P0436REFRACTORY IGA NEPHROPATHY. A MULTICYTOKINE NORMALIZED LEVELS THERAPY FOR T CELLS IMBALANCE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
MIGUEL URIOL ◽  
Aina Obrador Mulet ◽  
Ana Tugores ◽  
Vanessa Daza ◽  
Ana Gomez ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Sequential Treatment ◽  
Induction Phase ◽  
Lysosomal Activity ◽  
Receptor Activator ◽  
Initial Effect ◽  
Previously Treated ◽  
Inflammatory Milieu ◽  
Changes Over Time ◽  
Time Point

Abstract Background and Aims Interleukine-17(IL-17) is a pro-inflammatory cytokine which influences in glomerulonephritis (GN) in animal models. IgA nephropathy (IgAN) is a primary GN with auto-inflammatory and autoimmune features. Imbalances in Th1/Th17 and Treg/Th17 have been associated with the pathogenesis of the IgAN. We evaluated the effect of sequential treatment with a selective vitamin D receptor activator and with an IL-17 blocker in patients with refractory IgA GN (r-IgAN). Method Five patients with r-IgAN (previously treated with steroids, mycophenolate, tacrolimus and a renin-angiotensin-aldosterone system inhibitor) were treated initially with paricalcitol and six months later with secukinumab (IL-17A blocker) with the objective to improve anti-inflammatory and subsequentially inhibit pro-inflammatory milieu, respectively. We evaluate the evolution of the proteinuria, haematuria, plasma creatinine and urinary N-acetyl-beta-D-glucosaminidase: u-NAG, as a measure of lysosomal activity during the first month of treatment (induction phase) and at month 3 after treatment. We also evaluate the evolution of the evolution of the Th1/Th17 and Treg/Th17 ratio in whole blood. We evaluated the changes at month (M) 0, 1 and 3. Results Five males were included. Age: 43±11 years. Proteinuria (24h-collected) decreased along the study from 3.5, 2.1 to 1.6g (P<0.01) at M0, M1 and M3 respectively. Four (80%) patients who presented haematuria at month 0 disappeared at month 3. Creatinine did not show changes over time (1.84, 1.88 and 1.95 mg/dl for M0, M1 and M3, P=0.44). uNAG increased after induction phase from 7.2 to 9.8(P= 0.01) and finally decreased to 8.3 at month 3(P=1, respect to month1). Uric acid decreased but not significantly from 8.0, 7.1 and 7.6g/dl at any time point. The ratio Th1/Th17 and Treg/TH17 changed from the month 0 to month 3, from 1.8 to 2.6 (P =0.25) and 0.23 to 0.32 (P=0.16), respectively. Conclusion Sequential treatment was associated with a reduction in proteinuria and haematuria was well controlled. The changes in u-NAG suggest and intensive initial effect on the lysosomal activity since no changes in renal function was observed. The theoretical benefit of the Th1/Th17 and Treg/Th17 ratio represents a new modality of treatment that need to be rigorously evaluated for its clinical implication in r-IgAN patients.

scholarly journals Rab11A Functions as a Negative Regulator of Osteoclastogenesis through Dictating Lysosome-Induced Proteolysis of c-fms and RANK Surface Receptors

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2384 ◽  
Author(s):  
Yuka Okusha ◽  
Manh Tien Tran ◽  
Mami Itagaki ◽  
Chiharu Sogawa ◽  
Takanori Eguchi ◽  
...  
Keyword(s):  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Negative Regulator ◽  
Immunocytochemical Staining ◽  
Nuclear Factor ◽  
Lysosomal Activity ◽  
Late Endosomes ◽  
Early Endosomes ◽  
Receptor Activator

Osteoclast differentiation and activity are controlled by two essential cytokines, macrophage colony-stimulating factor (M-CSF) and the receptor activator of nuclear factor-κB ligand (RANKL). Rab11A GTPase, belonging to Rab11 subfamily representing the largest branch of Ras superfamily of small GTPases, has been identified as one of the crucial regulators of cell surface receptor recycling. Nevertheless, the regulatory role of Rab11A in osteoclast differentiation has been completely unknown. In this study, we found that Rab11A was strongly upregulated at a late stage of osteoclast differentiation derived from bone marrow-derived macrophages (BMMs) or RAW-D murine osteoclast precursor cells. Rab11A silencing promoted osteoclast formation and significantly increased the surface levels of c-fms and receptor activator of nuclear factor-κB (RANK) while its overexpression attenuated osteoclast formation and the surface levels of c-fms and RANK. Using immunocytochemical staining for tracking Rab11A vesicular localization, we observed that Rab11A was localized in early and late endosomes, but not lysosomes. Intriguingly, Rab11A overexpression caused the enhancement of fluorescent intensity and size-based enlargement of early endosomes. Besides, Rab11A overexpression promoted lysosomal activity via elevating the endogenous levels of a specific lysosomal protein, LAMP1, and two key lysosomal enzymes, cathepsins B and D in osteoclasts. More importantly, inhibition of the lysosomal activity by chloroquine, we found that the endogenous levels of c-fms and RANK proteins were enhanced in osteoclasts. From these observations, we suggest a novel function of Rab11A as a negative regulator of osteoclastogenesis mainly through (i) abolishing the surface abundance of c-fms and RANK receptors, and (ii) upregulating lysosomal activity, subsequently augmenting the degradation of c-fms and RANK receptors, probably via the axis of early endosomes–late endosomes–lysosomes in osteoclasts.

scholarly journals Modulatory Effect of 1,25-Dihydroxyvitamin D3on IL1β-Induced RANKL, OPG, TNFα, and IL-6 Expression in Human Rheumatoid Synoviocyte MH7A

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Xiaoke Feng ◽  
Chengyin Lv ◽  
Fang Wang ◽  
Ke Gan ◽  
Miaojia Zhang ◽  
...  
Keyword(s):  
Biological Function ◽  
Bone Erosion ◽  
Osteoclast Formation ◽  
Nuclear Factor ◽  
Rankl Expression ◽  
Potent Inducer ◽  
Receptor Activator ◽  
Inflammatory Milieu ◽  
Vitamin D Supplement ◽  
Inflammatory Action

Receptor activator of nuclear factorκB ligand (RANKL) plays a crucial role in the bone erosion of rheumatoid arthritis (RA) by prompting osteoclastogenesis. Considering that 1,25(OH)2D3has been suggested as a potent inducer of RANKL expression, it should clarify whether vitamin D supplement could result in RANKL overexpression and thereby facilitate excessive osteoclastogenesis and bone resorption in RA. Here, we investigated modulatory effect of 1,25(OH)2D3on the expression of RANKL and its decoy receptor osteoprotegerin (OPG) in an inflammatory condition of human rheumatoid synoviocyte MH7A. MH7A cells were stimulated with IL1βand then treated with different concentrations of 1,25(OH)2D3for 48 h. A significantly elevated OPG/RANKL ratio and markedly decreased levels of IL-6 and TNFβmRNA expression in cells and IL-6 protein in supernatants were observed in IL1β-induced MH7A in the presence of 1,25(OH)2D3compared with those in the absence of it. Osteoclast formation was obviously decreased when RAW264.7 cells were treated with both 1,25(OH)2D3and IL1β. In summary, although it has a biological function to induce RANKL expression, 1,25(OH)2D3could upregulate OPG/RANKL ratio and mediate anti-inflammatory action in an inflammatory milieu of synoviocyte, contributing to the inhibition of inflammation-induced osteoclastogenesis in RA.

scholarly journals Cool enough to induce hypothermia?

2014 ◽  
Author(s):  
Jure Fluher ◽  
Andrej Markota ◽  
Andraž Stožer ◽  
Andreja Sinkovič
Keyword(s):  
Ambient Temperature ◽  
Normal Saline ◽  
Mild Hypothermia ◽  
Aluminum Foil ◽  
Induction Phase ◽  
Fluid Temperature ◽  
Flow Rates ◽  
Venous Cannula ◽  
The Mean ◽  
Time Point

Background Infusion of cold fluids can be used to induce hypothermia after cardiac arrest. Fluid temperature higher than 4°C could increase the volume needed, prolong the induction phase and/or contribute to complications. In this study, we analyzed the effect of flow rate and venous tubing insulation on the fluid temperature at the level of the intravenous (iv.) cannula, when infusing cold saline. We also analyzed the warming rate of 0.5 L bags of normal saline wrapped in ice packs and without ice packs. Methods All measurements were performed at ambient temperature 23°C, constant humidity of 40 % and without exposure to direct sunlight. 0.5L bags containing normal saline were stored in refrigerated conditions for at least 24 hours prior to usage, mean initial temperature in the bags was 3.96 ± 0.17°C. For measurements of temperature at the level of the venous cannula during an infusion, 0.5 L bags of normal saline were connected to venous tubing and iv. cannulas. 10 measurements of fluid temperature in the cannula and in the bag were performed (with one digital filament thermometers inserted in the bag and one in the cannula) at flow rates 10, 30, 60 and 100 ml/min. Measurements were repeated with just the venous tubing wrapped in aluminum foil for thermal insulation. 3 sets of measurements with 0.5 L bags of normal saline wrapped in ice packs and 3 sets without ice packs were made for the analysis of the rate of warming. Temperature of the fluid in the bag was recorded at 5 min intervals for 120 min with a digital filament thermometer inserted in the fluid. Results With non-insulated tubing, we observed significantly higher temperatures in the cannula compared to temperatures in the bag at all flow rates (all p<0.0001, differences between temperature in the cannula and temperature in the bag 8.8 ± 0.1°C, 4.8 ± 0.1°C, 4.1 ± 0.2°C and 3.0 ± 0.1°C at flow rates 10, 30, 60 and 100 ml/min, respectively). Temperature gain with insulated tubing was significantly lower compared to non-insulated tubing at all flow rates (p<0.0001), but also statistically significant at all flow rates (all p<0.0001, differences between temperature in the cannula and temperature in the bag 5.8 ± 0.1°C, 3.1 ± 0.2°C, 1.2 ± 0.4°C and 0.3 ± 0.1°C at flow rates 10, 30, 60 and 100 ml/min, respectively). Temperature differences between cannula and bag were also statistically different for different flow rates (all p<0.0001), for both insulated and non-insulated tubing. More specifically, the temperature differences at higher flow rates were significantly smaller for every pair of successive rates (i.e., 30 vs. 10, 60 vs. 30 and 100 vs. 60 ml/min). The mean rate of warming of bags not wrapped in ice packs was 6.9°C/h. The mean rate of warming of bags wrapped in ice packs was 3.4°C/h. The temperature of fluid in the bags wrapped in ice packs was significantly lower than in the not wrapped bags at every time point (from the time point at 5 minutes to 120 minutes, p<0.0001 for all time points). Conclusion When inducing mild hypothermia at ambient temperature 23°C we suggest using high flow rates (at least 100 ml/min) and heat insulated venous tubing to avoid excessive fluid temperature gain. Bags of cold fluid should be taken from the refrigerator just before starting the infusion and kept wrapped in ice packs to prevent warming.

scholarly journals Angular changes in implants placed in the anterior maxillae of adults: A cephalometric pilot study

2020 ◽  
Author(s):  
Balazs Feher ◽  
Reinhard Gruber ◽  
Andre Gahleitner ◽  
Ales Celar ◽  
Philipp Luciano Necsea ◽  
...  
Keyword(s):  
Pilot Study ◽  
Growth Disorders ◽  
Anterior Maxilla ◽  
Explanatory Factors ◽  
Skeletal Malformations ◽  
Implant Placement ◽  
Changes Over Time ◽  
Single Implant ◽  
Time Point

AbstractObjectivesCompletion of adolescent growth represents the earliest time point for implant placement, yet craniofacial growth persists into adulthood and may affect implant position. We aimed to assess whether implants placed in the anterior maxillae of adults show angular changes.MethodsWe conducted a cephalometric pilot study in postpubertal patients with no growth disorders, skeletal malformations, or parafunctions. The patients received a single implant in the anterior maxilla and no orthodontic or orthognathic treatment afterwards. We measured angular changes on cephalograms taken immediately and at least 5 years postoperatively in a standardized setting.ResultsIn a total of 21 patients (30.2 ± 11.5 years at surgery) after a mean follow-up time of 8.6 ± 1.3 years, 62% of implants showed counterclockwise rotations (1.8 ± 1.0 degrees) and 19% of implants showed clockwise rotations (2.4 ± 1.1 degrees). Angular changes were more frequent in males (100% vs. 58%) and patients under 30 at surgery (85% vs. 63%). Mean absolute differences were larger in males (1.8 ± 1.0 degrees vs. 1.3 ± 1.4 degrees) and patients under 30 at surgery (1.5 ± 1.4 degrees vs. 1.1 ± 1.4 degrees). Regression analysis did not identify explanatory factors for the observed changes.ConclusionsImplants placed in the anterior maxillae of adults show modest angular changes over time.Clinical relevanceChanges in implant angles have potential functional and esthetic consequences.

scholarly journals Time-varying impact of U.S. financial conditions on China's inflation: a perspective of different types of events

2021 ◽  
Vol 5 (4) ◽  
pp. 604-622
Author(s):  
Yanhong Feng ◽  
◽  
Shuanglian Chen ◽  
Wang Xuan ◽  
Tan Yong ◽  
...  
Keyword(s):  
Financial Market ◽  
Trade Flow ◽  
Time Varying ◽  
Vector Autoregressive ◽  
Financial Conditions ◽  
Time Varying Parameter ◽  
Different Types ◽  
Changes Over Time ◽  
Over Time ◽  
Time Point

<abstract> <p>In recent years, the frequency adjustment of U.S. monetary policy has a dynamic and global impact on other countries' economy. Based on the financial conditions index (FCI), the paper employs the time-varying parameter vector autoregressive model with stochastic volatility (TVP-VAR-SV) and spillover index respectively to investigate the time-varying impact of U.S. financial conditions (UFCI) on China's inflation (CINF) and its impact mechanisms. Some results are achieved as follows: first, the impacts of UFCI on CINF vary greatly over time both in the dimension of action duration and time point. Second, the effects of UFCI on CINF directly relate to different types of major events, and they are heterogeneous in action duration, degree, direction as well as the trend and range of fluctuations. In addition, UFCI can work on CINF through trade flow and China's financial market, and the China's financial market plays a main conductive role, and its conductive effect changes over time.</p> </abstract>

Molecular Monitoring of Residual Disease (MRD) during Induction and Intensification Phases in Low Risk Adult B Cell ALL Treated According to the MRC UKALL12 Protocol.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1466-1466 ◽  
Author(s):  
Letizia Foroni ◽  
Wayne Mitchell ◽  
Lena J. Rai ◽  
Anouska Casanova ◽  
Gareth Gerrard ◽  
...  
Keyword(s):  
B Cell ◽  
Residual Disease ◽  
Induction Phase ◽  
Molecular Monitoring ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Significant Parameter ◽  
Standard Risk ◽  
Time Point

Abstract Introduction and aims. Molecular monitoring of minimal residual disease (MRD) using Immunoglobulin (IG) and T cell receptor (TCR) targets has provided an independent and prognostically significant parameter of outcome in adult and childhood acute lymphoblastic leukaemia (ALL). The aim of our study was to evaluate the impact of molecular tests carried out during the first 20 to 24 weeks of chemotherapy for MRD in a standard risk group of adult B cell ALL patients. Patients and Methodology. We evaluated MRD tests in 63 patients with B cell ALL (37M/26F). Median age of our cohort was 24 yrs (range: 15.5–54.6 yrs) while median WBC was 9.9 (range: 1.1–553 × 109l). All were negative for the t(9;22) or t(4;11) translocation and received standard induction chemotherapy or auto stem cell transplant (A-SCT) only. All patients had at least one molecular marker which was tested by quantitative or semi-quantitative PCR with sensitivity ≥1E4 and all tests were carried out at time of morphological remission. End-points were relapse or continuous clinical remission (CCR) with follow up ≥12 months. Time point for molecular evaluation were post induction phase 1, TP1 (up to 1.8 mo), post induction phase 2 (1.8–3.5 mo), post intensification (3.5–5.7 mo). Median follow up was 92 months for patients in CCR (range 12–141 mo) and 15.5 months for patients who relapsed (range: 2.4–49 mo). Results. Thirty-five patients in complete morphological remission were tested at TP1. Relapse free survival (RFS) tests showed a statistically significant correlation (p=0.02) between MRD positive tests and relapse (n=19 pts) and MRD negative tests (n=16 pts) and relapse free survival. In addition, pts with resistant disease at TP1 (n=10; not included above) and MRD positive pts were indistinguishable as far as relapse FS and both faired extremely poorly (Figure A). Thirty patients were analysed at TP2. RFS confirmed the significant association between MRD positivity and poor outcome (n=16 pts) and MRD negativity and CCR (n=14 pts) (p=0.03) (Figure B). MRD data were also available for 43 patients at TP3. Association of MRD positive tests (n=15 pts) and MRD negative tests (n=28 pts) with poor and good outcome, respectively (p=0.0006) (Figure C) was strongest at this time point. Outcome correlated with level of MRD at all time points, with poorer outcome in patients with MRD &gt;1E3. Conclusions. Molecular monitoring during induction and intensification for standard risk B cell ALL patients treated with UKALL12 protocol provides a prognostically significant parameter for the management of adult ALL in otherwise morphological remission and may in the future be used for patients’ stratification. Figure Figure

scholarly journals Osteoprotegerin and Ligand of Receptor Activator of Nuclear Factor

2009 ◽  
Vol 79 (2) ◽  
pp. 292-298 ◽  
Author(s):  
Lijun Tan ◽  
Yijin Ren ◽  
Jun Wang ◽  
Lingyong Jiang ◽  
Hui Cheng ◽  
...  
Keyword(s):  
Null Hypothesis ◽  
Tooth Movement ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Nuclear Factor ◽  
Linear Phase ◽  
Three Phase ◽  
Receptor Activator ◽  
Pressure Area ◽  
Time Point

Abstract Objective: To test the null hypothesis that increased tooth displacement in ovariectomized rats is not related to differential expressions of OPG and RANKL in the periodontium. Materials and Methods: Eighty-four 12-week female rats were used; half were ovariectomized and half were not. Three months later, the maxillary first molar was moved mesially. Groups of rats were sacrificed at days 0, 1, 3, 5, 7, 10, and 14 after activation. Tooth movement was measured at each time point. OPG and RANKL expressions were examined through immunohistochemistry. Results: Ovariectomized and nonovariectomized rats showed three-phase tooth movement. In both groups, OPG expression increased at the tension area and RANKL increased at the pressure area. The OPG/RANKL ratio coincided with tooth movement, especially in the linear phase from 7 to 14 days. Conclusions: The null hypothesis is rejected. The increased rate of tooth movement in ovariectomized rats was related to differential expressions of OPG and RANKL.

Validation and Discovery in Markov Models of Genetics Data

2004 ◽  
Vol 3 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Victor De Gruttola ◽  
Andrea S Foulkes
Keyword(s):  
Markov Models ◽  
Molecular Level ◽  
Homogeneous Markov Process ◽  
Global Test ◽  
First Order ◽  
Chi Squared ◽  
Markov Assumption ◽  
Changes Over Time ◽  
Over Time ◽  
Time Point

Markov models provide a natural framework for modeling cellular and molecular level changes over time. Kalbfleisch and Lawless propose using a Chi-squared statistic for assessing the appropriateness of assuming a first-order, homogeneous Markov process. While this statistic provides a global test of the Markov assumption, it does not permit identification of individual departures. We consider two approaches for discovering specific departures from the Markov assumption. First, we propose a diagnostic that tests whether the number of observed transitions out of a given state at a given time point is different than expected. Second, we construct statistics based on the number of observations in each state at each time point. In both cases, we construct multiple correlated statistics and testing is achieved through simulations. These approaches are applied to HIV genetics sequences measured over time.

Development of Molecular Mutations during the Evolution of Therapy-Related MDS and Therapy-Related AML

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4624-4624
Author(s):  
Wolfgang Kern ◽  
Manja Meggendorfer ◽  
Tamara Alpermann ◽  
Andreia de Albuquerque ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Gene Panel ◽  
Employment Equity ◽  
Time Points ◽  
Number Of Patients ◽  
Patients At Risk ◽  
Previously Treated ◽  
Equity Ownership ◽  
Time Point

Abstract Introduction: Therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) develop after the application of chemotherapy for malignancies in a significant number of patients (pts). Mutations in TP53 have been described recently to be present even before chemotherapy for the prior malignancy and thus also before any sign of t-MDS or t-AML. Data suggested that chemotherapy selected the TP53mutated clone which evolved to t-MDS/t-AML. More comprehensive genetic analyses, however, have been lacking so far. Aim: To identify molecular mutations by a comprehensive gene panel in pts at t-MDS/t-AML diagnosis and to backtrack them to prior time points. Patients and Methods: We searched our database for pts diagnosed with t-MDS or t-AML for whom in addition ≥1 prior peripheral blood or bone marrow sample from assessment of a previously treated malignancy was stored. Diagnosis of t-MDS and t-AML was performed by cytomorphology, cytochemistry and cytogenetics according to WHO classification 2008 in all cases. A total of 11 pts were identified (3/8 females/males; median age at t-MDS/t-AML diagnosis 72 years, range 50-81 years). 8 pts had t-MDS and 3 had t-AML. All pts had received chemotherapy for CLL before. All pts underwent mutation analysis at t-MDS/t-AML diagnosis by a 26 gene panel targeting ASXL1, BCOR, BRAF, CBL, DNMT3A, ETV6, EZH2, FLT3-TKD, GATA1, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PHF6, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF1, and WT1. The library was generated with the ThunderStorm (RainDance Technologies, Billerica, MA) and sequenced on MiSeq instruments (Illumina, San Diego, CA). Specific mutations identified at t-MDS/t-AML diagnosis were selectively analyzed in prior samples of the respective patients. Mutations were considered for this analysis only if they were present at t-MDS/t-AML diagnosis at mutation loads clearly higher than residual CLL infiltration. Accordingly, mutations were excluded from this analysis if their load was in the range of residual CLL infiltration or lower. One not yet described genetic variant was also excluded. Results: 13 mutations were identified at t-MDS/t-AML diagnosis in 8/11 pts. While in 3 pts no mutations were found, 5 pts had 1 mutation, 2 had 2, and 1 had 4 mutations. Mean number of mutations per pt was 1.6. TP53 was mutated most frequently (n=5), RUNX1 was mutated in 2 pts, and FLT3-TKD, IDH2, KRAS, NPM1, NRAS, and U2AF1 in 1 pt each. Mean mutation load was 27% (range 4-48%) while mean CLL infiltration at the same time point was 2% (range 0-4%). Thus, the attribution of the described mutations to t-MDS/t-AML is highly likely. We then analyzed a total of 13 samples (8 bone marrow, 5 peripheral blood) drawn prior to t-MDS/t-AML diagnosis from the 8 pts for the respective mutations identified at t-MDS/t-AML diagnosis. In 5/8 patients the respective specific mutations identified at t-MDS/t-AML diagnosis were found in at least one prior sample. Genes found mutated in the prior samples were TP53 in 2 cases and IDH2, KRAS, NPM1, RUNX1, and U2AF1 in 1 case each. Mutation loads in general were lower in prior samples as compared to samples at t-MDS/t-AML diagnosis (median 54-fold lower, range 1.5 to 205-fold), except for one sample with a similar load at both time points which both times was clearly higher than the residual CLL infiltration (50% and 42% vs. 9% and 4%). Specifically, in 3/4 patients with samples available from the time point of CLL diagnosis all of these mutations (n=4) were not detectable at a sensitivity level of 1% while in 1 patient 2 mutations were not detectable and a U2AF1mutation was identified with a 1.9% load. This further supports the concept of these mutations being related to a pre-malignant clone which in the majority of cases might have been present at undetectable levels at the time point of CLL diagnosis or which even developed only during chemotherapy and later evolved into t-MDS/t-AML. The mean interval from first detection of the respective mutations to t-MDS/t-AML diagnosis was 10 months (range 4-25 months). Conclusions: Mutational screening applying a 26 gene panel identified molecular mutations in the majority of pts. These mutations were present up to 2 years before t-MDS/t-AML diagnosis. Further studies focusing on patients at risk of t-MDS/t-AML should clarify the role of early molecular screening helping to potentially improve diagnosis and management of t-MDS/t-AML. Disclosures Kern: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. de Albuquerque:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Serum Profile of microRNAs Linked to Bone Metabolism During Sequential Treatment for Postmenopausal Osteoporosis

2020 ◽  
Vol 105 (8) ◽  
pp. e2885-e2894 ◽  
Author(s):  
Maria P Yavropoulou ◽  
Athanasios D Anastasilakis ◽  
Polyzois Makras ◽  
Athanasios Papatheodorou ◽  
Martina Rauner ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Sequential Treatment ◽  
Single Center ◽  
Open Label ◽  
Relative Expression ◽  
Naive Group ◽  
Subgroup Analyses ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Sequential Treatments

Abstract Context Serum expression of microRNAs (miRs) related to bone metabolism is affected by antiosteoporotic treatment. Objective To investigate the effect of sequential treatments on miR expression in postmenopausal women with osteoporosis. Design Observational, open label, nonrandomized clinical trial. Setting A single-center outpatient clinic. Patients and Interventions Denosumab (Dmab) was administered for 12 months in 37 women who were treatment-naïve (naïve group) (n = 11) or previously treated with teriparatide (TPTD group) (n = 20) or zoledronate (ZOL group) (n = 6). Main Outcome Measures Relative serum expression of miRs linked to bone metabolism at 3 and 6 months of Dmab treatment. Results Baseline relative expression of miR-21a-5p, miR-23a-3p, miR-29a-3p, and miR-338-3p was higher in the TPTD group, while the relative expression of miR-21a-5p was lower in the ZOL group compared to the naïve group. Dmab decreased the relative expression of miR-21a-5p at 3 months (fold change [FC] 0.43, P &lt; 0.001) and 6 months (FC 0.34, P &lt; 0.001), and miR-338-3p and miR-2861 at 6 months (FC 0.31, P = 0.041; FC 0.52, P = 0.016, respectively) in the whole cohort. In subgroup analyses, Dmab decreased the relative expression of miR-21a-5p, miR-29a-3p, miR-338-3p, and miR-2861 at 3 months (FC 0.13, P &lt; 0.001; FC 0.68, P = 0.044; FC 0.46, P = 0.012; and FC 0.16, P &lt; 0.001, respectively) and 6 months (FC 0.1, P &lt; 0.001; FC 0.52, P &lt; 0.001; FC 0.04, P = 0.006; and FC 0.2, P &lt; 0.001, respectively) only within the TPTD group. Conclusions TPTD treatment potentially affects the expression of the pro-osteoclastogenic miR-21a-5p and miRs related to the expression of osteoblastic genes RUNX2 (miR23a-3p), COL1 (miR-29a-3p), and HDAC5 (miR-2861), while sequential treatment with Dmab acts in the opposite direction.

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