroups. In addition, in a cohort of 43 adult AML patients, its homolog hsa-miR-193a-3p was significantly upregulated in APL cases (p=0.0025, n=7) compared to bone marrow from healthy donors (n=5). To assess the impact of the miR-193 family members on AML maintenance and development, we lentivirally expressed miR-193a/b in the MLL-rearranged cell lines ML2 and THP1, which induced monocytic differentiation in concert with calcitriol treatment, measured by CD11b/CD14 expression (p=0.024). Consistently, enforced miR-193-expression led to a significant growth disadvantage in ML2 and THP1 cells (p=<0.001 and p=0.02, respectively) as well as to reduced colony formation (p=0.008) in methylcellulose-based colony-forming unit (CFU) assays. Noteworthy, these effects were not restricted to MLL-rearranged AML cell lines only, but were also evident in six other AML cell lines representing the most common AML subgroups, such as t(8;21) and t(15;17). Beyond the growth-suppressive and differentiation-inductive effect of miR-193 in human AML cell lines, overexpression of miR-193a caused a significant decrease of proliferation in murine bone marrow cells immortalized in vitro by retroviral expression of Hoxa9 or Hoxa9 and Meis1 (p=0.019 and p=0.008, respectively). Based on these findings in AML, we further investigated the impact of the miR-193 family on normal hematopoiesis. We retrovirally expressed miR-193a in 32D cells treated with granulocyte-colony stimulating factor (G-CSF), which resulted in a strong induction of myeloid differentiation already after day 2 (p=0.006) as assessed by CD11b/Gr-1 surface marker expression. We lentivirally transduced mouse lineage negative (Lin-) HSPCs and transplanted them into irradiated isogenic recipients. Bleedings performed on weeks 4, 8 and 11, as well as the examination of the bone marrow on week 11, showed a severe competitive disadvantage of miR-193-transduced cells (week 11: 2% GFP+ miR-193- vs. 25% GFP+ miR-NSC-transduced cells). These results were further refined using highly purified ESLAM (CD45+ EPCR+ CD48− CD150+) HSCs which failed to reconstitute hematopoiesis when overexpressing miR-193a, indicated by the absence of miR-193a/GFP+ cells at week 8 post transplantation. These observations might be explained by a potent G1 cell cycle arrest in HSPCs when overexpressing miR-193a/b (4-fold decrease in the S phase population) and induction of apoptosis. Our results in normal and malignant hematopoiesis suggested that the miR-193 family acts globally through targeting relevant stem cell pathways. To validate this hypothesis we quantified the knockdown of ten predicted miR-193 target genes. qRT-PCR analysis confirmed the down regulation of KIT, KRAS, SOS2 (key components of the MAPK signaling pathway) and CCND1, a CDK regulator of G1/S phase transition. We propose a dual regulatory platform where firstly, miR-193 targets CCND1 and controls the cell cycle kinetics of stem cells. Secondly, miR-193 interferes with the KIT proto-oncogene and the RAS pathway thereby inhibiting crucial pro-proliferation and anti-apoptotic signaling cascades. Taken together, we identified the miR-193 family as a pan-tumor suppressor in childhood and adult AML. Its anti-leukemic effect is mediated by targeting the stem cell KIT/SOS2/RAS/RAF axis. Disclosures No relevant conflicts of interest to declare.

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Roth, Robert I. "Hemoglobin Enhances the Binding of Bacterial Endotoxin to Human Endothelial Cells." Thrombosis and Haemostasis 76, no. 02 (1996): 258–62. http://dx.doi.org/10.1055/s-0038-1650565.

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SummaryHuman endothelial cells, when incubated with bacterial endotoxin (lipopolysaccharide, LPS), modify their surface in association with prominent production of procoagulant tissue factor (TF) activity. This deleterious biological effect of LPS has been shown previously to be enhanced approximately 10-fold by the presence of hemoglobin (Hb), a recently recognized LPS binding protein that causes disaggregation of LPS and increases the biological activity of LPS in a number of in vitro assays. The present study was performed to test the hypothesis that Hb enhances the LPS-induced procoagulant activity of human umbilical vein endothelial cells (HUVEC) by increasing LPS binding to the cells. The binding of 3H-LPS to HUVEC was determined in the absence or presence of Hb or two other known LPS-binding proteins, human serum albumin (HSA) and IgG. LPS binding was substantially increased in the presence of Hb, in a Hb concentration-dependent manner, but was not increased by HSA or IgG. Hb enhancement of LPS binding was observed in serum-free medium, indicating that there was no additional requirement for any of the serum factors known to participate in the interaction of LPS with cells (e.g., lipopolysaccharide (LPS)-binding protein (LBP) and soluble CD14 (sCD14)). Hb enhancement of LPS binding also was observed in the more physiologic condition of 100% plasma. LPS-induced TF activity was stimulated by Hb, but not by HSA or IgG. In serum-free medium, TF activity was not stimulated under any of the conditions tested. Ultrafiltration of LPS was dramatically increased after incubation with Hb but not with HSA or IgG, suggesting that LPS disaggregation by Hb was responsible for the enhanced binding of LPS to HUVEC and the subsequent stimulation of TF activity.

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Barros Junior, Edson Alves de, Marisa de Cassia Registro Fonseca, Salomão Chade Assan Zatiti, Abimael Caetano do Nascimento, Luis Guilherme Rosifini Alves Rezende, and Nilton Mazzer. "Os efeitos do ultrassom na cicatrização de tendões flexores de coelhos após reparo." ARCHIVES OF HEALTH INVESTIGATION 9, no. 6 (December 24, 2020): 651–54. http://dx.doi.org/10.21270/archi.v9i6.5279.

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Introdução: O efeito terapêutico do ultrassom no processo cicatricial dos tendões flexores permanece controverso na literatura. Objetivo: Avaliar morfologicamente os efeitos do ultrassom terapêutico na cicatrização de tendões flexores profundos de coelhos submetidos a tenotomia e posterior tenorrafia. Métodos: 30 coelhos foram divididos em dois grupos para tratamento com ultrassom e outro apenas para tenotomia. O ultrassom foi iniciado no 1º dia após tenorrafia e mantido até o 7º dia. Foram utilizadas frequência de 3MHz, intensidade de 0.4Wcm2 (SATA), ciclo de trabalho de 20% por 06 minutos. Cinco animais de cada grupo foram sacrificados no 8º, 15º e 30º dia de PO, tendo os tendões dissecados e analisados pela microscopia de luz quanto a reação inflamatória, grau de necrose, proliferação de fibroblastos, deposição de colágeno e formação de granuloma. Resultados: Não houve diferença estatisticamente significativa entre os grupos para nenhuma das variáveis analisadas (p = 0,0667 - 1.0000). Conclusão: O ultrassom não interferiu no reparo dos tendões flexores. Descritores: Ultrassom; Tendões; Suturas; Cicatrização. Referências Blume K, Matsuo E, Lopes MS, Lopes LG. Dosimetria proposta para o tratamento por ultrassom - uma revisão de literatura. Fisioter 2009;18(3):55-64. Acevedo B, Millis DL, Levine D, Guevara JL. Effect of therapeutic ultrasound on calcaneal tendon heating and extensibility in dogs. Front Vet Sci. 2019;6:185. Logan CA, Asnis PD, Provencher MT. The role of therapeutic modalities in surgical and nonsurgical management of orthopaedic injuries. J Am Acad Orthop Surg. 2017 Aug;25(8):556-68. Katzap Y, Haidukov M, Berland OM, Itzhak RB, Kalichman L. Additive effect of therapeutic ultrasound in the treatment of plantar fasciitis: a randomized controlled trial. J Orthop Sports Phys Ther. 2018;48(11):847-55. Ng GY, Fung DT. The effect of therapeutic ultrasound intensity on the ultrastructural morphology of tendon repair. Ultrasound Med Biol. 2007;33(11):1750-54. Olsson DC, Martins VMV, Pippi NL, Mazzanti A, Tognoli GK. Ultra-som terapêutico na cicatrização tecidual. Ciência Rural 2008; 38(4):1199-207. Romano CVG, Barbieri CH, Mazzer N, Volpon J, Shimano AC, Roncaglia FB. O ultrassom terapêutico não aumentou as propriedades mecânicas de tendões flexores após reparo. Acta Ortop Bras. 2010;18(1):10-4. Jackson BA, Schwane JA, Starcher BC. Effect of ultrasound therapy on the repair of Achilles tendon injuries in rats. Med Sci Sports Exerc. 1991;23(2):171-76. Gan BS, Huys S, Sherebrin MH, Scilley CG. The effects of ultrasound treatment on flexor tendon healing in the chicken limb. J Hand Surg Br. 1995;20(6):809-14. Ng GY, Ng CO, See EK. Comparison of therapeutic ultrasound and exercises for augmenting tendon healing in rats. Ultrasound Med Biol. 2004;30(11):1539-43. Matheus JPC, Oliveira FB, Gomide LB, Milani JGPO, Volpon JB, Shimano AC. Efeitos do ultrassom terapêutico nas propriedades mecânicas do músculo esquelético após contusão. Rev bras fisioter. 2008;12(3):241-47. Barros Júnior EA, Matias Júnior I, Capelosi GV, Vieira MCDV. Relação entre a técnica de sutura e a reabilitação no pós-operatório de tenorrafia dos flexores de dedos da mão: revisão da literatura. Saúde. 2015;4(1):55-72. Turner SM, Powell ES, Ng CS. The effect of ultrasound on the healing of repaired cockerel tendon: is collagen cross-linkage a factor? J Hand Surg Br. 1989;14(4):428-33. Venkatramani H, Varadharajan V, Bhardwaj P, Vallurupalli A, Sabapathy SR. Flexor tendon J Clin Orthop Trauma. 2019;10(5):853-61. Santos CA, Fialho HSA, Pinto JA, Alves MTS. Influência do ultrassom terapêutico na epífise de crescimento ósseo de coelhos. Fisioter Pesq. 2005;12(2):13-21. Fréz AR, Ariza D, Ferreira JRL, Alves EPB, Breda GR, Centenaro LA et al. Efeito do ultrassom terapêutico contínuo em placas epifisárias de coelhos. Rev Bras Med Esporte. 2006;12(3):150-52. Sardenberg T, Muller SS, Coelho KIR, Varanda D, Cortopassi AC, Pereira GJC. Lesão do tendão flexor: sutura na região avascular ou vascularizada? Estudo biomecânico e histopatológico em coelhos. Rev Bras Ortop. 2019;54(3):268-74. Enwemeka CS, Rodriguez O, Mendosa S. The biomechanical effects of low-intensity ultrasound on healing tendons. Ultrasound Med Biol. 1990;16(8):801-7. Tsai WC, Tang ST, Liang FC. Effect of therapeutic ultrasound on tendons. Am J Phys Med Rehabil. 2011;90(12):1068-73.

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Zhang, Qing-Bin, Si-Da Ruan, Yong Wu, Jin-Hua Zhang, Jian-Guang Lu, and Jun Feng. "Extending the in vivo Half-Life of Adalimumab Fab via Sortase A-Mediated Conjugation of Adalimumab Fab with Modified Fatty Acids." Pharmaceutical Fronts 02, no. 04 (December 2020): e160-e167. http://dx.doi.org/10.1055/s-0041-1728817.

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AbstractAdalimumab, a full-length monoclonal antibody, is widely used as an anti-tumor necrosis factor-α (anti-TNF-α) agent. In this article, we aimed to prolong the in vivo half-life of adalimumab antigen-binding fragment (Fab) through Sortase A (SrtA)-mediated conjugation of its Fab with fatty acid (FA). In our study, adalimumab Fab analog was prepared by adding an SrtA recognition sequence (LPETGG) and His6 tag to the heavy chain C-terminal of the Fab via (G4S)3 linker. Four FA motifs with different linkers were designed and synthesized by solid-phase methodology, then conjugated with the Fab analog using SrtA to produce Fab bioconjugates. The successful generation of four Fab bioconjugates (Fab–FA1, Fab–FA2, Fab–FA3, and Fab–FA4) was confirmed by SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) and mass spectrometry. Then, the bioactivities and half-life of these Fab bioconjugates were examined using TNF-α-/human serum albumin (HSA)-binding enzyme-linked immunosorbent assay, cytotoxicity assay, and pharmacokinetic study, respectively. All Fab bioconjugates exhibited similar TNF-α-neutralizing activities when compared with the Fab analog, even in the presence of albumin, indicating that there were no apparent influences on the functional site of Fab after FA modification. However, different degrees of affinity for HSA were observed among these Fab–FA bioconjugates, with Fab–FA3 exhibiting the maximal affinity. An in vivo study in mice further revealed remarkably improved pharmacokinetics of Fab– FA3 with a 15.2-fold longer plasma half-life (19.86 hours) compared with that of the Fab analog (1.31 hours). In summary, we have developed a novel long-acting adalimumab Fab bioconjugate, Fab–FA3, with more sustained in vivo activity, which can be used for drug development targeting TNF-α-mediated inflammatory diseases.

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Eide, Christopher A., Stephen E. Kurtz, Andy Kaempf, Nicola Long, Jessica Leonard, Bill H. Chang, Motomi Mori, Brian J. Druker, and Jeffrey W. Tyner. "Simultaneous Kinase Inhibition with Ibrutinib and BCL2 Inhibition with Venetoclax As a Therapeutic Strategy for Acute Lymphoblastic Leukemia." Blood 134, Supplement_1 (November 13, 2019): 3950. http://dx.doi.org/10.1182/blood-2019-131288.

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Background: In patients with acute lymphoblastic leukemia (ALL), patient outcomes vary considerably by patient age group, specific genetic subtypes, and treatment regimen. Large-scale sequencing efforts have uncovered a spectrum of mutations and gene fusions in ALL, suggesting that combinations of agents will be required to treat these diseases effectively. Previous preclinical studies have shown efficacy of the BCL2 inhibitor venetoclax alone or in combination in ALL cells (Chonghaile et al., Can Disc 2014; Leonard et al, STM 2018), and the multi-kinase inhibitor ibrutinib (approved for patients with chonic lymphoblastic leukemia (CLL)) has also shown potent activity in subsets of ALL (Kim et al., Blood 2017). However, the combination of ibrutinib and venetoclax has not been evaluated to date in patients with ALL. Methods: We used a functional ex vivo screening assay to evaluate the potential efficacy of the combination of ibrutinib and venetoclax (IBR+VEN) across a large cohort (n=808) of patient specimens representing a broad range of hematologic malignancies. Primary mononuclear cells isolated from leukemia patients were plated in the presence of graded concentrations of venetoclax, ibrutinib, or the combination of both FDA-approved drugs. IC50 and AUC values were derived from probit-based regression for each response curve. A panel of clinical labs, treatment information, and genetic features for tested ALL patient specimens was collated from chart review. Single and combination drug treatment sensitivity were compared within groups by Friedman test, across groups by Mann-Whitney test, and with continuous variables by Spearman rank correlation. Results: Consistent with clinical data and previous literature, IBR+VEN was highly effective in CLL specimens ex vivo (median IC50=0.015 µM). Intriguingly, among specimens from 100 unique ALL patients, we also observed that IBR+VEN demonstrated significantly enhanced efficacy by AUC and IC50 compared to either single agent (p<0.001; median IC50=0.018 µM). In contrast, evaluation of this combination on primary mononuclear cells from two healthy donors showed little to no sensitivity. Breakdown of combination sensitivity (as measured by AUC) by a variety of clinical and genetic features revealed no associations with gender or specimen type. Among continuous variables tested, age was modestly correlated with combination AUC (Spearman r = 0.26) and increased blasts in the bone marrow were associated with increased sensitivity to the combination (Spearman r = -0.41; p = 0.0068). More broadly, specimens from patients with B-cell precursor disease (B-ALL) were more sensitive to IBR+VEN than those with T-cell precursor leukemia (T-ALL) (p = 0.0063). Within the B-ALL patient samples, those harboring the BCR-ABL1 fusion were significantly less sensitive to IBR+VEN than other subtypes of B-ALL (p = 0.0031). Within the T-ALL subset, there was a trend toward reduced sensitivity in patients with evidence of mutations in NOTCH1, though statistical significance was not reached. Evaluation of the combination using an expanded 7x7 concentration matrix in human ALL cell lines revealed varying degrees of sensitivity. For example, IBR+VEN showed enhanced efficacy in RCH-ACV B-ALL cells and showed synergy for the majority of drug-pair concentrations by the highest single agent (HSA) method (ibrutinib, venetoclax, and combination IC50: 0.60, 3.4, and 0.28 uM, respectively). Conclusion: Our findings suggest that the IBR+VEN combination, currently approved for patients with CLL, also demonstrates impressive efficacy against primary leukemia cells from ALL patients, warranting further investigation as a treatment strategy in the clinic to continue to improve outcomes for patients. Disclosures Leonard: Amgen: Research Funding. Druker:Cepheid: Consultancy, Honoraria; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Gilead Sciences: Other: former member of Scientific Advisory Board; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding; Pfizer: Research Funding; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; Patient True Talk: Consultancy; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Beat AML LLC: Other: Service on joint steering committee; CureOne: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; Monojul: Other: former consultant; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees. Tyner:Petra: Research Funding; Agios: Research Funding; Array: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Syros: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Array: Research Funding; Aptose: Research Funding; Incyte: Research Funding; Syros: Research Funding; Takeda: Research Funding; Petra: Research Funding; Agios: Research Funding; Constellation: Research Funding; Aptose: Research Funding; Gilead: Research Funding; Incyte: Research Funding; AstraZeneca: Research Funding; Constellation: Research Funding; Janssen: Research Funding; Genentech: Research Funding.

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Chen, Jacky, Jay Wunder, Kim Tsoi, Nalan Gokgoz, and Irene Andrulis. "168 Expanding and characterizing tumor infiltrating lymphocytes from myxofibrosarcoma and undifferentiated pleomorphic sarcoma." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A178—A179. http://dx.doi.org/10.1136/jitc-2021-sitc2021.168.

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BackgroundSarcoma is a group of rare bone and soft tissue tumors with over 50 distinct subtypes. Survival rate ranges widely due to the lack of efficacious treatments. Immunotherapy, such as adoptive cell therapy (ACT), has drawn significant interest due to its minimal toxicity. In ACT, tumor infiltrating lymphocytes (TILs) are isolated from patients, expanded, and autologously infused back. We recently observed TILs’ presence in Undifferentiated Pleomorphic Sarcoma (UPS) and Myxofibrosarcoma (MFS) tumors and found that tumor’s PD-L1 overexpression is correlated with better clinical outcome in UPS but not MFS.1 The Th1 anti-tumoral inflammatory pathway was highly activated in the former cohort, which may explain the favorable outcome. We hypothesize that there are phenotypic and functional differences between TILs of UPS with differential PD-L1 expression, which may be related to clinical outcomes. However, sarcoma TILs are rare and challenging to culture, which significantly impedes their studies. We first aim to robustly expand sarcoma TILs to sufficient numbers.MethodsTumors’ PD-L1 expression was determined by RT-qPCR (table 1). To initiate the tumor-fragment (TF) method of TIL culturing, primary tumors were fragmented and cultured in IMDM, IL-2, and 10% HSA. We further optimized the TF protocol to expand rare sarcoma TILs. Rapid expansion protocol (REP) with anti-CD3/anti-CD28 co-stimulating beads was employed for additional expansion. During REP, TILs were co-treated with gamma-chain cytokines (IL-2, 7, 15, 21).ResultsOf the 15 MFS TIL populations expanded, only 40% achieved sufficient growth (1x106) for analysis (figure 1A). Our optimized TF protocol expanded TILs from 8 UPS cases with a 62.5% success rate (figure 1B). UPS TILs were further stimulated with REP and various gamma-chain cytokine treatments. In ACT, prolonged culturing with IL-2 is known to cause activation-induced cell death, problematic in clinical treatments. We demonstrated that treatments with a Trio-cocktail (IL-7, 15, and 21) or IL-15 alone can achieve TIL proliferation comparable to that of IL-2 (figure 2).Abstract 168 Figure 1Initial TIL Culturing with Tumor Fragment Method. Figure A.. The traditional tumor fragment protocol was used to expand TILs of four MFS cases. TILs were cultured and expanded from primary tumor fragments in IL-2 (6000IU/mL) supplemented complete media (CM) over four weeks in duration. Fifteen TIL populations were derived from the four MFS cases. Populations were categorized based on their growth rates and labeled as ‘1’ or ‘2’ representing ‘fast’ or ‘slow’ growing TILs, respectively. Additional populations ‘A’ and ‘B’ represent biological replicates. Population TIL164 ‘2’ had no replicates. At Week 4, populations’ cell counts were determined via hemocytometer. As shown, only 6 out of 15 populations achieved > 1x10^6 cells (40% success rate). Figure B. An optimized tumor fragment protocol was used to expand TILs of eight UPS cases. Optimization includes shortening the culturing duration from four weeks to two weeks, reducing frequency of cell culture disruption, and adjusting cell culture environments. TILs were expanded from primary tumor fragments in CM over two weeks in duration. At Week 2, populations’ cell counts were determined via hemocytometer. As shown, 5 out of 8 cases achieved >1x10^6 cells (62.5% success rate).Abstract 168 Figure 2Gamma-chain cytokine treatments of UPS TILs. Gamma-chain cytokine treatments of UPS TILs with CD3/CD28 stimulation. Magnetic Dynabeads coated with CD3 and CD28 monoclonal antibodies were used to stimulate cells at a bead to cell ratio of 1:3. In ACT, IL-2 is a gold-standard cytokine that facilitates potent T-cell growth. However, it is known to cause activation-induced cell death. Resulting TIL population also possesses an exhausted-effector phenotype with low durability. UPS TIL Case 52 and Case 166 were treated with various interleukins during two weeks of REP, including gamma-chain IL-7, 15, 21 and inflammatory IL-12. IL-7, IL-12, and IL-21 individually did not elicit significant T-cell growth. IL-15 alone and in combination with IL-7 and IL-21 yield growth comparable to IL-2. IL-2 was obtained from Novartis (50ng/mL). All other cytokines were obtained from PeproTech (25ng/mL).Abstract 168 Table 1Tumor PD-L1 RNA Expression. Four MFS and eight UPS cases were processed. Tumors’ PD-L1 RNA expression was determined via RT-qPCR and evaluated as a ratio with the housekeeping gene STAM2. TIL359’s PD-L1 status has yet to be evaluated.ConclusionsSarcoma infiltrates are difficult to culture, and their roles remain largely unstudied. By optimizing the TF protocol in conjunction with anti-CD3/CD28 treatments, we developed a robust in vitro pipeline to expand rare sarcoma TILs, enabling downstream characterization. We also demonstrated the potential for alternate gamma-chain cytokines to favorably replace IL-2 during TIL expansion. Future phenotypic and functional evaluation of UPS TILs would elucidate the impact of tumors’ differential PD-L1 expression on UPS patients‘ prognoses. These findings would inform the implementation of ACT in sarcoma treatments.ReferencesWunder J, Lee M, Nam J, Lau B, Dickson B, Pinnaduwage D, Bull S, Ferguson P, Seto A, Gokgoz N, Andrulis I. Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation. Onco Immunology 2020;9: e1737385-1- e1737385-13.Ethics ApprovalPatients provided signed consent before study entry, as approved by Mount Sinai Hospital’s Ethics Board (REB#01-0138-U).

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Dzilic, E., M. Kreibich, D. Santer, P. Moser, F. Nagel, J. Kremer, A. Baumgartner, M. Hasun, B. Podesser, and K. Trescher. "New NO Donor S-NO-HSA improves cardioplegic solutions." Thoracic and Cardiovascular Surgeon 60, S 01 (January 18, 2012). http://dx.doi.org/10.1055/s-0031-1297417.

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Kreibich, M., E. Dzilic, D. Santer, J. Krynicka, S. Hallström, BK Podesser, and K. Trescher. "NO-donor S-NO-HSA preserves cardiac function during local and global ischemia." Thoracic and Cardiovascular Surgeon 61, S 01 (January 23, 2013). http://dx.doi.org/10.1055/s-0032-1332461.

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Mejia, O. A. V., R. C. Souza, B. Meneghini, A. S. Santos, L. A. F. Lisboa, L. A. O. Dallan, E. Cunha-Neto, L. R. P. Ferreira, and F. B. Jatene. "Circulating miRNA-770-5p and miRNA-30d-5p as potential biomarkers in vasoplegic syndrome after on-pump coronary artery bypass surgery – PREVENT trial." European Heart Journal 43, Supplement_2 (October 1, 2022). http://dx.doi.org/10.1093/eurheartj/ehac544.2144.

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Abstract Introduction Vasoplegic syndrome (VS) is one of the most common unexpected complications following cardiothoracic surgery, approaching a 25% mortality rate. No standardized methods for diagnosing VS are available. A biomarker is a valuable tool in all fields of medicine, especially in cardiovascular disease when the patient has to undergo invasive surgery as on-pump CABG. MicroRNAs (miRNAs) have been studied and employed as biomarkers for numerous diseases, however, there are no studies regarding their expression in VS. Purpose To discover a new predictor of VS by comparing the miRNA profiles from patients who evolved to VS versus those who did not evolve after following Coronary artery bypass graft surgery (CABG). Methods A nested case-control study had an exploratory nature and involved an initial cohort of 87 patients who underwent on-pump CABG in elective or urgency procedures,considering the low surgical risk (STS score <2%). For this analysis, we compared 30 patients, divided into two groups: patients who evolved VS (VASO group, n=15) and who did not evolve VS (NONVASO group, n=15) after surgery. To perform the miRNA profiling, the target prediction, and identify the putative targets of the dysregulated miRNAs, the whole blood samples were collected after anesthetic induction and before incision in the chest (Figure 1A). Results We identified among the 754 screened miRNAs, eight differentially circulating miRNAs in the whole blood of VASO versus NONVASO groups (Figure 1B). Six miRNAs were increased (hsa-miR-548c-3p, hsa-miR-30d-5p, hsa-miR8 199b-5p, hsa-miR-183-3p, hsa-miR-571, hsa-miR-383-5p) and two were decreased (hsa-miR-1236-3p, hsa-miR-770-5p) and hsa-miR-1236-3p was not statistically significant (Figure 1C). The ROC curves for each single miRNAs yielded the top 2 highest AUC values of 0.8333 and 0.8178 for hsa-miR-770-5p and hsa-miR-30d-5p, respectively. The combination of these two miRNAs yielded an AUC value of 0.9615 with 84.6% sensitivity and 91.67% specificity in distinguishing patients from VASO from NONVASO groups showed a superior diagnostic power to that of a single miRNA (Figure 2). Computational analyses identified as the top enriched pathway the “Apelin Liver Signaling Pathway” with 14 out of 26 molecules within the pathway (53,8%) containing the higher number of targets of the dysregulated miRNAs. There was no statistical difference in preoperative, postoperative, EuroSCORE II, and variables comparing both groups. Conclusion(s) We showed that miRNA-770-5p and miRNA-30d-5p could be employed as potential biomarkers of VS, a new strategy to VS diagnosis since miRNAs expression could distinguish patients who could and could not evolve the disease. The capability of predicting VS with high accuracy would drastically change the clinical management and patient's referral to cardiac surgery by helping in decision-making once the clinical score risks proved to be unable to predict VS in low-risk patients. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Fundação de Amparo a Pesquisa de São Paulo - FAPESP

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Liao, Xian-min, Zheng Guan, Zhen-jin Yang, Li-ya Ma, Ying-juan Dai, Cun Liang, and Jiang-tian Hu. "Comprehensive analysis of M2 macrophage-derived exosomes facilitating osteogenic differentiation of human periodontal ligament stem cells." BMC Oral Health 22, no. 1 (December 27, 2022). http://dx.doi.org/10.1186/s12903-022-02682-5.

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Abstract Background The role of periodontal ligament stem cells (PDLSCs) and macrophage polarization in periodontal tissue regeneration and bone remodeling during orthodontic tooth movement (OTM) has been well documented. Nevertheless, the interactions between macrophages and PDLSCs in OTM remain to be investigated. Consequently, the present study was proposed to explore the effect of different polarization states of macrophages on the osteogenic differentiation of PDLSCs. Methods After M0, M1 and M2 macrophage-derived exosomes (M0-exo, M1-exo and M2-exo) treatment of primary cultured human PDLSCs, respectively, mineralized nodules were observed by Alizarin red S staining, and the expression of ALP and OCN mRNA and protein were detected by RT-qPCR and Western blotting, correspondingly. Identification of differentially expressed microRNAs (DE-miRNA) in M0-exo and M2-exo by miRNA microarray, and GO and KEGG enrichment analysis of DE-miRNA targets, and construction of protein–protein interaction networks. Results M2-exo augmented mineralized nodule formation and upregulated ALP and OCN expression in PDLSCs, while M0-exo had no significant effect. Compared to M0-exo, a total of 52 DE-miRNAs were identified in M2-exo. The expression of hsa-miR-6507-3p, hsa-miR-4731-3p, hsa-miR-4728-3p, hsa-miR-3614-5p and hsa-miR-6785-3p was significantly down-regulated, and the expression of hsa-miR-6085, hsa-miR-4800-5p, hsa-miR-4778-5p, hsa-miR-6780b-5p and hsa-miR-1227-5p was significantly up-regulated in M2-exo compared to M0-exo. GO and KEGG enrichment analysis revealed that the downstream targets of DE-miRNAs were mainly involved in the differentiation and migration of multiple cells. Conclusions In summary, we have indicated for the first time that M2-exo can promote osteogenic differentiation of human PDLSCs, and have revealed the functions and pathways involved in the DE-miRNAs of M0-exo and M2-exo and their downstream targets.

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Cometta, Silvia, Nathalie Bock, Sinduja Suresh, Tim R. Dargaville, and Dietmar W. Hutmacher. "Antibacterial Albumin-Tannic Acid Coatings for Scaffold-Guided Breast Reconstruction." Frontiers in Bioengineering and Biotechnology 9 (March 31, 2021). http://dx.doi.org/10.3389/fbioe.2021.638577.

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Infection is the major cause of morbidity after breast implant surgery. Biodegradable medical-grade polycaprolactone (mPCL) scaffolds designed and rooted in evidence-based research offer a promising alternative to overcome the limitations of routinely used silicone implants for breast reconstruction. Nevertheless, as with any implant, biodegradable scaffolds are susceptible to bacterial infection too, especially as bacteria can rapidly colonize the biomaterial surface and form biofilms. Biofilm-related infections are notoriously challenging to treat and can lead to chronic infection and persisting inflammation of surrounding tissue. To date, no clinical solution that allows to efficiently prevent bacterial infection while promoting correct implant integration, has been developed. In this study, we demonstrated for the first time, to our knowledge that the physical immobilization of 1 and 5% human serum albumin (HSA) onto the surface of 3D printed macro- and microporous mPCL scaffolds, resulted in a reduction of Staphylococcus aureus colonization by 71.7 ± 13.6% and 54.3 ± 12.8%, respectively. Notably, when treatment of scaffolds with HSA was followed by tannic acid (TA) crosslinking/stabilization, uniform and stable coatings with improved antibacterial activity were obtained. The HSA/TA-coated scaffolds were shown to be stable when incubated at physiological conditions in cell culture media for 7 days. Moreover, they were capable of inhibiting the growth of S. aureus and Pseudomonas aeruginosa, two most commonly found bacteria in breast implant infections. Most importantly, 1%HSA/10%TA- and 5%HSA/1%TA-coated scaffolds were able to reduce S. aureus colonization on the mPCL surface, by 99.8 ± 0.1% and 98.8 ± 0.6%, respectively, in comparison to the non-coated control specimens. This system offers a new biomaterial strategy to effectively translate the prevention of biofilm-related infections on implant surfaces without relying on the use of prophylactic antibiotic treatment.

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Guan, R., K. Zeng, Y. Q. Liu, C. Y. Liu, J. W. Li, B. Zhang, H. Q. Jiang, et al. "Potential role of circulating exosome miRNAs in left ventricular remodeling of patients with ST-segment elevation myocardial infarction." European Heart Journal 43, Supplement_2 (October 1, 2022). http://dx.doi.org/10.1093/eurheartj/ehac544.763.

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Abstract Background Left ventricular remodeling (LVR) in patients with ST-segment elevation myocardial infarction (STEMI) may lead to poor prognosis in which circulating exosome miRNAs play a critical role. The aim of the present study is to identify specific exosome miRNAs for LVR in patients with STEMI. Method Plasma exosome miRNAs were assessed in 20 patients (90% male, mean age of 66.95±1.65 years) 3–6 months after STEMI and 24 healthy individuals (83% male, mean age of 33.2±0.93 years) by using qPCR. Of the 20 patients, 8 had post-STEMI LVR according to echocardiographic evaluation, and the others did not. Clinical biochemical data including total cholesterol, HDL-C, LDL-C, LDH and NT-pro-BNP were collected from the patients with STEMI at same time as exosome miRNAs assessment. Specific exosome miRNAs for LVR were identified by using qPCR. Correlations between the dysregulated exosome miRNAs and the clinical biochemical parameters in patients with STEMI were analyzed using spearman correlation test. Results Five exosome miRNAs including hsa-miR-181a-3p (p<0.05, fold change = 0.59), let-7d-3p (p=0.01, fold change = 0.51), hsa-miR-224-5p (p<0.01, fold change = 0.11), hsa-miR-23a-3p (p<0.01, fold change = 1.42) and miR-874-3p (p<0.01, fold change = 0.48) were dysregulated in the post-STEMI patients comparing with the healthy individuals. Among them, the exosome miR-181a-3p (p=0.01, fold change = 0.09) and let-7d-3p (p=0.01, fold change = 0.16) were significantly lower expressed in patients with LVR compared to those without (Figure 1). There was no significant difference in expression of the other three miRNAs between patients with and without LVR. Exosome hsa-miR-874-3p positively associated with LDH (p<0.01, r=0.50) in all the patients with STEMI. In vitro cell culture confirmed that the miR-874-3p mimics upregulated expression of apoptosis related gene BMF (p<0.05, fold change = 1.7) in cardiomyocyte. Exosome hsa-miR-23a-3p and hsa-miR-224-5p positively correlated with both HDL-C (p<0.01, r=0.61; p=0.02, r=0.50) and LDL-C (p=0.02, r=0.50; p<0.05, r=0.52) in all patients with STEMI. No correlation between the dysregulated exosome miRNAs and cholesterol or NT-ProBNP was observed (Figure 2). Conclusions Circulating exosome miR-181a-3p and let-7d-3p might play a potential role in LVR in patients 3–6 months after STEMI. Exosome hsa-miR-874-3p might be associated with cardiomyocyte injury. Hsa-miR-23a-3p and hsa-miR-224-5p demonstrated an activity in regulation of lipid metabolism and biosynthesis in patients with STEMI. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): This work was supported by grants from the 3×3 Clinical Scientist Fund of Sun Yat-sen Memorial Hospital

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Нерсисян, С. А. "Izoformy mikrornk miR-148a i miR-203a predpolozhitel'no igrayut rol' supressorov kolorektal'nogo raka." Вестник Российского государственного медицинского университета, no. 2022(3) (May 2022). http://dx.doi.org/10.24075/vrgmu.2022.028.

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Izoformy mikroRNK — klass korotkih nekodiruyushchih RNK, osushchestvlyayushchih regulyaciyu ekspressii genov. Izoformy mikroRNK otlichayutsya ot kanonicheskih mikroRNK neskol'kimi nukleotidami na koncah molekuly, prichem variacii s 5′-koncov mikroRNK izmenyayut mnozhestvo genov-mishenej. Cel'yu raboty bylo provesti analiz funkcional'noj aktivnosti 5′-izoform mikroRNK v tkanyah kolorektal'nogo raka. Misheni 5′-izoform mikroRNK byli predskazany s pomoshch'yu bioinformaticheskih programm miRDB i TargetScan. Poluchennye dannye o mishenyah 5′-izoform mikroRNK byli integrirovany s dannymi sekvenirovaniya mRNK i izoform mikroRNK obrazcov pervichnyh kolorektal'nyh opuholej proekta The Cancer Genome Atlas Colon Adenocarcinoma. Dlya postroeniya seti vzaimodejstvij izoform mikroRNK, ih mishenej i transkripcionnyh faktorov po integrirovannym dannym ispol'zovali algoritm miRGTF-net. Pokazano, chto vysokoekspressirovannye pri kolorektal'nom rake izoformy mikroRNK, razlichayushchiesya odnim nukleotidom na 5′-konce molekuly, imeyut ne bolee 30% obshchih mishenej. V regulyatornoj seti vzaimodejstvij vyyavleny naibolee aktivnye izoformy mikroRNK. Urovni ekspressij kanonicheskoj mikroRNK hsa-miR-148a-3p i ee predskazannyh mishenej, yavlyayushchihsya regulyatorami kletochnoj proliferacii (CSF1, ETS1, FLT1, ITGA5, MEIS1, MITF, RUNX2), byli znachimo otricatel'no korrelirovany, otkuda mozhet sledovat' protivoopuholevaya rol' dannoj molekuly. Kanonicheskaya mikroRNK hsa-miR-203a-3p|0 i ee 5′-izoforma byli antikorrelirovany s razlichnymi genami-mishenyami, no pri etom obe potencial'no podavlyali ekspressiyu genov, vovlechennyh v epitelial'no-mezenhimnyj perekhod: SNAI2 i TNC.

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Ferraldeschi, Michela, Silvia Romano, Simona Giglio, Carmela Romano, Emanuele Morena, Rosella Mechelli, Viviana Annibali, et al. "Circulating hsa-miR-323b-3p in Huntington's Disease: A Pilot Study." Frontiers in Neurology 12 (May 5, 2021). http://dx.doi.org/10.3389/fneur.2021.657973.

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The momentum of gene therapy in Huntington's disease (HD) deserves biomarkers from easily accessible fluid. We planned a study to verify whether plasma miRNome may provide useful peripheral “reporter(s)” for the management of HD patients. We performed an exploratory microarray study of whole non-coding RNA profiles in plasma from nine patients with HD and 13 matched controls [eight healthy subjects (HS) and five psychiatric patients (PP) to minimize possible iatrogenic impact on the profile of non-coding RNAs]. We found an HD-specific signature: downregulation of hsa-miR-98 (fold change, −1.5, p = 0.0338 HD vs. HS, and fold change, 1.5, p = 0.0045 HD vs. PP) and upregulation of hsa-miR-323b-3p (fold change, 1.5, p = 0.0007 HD vs. HS, and fold change, 1.5, p = 0.0111 HD vs. PP). To validate this result in an independent cohort, we quantify by digital droplet PCR (ddPCR) the presence of the two microRNA in the plasma of 33 HD patients and 49 matched controls (25 HS and 24 PP patients). We were able to confirm that hsa-miR-323b-3p was upregulated in HD and premanifest HD vs. HS and PP: the median values (first–third quartile) were 4.1 (0.9–10.53) and 5.8 (1.9–10.70) vs. 0.69 (0.3–2.75) and 1.4 (0.78–2.70), respectively, p < 0.05. No significant difference was found for hsa-miR-98. To evaluate the biological plausibility of the hsa-miR-323b-3p as a component of the disease pathophysiology, we performed a bioinformatic analysis based on its targetome and the huntingtin (HTT) interactome. We found a statistically significant overconnectivity between the targetome of hsa-miR-323b-3p and the HTT interactome (p = 1.48e−08). Furthermore, there was a significant transcription regulation of the HTT interactome by the miR-323b-3p targetome (p = 0.02). The availability of handy, reproducible, and minimally invasive biomarkers coming from peripheral miRNome may be valuable to characterize the illness progression, to indicate new therapeutic targets, and to monitor the effect of disease-modifying treatments. Our data deserve further studies with larger sample size and longitudinal design.

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Yang, Jun, Xiaolong Yang, Joan M. Wrobel, Zsolt Paragi, Leonid I. Gurvits, Luis C. Ho, Kristina Nyland, Lulu Fan, and Daniel Tafoya. "Is there a sub-parsec-scale jet base in the nearby dwarf galaxy NGC 4395?" Monthly Notices of the Royal Astronomical Society, June 24, 2022. http://dx.doi.org/10.1093/mnras/stac1753.

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Abstract NGC 4395 is a dwarf galaxy at a distance of about 4.3 Mpc (scale: ∼0.021 pc mas−1). It hosts an intermediate-mass black hole (IMBH) with a mass between ∼104 and ∼105 solar masses. The early radio observations of NGC 4395 with the very long baseline interferometry (VLBI) network, High Sensitivity Array (HSA), at 1.4 GHz in 2005 showed that its nucleus has a sub-mJy outflow-like feature (E) extending over 15 mas. To probe the possibility of the feature E as a continuous jet with a base physically coupled with the accretion disc, we performed deep VLBI observations with the European VLBI Network (EVN) at 5 GHz, and analysed the archival data obtained with the HSA at 1.4 GHz in 2008, NSF’s Karl G. Jansky Very Large Array (VLA) at 12–18 GHz and the Atacama Large Millimetre/submillimetre Array (ALMA) at 237 GHz. The feature E displays more diffuse structure in the HSA image of 2008 and has no compact substructure detected in the EVN image. Together with the optically thin steep spectrum and the extremely large angular offset (about 220 mas) from the accurate optical Gaia position, we explain the feature E as nuclear shocks likely formed by the IMBH’s episodic ejection or wide-angle outflow. The VLA and ALMA observations find a sub-mJy pc-scale diffuse feature, possibly tracing a thermal free–free emission region near the IMBH. There is no detection of a jet base at the IMBH position in the VLBI maps. The non-detections give an extremely low luminosity of ≤4.7 × 1033 erg s−1 at 5 GHz and indicate no evidence of a disc-jet coupling on sub-pc scales.

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Ibañez-Perez, Jone, María Díaz-Nuñez, Marc Clos-García, Lucía Lainz, María Iglesias, Miren Díez-Zapirain, Aintzane Rabanal, et al. "microRNA-based signatures obtained from endometrial fluid identify implantative endometrium." Human Reproduction, August 27, 2022. http://dx.doi.org/10.1093/humrep/deac184.

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Abstract STUDY QUESTION Is it possible to use free and extracellular vesicle-associated microRNAs (miRNAs) from human endometrial fluid (EF) samples as non-invasive biomarkers for implantative endometrium? SUMMARY ANSWER The free and extracellular vesicle-associated miRNAs can be used to detect implantative endometrium in a non-invasive manner. WHAT IS KNOWN ALREADY miRNAs and extracellular vesicles (EVs) from EF have been described as mediators of the embryo–endometrium crosstalk. Therefore, the analysis of miRNA from this fluid could become a non-invasive technique for recognizing implantative endometrium. This analysis could potentially help improve the implantation rates in ART. STUDY DESIGN, SIZE, DURATION In this prospective study, we first optimized different protocols for EVs and miRNA analyses using the EF of a setup cohort (n = 72). Then, we examined differentially expressed miRNAs in the EF of women with successful embryo implantation (discovery cohort n = 15/validation cohort n = 30) in comparison with those for whom the implantation had failed (discovery cohort n = 15/validation cohort n = 30). Successful embryo implantation was considered when pregnancy was confirmed by vaginal ultrasound showing a gestational sac 4 weeks after embryo transfer (ET). PARTICIPANTS/MATERIALS, SETTING, METHODS The EF of the setup cohort was obtained before starting fertility treatment during the natural cycle, 16–21 days after the beginning of menstruation. For the discovery and validation cohorts, the EF was collected from women undergoing frozen ET on Day 5, and the samples were collected immediately before ET. In this study, we compared five different methods; two of them based on direct extraction of RNA and the other three with an EV enrichment step before the RNA extraction. Small RNA sequencing was performed to determine the most efficient method and find a predictive model differentiating between implantative and non-implantative endometrium. The models were confirmed using quantitative PCR in two sets of samples (discovery and validation cohorts) with different implantation outcomes. MAIN RESULTS AND THE ROLE OF CHANCE The protocols using EV enrichment detected more miRNAs than the methods based on direct RNA extraction. The two most efficient protocols (using polymer-based precipitation (PBP): PBP-M and PBP-N) were used to obtain two predictive models (based on three miRNAs) allowing us to distinguish between an implantative and non-implantative endometrium. The first Model 1 (PBP-M) (discovery: AUC = 0.93; P-value = 0.003; validation: AUC = 0.69; P-value = 0.019) used hsa-miR-200b-3p, hsa-miR-24-3p and hsa-miR-148b-3p. Model 2 (PBP-N) (discovery: AUC = 0.92; P-value = 0.0002; validation: AUC = 0.78; P-value = 0.0002) used hsa-miR-200b-3p, hsa-miR-24-3p and hsa-miR-99b-5p. Functional analysis of these miRNAs showed strong association with key implantation processes such as in utero embryonic development or transforming growth factor-beta signaling. LARGE SCALE DATA The FASTQ data are available in the GEO database (access number GSE178917). LIMITATIONS, REASONS FOR CAUTION One important factor to consider is the inherent variability among the women involved in the trial and among the transferred embryos. The embryos were pre-selected based on morphology, but neither genetic nor molecular studies were conducted, which would have improved the accuracy of our tests. In addition, a limitation in miRNA library construction is the low amount of input RNA. WIDER IMPLICATIONS OF THE FINDINGS We describe new non-invasive protocols to analyze miRNAs from small volumes of EF. These protocols could be implemented in clinical practice to assess the status of the endometrium before attempting ET. Such evaluation could help to avoid the loss of embryos transferred to a non-implantative endometrium. STUDY FUNDING/COMPETING INTEREST(S) J.I.-P. was supported by a predoctoral grant from the Basque Government (PRE_2017_0204). This study was partially funded by the Grant for Fertility Innovation (GFI, 2011) from Merck (Darmstadt, Germany). It was also supported by the Spanish Ministry of Economy and Competitiveness MINECO within the National Plan RTI2018-094969-B-I00, the European Union's Horizon 2020 research and innovation program (860303), the Severo Ochoa Centre of Excellence Innovative Research Grant (SEV-2016-0644) and the Instituto de Salud Carlos III (PI20/01131). The funding entities did not play any role in the study design, collection, analysis and interpretation of data, writing of the report or the decision to submit the article for publication. The authors declare no competing interests.

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Almutlaq, A., X. Gonzalez, R. Odia, X. Sun, R. Naja, P. Serhal, and S. B. SenGupta. "P-239 Embryonic quality assessment from microRNA profiling." Human Reproduction 37, Supplement_1 (June 29, 2022). http://dx.doi.org/10.1093/humrep/deac107.229.

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Abstract Study question Does the microRNA expression profile in blastocysts change with different embryonic quality parameters? Summary answer MicroRNA expression showed significant changes when aneuploidy was present, in day-6 compared to day-5 blastocysts and with different trophectoderm (TE) morphology grades. What is known already MicroRNA (miRNA) is a gene expression regulatory mechanism used as a diagnostic marker for some conditions. Despite the great magnitude of studies investigating the miRNA role in implantation and pregnancy complications, limited work has been done to evaluate it as a potential marker for preimplantation embryo quality. With the accelerated changes in gene expression at early embryos, the miRNA profile is a potential indicator of embryo quality. This study investigates the blastocyst miRNA profile in relation to three quality parameters: aneuploidy, the day of blastocyst formation and morphology. Study design, size, duration We collected 122 surplus embryos donated for research by 46 consenting couples from Centre for Reproductive and Genetic Health, London. All samples were ICSI derived blastocysts (day5/6) with PGT-A results. For aneuploidy status comparison, samples were categorized according to the number of chromosomes affected (single/multiple) and type of aneuploidy (gain/loss/partial), compared to euploid. The day of blastocyst development has (day5/day6) groups, and finally samples were compared based on TE morphology (excellent/good/fair). Participants/materials, setting, methods Frozen human embryos were individually thawed and transferred to a lysis buffer. The miRNAs were extracted from each sample then sequenced by next generation sequencing (NGS) using miRNA Library Kit (QIAGEN) with NextSeqTM 500 (illumina). The differential expression analysis was conducted using DESeq2 via GeneGlobe (QIAGEN). We set the significance cut-offs to (-2> foldchange >2) and (<0.05 FDR p-value). For gene ontology and pathway annotation, we used miRTargetLink 2.0 and miRPathDB 2.0 platforms. Main results and the role of chance Compared to the euploid blastocysts, all aneuploid categories, except the single chromosome aneuploidy, had significant differences in miRNA expression. Nine miRNAs were altered in the group with multiple aneuploidies, and one was highly upregulated in embryos with partial losses or gains. The majority of differentially expressed (DE) miRNAs in samples with whole chromosomal gain or loss were downregulated. Conversely, four miRNAs showed a significant increase in day-6 blastocysts compared to day-5. Morphology grade comparisons showed no differences between excellent and good TE; however, six miRNAs were significantly changed in fair TE compared to good. The frequently altered miRNAs in these comparisons were ( hsa-let-7c-5p, hsa-miR-206, hsa-miR-184 and hsa-miR-203a-3p ). Unsurprisingly, pathway annotation of the DE miRNAs showed an involvement of key biological processes, like apoptosis, cell-cycle and differentiation, signalling and gene expression regulation, in all groups. The pathways of note in aneuploid blastocysts included DNA damage response, intrinsic and extrinsic apoptotic signalling, and regulation of cell-cycle G1/S associated events. In blastocyst day5/day6 comparison, embryonic and organ development were the most involved pathways, while in TE morphology, kinase activity and phosphorylation along with apoptosis and DNA damage response were significant. Limitations, reasons for caution Differential expression analysis based on inner cell mass (ICM) morphology and blastocyst expansion were not applicable due to the inadequate number of embryos per group; as all the samples collected were in excellent or good quality. Wider implications of the findings Gene expression profiling of miRNAs in human blastocysts will potentially identify biomarkers predictive of implantation success. Trial registration number not applicable

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Gimenez-Escamilla, I., L. Perez-Carrillo, M. Portoles, L. Martinez-Dolz, E. Tarazon, and E. Rosello-Lleti. "Golgi Apparatus fragmentation in dilated cardiomyopathy and its relationship with the alteration of vesicular transport." European Heart Journal 43, Supplement_2 (October 1, 2022). http://dx.doi.org/10.1093/eurheartj/ehac544.2966.

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Abstract Background The Golgi Apparatus (GA) is an important membrane-bound organelle implied in many physiological events, as trafficking, processing and sorting of newly membrane and secretory proteins and lipids. Nevertheless, these functions can be dysregulated in a diversity of pathologies due to the alteration of the GA morphology, such as cardiovascular diseases. Previously, we described in dilated cardiomyopathy (DCM) alterations in shape and size of the secretion vesicles of GA that was related to a worse functional situation. The patients had smaller, more ellipsoidal and more numerous vesicles with a higher content of natriuretic peptides (1). This situation can be related with Golgi fragmentation, a status characterized by the presence of a dispersed GA both in physiological and pathophysiological conditions (2). However, a greater understanding of Golgi fragmentation in DCM is necessary. Purpose We attempted to analyse the components of the vesicular Golgi transport and the Golgi fragmentation in cardiac tissue samples from DCM patients, paying special attention to GM130, as one of the main molecules related with the Golgi fragmentation. Methods We analysed vesicular Golgi transport genes in human hearts by RNA-sequencing in 13 samples from DCM patients and 10 control hearts (CNT), and the miRNAs that regulate their expression by ncRNA sequencing (DCM, n=20; and CNT, n=8). Finally, we investigated changes in the protein levels of GM130 and its phosphorylated state (pGM130) by western blot with 22 DCM and 6 CNT samples in total. Results We found 134 differentially expressed genes related to the GA, and 15 of them were involved in the secretion of Golgi vesicles. Among these molecules, VAMP4, a v-SNARE related with the Golgi fragmentation, is found to be downregulated (−1.27-Fold; P<0.05). Moreover, we have observed a downregulation in the expression of GOLGA2, the gene that encodes GM130 (−1.24; P<0.05). Furthermore, its regulator, hsa-miR-17-5p (−1.42; P<0.01) was also downregulated. In this sense, we have found no changes in GM130 protein levels between DCM patients and CNT group. In contrast, pGM130, molecule that it has been used as a biomarker of Golgi fragmentation, was overexpressed in DCM patients (1.19; P<0.05). Conclusion We found a deregulation of genes related to the vesicle secretion in the GA, which together with the changes in vesicular morphology previously observed, suggests an alteration in the rate of secretion in response to the needs of the DCM patients. In addition, the increase in the phosphorylated protein GM130 suggests the presence of fragmentation in DCM patients that could be related to the alteration in vesicular transport. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Health Carlos III European Regional Development Fund (ERDF)

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