scholarly journals Estimation of impact of remodeling and microbial factors on the results of total endoprosthesis of a knee joint in patients, suffering rheumatoid arthritis

2019 ◽  
Vol 86 (6) ◽  
pp. 38-42
Author(s):  
S. І. Gerasymenko ◽  
М. V. Pоlulyakh ◽  
L. М. Panchenko ◽  
О. B. Lyutko ◽  
А. М. Babko ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Marrow ◽  
Knee Joint ◽  
Stromal Cells ◽  
Proximal Part ◽  
Operative Specimen ◽  
Total Endoprosthesis ◽  
The Difference ◽  
High Level ◽  
The Impact

Objective. To estimate the impact of remodelling and microbial factors on the results of total endoprosthesis (ТЕP) of the knee joint in patients, suffering rheumatoid arthritis (RА). Маterials and methods. The results of microbiological investigations of operative specimen were compared with results of cloning of the stem stromal cells of the bone marrow. Міcrobiologically and microscopically there were studied 247 specimen of operative material, obtained during performance of primary TЕP of a knee joint in 64 patients, suffering RA. Results. As the investigations have shown, in 1 сm³ of spongious bone of distal femur there is in 1.4 times more a general quantity of cells, containing the nuclei, than in 1 сm3 of spongious bone of proximal tibiae (the difference is not statistically significant). In distal part of femur the quantity of a colony-creating units of fibroblasts (CCUF) in 1 сm³ is in a 9.8 times lower, than the CCUF quantity in 1 сm³ in proximal part of tibiae (the difference is statistically significant), аnd the efficacy of the CCUF cloning is accordingly more than in 2.1 times lower (difference is statistically nonsignificant). Conclusion. High level of contamination of predominantly gram-positive microorganisms of the bone operative material, obtained while primary TEP of a knee joint in 82.8% patients, suffering RA, have a strong (almost a functional one) linear adverse correlation (coefficient r = -0.98) with osteogenic аctivity of the stem stromal cells in the bone marrow, which form a knee joint, what necessitates overestimation of approaches, concerning preparation and performance of surgical intervention for guaranteeing the efficacy of orthopedic treatment and standards of the protocols.

scholarly journals The Impact of CEOs' Compensations on Cost Stickiness in Industrial Companies Listed on the Amman Stock Exchange

2021 ◽  
Vol 15 (1) ◽  
pp. 152
Author(s):  
Lina Fuad Hussien
Keyword(s):  
Stock Exchange ◽  
Industrial Companies ◽  
Level Of Activity ◽  
Cost Behavior ◽  
Study Population ◽  
The Difference ◽  
High Level ◽  
The Cost ◽  
The Impact ◽  
Cost Stickiness

The purpose of this study is to analyze the asymmetry in cost behavior (cost stickiness) and to identify the impact of CEOs' compensation on the degree of cost stickiness behavior. The study population consists of the public shareholding companies listed on the ASE, which number (56) industrial company. Data were collected from (35) industrial companies for the period (2009 - 2019). To measure the degree of costs stickiness, The Model of Weiss (2010) was used. The Model of Weiss (2010) takes into account the costs and changes in the level of activity (sales) for the last four quarters of the company, Weiss (2010) model constructs the difference in logarithmic ratios of changes in cost. The study found that the CEO's compensation in Jordanian industrial companies consists of two forms. The companies pay fixed salaries or performance-related bonuses. The study found that the form of compensation that is paid to the CEO affects the behavior of managers. The results indicated that the performance-related rewards are accompanied by a decrease in the level of cost stickiness, and the compensation paid in the form of fixed salaries are accompanied by a high level of cost stickiness. The study recommends that companies should understand the role of the compensation form in administrative decisions, especially with regard to resource modifications, as management motives in relation to resource modifications must be taken into account because of their clear and direct impact on the cost structure of companies.

scholarly journals The Effect of Attribute Alignability on Product Purchase: The Moderating Role of Product Familiarity and Self-Construal

2021 ◽  
Vol 12 ◽  
Author(s):  
Yong Zhang ◽  
Yuwen Wen ◽  
Min Hou
Keyword(s):  
Structural Alignment ◽  
Personal Characteristics ◽  
Product Positioning ◽  
Self Construal ◽  
The Difference ◽  
Product Familiarity ◽  
High Level ◽  
The Impact ◽  
Moderating Role

Previous studies on the Structural Alignment Model suggest that people compare the alignable attributes and nonalignable attributes during the decision-making process and preference formation process. Alignable attributes are easier to process and more effective in clue extracting. Thus, it is believed that people rely more on alignable than nonalignable attributes when comparing alternatives. This article supposes that consumers’ product experience and personal characteristics also play a significant role in regulating consumers’ reliance on attribute alignability. The authors conducted three experiments to examine the moderating role of consumers’ product familiarity and self-construal in the impact of attribute alignability on consumer product purchase. The results show the following: (1) When making a purchase decision, consumers with a high level of product familiarity will rely more on nonalignable attributes, while those with a low level of product familiarity will rely more on alignable attributes. (2) The difference in consumer dependency on attribute alignability is driven by their perceived diagnosticity of attributes. (3) The dependency of consumers with different levels of familiarity on attribute alignability will be further influenced by consumers’ self-construal. Individuals with interdependent self-construal rely more on alignable attributes when unfamiliar with the product, while relying more on nonalignable attributes when familiar with the product. Individuals with independent self-construal, however, rely more on nonalignable attributes regardless of the degree of product familiarity. The conclusions of this paper can be used as references for enterprises to establish product positioning and communication strategies.

Revalidation of the Flipi Score in the Era of Immunotherapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4437-4437
Author(s):  
German Stemmelin ◽  
Carlos Doti ◽  
Claudia Shanley ◽  
Jose Ceresetto ◽  
Oscar Rabinovich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Univariate Analysis ◽  
Risk Groups ◽  
Marrow Transplant ◽  
Intermediate Risk ◽  
Significant Difference ◽  
The Difference ◽  
The One ◽  
The Impact

Abstract The FLIPI prognosis score for follicular lymphoma (FL) was developed based on cases diagnosed between 1985 and 1992, and treated with different schemes that did not include rituximab (R). In the present study, we report the evolution of all FL treated in a single institution through the last decade and analize whether FLIPI mantains its effectiveness to identify different risk groups within patients treated with the new therapeutic alternatives available. Material and Methods: We identified sixty two patients with diagnosis of grade I-II-IIIa FL. Patients characteristics: median age 57.5 yr (r, 30–80); 36 males; 63% stages III–IV, and 37% with bone marrow infiltration at the time of diagnosis. Thirty eight percent had a low risk by FLIPI, 34% had an intermediate risk and 27.4% had a high risk. In 19 pts (30.6%) the initial decision was “watch and wait” but 82% received a form of treatment at some point. R was used in 36 pts (58%) with some of the following regimes: chemotherapy (chemo) + R and/or R as consolidation therapy and/or R as monotherapy and/or R as maintenance therapy. Of all prescribed treatments (excluding R as monotherapy and/or maintenance treatment), 52.8% were chemo alone, 20.2% chemo + R, 21.3% radiotherapy and 5.6% received a bone marrow transplant. Results: we considered the analysis of overall survival (OS) the most appropiate approach, since most treatments were seeking the control of the FL, and not the complete remission or cure. The follow up median time was 53.2 months ± 34.8 1SD. The 5-yr OS for the 62 pts was 81.8% ± 11.3 CI 95%. The 5-yr OS for those with a low, intermediate and high risk FLIPI was 100% −5, 84.2% ± 21 and 52% ±26.2, respectively. The difference in 5-yr OS was statistically significant between low and high risk, intermediate and high risk, but failed to prove a significant difference between low and intermediate risk. Among the different risk factors tested in a univariate analysis only age ≥ < 60 yr old demonstrated a significant difference, 60.7% vs 90%, respectively. Conclusions: The 5-yr OS in our series is higher than the one described in the original FLIPI study (Blood2004; 104:1258–65) which was 81.8% vs 71% for the whole group; 90% vs 78.1% for pts <60 yr old; 60.7% vs 57.7% for ≥ 60 yr old; 100% vs 90.6% for low FLIPI and 84.2% vs 77.6% for intermediate FLIPI. The only group that failed to prove an improvement was the high risk FLIPI with 52% vs 52.5%. The impact of novel therapies was more evident in patients with a low or intermediate FLIPI and was even more evident in patients younger than 60 yr old. According to our results, FLIPI maintains its effectiveness in differentiating two risk groups, i.e., low-intermediate vs high. We believe that the OS curves will probably continue to improve as the treatments that are considered today as the most effective ones, were just included in our series in the last three years.

Hyperactive Non-Canonical TGF-β Pathway Signaling in Fanconi Anemia Bone Marrow Stromal Cells Contributes to Growth Suppression

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1039-1039
Author(s):  
Kevin O'Connor ◽  
Sofia Vidal-Cardenas ◽  
Haojian Zhang ◽  
Alfredo Rodriguez ◽  
Lisa Moreau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Signaling Pathway ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Bone Marrow Failure ◽  
Genotoxic Stress ◽  
Growth Suppression ◽  
Marrow Stromal Cells ◽  
Growth Defect ◽  
High Level

Abstract Introduction: Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients develop bone marrow failure during the first decade of life due to attrition of hematopoietic stem cells (HSCs). FA is caused by autosomal recessive or X-linked mutations in one of nineteen FANC genes, the products of which cooperate in the FA/BRCA DNA repair pathway and regulate cellular resistance to genotoxic DNA cross-linking agents. Although its mechanism is unknown, bone marrow failure in FA may be the result, directly or indirectly, of hyperactivation of cell-autonomous or microenvironmental growth-suppressive pathways induced, in part, due to genotoxic stress. We have recently identified canonical transforming growth factor-β (TGF-β) pathway-mediated growth suppression of HSCs as a cause of bone marrow failure in FA (Zhang H et al, Cell Stem Cell, 2016). We have shown that TGF-β pathway inhibition rescues genotoxic stress, proliferation defects and engraftment defects of FA-deficient HSCs, and ameliorates bone marrow failure in FA mice. Previous studies have suggested that bone marrow stromal fibroblasts from human FA patients and FA pathway-deficient mouse models, like HSCs, are hypersensitive to genotoxic stress and have impaired growth. Here, we therefore investigated the possible suppressive function of the TGF-β pathway in bone marrow stromal cells derived from FA mice and patients with FA. Methods: We established primary stromal cell lines from bone marrow of FA-deficient mice (Fancd2-/- mice) or wild-type sibling control mice. Primary bone marrow stromal cultures were also established from FA patients or normal healthy donors. The stromal cells were characterized and evaluated for growth kinetics, mitomycin C (MMC) sensitivity, chromosome breakage, inflammatory signals and response to the TGF-β inhibitors. CRISPR/Cas-9 technology was used to knockdown specific genes in stromal cells. Results: As expected,the primary bone marrow stromal cells from Fancd2-/- mice exhibited classical FA phenotypes, including hypersensitivity to a DNA cross-linking agent, MMC, and increased MMC-induced chromosomal radials. Fancd2-/- stromal cells also demonstrated a growth defect characterized by an enrichment of cells in G1 and elevated p21 expression. Interestingly, the FA stromal cells derived from FA patients or from Fancd2-/- mice expressed constitutively elevated levels of phosphorylated (activated) ERK1/2 (pERK) compared to control cells. In order to determine whether the factor responsible for inducing ERK1/2 phosphorylation in the murine FA stromal cells was cell-intrinsic or cell-extrinsic, we examined the conditioned media from the stromal cells. Indeed the FA stromal cells secreted a high level of TGF-β cytokine responsible for increased pERK levels, and expressed a high level of secreted TGF-β mRNA. The high level of pERK indicated that the TGF-β non-canonical pathway was hyperactive in the FA stromal cells. Interestingly, CRISPR/Cas9-mediated knockdown of Tgfbr1 or inhibition of the TGF-β pathway by a treatment with a small molecule inhibitor of TGFβR1 or a neutralizing antibody against TGF-β in these cells reduced pERK levels, promoted DNA repair and rescued MMC sensitivity. In addition, a MEK inhibitor also significantly improved the clonogenic growth of Fancd2-/- stromal cells. However, CRISPR/Cas9-mediated knockdown of Smad3, a downstream target of the canonical TGF-β pathway, did not rescue the growth inhibition of FA stromal cells in MMC, further indicating that hyperactivation of the canonical pathway is less relevant to their growth defect. Collectively, these results demonstrated that the hyperactive TGF-β pathway increases phosphorylation of ERK1/2 in FA stromal cells through the non-canonical signaling pathway and impairs their growth after genotoxic stress. Conclusions: The primary FA bone marrow stromal cells exhibit hyperactive non-canonical TGF-β pathway signaling and blocking this pathway improves their growth under genotoxic stress. The TGF-β signaling pathway-mediated growth suppression in bone marrow stromal cells may account, at least in part, for defective microenvironment, impaired HSC function and bone marrow failure in FA. This work suggests that the TGF-β signaling pathway may be a potential therapeutic target for the treatment of bone marrow failure in FA. Disclosures Shimamura: TransCellular Therapeutics: Other: Husband is founder. No revenue to date.; Novartis: Other: In discussion regarding possible clinical trial for aplastic anemia; Glaxo Smith Kline: Honoraria.

scholarly journals DO RISK, BUSINESS CYCLE, AND COMPETITION AFFECT CAPITAL BUFFER? AN EMPIRICAL STUDY ON ISLAMIC BANKING IN ASEAN AND MENA

2018 ◽  
Vol 3 (2) ◽  
Author(s):  
Novita Kusuma Maharani ◽  
Bowo Setiyono
Keyword(s):  
Business Cycle ◽  
Islamic Banks ◽  
Banking Supervision ◽  
Minimum Capital ◽  
The Difference ◽  
Conventional Banks ◽  
High Level ◽  
The Impact ◽  
The Relationship ◽  
Unbalanced Panel Data

Basel III guidelines were released in 2010 by the Basel Committee on Banking Supervision (BCBS) as a revision of the previous Basel guidelines with the aim of strengthening the bank's capital and liquidity of banks. BCBS formulate a new policy that is the capital buffer. Capital Buffer is the difference between the minimum capital required by regulators with its overall capital and is considered a "cushion" against the shocks of the financial crisis. This study examine the impact of risk, business cycle, and competition on banks’ capital buffer. This paper used the sample of Islamic banks and conventional banks in ASEAN and MENA in the period 2011-2015 with unbalanced panel data. Using System GMM method to test the characteristics of Islamic banks in managing its capital. The finding indicates that the degree of capital buffer in islamic banks tend to adjust its risk. The result also shows that capital buffer decrease during economic expansion where banks act aggressively by extending their lending activities. The relationship between capital buffer and competition is positive in that the high level of competition to motivate banks to have higher capital.

scholarly journals Characterization of the Hematopoietic Supporting Activity of Osteoblasts Derived from Bone Marrow Mesenchymal Stromal Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4358-4358
Author(s):  
Manal Alsheikh ◽  
Roya Pasha ◽  
Nicolas Pineault
Keyword(s):  
Bone Marrow ◽  
Osteogenic Differentiation ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Conflicts Of Interest ◽  
Soluble Factors ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
The Impact ◽  
Myeloid Progenitors

Abstract Osteoblasts (OST) found within the endosteal niche are important regulators of Hematopoietic Stem and Progenitor Cells (HSPC) under steady state and during hematopoietic reconstitution. OST are derived from mesenchymal stromal cells (MSC) following osteogenic differentiation. MSC and OST secrete a wide array of soluble factors that sustain hematopoiesis. Recently, we showed that media conditioned with OST derived from MSC (referred as M-OST) after 6 days of osteogenic differentiation were superior to MSC conditioned media (CM) for the expansion of cord blood (CB) progenitors, and CB cells expanded with M-OST CM supported a more robust engraftment of platelets in NSG mice after transplantation. These findings raised the possibility that M-OST could be superior to MSC for the ex vivoexpansion HSPC. In this study, we set out to test the hypothesis that the growth modulatory activity of M-OST would vary as a function of their maturation status. The objectives were to first monitor the impact of M-OST differentiation and maturation status on the expression of soluble factors that promote HSPC expansion and in second, to investigate the capacity of M-OST CMs prepared from M-OST at distinct stages of differentiation to support the expansion and differentiation of HSPCs in culture. M-OST at distinct stages of differentiation were derived by culturing bone marrow MSC in osteogenic medium for various length of time (3 to 21 days). All CB CD34+ enriched (92±7% purity) cell cultures were done with serum free media conditioned or not with MSC or M-OST and supplemented with cytokines SCF, TPO and FL. We first confirmed the progressive differentiation and maturation of M-OST as a function of osteogenic culture length, which was evident by the induction of the osteogenic transcription factors Osterix, Msx2 and Runx2 mRNAs, the gradual increase in osteopontin and alkaline phosphatase positive cells and quantitative increases in calcium deposit. Next, we investigated the expression in MSC and M-OSTs of genes known to collaborate for the expansion of HSPCs by Q-PCR. Transcript copy numbers for IGFBP-2 increased swiftly during osteogenic differentiation, peaking at day-3 (˃100-fold vs MSC, n=2) and returning below MSC level by day-21. In contrast, ANGPTL members (ANGPTL-1, -2, -3 and -5) remained superior in M-OSTs throughout osteogenic differentiation with expression levels peaking around day 6 (n=2). Next, we tested the capacity of media conditioned with primitive (day-3, -6), semi-mature (day-10, -14) and mature M-OST (day-21) to support the growth of CB cells. All M-OST CMs increased (p˂0.03) the growth of total nucleated cells (TNC) after 6 days of culture compared to non-conditioned medium used as control (mean 2.0-fold, n=4). Moreover, there was a positive correlation between cell growth and M-OST maturation status though differences between the different M-OST CMs tested were not significant. The capacity of M-OST CMs to increase (mean 2-fold, n=4) the expansion of CD34+ cells was also shared by all M-OST CMs (p˂0.05), as supported by significant increases with immature day-3 (mean ± SD of 18 ± 6, p˂0.02) and mature day-21 M-OST CMs (14 ± 5, p˂0.05) vs. control (8 ± 3, n=4). Conversely, expansions of TNC and CD34+ cells in MSC CM cultures were in-between that of control and M-OST CMs cultures. Interestingly, M-OST CMs also modulated the expansion of the HSPC compartment. Indeed, while the expansion of multipotent progenitors defined as CD34+CD45RA+ was promoted in control culture (ratio of 4.5 for CD34+CD45RA+/CD34+CD45RA- cells), M-OST CMs supported greater expansion of the more primitive CD34+CD45RA- HSPC subpopulation reducing the ratio to 3.3±0.4 for M-OST cultures (cumulative mean of 10 cultures, n=2). Moreover, the expansions of CD34+CD38- cells and of the long term HSC-enriched subpopulation (CD34+CD38-CD45RA-Thy1+) in M-OST CM cultures were respectively 2.7- and 2.8-fold greater than those measured in control cultures (n=2-4). Finally, the impact of M-OST CMs on the expansion of myeloid progenitors was investigated using a colony forming assay; expansion of myeloid progenitors were superior in all M-OST CM cultures (1.6±0.2 fold, n=2). In conclusion, our results demonstrate that M-OST rapidly acquire the expression of growth factors known to promote HSPC expansion. Moreover, the capacity of M-OST CMs to support the expansion of HSPCs appears to be a property shared by M-OST at various stages of maturation. Disclosures No relevant conflicts of interest to declare.

scholarly journals TGF-β Signaling in Stromal Cells Contributes to Myelofibrosis, but Not Niche Disruption, in Myeloproliferative Neoplasms

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1463-1463
Author(s):  
Juo-Chin Yao ◽  
Daniel C. Link
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Myeloproliferative Neoplasms ◽  
Extramedullary Hematopoiesis ◽  
Bone Marrow Niche ◽  
Kit Ligand ◽  
Ligand Expression ◽  
The Impact ◽  
Hematopoietic Niche

Abstract Myeloproliferative neoplasms are associated with significant alterations in the bone marrow microenvironment that contribute to disease pathogenesis. The most striking alteration is the development of myelofibrosis, which is characterized by extensive collagen deposition in the bone marrow and is associated with a poor prognosis. Recent evidence suggests that expression of key niche factors, including CXCL12 (stromal derived factor-1, SDF-1) and Kit ligand are reduced in MPNs. This is relevant, since studies by our group and others have shown that deleting these niche factors from stromal cells results in a shift in hematopoiesis from the bone marrow to spleen. Indeed, a prominent feature of MPN is the development of splenomegaly and extramedullary hematopoiesis. There is evidence implicating inflammatory mediators in the development of myelofibrosis. In particular, increased production of TGF-β produced by megakaryocytes and monocytes is found in most patients with MPNs. To assess the role of TGF-β signaling in mesenchymal stromal cells in the bone marrow in the development of myelofibrosis, we generated Osx-Cre; Tgfbr2 f/- mice, in which TGF-β signaling is abrogated in all bone marrow mesenchymal stromal cells (including Lepr + stromal cells), but not endothelial cells or hematopoietic cells. We transplanted MPL W515L transduced hematopoietic stem and progenitor cells (HSPCs) or JAK2 V617F bone marrow into these mice and quantified myelofibrosis using reticulin staining and Collagen 1 and 3 immunostaining. We previously reported that deletion of TGF-β signaling in mesenchymal stromal cells in these mice abrogated the development of myelofibrosis, and we presented evidence that this was mediated by non-canonical JNK-dependent TGF-β signaling. Here, we describe the impact of stromal TGF-β signaling on the bone marrow hematopoietic niche in MPN. MPL W515L transduced HSPCs were transplanted into Osx-Cre; Tgfbr2 f/- mice, and the impact on hematopoietic niche disruption and development of extramedullary hematopoiesis was assessed. In control recipients, transplantation of MPL W515L HSPCs resulted in marked decreases in bone marrow Cxcl12 and Kit ligand expression (Figure 1A-B). Surprisingly, a similar decrease was observed in Osx-Cre; Tgfbr2 f/- recipients. The loss of these key niche factors is predicted to impair hematopoietic niche function in the bone marrow. Consistent with this prediction, total bone marrow cellularity and HSC number were significantly reduced in both control and Osx-Cre; Tgfbr2 f/- recipients (Figure 1C-D). Finally, disruption of the bone marrow niche is often associated with extramedullary hematopoiesis. Indeed, a significant increase in spleen size and spleen HSCs and erythroid progenitors was observed in control recipients (Figure 1E-G). Again, a similar phenotype was observed in Osx-Cre; Tgfbr2 f/- recipients. Collectively, these data show that TGF-β signaling in bone marrow mesenchymal stromal cells is required for the development of myelofibrosis but not hematopoietic niche disruption in MPNs. Thus, these data show for the first time that the signals that induce a fibrogenic program in bone marrow mesenchymal stromal cells are distinct from those that suppress Cxcl12 and Kit ligand expression. Our data show that the fibrogenic program is dependent on non-canonical JNK-dependent TGF-β signaling, while the signals that regulate niche factor expression remain unknown. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Intrinsic Type 1 Interferon (IFN1) Profile of Uncultured Human Bone Marrow CD45lowCD271+ Multipotential Stromal Cells (BM-MSCs): The Impact of Donor Age, Culture Expansion and IFNα and IFNβ Stimulation

Biomedicines ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 214
Author(s):  
Payal Ganguly ◽  
Agata Burska ◽  
Charlotte Davis ◽  
Jehan J. El-Jawhari ◽  
Peter V. Giannoudis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Gene Expression Signature ◽  
Proliferative Potential ◽  
Donor Age ◽  
Hematopoietic Stem ◽  
Type 1 Interferon ◽  
The Impact

Skeletal aging is associated with reduced proliferative potential of bone marrow (BM) multipotential stromal cells (MSCs). Recent data suggest the involvement of type 1 interferon (IFN1) signalling in hematopoietic stem cell (HSC) senescence. Considering that BM-HSCs and BM-MSCs share the same BM niche, we investigated IFN1 expression profile in human BM-MSCs in relation to donor age, culture-expansion and IFN1 (α and β) stimulation. Fluorescence-activated cell sorting was used to purify uncultured BM-MSCs from younger (19–41, n = 6) and older (59–89, n = 6) donors based on the CD45lowCD271+ phenotype, and hematopoietic-lineage cells (BM-HLCs, CD45+CD271−) were used as controls. Gene expression was analysed using integrated circuits arrays in sorted fractions as well as cultured/stimulated BM-MSCs and Y201/Y202 immortalised cell lines. IFN1 stimulation led to BM-MSC growth arrest and upregulation of many IFN1-stimulated genes (ISGs), with IFNβ demonstrating stronger effects. Uncultured MSCs were characterised by a moderate-level ISG expression similar to Y201 cells. Age-related changes in ISG expression were negligible in BM-MSCs compared to BM-HLCs, and intracellular reactive oxygen species (ROS) levels in BM-MSCs did not significantly correlate with donor age. Antiaging genes Klotho and SIRT6 correlated with more ISGs in BM-MSCs than in BM-HLCs. In patients with osteoarthritis (OA), BM-MSCs expressed considerably lower levels of several ISGs, indicating that their IFN1 signature is affected in a pathological condition. In summary, BM-MSCs possess homeostatic IFN1 gene expression signature in health, which is sensitive to in vitro culture and external IFN1 stimulation. IFN signalling may facilitate in vivo BM-MSC responses to DNA damage and combating senescence and aberrant immune activation.

Voruciclib plus venetoclax show high efficacy for CLL b cells on human stromal cells.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20009-e20009
Author(s):  
Connie Lesnick ◽  
Jamie Wood ◽  
Sameer Ashok Parikh ◽  
Neil E. Kay
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Stromal Cells ◽  
Synergistic Effects ◽  
Lymphocytic Leukemia ◽  
Healthy Human ◽  
Molar Ratios ◽  
Risk Patients ◽  
Risk Of Disease ◽  
The Impact

e20009 Background: Although treating B-Chronic Lymphocytic Leukemia (CLL) with small molecule inhibitors has shown promise, a lasting cure for this disease has yet to be found. Further treatments directed at key molecular targets in the CLL B cell need development for patients with adverse prognostic factors, and relapsed/refractory patients. We evaluated the impact of two novel drugs with non-overlapping mechanisms of action on CLL B cells: Voruciclib, a cyclin dependent kinase (CDK) inhibitor targeting CDKs 9, 6, 4, 1 and Venetoclax a BCL-2 inhibitor. To mimic the protective effect of the CLL micro-environment these experiments were done with CLL cells cocultured in the presence of bone marrow mesenchymal stromal cells (BMSC). Methods: Voruciclib, (MEI Pharma) and Venetoclax were tested for killing activity alone and in combination against CLL cells cocultured with healthy human bone marrow MSC. CLL B cells were from untreated patients stratified on risk of disease progression. Low risk had mutated and high risk patients had unmutated IVGH genetic status. CLL cells were cultured on BMSC’s with a series of escalating doses of individual drugs and drug combinations at fixed molar ratios then Annexin/PI stained for viability testing by flow cytometry. Killing curves generated for each drug/combination were analyzed by the combination index (C.I.) approach of Chou and Talalay with Calcusyn, characterizing interactions as synergistic, additive or inhibitory. C.I. value hierarchy classes synergy as moderate (0.7-0.9), synergistic (0.3-0.7), strong (0.1-0.3) and very strong (below 0.1). Results: CLL cells with unmutated IGVH status were more sensitive to Voruciclib than mutated IGVH both with and without BMSC’s. The combination Voruciclib +Venetoclax showed synergism for all patients regardless of risk; half strongly to very strongly (Table). Similar synergistic effects were seen with relapsed/refractory patients. Conclusions: Based on these preclinical data, Voruciclib + Venetoclax is a very promising combination to improve treatment of CLL patients. We speculate that CDK9 inhibition, which regulates transcription of Mcl-1, with Bcl-2 inhibition results in potent apoptosis induction in CLL B cells. [Table: see text]

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