Decreased Thymosin Beta 4 Expression Results in Poor Prognosis and Decreased Survival in Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1703-1703
Author(s):  
Jo Caers ◽  
Dirk Hose ◽  
Ine Kuipers ◽  
Tomas Jan Bos ◽  
Els Van Valckenborgh ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Metastatic Potential ◽  
Suppressor Gene ◽  
Inhibitory Effect ◽  
High Dose Chemotherapy ◽  
Tumor Formation ◽  
High Dose ◽  
Thymosin Beta 4 ◽  
Qrt Pcr

Abstract Thymosin beta 4 (Tβ4) is a small cytoplasmic and nuclear protein involved in different cellular processes including differentiation, migration and proliferation. It is overexpressed in several malignant cells, resulting in an increased angiogenic respons and metastatic potential of tumor cells. In the current study we wanted to evaluate the expression of Tβ4 in primary human multiple myeloma cells (MM) and murine 5TMM cells. Microarray analysis and qRT-PCR of 171 MM patients treated with high dose therapy and autologous stem cell transplantation, showed that MM cells display a decreased Tβ4 expression compared to plasma cells from healthy individuals. We investigated whether Tβ4 expression in MM cells influences the event free (EFS) and overall survival (OAS) of these patients. As Tβ4 was expressed in all MM cells, we compared survival of patients with Tβ4 expression in MM cells in the upper thirtile (Tβ4high MMC) against the lowest thirtile (Tβ4low MMC). Patients with Tβ4high MMC had an increased EFS (P< 0.05) and also their OAS tended to be longer. A similar observation was made in the 5TMM model where qRT-PCR and ELISA revealed a decreased expression of Tβ4 in BM samples from 5T33MM and 5T2MM diseased mice compared to control mice. To study the functionality of Tβ4, we overexpressed Tβ4 in 5T33MMvitro (5T33MMvt) cells by lentiviral transduction. These 5T33MMvt-Tβ4+ cells demonstrated a significantly decreased proliferative capacitity and an increased sensitivity to different anti-myeloma agents (bortezomib, melphalan, dexamethasone) compared to control 5T33MMvt cells. Furthermore, injection of 5T33MMvt-Tβ4+ cells in C57BlKaLwRij mice resulted in a significant decreased tumor formation (paraprotein concentration was 1.92 g/dl versus 3.74 g/dl for untransduced cells, p<0.05) and a prolonged survival compared to mice injected with untransduced 5T33MMvt cells (respectively 65.9 days versus 88.9 days, p< 0.05). In conclusion, we found a decreased Tβ4 expression in human and murine MM cells compared to normal plasma cells. In our cohort of MM patients treated with high-dose chemotherapy, low expression of TB4 identifies a group of patients with adverse prognosis while in the murine 5TMM33vt model, overexpression of Tβ4 resulted in an inhibitory effect on tumor formation suggesting a role of Tβ4 as a tumor suppressor gene in MM.

PTEN Gene Deletions in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4889-4889
Author(s):  
Xiao Ying Qi ◽  
A. Keith Stewart ◽  
Hong Chang
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
Myeloma Cell ◽  
Suppressor Gene ◽  
High Dose Chemotherapy ◽  
Pten Gene ◽  
Allelic Loss ◽  
High Dose ◽  
13Q Deletion

Abstract PTEN, a tumor suppressor gene, negatively regulates the anti-apoptotic action of akt phosphorylation. Allelic loss or mutation of this gene has been detected in many solid tumors and more recently in human myeloma cell lines (HMCLs). Expression of PTEN has resulted in growth inhibition and apoptosis of a HMCL, suggesting that it may play a role in the pathogenesis of multiple myeloma (MM). However, the PTEN status in tumor cells from patients with MM has not been determined. Using a triple staining method combining staining for cytoplasmic light chains and fluorescence in situ hybridization (FISH) with chromosome 10-centromere and PTEN-gene specific probes, we analyzed clonal plasma cells from 71 patients with MM, 10 with plasma cell leukemia (PCL) and 10 HMCLs. Hemizygous PTEN deletions were detected in 4 of 71 (5.6%) MM patients, 2 of 10 (20%) PCLs, and 2 of 10 (20%) HMCLs. The percentages of clonal plasma cells containing PTEN deletions ranged from 21–90% (median, 56%). Three of the 4 patients with PTEN deletions were detected at diagnosis with stage III disease (Duire-Salmon) and 1 was detected at relapse. Two patients had IgG kappa, 1 IgG lambda and 1 free lambda light chain. To correlate the PTEN status with other known genetic abnormalities in MM, we investigated 4 MM and 2 PCLs with PTEN deletions using FISH for chromosome13q, p53 status, translocations t(11;14), t(4;14) and t(14;16). One MM had a 13q deletion, 1 PCL had a t(11;14), and the other PCL had a t(14;16), a 13q deletion and a p53 deletion. All 4 MM patients with hemizygous PTEN deletions received melphalan based high-dose chemotherapy and autologous stem cell support. Their median overall survival (OS) was 48.1months, and progression free survival (PFS) was 42.8 months as compared to patients without PTEN deletions (OS, not reached, PFS, 25.8 months) (p=0.51 for OS, p=0.67 for PFS). Our results indicate that PTEN deletions are uncommon in MM patients and therefore unlikely represent a primary event for MM. PTEN deletions appear to occur in the advance stage of the disease, and are more frequently involved in PCL or HMCLs suggesting that deletions of PTEN may be associated with disease progression in a subset of MM.

scholarly journals Symptomatic Outcome of CTDa In Multiple Myeloma Patients

KYAMC Journal ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 124-128
Author(s):  
Zulfia Zinat Chowdhury ◽  
Mohammad Ali ◽  
AKM Mynul Islam ◽  
Salina Haque ◽  
Tamanna Bahar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Cost Effective ◽  
Complete Response ◽  
High Dose Chemotherapy ◽  
Albumin Level ◽  
High Dose ◽  
Female Ratio ◽  
Stem Cell Rescue ◽  
Bone Marrow Plasma

Background: Multiple Myeloma (MM) represents approximately 15% of all hematological malignancies. Despite the use of high-dose chemotherapy followed by stem cell rescue MM remains incurable at present. The goal is to control the disease as much as possible, providing the best quality of life to patients for the longest duration. Currently, CTDa (attenuated Cyclophosphamide, Thalidomide, Dexamethasone) is the best option of treatment as it is cost-effective, with no need for hospitalization with a good response. Objective: To find out the symptomatic responses and toxicities of CTDa in Multiple Myeloma patients. Materials and Methods: 25 patients of newly diagnosed MM patients were treated in the Haematology Department, Bangabandhu Sheikh Mujib Medical University (BSMMU) from July 2016 to July 2017. The mean age of the patients was 54 years, Male female ratio was 1.5:1 and most of the patients were farmers. After induction of 4 to 6 cycles of CTDa all patients were followed up at 6th and 12th weeks. At follow up we evaluated improvement of weakness, bone pain, Hb%, ESR, monoclonal protein, ß2microglobulin, bone marrow plasma cells and serum calcium and albumin level. Adverse effects, such as peripheral neuropathy, thromboembolic events, hyperglycemia, constipation, rash, and somnolence were also assessed. Results: Among 25 patients, complete response achieved only 13 patients (52%), where 20% and 16% of patients belonged to partial or no response respectively. The death occurred in 2 cases (12%). Conclusion: CTDa is a gentle approach to treat an especially frail group of patients, since virtually all patients ultimately relapse. KYAMC Journal Vol. 11, No.-3, October 2020, Page 124-128

A Gene Expression Based Proliferation Index as Independent Prognostic Factor in Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1667-1667
Author(s):  
Dirk Hose ◽  
Thierry Rème ◽  
Thomas Hielscher ◽  
Jérôme Moreaux ◽  
Tobias Meißner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Prognostic Factor ◽  
Plasma Cells ◽  
Early Stage ◽  
High Dose Chemotherapy ◽  
Continuous Variable ◽  
Proliferation Index ◽  
High Dose ◽  
Myeloma Cells

Abstract BACKGROUND. The proliferation-rate of primary myeloma cells is a strong adverse prognostic factor in various trials, but not routinely assessed, partially due to effort in obtaining it. AIM. As gene-expression profiling is increasingly considered a standard diagnostics in myeloma, we investigated the possibility to develop a prognostically relevant gene-expression based proliferation index (GPI). PATIENTS AND METHODS. Gene expression was determined by Affymetrix DNA-microarrays in 784 samples including two independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. The GPI was derived by selecting genes associated with proliferation (in terms of gene ontology) differentially expressed in proliferating malignant (human myeloma cell lines) and benign (plasmablastic) cells compared to non-proliferating, non-malignant cells (normal plasma cells and memory B-cells). The GPI comprises the sum of the expression values of 50 genes (ASPM, AURKA, AURKB, BIRC5, BRCA1, BUB1, BUB1B, CCNA2, CCNB1, CCNB2, CDC2, CDC20, CDC25C, CDC6, CDCA8, CDKN3, CEP55, CHEK1, CKS1B, CKS2, DLG7, ESPL1, GINS1, GTSE1, KIAA1794, KIF11, KIF15, KIF20A, KIF2C, KNTC2, MAD2L1, MCM10, MCM6, MKI67, NCAPD3, NCAPG, NCAPG2, NEK2, NPM1, PAK3, PCNA, PGAM1, PLK4, PTTG1, RACGAP1, SMC2, SPAG5. STIL, TPX2, ZWINT). Proliferation of primary myeloma cells was assessed by propidium iodinestaining (n=67). Chromosomal aberrations were assessed by comprehensive iFISH using a set of probes for the chromosomal regions 1q21, 6q21, 8p21, 9q34, 11q23, 11q13, 13q14.3, 14q32, 15q22, 17p13, 19q13, 22q11, as well as the translocations t(4;14)(p16.3;q32.3) and t(11;14)(q13;q32.3). RESULTS. In the two groups, 39 and 32 percent of primary myeloma cells show a GPI above the median plus three standard deviations of normal bone marrow plasma cells, respectively. The GPI is significantly higher in advanced- compared to early-stage myeloma (P=.001) and in patients harboring a gain of 1q21 (n=95, P<0.001). It correlates significantly with proliferation as determined by propidium iodine in primary myeloma cells (rs=.52, P<.001, n=67). The GPI as continuous variable is significantly predictive for event-free survival (EFS, n=120, P<.001, n=345, P<.001, respectively) and overall survival (OAS, n=345, P<.001) in patients treated with high-dose chemotherapy, independent of serum-β2-microglobulin (B2M) or ISS-stage. A GPI above the median (GPIhigh) delineated significantly inferior EFS (n=168, 41.6 vs. 26 months, P=.04, HR 1.57, CI [1.02,2.42]; n=345, 68.6 vs. 45.2 months, HR 1.55, CI [1.16,2.09], P=.003) and OAS (n=345, P<.001) in two independent cohorts of patients undergoing high-dose chemotherapy. By using B2M above 3.5 mg/l and GPI as staging variables, four groups with difference in median EFS (n=345, B2M <3.5mg/l, GPIhigh/low 76.1 months; B2M < 3.5mg/l, GPIhigh 62.4 months, B2M ≥3.5mg/l, GPIlow 41.8 months, B2M ≥3.5mg/l, GPI 36.1 months, P<.001) and OAS can be delineated. CONCLUSION. The GPI represents a validated tool for the assessment of proliferation in multiple myeloma patients, allows a risk stratification in terms of proliferation either alone or in combination with B2M or ISS, respectively, and has the potential to be used within a risk adapted targeting of anti-proliferative treatment.

Immunoglobulin D Multiple Myeloma Involving the Sella Manifesting as Oculomotor Palsy

Neurosurgery ◽  
2010 ◽  
Vol 67 (2) ◽  
pp. E505-E506 ◽  
Author(s):  
Junya Fukai ◽  
Masaharu Nohgawa ◽  
Yuji Uematsu ◽  
Toru Itakura ◽  
Ichiro Kamei
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Ct Scanning ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Oculomotor Palsy ◽  
Initial Manifestation ◽  
Systemic Treatments ◽  
Immunoglobulin D ◽  
Sellar Lesion

Abstract OBJECTIVE Immunoglobulin D multiple myeloma (IgD MM) is an uncommon type of MM characterized by an aggressive clinical behavior and a short survival time. We report a rare case in which oculomotor palsy caused by a sellar lesion was the initial manifestation of IgD MM; systemic treatments were beneficial in this case. CLINICAL PRESENTATION A 61-year-old man presented with diplopia, left-sided ptosis, and retro-orbital pain. An examination revealed left cranial nerve (CN) III and IV palsies. CT scanning demonstrated a mass in the sellar and parasellar regions and partial destruction of the left side of the dorsum sellae. MRI revealed that the mass extended into the left cavernous sinus with minimal suprasellar extension. An endocrinologic evaluation did not reveal any abnormality. At the time of admission, the patient had no symptoms of MM. INTERVENTION A transsphenoidal resection was performed. Histopathologic examination revealed a tumor consisting of plasma cells. Appropriate laboratory studies, a bone scan, and a bone marrow biopsy led to a diagnosis of IgD lambda-type MM. High-dose chemotherapy followed by autologous peripheral blood stem cell transplantation was therapeutically beneficial. The patient's symptoms were gradually relieved. CONCLUSION This case demonstrates that an unusual sellar tumor might be the first manifestation of IgD MM. Careful observation can suggest a possible non-pituitary etiology for a tumor, leading to appropriate diagnostic and therapeutic procedures.

Purging of Autologous Peripheral-Blood Stem Cells Using CD34 Selection Does Not Improve Overall or Progression-Free Survival After High-Dose Chemotherapy for Multiple Myeloma: Results of a Multicenter Randomized Controlled Trial

2001 ◽  
Vol 19 (17) ◽  
pp. 3771-3779 ◽  
Author(s):  
A. Keith Stewart ◽  
Robert Vescio ◽  
Gary Schiller ◽  
Oscar Ballester ◽  
Stephen Noga ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
High Dose Chemotherapy ◽  
Phase Iii ◽  
High Dose ◽  
Free Survival ◽  
Disease Free ◽  
Cd34 Selection

PURPOSE: Although high-dose chemotherapy supported by autologous peripheral-blood progenitor-cell (PBPC) transplantation improves response rates and survival for patients with multiple myeloma, all patients eventually develop progressive disease after transplantation. It has been hypothesized that depletion of malignant plasma cells from autografts may improve outcome by reducing infused cells contributing to relapse. PATIENTS AND METHODS: A randomized phase III study using the CEPRATE SC System (Cellpro, Bothell, WA) to enrich CD34+ autograft cells and passively purge malignant plasma cells was completed in 190 myeloma patients randomized to receive an autograft of CD34-selected or unselected PBPCs. RESULTS: After CD34 selection, tumor burden was reduced by 1.6 to 6.0 logs (median, 3.1), with 54% of CD34-enriched products having no detectable tumor. Median time to count recovery, number of transfusions, transplantation-related mortality, and days in hospital were equivalent between the two transplantation arms. With a median follow-up of 37 months, 33 patients (36%) in the selected and 34 patients (35%) in the unselected arm had died (P = .784). Median overall survival in the selected arm was reached at 50 months and is not reached at this time in the unselected arm (P = .78). Median disease-free survival was 100 versus 104 weeks (P = .82), with 67% of patients in the selected arm and 66% of patients in the unselected arm relapsing. CONCLUSION: This phase III trial demonstrates that although CD34 selection significantly reduces myeloma cell contamination in PBPC collections, no improvement in disease-free or overall survival was achieved.

ASH evidence-based guidelines: what is the role of maintenance therapy in the treatment of multiple myeloma?

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 587-589 ◽  
Author(s):  
Irene M. Ghobrial ◽  
A. Keith Stewart
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Plasma Cells ◽  
High Dose Chemotherapy ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Lytic Lesions ◽  
Treatment Plans ◽  
Evidence Based Guidelines

Abstract A 51-year-old male was diagnosed with an IgA multiple myeloma (MM) after having back pain for several months. His bone marrow showed 30% involvement with plasma cells and his cytogenetics showed t(4:14). His β2-microglobulin was 6.5 mg/dL at diagnosis and he had multiple lytic lesions, along with a creatinine of 2.3 mg/dL and significant anemia. Induction therapy with lenalidomide, bortezomib and dexamethasone was used, and he was able to achieve complete remission after 4 cycles of therapy. He then went on to receive high-dose chemotherapy with a single autologous stem cell transplant. He tolerated it well and now comes to discuss follow-up treatment plans. He wants to discuss maintenance therapy.

Mechanism of Arsenic Trioxide-Induced Apoptosis on Multiple Myeloma Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4904-4904
Author(s):  
Xiaohong Zhang ◽  
Yun Liang ◽  
Lida Su
Keyword(s):  
Multiple Myeloma ◽  
Cell Culture ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Plasma Cells ◽  
Constitutive Expression ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Apoptosis Rate ◽  
M Phase

Abstract Multiple myeloma (MM) is an incurable B-cell malignancy. High-dose chemotherapy with stem cell support has achieved higher response rates than conventional therapy, but few patients remain in long-term remission. Arsenic trioxide (As2O3) is an effective treatment for acute promyelocytic leukemia. Current clinical studies are investigating arsenic as a therapeutic agent for malignancies. The mechanism of cytotoxicity inducted by As2O3 has not been known thoroughly. Constitutively activated NF-κB is a characteristic of different tumor entities including MM clones and malignant plasma cells from MM patients. It plays an important role in maintaining tumor cell proliferation and protecting cell from apoptosis. The study was to explore the possible mechanism of As2O3 effects on MM lines. Materials and methods: The human MM cell lines of KM3 and RPMI8226 were provided by Hematology Institution of Zhejiang University. The concentration of As2O3 in cell culture system was from 0.5μmol/L to 20μmol/L, 24 hours was selected as the termination point of cell culture. Cell culture without As2O3 and first-antibody-dismissed test were enrolled as controls. Both of the MM lines were treated with As2O3 in various concentrations. The restrained proliferation was observed by drawing growth curve. MTT bioassay was used to examine the effect of As2O3 on cell growth and the concentration of 50% growth inhibition( IC50) calculated respectively. Apoptosis and changes of IκB-α protein was observed by flow cytometry(FCM). Changes and subcellular localization of IκB-α protein were observed by fluorescence microscopy. Western blot was also used to analyze the expression of NF-κB in nuclear. Results: As2O3 inhibited the proliferation of both MM lines, and IC50 of KM3 and RPMI8226 was 9.61μmol/L and 8.01μmol/L respectively. After exposure to As2O3, both of the lines were induced to apoptosis. With As2O3 concentration varied from 0.5μmol/L to 20μmol/L the apoptosis rate of KM3 and RPMI8226 was concentration-dependent measured by FCM. After 24 hours treated with 20μmol/L As2O3, the apoptosis rate of KM3 cells was 41.18% while that of RPMI8226 was 65.25%. It seemed that RPMI8226 cell was more sensitive to As2O3. FCM analysis showed a significant increase in the percentage of G2/M phase cells, from 13.74% to 41.72%, and a decrease percentage of S phase cells from 35.11% to 23.96%. The level of IκB-α in cytoplasm was down-regulated after As2O3 stimulation in both cell lines. The down-regulation of IκB-α from 79.68% to 51.57% was confirmed by FCM in KM3 treated with 10μmol/L As2O3 (p<0.01), the effect was concentration-dependent. While the IκB-α in RPMI8226 changed from 79.72% to 34.08% (p<0.01). Immunofluorescence assay showed that IκB-α localized in cytoplasm mostly. The level of IκB-α protein was down-regulated after As2O3 stimulation. The results showed that KM3 and RPMI8226 lines expressed constitutively activity NF-κB and As2O3 down-regulated the constitutive expression of NF-κB in both cell lines but with different kinetics. Conclusions: As2O3 could not only inhibit the proliferation but also induce apoptosis of KM3 and RPMI8226 cells. The mechanisms of its effect on MM cells may include decreasing the constitutive activity of NF-κB, subsequently down-regulating the expression of various gene products controlled by NF-κB, thus inducing apoptosis in MM cells. As2O3 could inhibit the proliferation of MM cells by changing MM cell cycle and inducing G2/M phase arrest.

Bone Morphogenic Protein 6: A Prognostic Factor Expressed by Normal Plasma Cells and Multiple Myeloma Cells Inhibiting Their Proliferation and Angiogenesis Induction

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2701-2701
Author(s):  
Anja Seckinger ◽  
Tobias Meißner ◽  
Jérôme Moreaux ◽  
Hartmut Goldschmidt ◽  
Axel Benner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Cell Lines ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Myeloma Cells

Abstract BACKGROUND: Pathogenesis of multiple myeloma is partly attributed to an aberrant expression of proliferation-, pro-angiogenic and bone-metabolism modifying factors by malignant plasma-cells. AIM. Given the long and variable time-span from first diagnosis of early-stage plasma-cell dyscrasias to overt myeloma and the low proliferation rate of malignant plasma-cells, we hypothesize these to concomitantly express a novel class of anti-proliferative factors of potential prognostic relevance. Here, bone morphogenic proteins (BMPs) represent possible candidates, as they inhibit proliferation, stimulate bone formation, and have an impact on the survival of cancer patients. PATIENTS AND METHODS. We assessed expression of BMPs and its receptors by Affymetrix DNA-microarrays (n=434) including CD138-purified primary myeloma-cell-samples, normal bone-marrow plasma-cell-samples, polyclonal plasmoblasts-samples, human myeloma-cell-lines (HMCL), and whole bone-marrow. Presence and differential gene expression was determined by PANP-algorithm and empirical Bayes statistics. Event-free (EFS) and overall survival (OAS) were investigated for the 168 patients undergoing high-dose chemotherapy (HM-group) using Cox’s proportional hazard model. Findings were validated using the same strategy on an independent group of 345 patients from the Arkansas-group. For validation, quantitative real-time PCR and flow cytometry were performed. In vitro induction of angiogenesis was assessed using the AngioKit-assay. Effect of BMP6 on proliferation of HMCL was assessed by 3H-thymidine uptake. RESULTS. BMP6 is the only BMP expressed by normal- (13/14 samples) and malignant plasma-cells (228/233 samples). It is significantly lower expressed in proliferating non-malignant plasmablastic cells and human myeloma cell-lines. In vitro, BMP6 significantly inhibits proliferation of myeloma-cell-lines with an IC50 ranged from 0.08–2.15μg/ml, survival of primary myeloma-cells, and in vitro tubule formation down to the level of the negative control. High BMP6-expression in malignant plasma cells delineates significantly superior overall-survival for patients undergoing high-dose chemotherapy in both independent series of patients (n=168, P=.02 and n=345, P=.03, respectively, see below). CONCLUSION. With BMP6 we report for the first time the autocrine expression of a prognostically relevant anti-angiogenic and anti-proliferative factor and its receptors by normal and malignant plasma-cells. Figure Figure

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